MXPA06011464A - Mitotic kinesin inhibitors - Google Patents

Abstract

The present invention relates to compounds that are useful for treating cellular proliferative diseases, for treating disorders mediated, at least in part, by KSP, and for inhibiting KSP. The invention also related to pharmaceutical compositions comprising such compounds, methods of treating cancer by the administration of such compositions, and processes for the preparation of the compounds. Compounds of the invention have the following formula:formula (I).

Description

MITOTIC QUINESIN INHIBITORS Field of the Invention The present invention relates to compounds that are useful for treating disorders mediated, at least in part, by KSP, and pharmaceutically acceptable salts, esters or prodrugs thereof, compositions of these compounds together with pharmaceutically acceptable carriers. BACKGROUND OF THE INVENTION Kinestones are motor proteins that use adenosine triphosphate to bind to microtubules and generate mechanical strength. The kinesins are characterized by a motor domain which has approximately 350 amino acid residues. The crystal structures of several kinesin engine domains have been resolved. Currently, approximately one hundred kinesin-related proteins (KRPs) have been identified. Kinesins are involved in a variety of cellular biological processes which include the transport of organelles and vesicles, and maintenance of the endoplasmic reticulum. Several KRPs interact with microtubules of mitotic use or with chromosomes directly and seem to play a pivotal role during the mitotic stages of the cell cycle. These mitotic KRPs are of particular interest for the development of therapeutics for cancer.

REF: 176244 The kinesin use protein (KRP) (also known as Eg5, HsEg5, KNSLl or KIFII) is one of several motor proteins such as kinesin that are localized in mitotic use and is known to be required for training and / or function of bipolar mitotic use. In 1995, it was shown that depletion of KSP using an antibody directed against the C-terminus of KSP stops HeLa cells in mitosis with microtubular monoastral arrays (Blangy et al., Cell 83: 1159-1169, 1995). Mutations in the bimC and cut7 genes, which are considered to be KSP homologues, cause failure in centrosome separation in Aspergillus nidulans - (Enos, AP, and NR Morris, Cell 60: 1019-1027, 1990) and Schizosaccharomyces pombe (Hagan, I., and Yanagida, 'Nature 347: 563-566, 1990). Treatment of cells with either ATRA (all trans-retinoic acid), which reduces the expression of KSP at the protein level, or depletion of KSP using antisense oligonucleotides reveals significant growth inhibition in pancreatic carcinoma cells DAN-G indicating that KPS may be involved in the antiproliferative action of all trans-retinoic acid (Kaiser, A., et al., J. Biol. Che. 274, 18925-18931, 1999). Interestingly, pEg2 protein kinase related to Xenopus laevis is shown to associate and phosphorylate XIEg5 (Giet, R., et al., J. Biol. Chem. 274: 15005- 15013, 1999). The potential substrates of kinases related to Aurora are of particular interest for the development of drugs for cancer. For example, the Aurora I and 2 kinases are overexpressed at the protein and AKN levels and the genes are amplified in patients with colon cancer. The first small cell permeable molecule inhibitor for KSP, "monastrol" showed that it stops cells with monopolar uses without affecting microtubule polymerization as conventional chemotherapeutics such as taxanes and vinca alkaloids do (Mayer, TU, et al., Science 286: 971-974, 1999). Monastrol is identified as an inhibitor in screens based on the phenotype and this suggests that this compound can serve as a leader for the development of anticancer drugs. Inhibition is determined to be non-competitive with respect to adenosine triphosphate and to be rapidly reversible (DeBonis, S., et al., Biochemistry 42: 338-349, 2003; Kapoor, TM, et al., J. Cell Biol. 150: 975-988, 2000). In light of the importance of the improved chemotherapeutics, there is a need for KSP inhibitors that are effective in vivo inhibitors of KSP and KSP-related proteins. SUMMARY OF THE INVENTION The present invention relates to compounds that they are useful for treating disorders mediated, at least in part, by KSP, and for inhibiting KSP. The present invention provides inhibitors of small KSP molecule, pharmaceutical compositions which contain such inhibitors, methods for treating patients with such pharmaceutical compositions, and methods for preparing such pharmaceutical compositions and inhibitors. Inhibitors can be used in the prophylaxis and / or treatment of disorders mediated, at least in part, by KSP, such as cell proliferative diseases or cancer. The compounds of the invention can be illustrated by the formula I: or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof, wherein: R1 is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, halo, cyano, nitro, carboxy, hydroxy, alkoxy, aryloxy, heterocyclyloxy, aminocarbonyl, aminocarbonyloxy, alkylcarbonyloxy, arylcarbonyloxy, heterocyclylcarbonyloxy, alkoxycarbonyl, aryloxycarbonyl, heterocyclyloxycarbonyl, amino, alkylcarbonylamino, arylcarbonylamino, heterocyclylcarbonylamino, alkoxycarbonylamino, aryloxycarbonylamino, heterocyclyloxycarbonylaird.no, alkylsulfonylamino, arylsulfonylamino, heterocyclylsulfonylamino, aminosulfonyl, alkylsulfonyl, aryisulfonyl, and heterocyclylsulfonyl; R 2 is selected from the group consisting of hydrogen, alkenyl, alkenyl, alkynyl, aryl, heterocyclyl, carboxy, alkoxycarbonyl, aryloxycarbonyl, heterocyclyloxycarbonyl and aminocarbonyl; R3 is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl and heterocyclyl, or R2 and R3, together with the carbon atom to which they are attached can form a carbocyclic or heterocyclic ring, which has from 3 to 8 atoms in the ring, wherein 1 to 3 ring atoms, of the heterocyclic ring are selected from the group consisting of N, O and S; R 4 are selected from the group consisting of hydrogen, alkyl, aryl and heterocyclyl; R5 is selected from the group consisting of hydrogen, alkyl, aryl, heterocyclyl, alkoxycarbonyl, aryloxycarbonyl, heterocyclylcarbonyl, aminocarbonyl, alkylcarbonyl, arylcarbonyl, heterocyclylcarbonyl, alkylsulfonyl, aryisulfonyl and heterocyclylsulfonyl; R6 is selected from the group consisting of hydrogen, alkyl, aryl, heterocyclyl, hydroxy, alkoxy, aryloxy, heterocyclyloxy, amino, alkylsulfonyl, arylsulfonyl and heterocyclylsulfonyl, alkylcarbonyloxy, arylcarbonyloxy, heterocyclylcarbonyloxy, alkoxycarbonyl, aryloxycarbonyl, heterocyclyloxycarbonyl, alkoxycarbonylamino, aryloxycarbonylamino, heterocyclyloxycarbonylamino, alkylcarbonylamino, arylcarbonylamino, heterocyclylcarbonylamino, aminocarbonyloxy, alkylsulfonylamino, arylsulfonylamino, heterocyclylsulfonylamino, and aminosulfonyl; and R7 is selected from the group consisting of hydrogen, alkyl, aryl and heterocyclyl, or R6 and R7, can be taken together with the atoms to which they are attached to form a heterocyclic ring, which has 5 to 8 ring atoms , wherein 1 to 3 ring atoms of the heterocyclic ring are selected from the group consisting of N, 0 and S. In one embodiment, the compounds of this invention are illustrated by the compound of formula II: or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof, wherein R1, R2, R3, R4 and R5 are as defined above; m is 0, 1, 2, or 3; q is 1, 2, or 3; and • and R8 is selected from the group consisting of alkyl, aryl, and heterocyclyl. Formula II also includes the tautomer of formula II, illustrated as the formula Il-a: In another embodiment, the compounds of this invention are illustrated by a compound of formula III: Or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof wherein: R1, R2, R3, R4, R5 are as defined above: m is 0, 1, 2, or 3; and R8 is selected from the group consisting of alkyl, aryl and heterocyclyl. In yet another embodiment, the compounds of this invention are illustrated by a compound of formula IV: IV wherein A and B are independently selected from the group consisting of aryl, heteroaryl, heterocyclyl, cycloalkyl, all of which may be substituted with 1 to 4 substituents selected from the group consisting of alkyl, alkoxy, halo, hydroxy and nitro; n is 1, 2 or 3; m is 0, 1, 2, or 3; p is 1, 2, 3, or 4; R8 is alkyl, aryl and heterocyclyl; R9 is C to C3 alkyl; R10 and R11 are independently selected from the group consisting of hydrogen and Ci to C4 alkyl.

In one embodiment, R1 is alguilo. In another embodiment, R1 is alkyl substituted with aryl or heterocyclyl. In yet another embodiment, R1 is benzyl. In one embodiment, R 2 is H. In one embodiment, R 3 is alkyl, alkenyl, alkynyl, aryl, or heterocyclyl. In another embodiment, R3 is ethyl, isopropyl, cyclopropyl, phenyl, thienyl, or pyridinyl. In yet another embodiment, R3 is ethyl or isopropyl. In one embodiment, R4 is alkyl. In another modality, R 4 is 2-aminoethyl, 3-aminopropyl, 4-axainobutyl, 3- (methylamino) propyl, or 3- (ethylamino) propyl. In yet another embodiment, R 4 is 3-aminopropyl, 3- (methylamino) propyl, or 3- (ethylamino) propyl. In one embodiment, R5 is arylcarbonyl or heterocyclylcarbonyl. In another embodiment, R5 is benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-methylbenzoyl, 3-fluoro-4-ethylbenzoyl, or 4-trifluoromethylbenzoyl. In yet another embodiment, R 4 is 4-bromoenzyl, 3-fluoro-4-methylbenzoyl or 4-methylbenzoyl. In one embodiment, R6 and R7, together with the pendant atoms therefor, form a heterocyclic ring. In another embodiment, R6 and R7 together with the pendant atoms thereto join to form 4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2- a] pyrimidin-2-yl.

In one embodiment, m is 0. In one embodiment, when m is 1, 2 or 3, R8 is alkyl. In another embodiment, R8 is methyl. In one embodiment, m is 1. In another embodiment, q is 2. In still other embodiments p is 3. In yet another embodiment, n is 1. In one embodiment, R9 is ethyl, isopropyl, cyclopropyl, or propyl. In yet another embodiment, R9 is ethyl or isopropyl. In one modality, a is aril. In another embodiment, A is phenyl. In one embodiment, B is aryl. In another embodiment, B is aryl substituted with alkenyl and / or halo. In yet another embodiment B is phenyl substituted with methyl, fluorine and / or bromine. In one embodiment, both R10 and R11 are both hydrogen. In another embodiment, one of R10 and R11 is hydrogen and the other is ethyl or methyl. The compounds within the scope of the invention are exemplified by those indicated in Table 1 as follows: Table 1 Specific examples of the compounds of the invention include: N- (3-aminopropyl) -N- [1- (3-benzyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [l, 2- a] pyrimidin-2-yl) propyl] -4-bromobenzamide; N- (3-aminopropyl) -N- [l- (3-benzyl-4-oxo-6,7, 8,9-tetrahydro-4H-pyrido [1,2- a] pyrimidin-2-yl) -2 -methylpropyl] -4- methylbenzamide; N- (3-aminopropyl) -N- [1- (3-benzyl-8-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2- a] pyrimidin-2-N- il) propyl] -4-methylbenza ida; N- (3-aminopropyl) -N- [l- (3-benzyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2- a] pyripddin-2-yl) -2 -methylpropyl] -3-fluoro-4-methylbenzamide; N- (3-ethylaminopropyl) -N- [l- (3-benzyl-4-oxo-6,7, 8,9-tetrahydro-4H-pyrido [1,2- a] pyrimidin-2-yl) -2 -methylpropyl] -4-methylbenzamide; N- (3-ethylaminopropyl) -N- [l- (3-benzyl-4-oxo-6,7, 8,9-tetrahydro-4H-pyrido [1,2- a] pyrimidin-2-yl) -2 -methylpropyl] -3-fluoro-4-methylbenzamide; and N- (3-methylaminopropyl) -N- [1- (3-benzyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2- a] pyrimidin-2-yl) - 2-methylpropyl] -4-methylbenza ida. The compounds of this invention may exhibit stereoisomerism by virtue of the presence of one or more asymmetric or chiral centers in the compounds. The present invention contemplates the various stereoisomers and mixtures thereof. Certain compounds of the invention comprise asymmetrically substituted carbon atoms. Such asymmetrically substituted carbon atoms can result in the compounds of the invention which comprise mixtures of stereoisomers on a particular asymmetrically substituted carbon atom or a simple stereoisomer. As a result, racemic mixtures, mixtures of diastereomers, single enantiomer, as well as single diastereomers of the compounds of the invention are included in the present invention. The terms of configuration "S" and "R", as used herein, are as defined by the IUPAC 1974"RECOMMENDATIONS FOR SECTION E, FUNDAMENTAL STEREOCHEMISTRY", Puré Appl. Chem. 45:13 30, 1976. The desired enantiomers can be obtained by the chiral synthesis from commercially available chiral starting materials by methods well known in the art, or they can be obtained from the mixtures of the enantiomers by separating the desired enantiomer by using known techniques. The compounds of this invention may also exhibit geometric isomerism. Geometric isomers include the cis and trans forms of compounds of the invention having alkenyl or alkenylenyl moieties. The present invention comprises the individual geometric isomers and stereoisomers and mixtures thereof. DETAILED DESCRIPTION OF THE INVENTION A. Definitions The following definitions are provided for a better understanding of the invention and are used throughout. request. It is understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of the present invention. It should be understood that as used herein and in the claims, the singular forms "one, one" "and" and "the, the, the," include plural references unless the context clearly dictates otherwise. In this specification and in the claims that follow, reference is made to a number of terms which must be defined to have the following meanings. Generally, the reference to a certain element such as hydrogen or H is understood to include all isotopes of that element. For example, if a group R is defined to include hydrogen or H, it also includes deuterium or tritium. The term "alkyl" refers to both "unsubstituted alkyl" and "substituted alkyl" groups. The phrase "unsubstituted alkyl" refers to aliphatic, monovalent groups, and includes saturated straight-chain or branched radicals having from 1 to 20 carbon atoms. "Unsubstituted alkyl" refers to alkyl groups that do not contain heteroatoms. In this way the phrase includes the groups' straight chain alkyl such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl 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 the form of example: -CH (CH3) 2, -CH (CH3) (CH2CH3), -CH (CH 2 CH 3) 2, -CH (CH 3) 3, - CH (CH 2 CH 3) 3, -CH 2 CH 2 (CH 3) 2, -CH 2 CH (CH 3) (CH 2 CH 3), -CH 2 CH (CH 2 CH 3) 2, - CH 2 C (CH 3) 3 , -CH2C (CH2CH3), -CH (CH3) CH (CH3) (CH2CH3), CH2CH2CH (CH3) 2, -CH2CH2CH (CH3) (CH2CH3), -CH2CH2CH (CH2CH3) 2, CH2CH2C (CH3) 3, -CH2CH2C (CH2CH3), -CH (CH3) CH2CH (CH3) 2, CH (CH3) CH (CH3) CH (CH3) 2, -CH (CH2CH3) CH (CH3) CH (CH2CH3), and others. The phrase also includes cyclic alkenyl groups also referred to herein as "cycloalkyl". Such groups may have single or multiple cyclic rings and may include, by the example form only, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl and such rings substituted with straight or branched chain alkyl groups as defined above. Thus, the phrase "alkyl" includes primary alkyl groups, secondary alkyl groups, and tertiary alkyl groups. Preferred alkyl groups include straight or branched chain alkyl groups having 1 to 12 carbon atoms and cyclic alkyl groups having 3 to 12 carbon atoms. Additional preferred alkyl groups include straight or branched chain alkyl groups that have 1 to 6 carbon atoms and cyclic alkyl groups having 3 to 8 carbon atoms, "Ci-Ce alkyl" refers to a straight, branched or cyclic hydrocarbon radical, which contains from 1 to 6 carbon atoms. The phrase "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 to non-hydrogen and non-carbon atoms such as, but not limited to, a halogen atom 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, algeryl and aryl sulfide groups, sulfone groups (-S02), sulfonyl groups (-S02-), and sulfoxide groups (-S (= 0) -); a nitrogen atom in groups such as amins, amides, alkylamines, dialkylamines, arylamines, alkylarylamines, diarylamines, N-oxides (N-> 0), imides (-C (= 0) -NH-C (= 0) - ), and enamines (-C = C-NH2); a silicon atom in groups such as in trialkylsilyl groups (-Si (alkyl) 3 where each alkyl group may be the same or different), dialkylarylsilyl (-si (alkyl) 2 (aryl) groups, wherein each alkyl group may be the same or different), alkyldiarylsilyl groups (-Si (alkyl) (aryl) 2, wherein each aryl group can be the same or different), and triarylsilyl groups (-Si (aryl) 3) where each aryl group can be the same or different); and other heteroatoms in several different groups.

Substituted alkyl groups also include groups in which one or more bonds to a carbon or hydrogen atom are replaced by a higher order bond (e.g., a double or triple bond) to a heteroatom such as oxygen to oxo, carbonyl, carboxyl, and ester groups; nitrogen in groups such as imines (-C = N-R), oximes (-C = N-OH), hydrazones (-C = NNH2), and nitriles (-C = N). Substituted alkyl groups further include alkyl groups in which one or more bonds to a carbon or hydrogen atom is replaced by a bond to an aryl, heterocyclyl 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 is / are replaced (two) 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 is replaced by a bond to an oxygen atom such that the substituted alkyl group contains a hydroxyl, alkoxy, or aryloxy group. Other preferred substituted alkyl groups include alkyl groups having an amine group, or a substituted or unsubstituted alkylamino, dialkylamino, arylamino, (alkyl) (aryl) amino, diarylamino, heterocyclylamino, diheterocyclylamino, (alkyl) (heterocyclyl) amino or (aryl) (heterocyclyl) amino. Still other preferred substituted alkyl groups include those in which one or more bonds to carbon or hydrogen atoms 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 ) 2 (CH3, -CH2OCH2NH2, and -C02CH. Examples of substituted alkyl substituents include but are not limited to: -CH20H, -OH, -0CH3, -OC2H5, -0CF3, -0C (= 0) CH3, -0C (= 0) NH2, -OC (= 0) N (CH3) 2, -CN, -N02, -C (= 0) CH3, -C02H, -C02CH3, C0NH2, -NH2, -N (CH3) 2, -NHS02CH3, -NHC0CH3, -NHC (= 0) O (CH3), -NHS02CH3, -S02CH3, -S02NH2, and halo. "Cycloalkyl" refers to mono-polycyclic alkyl groups in which all ring atoms are carbon Typical cycloalkyl substituents have from 3 to 8 ring atoms When used in connection with cycloalkyl substituents, the term "polycyclic" refers herein to non-fused, fused alkyl cyclic structures The phrase "alkenyl" refers to both "unsubstituted alkenyl" and "substituted alkenyl" groups The phrase "unsubstituted alkenyl" refers to chain groups line al and branched and cyclic (but not aromatic) such as those described with respect to unsubstituted alkyl groups as defined above, except that at least one double bond exists between two carbon atoms. Examples include, but are not limited to vinyl, -CH = C (H) (CH3), and -CH = C (CH3) 2, -C (CH3) = C (H) 2, C (CH3) = C (H) (CH3), -C (CH2CH3) = CH2, cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, and hexadienyl among others. "C2-C6 alkenyl" means an alkenyl radical which has from 2 to 6 atoms. The phrase "substituted alkenyl" has the same meaning with respect to the alkenyl groups that the substituted alkyl groups have with respect to the unsubstituted alkyl groups. A substituted alkenyl group includes alkenyl groups in which a non-carbon or hydrogen atom is bonded to a carbon with double bond to another carbon and those in which one of the non-carbon or hydrogen atoms is bonded to a non-carbon involved in a double bond to another carbon. The phrase "alkynyl" refers to both "unsubstituted alkynyl" groups and "substituted alkynyl" groups. The phrase "unsubstituted alkynyl" refers to straight and branched chain groups such as those described with respect to unsubstituted alkyl groups as defined above, except that at least one triple bond exists between two carbon atoms. Examples include, but are not limited to, -C = C (H), -C = C (CH3), G = C (CH2CH3), -C (H2) C = C (H), -C (H) 2C = C (CH3) and -C (H) 2C = C (CH2CH3) among others. "C2-C6 alkynyl" means an alkynyl radical which has from 2 to 6 carbon atoms. The phrase "substituted alkynyl" has the same meaning with respect to alkynyl groups that the substituted alkyl groups have with respect to unsubstituted alkyl groups. A substituted alkynyl group includes alkynyl groups in which a non-carbon or hydrogen atom is bonded to a carbon with triple bond to another carbon and those in which a non-carbon or hydrogen atom is bonded to a carbon not involved in a triple link to another carbon. The phrase "aryl" refers to both an "unsubstituted aryl" and "substituted aryl" group. The phrase "unsubstituted aryl" refers to monocyclic and polycyclic aromatic groups which have from 6 to 14 carbon atoms, "unsubstituted aryl" refers to aryl groups that do not contain heteroatoms. Thus the phrase includes, but is not limited to, groups such as phenyl, biphenyl, anthracenyl, naphthenyl by the example form. A preferred unsubstituted aryl group is phenyl. The unsubstituted aryl groups can be bonded to one or more carbon atoms, oxygen atoms, nitrogen atoms, and / or sulfur atoms, in the parent compound outside the ring structure.

The phrase "substituted aryl group" has the same meaning with respect to unsubstituted aryl groups that substituted alkyl groups have with respect to unsubstituted alkyl groups. However, a substituted aryl group also includes aryl groups in which one of the aromatic carbons is bonded to one of the non-carbon or non-hydrogen atoms described above and also includes aryl groups in which one or more aromatic carbons of the group aryl is linked to a substituted, unsubstituted alkyl, alkenyl, or alkynyl group as defined above. This includes linking arrangements in which two carbon atoms of an aryl group are bonded to two carbon atoms of an alkyl, alkenyl, or alkynyl group to define a fused ring system (eg, dihydronaphthyl or tetrahydronaphthyl). Thus, the phrase "substituted aryl" includes, but is not limited to tolyl and hydroxyphenyl among others. Preferred substituents include straight or branched chain alkyl groups, -CH3, -C2Hs, -CH20H, -OH, -0CH3, -0C2H5, -0CF3, -0C (= 0) CH3, -0C (= 0) MH2, - OC (= 0) N (CH3) 2, -CN, -N02, -C (= 0) CH3, -C02H, C02CH3, -CONH2, -NH2, -N (CH3) 2, NHS02CH3, -NHCOCH3, -NHC (= 0) 0CH3, -NHS02CH3, -S02CH3, -S02NH2 and halo. "Aralkyl" or "arylalkyl" refers to an alkyl group substituted with an aryl group. Typically, 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 employed in compounds herein include, for example, benzyl, picolyl, and the like. The phrase "carbocyclic" refers to both "unsubstituted carbocyclic" and "substituted carbocyclic" groups. The phrase "unsubstituted carbocyclic" refers to both aromatic and non-aromatic ring compounds which include monocyclic, bicyclic and polycyclic ring compounds such as cycloalkyl or aryl groups. The phrase "heterocyclyl" refers to both "unsubstituted heterocyclyl" and "substituted heterocyclyl" groups. The phrase "unsubstituted heterocyclyl" refers to both aromatic and non-aromatic ring compounds which include monocyclic, bicyclic and polycyclic ring compounds such as, but not limited to, quinuclidinyl, which contain 3 or more ring members of the which one or more is a heteroatom such as, but not limited to, N, 0 and S. Although the phrase "unsubstituted heterocyclyl" includes fused heterocyclic rings such as benzimidazolyl, it does not include heterocyclyl groups having other groups such as alkyl or the halo linked to one of the ring members since composite such as 2-methylbenzimidazolyl are substituted heterocyclyl groups. Examples of heterocyclyl groups include, but are not limited to, rings of 3 to 8 unsaturated members containing 1 to 4 nitrogen atoms such as, but not limited to pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, dihydropyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (for example 4H-1, 2,4-triazolyl, 1H-1, 2,3-triazolyl, 2H-1,2,3-triazolyl etc.), tetrazolyl (for example, 1H-tetrazolyl, 2H- tetrazolyl, etc.); saturated 3 to 8 membered rings which contain 1 to 4 nitrogen atoms such as, but not limited to, pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl; condensed unsaturated heterocyclic groups which contain 1 to 4 nitrogen atoms such as, but not limited to, indolyl, isoindolyl, indolinyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl; rings of 3 to 8 unsaturated members which contain 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms such as, but not limited to, oxazolyl, isoxazolyl, oxadiazolyl (for example, 1,2,4-oxadiazolyl, 1, 3, -oxadiazolyl, 1, 2, 5-oxadiazolyl, etc.), saturated 3 to 8 membered rings which contain 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms such as, but not limited to, morpholinyl; Heterocyclic condensed groups unsaturated which contain 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, benzoxazolyl, benzoxadiazolyl, benzoxazinyl (for example 2H-1,4-benzoxazinyl etc); rings of 3 to 8 unsaturated members which contain 1 to 3 sulfur atoms and 1 to 3 nitrogen atoms such as, but not limited to, thiazolyl, isothiazolyl, thiadiazolyl (for example 1, 2,3-thiadiazolyl, 1, 2 , 4-thiadiazolyl, 1,3-thiadiazolyl, 1,2,5-thiadiazolyl, etc.); 3 to 8 saturated member rings which contain 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms such as, but not limited to thiazaolodinyl; saturated or unsaturated 3 to 8 membered rings which contain 1 to 2 sulfur atoms such as, but not limited to, thienyl, dihydrodithiinyl, dihydrodicyl, tetrahydrothiophene, tetrahydrothiopyran, unsaturated condensed heterocyclic rings which contain 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms such as, but not limited to, benzothiazolyl, benzothiadiazolyl, benzothiazinyl (for example 2H-1, 4-benzothiazinyl, etc.), dihydrobenzothiazinyl (for example 2H-3, 4-dihydrobenzothiazinyl, etc.), rings of 3 to 8 unsaturated members which contain oxygen atoms such as, but not limited to, furyl; unsaturated condensed heterocyclic rings which contain 1 to 2 oxygen atoms such as benzodioxolyl (for example, 1,3-benzodioxoyl, etc.); rings from 3 to 8 unsaturated members which contain an oxygen atom and 1 to 2 sulfur atoms such as, but not limited to, dihydrooxathiinyl; rings of 3 to 8 saturated members which contain 1 to 2 oxygen atoms and 1 to 2 sulfur atoms such as 1, -oxatiano; unsaturated condensed rings which contain 1 to 2 sulfur atoms such as benzothienyl, benzodithiinyl; and unsaturated condensed heterocyclic rings which contain an oxygen atom and 1 to 2 oxygen atoms such as benzoxathiinyl. Heterocyclyl groups also include those described above in which one or more S atoms in the ring has double bond to one or two oxygen atoms (sulfoxides and sulfones). For example, heterocyclyl groups include tetrahydrothiophene, tetrahydrothiophene oxide, and tetrahydrothiophene 1,1-dioxide. Preferred heterocyclyl groups contain 5 or 6 membered rings. More preferred heterocyclyl groups include morpholine, piperazine, piperidine, pyrrolidine, imidazole, pyrazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, thiomorpholine, thiomorpholine in which the S atom of the thiomorpholine is linked to one or more O atoms, pyrrole, homopiperazine, oxazolidin-2-one, pyrrolidin-2-one, oxazole, quinuclidine, thiazole, isoxazole, furan and tetrahydrofuran. The phrase "substituted heterocyclyl" refers to an unsubstituted heterocyclyl group as defined above in which one or more of the ring members are linked to a non-hydrogen atom as described above with respect to substituted alkoyl groups and substituted aryl groups. Examples include, but are not limited to 2-methylbencipddazolyl, 5-methylbenzimidazolyl, 5-chlorobenzthiazolyl, 1-methylpiperazinyl and 2-chloropyridyl among others. The phrase "heteroaryl" refers to both "unsubstituted heteroaryl" and "substituted heteroaryl" groups. The term "unsubstituted heteroaryl", as used herein, refers to a cyclic or bicyclic radical which has from 5 to 10 ring atoms in each ring of which a cyclic or bicyclic ring atom is selected from S , 0 and N; zero, one or two ring atoms are additional heteroatoms independently selected from S, O and N; and the remaining ring atoms are carbon, the "radical that is attached to the rest of the molecule by means of the ring atoms, such as, for example, pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl and naphthyridinyl and the like The term "substituted heteroaryl" refers to an unsubstituted heteroaryl group as defined above in which one or more of the ring members are linked to an atom other than hydrogen as described above with respect to substituted alkyl groups and substituted aryl groups. Preferred substituents include straight and branched chain alkyl groups -CH3, -C2H5, -CH2OH, -OH, -OCH3, -OC2H5, -OCF3, -OC (= 0) CH3, -OC (= 0) NH2, -OC (= 0) N (CH3) 2, - CN, -NO2, -C (= 0) CH3, -C02H, -C02CH3, CONH2, -NH, -N (CH3) 2, - NHS02CH3, -NHCOCH3, -NHC (= 0) OCH3, -NHS02CH3, -S02CH3, -S02NH2 and halo. The term "biaryl" refers to a group or substituent to which two aryl groups, which are not fused together, are linked. Exemplary biaryl compounds include, for example, phenylbenzene, diphenyldiazene, 4-methylthio-1-phenylbenzene, phenoxybenzene, (2-phenylethynyl) -endene, diphenylketone, (4-phenylbuta-1, 3-diinyl) -enol, phenylbenzylamine, (phenylmethoxy) ) benzene and the like. Optionally optionally substituted biaryl groups include: 2- (phenylamino) -N- [4- (2-phenylethynyl) phenyl] acetamide, 1,4-diphenylbenzene, N- [4- (2-phenylethynyl) phenyl] -2- [benzylamino] acetamide, 2-amino-N- [4- (2-phenylethynyl) phenyl] propanamide, 2-amino-N- [4- (2-phenylethynyl) phenyl] acetamide, 2- (cyclopropylamino) -N- [ 4- (2-phenylethynyl) phenyl] acetamide, 2- (ethylamino) -N- [4- (2-phenylethynyl) phenyl] acetamide, 2 - [(2-methylpropyl) amino] -N- [4- (2- phenylethynyl) phenyl] acetamide, 5-phenyl-2H-benzo [d] l, 3-dioxolene, 2-chloro-l-methoxy-4-phenylbenzene, 2 - [(imidazolylmethyl) amino] -N- [4- (2-phenylethynyl) phenyl] acetamide, 4-phenyl-1-phenoxybenzene, N- (2-aminoethyl) [4- (2-phenylethynyl) phenyljcarboxamide, 2-. { [(4- fluorophenyl) methyl] amino} -N- [4- (2-phenylethynyl) phenyl] acetamide, 2-. { [(4-methylphenyl) methyl] amino} -N- [4- (2-phenylethynyl) phenyl] acetamide, 4-phenyl-1- (trifluoromethyl) benzene, l-butyl-4-phenylbenzene, 2- (cyclohexylamino) -N- [4- (2-phenylethynyl) phenyl] acetamide, 2- (ethylmethylamino) -N- [4- (2-phenylethynyl) phenyl] acetamide, 2- (butylamino) -N- [4- (2-phenylethynyl) phenyl] acetamide, N- [4- ( 2-phenylethynyl) phenyl] -2- (4-pyridylamino) acetamide, N- [4- (2-phenylethynyl) phenyl] -2- (quinuclidin-3-ylamino) acetamide, N- [4- (2-phenylethynyl) phenyl] pyrrolidin-2-ylcarboxamide, 2-amino-3-methyl-N- [4- (2-phenylethynyl) phenyl] butanamide, 4- (4-phenylbuta-l, 3-diinyl) phenylamine, 2- (dimethylamino) -N- [4- (4-phenylbuta-l, 3-diinyl) phenyl] acetamide, 2- (ethylamino) -N- [4- (4-phenylbuta-1,3-dinyl) phenyl] acetamide, 4-ethyl -l-phenylbenzene, l- [4- (2-phenylethynyl) phenyl] ethan-l-one, N- (1-carbamoy1- -hydroxypropyl) - [4- (4-phenylbuta-l, 3-dinyl) phenyl] carboxamide, N- [4- (2-phenylethynyl) phenyl] propanamide, 4-methoxyphenol phenyl phenyl ketone, phenyl-N-benzamide, (tert-butoxy) -N - [(4-phenylphenyl) methyl] carboxamide, 2- (3 -phenyl phenoxy) ethanohydroxamic, 3-phenylphenyl propanoate, 1- (4-ethoxyphenyl) -4-methoxybenzene, and [4- (2- phenylethynyl) phenyl] pyrrole. The term "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, phenylpyrazole, 5- (2-phenylethynyl) -1,3-dihydropyrimidine-2-dione, 4-phenyl- 1,2,3-thiadiazole, 2- (2-phenylethynyl) pyrazine, 2-phenylthiophene, phenylimidazole, 3- (2-piperazinylphenyl) furan, 3- (2,4-dichlorophenyl) -4-methylpyrrole, and the like. Preferred optionally substituted heteroarylaryl groups include: 5- (2-phenylethynyl) pyrimidine-2-ylamine, l-methoxy-4- (2-thienyl) benzene, l-methoxy-3- (2-thienyl) benzene, 5-methyl -2-phenylpyridine, 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, - [(4-methylpiperazinyl) methyl] -2-phenylthiophene, 2- (4-ethylphenyl) thiophene, 4-methylthio-l- (2-thienyl) benzene, 2- (3-nitrophenyl) thiophene, (tert-butoxy) ) -N- [(5-phenyl (3-pyridyl)) methyl] carboxamide, hydroxy-N - [(5-phenyl (3-pyridyl)) methyl] amide, 2- (phenylmethylthio) iridine, and benzylimidazole. The term "heteroaryl heteroaryl" refers to a biaryl group where both aryl groups is a heteroaryl group. Exemplary heteroarylheteroaryl groups include, for example, 3-pyridylimidazole, 2-imidazolylpyrazine and similar. Preferred optionally substituted heteroaryl heteroaryl groups include: 2- (4-piperazinyl-3-pyridyl) furan, diethyl (3-pyrazin-2-yl (4-pyridyl)) amine, and dimethyl. { 2- [2- (5-Methylpyrazin-2-yl) ethynyl] (4-pyridyl) amine The substitution group may itself be substituted The substituted group in the substitution group may be carboxyl; halo; nitro , amino, cyano, hydroxy, alkoyl, alkoxy, aminocarbonyl, -SRa, thioamide, -S03H, -S02Ra or cycloalkyl, wherein Ra is typically hydrogen, hydroxyl or alkyl.When the substituent includes a straight chain group, the substitution may occur either within the chain (e.g., 2-hydroxypropyl, 2-aminobutyl, and the like) or at the chain termination (e.g., 2-hydroxyethyl, 3-cyanopropyl, and the like). linear, branched or cyclic chain of covalently bonded carbon or heteroatoms "Halogen" or "halo" refers to 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 a radical alkoxy substituted with one or more halogen atoms. "Ciano" refers to -CN. "Nitro" refers to -N02. "Carboxy" or "carboxyl" refers to -C (= O) -0H.

"Hydroxy" or "hydroxyl" refers to -OH. "Alkoxy" refers to -O-alkyl. Representative examples of alkoxy groups include methoxy, ethoxy, t-butoxy, trifluoromethoxy, and the like. "Aryloxy" refers to -O-aryl. Representative examples of aryloxy groups include phenoxy, naphthoxy and the like. "Heterocyclyloxy" refers to -O-heterocyclyl. "Carbonyl" refers to the divalent group -C (= 0) -. "Ester" refers to the divalent group -C (= 0) 0-. "Tiol" refers to the group -SH. "Alkylsulfides" or "alkylthio" refers to the group -S-alkyl. "Arylsulfides" or "arylthio" refers to the group -S-aryl. "Alkylcarbonyloxy" refers herein to the group -OC (= 0) -alkyl. "Arylcarbonyloxy" refers herein to the group -0C (= 0) -aryl. "Heterocyclycarbonyloxy" refers to the group -OC (= 0) -heterocyclyl. The phrase "amino" refers to both the "unsubstituted amino" and "amino substituted" groups. "Unsubstituted amino" refers to the -NH2 group herein.

"Substituted amino" or "substituted amine" refers herein to the group NRbR wherein each R is independently selected from H, alkyl, aryl, heteroaryl, or heterocyclyl. The term "alkylamino" refers herein to the group -NRcRd wherein Rc is alkyl and Rd is H or alkyl. The term "dialkylamino" refers to the group -NRCRC wherein each Rc may be the same or different alkyl. The term "arylamino" refers herein to the group -NRcRf where Rc is aryl and Rf is hydrogen, alkyl, aryl, heteroaryl or heterocyclyl. The term "alkylarylamino" refers to the group -NRcRe wherein Rc is alkyl and R3 is aryl. The term "diarylamino" refers to the group NReRe wherein each Re can be from the same aryl or different. The term "heterocyclylamino" refers to the group -NRRg wherein each Rb is as defined herein and Rg is heterocyclyl. The term "diheterocyclylamino" refers to the group -NRgRg, wherein each Rg is the same heterocyclyl or different. The term "(alkyl) (heterocyclic) mino" refers to the group -NRcRg where Rc and Rg are as defined above. The term "(aryl) (heterocyclyl) amino" refers to the group -NReRg, wherein Rc and Rg are as defined herein. "Aminocarbonyl" or "amide" refers herein to the group -C (0) -NH2 or -C (0) -NRRb where each Rb is independently selected from H, alkyl, aryl, heteroaryl or heterocyclyl. The term "alkylaminocarbonyl" refers to the present to amide -C (0) -NRcRd wherein Rc is alkyl and Rd is H or alkyl. The term "arylaminocarbonyl" refers herein to the amide -C (0) -NReRf where Re is aryl and Rf is hydrogen, alkyl, aryl, heteroaryl, or heterocyclyl. Representative aminocarbonyl groups include, for example, those shown below. This aminocarbonyl group can also be substituted as will be apparent to those having experience in the techniques of organic and medicinal chemistry together with the description of the present "Aminocarbonyloxy" refers to the group -0-C (= 0) ammo, "To inooxycarbonyl" refers to the group -C (= 0) -0-ammo, "Alkylcarbonyl" refers to the group -C (O) -alkyl . "Arylcarbonyl" refers to the group -C (= 0) -aryl. "Heterocyclylcarbonyl" refers to the group -C (= 0) -heterocyclyl.

"Alkoxycarbonyl" or "carboxyalkyl" refers to the group -C (= 0) -O-alkyl. Representative alkoxycarbonyl groups include, for example, those shown below. These alkoxycarbonyl groups can be further substituted as will be apparent to those having experience in the medicinal and organic chemistry techniques together with the description herein. and "Aryloxycarbonyl" refers to ~ C (= 0) -O-aryl. "Heterocyclyloxycarbonyl" refers to -C (= 0) -0-heterocyclyl. "Alkylcarbonylamino" refers herein to -N (Rb) C (= 0) -alkyl wherein Rb is as defined above. Representative alkylcarbonylamino groups include, for example, -NHC (= 0) CH2, -NHC (= 0) CH2CH3, -NHC (= 0) CH2NH (CH) 3, NHC (= 0) CH2N (CH3) 2, or - NHC (= 0) (CH2) 30H. These groups can also be substituted as will be apparent to those who have experience in organic chemical techniques and medicinal products together with the description of the present. "Arylcarbonylamino" refers herein to a -N (Rb) C (= 0) -aryl, wherein Rb is as defined above. "Heterocycliccarbonylamino" refers herein to -N (Rb) C (= 0) -heterocyclyl wherein Rb is as defined above. "Alkoxycarbonylamino" refers herein to -N (Rb) C (= 0) O-alkyl wherein Rb is as defined above. "Aryloxycarbonylamino" refers herein to -N (Rb) C (= 0) O-aryl wherein Rb is as defined above. "Heterocyclyloxycarbonylamino" refers herein to -N (Rb) C (= 0) -heterocyclyl wherein Rb is as defined above. "Sulfonyl" refers to the group -S02- "Alkylsulfonylamino" refers herein to -NRbS (= 0) 2-alkyl wherein Rb is as defined above. "Arylsulfonylamino" refers herein to -NRbS (= 0) 2-aryl wherein Rb is as defined above. "Heterocyclylsulfonylamino" refers herein to -NRS (= 0) 2-heterocyclyl wherein Rb is as defined above. "Aminosulfonyl" refers herein to -S (= 0) 2NRRb wherein each Rb is independently selected of H, alkyl, aryl, heteroaryl, or heterocyclyl. "Alkylsulfonyl" refers herein to -S (= 0) 2-alkyl. The alkylsulfonyl groups used in compounds of the present invention are typically alkylsulfonyl groups having from 1 to 6 carbon atoms in their main structure. Thus, typical alkylsulfonyl groups employed in compounds of the present invention include, for example, methylsulfonyl (ie, where the alkyl is methyl), ethylsulfonyl (ie, where the alkyl is ethyl), propylsulfonyl (i.e. where alkyl is propyl), and the like. "Aryisulfonyl" refers herein to -S (= 0) 2-aryl. "Heterocyclylsulfonyl" refers herein to -S (= 0) 2-heterocyclyl. The term "sulfonamido" refers herein to -S02NH2. The term "protected" with respect to the hydroxyl groups, amine groups, and sulfhydryl groups refers to forms of these functionalities which are protected from the undesirable reaction with a protecting group known to those skilled in the art such as those indicated in Protective Groups in Organic Synthesis, Greene, TW; Wuts, P. G. M., John Wiley & Sons, New York, NY, (3rd edition, 1999) which can be added or removed using the procedures indicated in it. Examples of protected hydroxyl groups include, but are not limited to, silyl ethers, such as those obtained by the reaction of a hydroxyl group with a reagent such as, but not limited to, t-butyldimethyl-chlorosilane, trimethylchlorosilane, triisopropylchlorosilane, triethylchlorosilane, substituted methyl and ethyl ethers such as, but not limited to, methoxymethyl ether, methylthiomethyl ether, benzyloxymethyl ether, t-butoxymethyl ether, 2-methoxyethoxymethyl ether, tetrahydropyranyl ethers, 1-ethoxyethyl ether, allyl ether, benzyl ether; esters such as, but not limited to, benzoyl formate, formate, acetate, trichloroacetate and trifluoroacetate. Examples of protected amine groups include, but are not limited to, amides such as formamide, acetamide, trifluoroacetamide, and benzamide; imides, such as phthalimide, and dithiosuccinimide; and others. Examples of protected sulfhydryl groups include, but are not limited to, thioethers such as S-benzyl thioether and S-R-picolyl thioether; substituted S-methyl derivatives such as emitted, dithio and aminothio acetals; and others. The free form of compounds of the formulas I-I, as well as the pharmaceutically acceptable salts, stereoisomers, and prodrugs thereof are included in the invention. As used herein, the term "salts "pharmaceutically acceptable" refers to the non-toxic acid or alkaline earth metal salts of the compounds of the formula I-IV These salts can be prepared in situ during the final isolation and purification of the compounds of the formulas I-IV, or by reacting the basic or acid functions separately 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, benzenesulfonate, bisulfate, butyrate, camphorrate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecyl sulfate, ethanesulfonate, glycoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethane sulfoant, lactate maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylproyonate, picrate, pivalate, propionate, succinate, sulfate, tartrate , thiocyanate, p-toluenesulfonate and undecanoate. Also, the groups containing the basic nitrogen can be quaternized with such agents as the 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 as benzyl and phenethyl bromides, and others. The products soluble or dispersible in water or oil are therefore obtained. Examples of acids which can be used to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, sulfuric acid and phosphoric acid and such organic acids as oxalic acid, maleic acid, methanesulfonic acid, succinic acid and citric acid. The basic addition salts can be prepared in situ during the isolation and final purification of the compounds of the formulas I-IV, or separately by reacting portions of the carboxylic acid 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. Pharmaceutically acceptable salts include, but are not limited to, cations based on the alkali and ferrous alkali metals, such as sodium, lithium, potassium, calcium, magnesium, aluminum salts and the like, as well as ammonium, quaternary ammonium and amine cations , including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine and the like. Other representative organic amines useful for the formation of basic addition salts include diethylamine ethylene diamine, ethanolamine, diethanolamine, piperazine and the like. As used herein, the term "pharmaceutically acceptable ester" refers to esters which can be hydrolyzed in vivo and include those that decompose in the human body to leave the parent compound or a salt thereof. Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl portion advantageously has no more than 6 carbon atoms. Representative examples of particular esters include, but are not limited to, formates, acetates, propionates, butyrates, acrylates and ethylsuccinates. The term "pharmaceutically acceptable prodrugs" as used herein refers to these prodrugs of the compounds of the present invention which are, within the scope of the medical judgment served, suitable for use in contact with the tissues of humans and animals. inferiors without prolonged toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio and effective for their intended use, as well as zwitterionic forms, where possible, of the compounds of the invention. The term "prodrug" refers to compounds that are rapidly transformed in vivo to produce the parent compound of the above formula, for example by hydrolysis in blood. A discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol.14 of the A.C.S Symposium Series, and in Edward B. Roche, ed. Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference. The term "anticancer agent" refers to agents synthesized or modified in the laboratory which have anticancer activity. An "anticancer" agent in this context will inhibit tumor growth. The term "inhibit growth" indicates that the rate of increase in tumor size and / or weight is reduced. Thus, the term includes situations in which tumor size and / or weight increase but in a reduced proportion, as well as situations where tumor growth is arrested. If an enzyme activity assay is used to screen the inhibitors, one can make changes in uptake / efflux, solubility, half-life, etc. to the compounds in order to correlate the enzyme inhibition with growth inhibition. This term is more fully described in the next section. The subject invention also includes isotopically labeled compounds, which are structurally identical to those described above, but by the fact that one or more atoms are replaced by an atom which has an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2H, 3H, 13C, 14C, 15N, 180, 170, 31P , 32P, 35S, 18F and 36C1, respectively. The compounds of the present invention, prodrugs thereof, and pharmaceutically acceptable acceptable salts of the compounds and prodrugs which contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of the present invention. Certain isotopically labeled compounds of the present invention, for example those in which reactive isotopes such as 3H and 14C are incorporated, are useful in drug and / or substrate tissue distribution assays. The tritiated isotopes, i.e., 3H, and carbon-14, i.e., 14C, are particularly preferred for their ease and detectability. In addition, substitution with heavier isotopes such as deuterium, i.e., 2H, can produce certain therapeutic advantages that result from increased metabolic stability, for example medium or reduced life dose requirements in vivo and, therefore, can be preferred in some circumstances. The isotopically labeled compounds of this invention and prodrugs thereof can generally be prepared by carrying out known or reference procedures and by replacing an isotopically readily available etchant reagent with a non-isotopically labeled reagent. B. Uses, Doses and Administration The present invention provides novel compounds, pharmaceutical compositions which include the compounds, methods for inhibiting KSP, and methods for treating KSP mediated diseases including cell proliferative disorders, such as cancer. In one aspect, the present invention provides methods for treating human or animal subjects suffering from a cell proliferative disease. The term "cell proliferative disorder" or "cell proliferative disorder" refers to diseases which include, for example, cancer, tumor, hyperplasia, restenosis, cardiac hypertrophy, immune disorder and inflammation. The present invention provides methods for treating a human or animal subject in need of such treatment, which comprises administering to the subject a therapeutically effective amount of a compound of the formulas I-IV, either alone or in combination with other anticancer agents. The compounds of the invention are useful in vitro or in vivo to inhibit the growth of cancer cells. The term "cancer" refers to cancerous diseases which include, for example, lung and bronchi; prostate, breast; pancreas; colon and rectum; thyroid; stomach; liver and intrahepatic bile duct; Kidney kidney and pelvis; urinary bladder; uterine body; uterine cervix; ovaries; 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 colon hair. The cancer also includes tumors or neoplasms selected from the group consisting of carcinomas, adenocarcinomas and sarcomas. Additionally, the type of cancer can be selected from the group consisting of growth of solid tumors / malignancies, myxoid and round cell carcinoma, locally advanced tumors, human soft tissue carcinoma, cancer metastasis, squamous cell carcinoma, squamous cell carcinoma of the esophagus , oral carcinoma, cutaneous T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, adrenal cortex cancer, ACTH products tumors, non-small cell cancers, breast cancer, gastrointestinal cancers, urological cancers, malignancies of the genital tract female, malignancies of the male genital tract, kidney cancer, brain cancer, bone cancers, skin cancers, thyroid cancer, retinoblastoma, neuroblastoma, peritoneal effusion, malignant pleural effusion, mesothelioma, Wilms tumors, pancreatic cancer, trophoblastic neoplasms, hemangiopericytoma and Kaposi's sarcoma. In still another preferred embodiment, the cell proliferative disorder is selected from the group consisting of diseases mediated by angiogenesis, benign tumors, acoustic neuromas, neurofibromas, pyogenic granulomas, cancer of the biliary tract, choriocarcinoma, cancer of the esophagus, gastric cancer, intraepithelial neoplasms, cancer of the lung, neuroblastomas, chronic myelogenous leukemia, acute myelogenous leukemia, and multiple myeloma. The compounds can be used alone or in compositions together with a pharmaceutically acceptable carrier or excipient. Suitable pharmaceutically acceptable carriers or excipients include, for example, processing agents and modifiers and drug delivery enhancers, such as, for example, calcium phosphate, magnesium stearate, talc, monosaccharides, disaccharides, starch, gelatin, cellulose, methylcellulose, sodium carboxymethylcellulose, dextrose, hydroxypropyl-β-cyclodextrin, polyvinylpyrrolidinone, low melting point waxes, anion exchange resins, and the like, as well as combinations of any two or more thereof. Other pharmaceutically acceptable excipients Suitable embodiments are described in "Remington" s Pharmaceutical Sciences "Mack Pub. Co., New Jersey, 1991, incorporated herein by reference In one aspect, the present invention provides pharmaceutical compositions which comprise at least one compound of the formulas I-IV together with a pharmaceutically acceptable carrier suitable for administration to a human or animal subject, either alone or together with other anticancer agents, The effective amounts of the compounds of the invention generally include any amount sufficient to inhibit the activity of KSP. by the assay described herein, by other assays of KSP activity known to those of ordinary skill in the art, or by detecting an inhibition or alleviation of cancer symptoms.The amount of the active ingredient that can be combined with the carrier materials to produce a single dose 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 which include the activity of the specific compound employed, age, body weight, general health, sex, diet, time of administration , route of administration, rate of excretion, drug combination, and the severity of the particular disease that is under therapy. The therapeutically effective amount for a given situation can be easdetermined by routine experimentation and is within the experience and judgment of the ordinary clinician. For the purposes of the present invention, a therapeutically effective dose will generally be a total dadose administered to a host in single or divided doses which may be in amounts of, for example, 0.001 to 1000 mg / kg of body weight daand more preferred from 1.0 to 30 mg / kg of body weight da The unit dose compositions may contain such amounts of submultiples thereof to make the dadose. 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 compound of the effective formulas I-IV to reduce or prevent the cell proliferation or tumor growth in the subject. 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 medicine for the treatment of cancer. 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 which comprises administering to the subject an amount of a compound of the formulas I-IV effective to reduce or prevent proliferation. cell in the subject in combination with at least one additional agent for the treatment of cancer. A number of anticancer agents suitable for use as combination therapeutics are 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 (for example, enzymes); drugs; biological mimetics; alkaloids; alkylating agents; antitumor antibiotics; antimetabolites; hormones; platinum compounds; monoclonal antibodies conjugated with anticancer drugs, toxins and / or radionuclides; biological response modifiers (for example, interferons [for example, IFN-a] and interleukins [for example IL-2]; adoptive immunotherapy agents; hematopoietic growth factors that induce the differentiation of tumor cells (for example, all-trans-retinoic acid); gene therapy reagents; reagents and nucleotides of antisense therapy; tumor vaccines; inhibitors of angiogenesis, and the like. Other numerous examples of the chemotherapeutic compounds and anticancer therapies suitable for co-administration with the described compounds of the formulas I-IV are known to those skilled in the art. In preferred embodiments, the anti-cancer 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 (EGFR) kinase inhibitor, vascular growth factor receptor (VGFR). its acronym in English), inhibitor of fibroblast growth factor receptor (FGFR) kinase, platelet-derived growth factor receptor (PGFR) kinase inhibitor, and Bcr-abl kinase inhibitors such as STI-571, Gleevec, and Gli ec)); antisense molecules; antibodies (e.g., Herceptin and Rituxan); anti-estrogens (for example, raloxifene and tamoxifen); anti-androgens (eg, flutamide, bicalutamide, finasteride, aminoglutetamide, ketoconazole, and corticosteroids); inhibitors of cyclooxygenase 2 (COX-2) (for example, Celecoxib, meloxicam, NS-398, and nonsteroidal anti-inflammatory drugs (NSAIDS)); and cancer chemotherapeutic drugs (e.g., 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 cytosines; and is urosprine; and similar. The present invention provides compounds that are inhibitors of KSP. The 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 cell growth and / or cancer mediated by KSP. In particular, the compounds are useful in the treatment of human or animal (e.g., murine) cancer. The compounds of the invention are useful in the treatment of cancers, such as, for example, lung and bronchi; prostate; mom; bread boxes; colon and rectum; thyroid; stomach; liver and intrahepatic bile duct; Kidney kidney and pelvis; urinary bladder; uterine body: uterine cervix; ovary; multiple mileoma; 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.

In another embodiment, the invention provides methods for treating a KSP mediated disorder in a human or animal subject which comprises administering to a human or animal subject in need of such treatment a therapeutically effective amount of a compound of the formulas I-IV. . The term "KSP mediated disorder" refers to a disorder that can be beneficially treated by the inhibition of KSP.

As used entirely here, this disorder is referred to a disorder mediated, at least in part, by KSP. In one method, an effective amount of a compound of the formulas I-IV is administered to a patient (e.g., a human or animal subject) in need thereof to mediate (or modulate) the activity of the KSP. In some embodiments of the method for inhibiting KSP using a compound of formulas I-IV, the IC50 value of the compound is less than or equal to 1 mM with respect to KSP. In other embodiments, the IC50 value is less than or equal to 100 μM, is less than or equal to 25 μM, is less than or equal to 10 μM, is less than or equal to 1 μM, is less than or equal to 0.1 μM , is less than or equal to 0.050 μM, is less than or equal to 0.10 μM. C. Compositions and / or Pharmaceutical Formulations The pharmaceutical compositions of the present invention comprise a therapeutically effective amount of a compound of the present invention formulated together with one or more pharmaceutically acceptable carriers. As used in herein, the term "pharmaceutically acceptable carrier" means a solid, semi-solid or non-toxic, diluent, inert filler, an auxiliary encapsulating material or formulation of any type. Some examples of materials which can serve as pharmaceutically acceptable carriers are sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; jelly; talcum powder; excipients such as cocoa butter and waxes for suppositories; oils such as peanut oil, cottonseed oil; sunflower oil; Sesame oil; olive oil; corn oil and soybean oil; glycols; such as propylene glycol; esters such as ethyl oleate and ethyl laurate; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline solution; Ringer's solution; ethyl alcohol; and phosphate buffer solutions; as well as other compatible non-toxic lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweeteners, flavoring and perfumery agents, preservatives and antioxidants may also be present in the composition , according to the judgment of formulator. The pharmaceutical compositions of this invention can be administered to humans and other animals, orally, rectally, parentally, intracisternally, intravaginally, intraperitoneally, topically (as powders, ointments or drops), buccally, or as an oral or nasal dispersion, or an aerosol. liquid or dry powder formulation for inhalation. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate. , benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, nutmeg, corn, germ, olive, castor bean and garlic oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. In addition to the inert diluents, the oral compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweeteners, flavors and perfumery agents. Injectable preparations, for example, Sterile injectable aqueous suspensions or oleoginases 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, a suspension or emulsion in a non-toxic parentally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspension medium. For this purpose any soft fixed oil can be employed including synthetic mono or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables. The injectable formulations can be sterilized, for example, by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium before use. In order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be done by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The The absorption ratio of the drug then depends on its rate of dissolution which, in turn, may depend on the size of the crystal and the crystalline form. Alternatively, the delayed absorption of a parentally administered drug form can be accomplished by dissolving or suspending the drug in an oily vehicle. Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled.

Examples of other biodegradable polymers include poly (orthoesters) and polyanehydrides. Depot injectable formulations can also be prepared by entrapping the drug in liposomes or microemulsioens which are compatible with body tissues. Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at room temperature. body temperature and therefore melt in the rectum or vaginal cavity and release the active compound. The solid dosage forms for oral administration they include capsules, tablets, pills, powders, and granules. In such solid dose forms, the active compound is mixed with at least one pharmaceutically inert excipient or carrier such as sodium citrate or dicalcium phosphate and / or fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and salicylic acid, b) binders such as, for example, carboxymethyl cellulose, alginates, gelatin, polyvinyl pyrrolidinone, sucrose and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, starch potato or tapioca, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, acetyl alcohol and glycerol monostearate, h) absorbents such as kaolin clay and bentonite and i) lubricants such as talc, calcium stearate, magnesium stearate, pol solid ethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills the dosage form can also comprise buffering agents. Solid compositions of a similar type can also be employed as fillers in soft and hard filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and may also be of a composition that releases the active ingredient only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which may be used include polymeric substances and waxes. The active compounds may also be in micro-encapsulated form with one or more excipients as indicated above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, coatings that control release, and other coatings well known in the pharmaceutical formulating art. In such solid dose forms the active compound can be mixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, for example, tableting lubricants and other tableting aids such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and may also be of a composition that they release the active ingredient only, or preferentially in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which may be used include polymeric substances and waxes. Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservatives or buffers as may be required. Ophthalmic formulations, eye drops, and the like are also contemplated as being within the scope of this invention. The ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients such as human and vegetable fats, oils, waxes, paraffins, starch, tragacanth, derivatives of cellulose, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof. The compositions of the invention can also be formulated for delivery as a liquid aerosol or inhalable dry powder. The liquid aerosol and the inhalable dry powder formulations are preferably supplied throughout the endobronchial tree to the terminal bronchioles and eventually to the parenchymal tissue. Aerolized formulations of the invention can be delivered using an aerosol forming device, such as a nozzle, vibrating porous plate or ultrasonic nebulizer, preferably selected to allow the formation of aerosol particles having an average mass average diameter predominantly between 1 at 5 μM. In addition, the formulation preferably has equilibrium in the concentration of ionic concentration of osmolarity and chloride concentration, and the smallest aerosolizable volume capable of delivering the effective dose of the compounds of the invention to the site of infection. Additionally, the aerolized formulation preferably does not adversely impair the functionality of the respiratory tract and does not cause undesirable side effects. Suitable aerosolization devices for administration of aerosol formulations of the invention include, for example, mouthpiece, vibrating porous plate, ultrasonic nebulizers and energized dry powder inhalants, which are capable of nebulizing the formulation of the invention in aerosol particle size predominantly in the size range of 1-5 μM. Predominantly in this application means that at least 70% but preferably more than 90% of all aerosol particles generated are in the range of 1 to 5 μM. A jet nebulizer works by air pressure to break the liquid solution into aerosol droplets. Vibrating porous plate nebulizers work by using a sonic vacuum produced by a rapidly porous vibrating plate to extrude a drop of solvent through a porous plate. An ultrasound nebulizer works by a piezoelectric crystal that breaks a liquid into small aerosol droplets. A variety of suitable devices are available, including, for example, AeroNeb® and AeroDose® vibrant porous plate nebulizers (AeroGen, Inc., Sunnyvale, California), Sidestream® nebulizers (Medic-Aid Ltd., West Sussex, England), Pari LC® and Pari LC Star® jet nebulizers (Pari Respiratory Equipment, Inc., Richmond, Virginia) and Aerosonic® (DeVillbis Medizinische Produkte (Deutschland) GmbH, Heiden, Germany) and UltraAir® nebulizers (Omron Healthcare, Inc., Vernon Hills, Illinois). The compounds of the invention can also be formulated for use as topical powders and sprays which may contain, in addition to the compounds of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. The dispersions may additionally contain propellants such as chlorofluorohydrocarbons. Transdermal patches have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or supplying the compound in the appropriate medium. The absorption enhancers can also be used to increase the flow of the compound between the skin. The speed can be controlled by either providing a membrane that controls the speed or by dispersing the compound in a polymer or gel matrix. According to the methods of the treatment of the present invention, cancers are treated or prevented in a patient such as a human or a lower mammal by administering to the patient a therapeutically effective amount of a compound of the invention, in such amounts and by such time as necessary to achieve the desired result. By a "therapeutically effective amount" of a compound of the invention is meant a sufficient amount of the compound to treat cancer, at a reasonable benefit / risk ratio to any medical treatment. It will be understood, however, that the total daily use of The compounds and compositions of the present invention will be decided by the attending physician within the scope of the responsible medical judgment. The therapeutically specific effective dose level for any particular patient will depend on a variety of factors which include the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincident with the specific compound used; and similar factors well known in the medical arts. The total daily dose of the compounds of this invention administered to a human or other mammal in single or divided doses may be in amounts, for example, from 0.01 to 50 mg / kg of body weight or more usually from 0.1 to 25 mg / kg of body weight. The single dose compositions may contain such amounts or submultiples thereof to make the daily dose. In general, treatment regimens according to the present invention comprise administering to a patient in need of such treatment from about 10 mg to about 2000 mg of the compounds of this invention per day in single doses multiple Formulation methods are well known in the art and are described, for example, in Remington; The Science and Practice of Pharmacy, Mack Publishing Company, Easton, PA, 19th edition (1995). The pharmaceutical compositions for use in the present invention may be in the form of liquid, sterile, non-pyrogenic solutions or suspensions, coated capsules, suppositories, lyophilized powders, transdermal patches or other forms known in the art. A "kit" as used in the present application includes a container for containing the pharmaceutical compositions and may also include divided containers such as a divided bottle or a divided sheet pack. The container may be in a conventional form or form as is known in the art which is made of a pharmaceutically acceptable material, for example, a paper or cardboard box, a glass or plastic bottle or bottle, a resealable bag (for example, example, to maintain a "filling" of tablets for placement in a different container), or an ampoule packet with individual doses for pressing the package according to a therapeutic program. The container employed may depend on the exact dosage form involved, for example a conventional carton can not generally be used to maintain a liquid suspension. It is feasible that more than one recipient can be used together with a simple package to sell a simple dosage form. For example, the tablets may be contained in a bottle which in turn is contained within a box. An example of such equipment is a so-called ampoule package. Ampoule packs are well known in the packaging industry and are widely used for packaging dosage forms of pharmaceutical unit (tablets, capsules, and the like). The ampoule packages generally consist of a sheet of relatively rigid material covered with a sheet of preferably transparent plastic material. During the packing process, the grooves in the plastic sheet are formed. The slots have the size and conformation of individual tablets or capsules to be packaged or they can be sized and shaped to accommodate the multiple tablets and / or capsules to be packaged. Next, the tablets or capsules are placed in the recesses accordingly and the sheet of relatively rigid material is sealed against the plastic sheet on the face of the sheet which is opposite from the direction in which the recesses are formed. As a result, the tablets or capsules are individually sealed or collectively sealed, as desired, in the recesses between the plastic sheet and the sheet. Preferably the strength of the blade is such that The tablets or capsules can be removed from the ampoule pack by manually applying pressure in the recesses so that an opening is formed in the leaf at the recess site. The tablet or capsule can then be removed through the opening. It may be desirable to provide a written memory aid, where the written memory aid is of the type that contains information and / or instructions for the physician, pharmacist or other provider or health care subject, for example, in the form of numbers of follow-ups of the tablets or capsules where the numbers correspond to the days of the regime to which the tablets or capsules so specified must be ingested or a card which contains the same type of information. Another example of such a memory aid is a calendar printed on the card for example, as follows "First week, Monday, Tuesday," etc. "Second week, Monday, Tuesday ..." etc. Other variations of the memory aids will be easily apparent. A "daily dose" may be a single tablet or capsule or several tablets or capsules to be taken on a given day. When the kit contains separate compositions, a daily dose of one or more compositions of the kit may consist of a tablet or capsule while a daily dose of another or more compositions of the kit may consist of several tablets or capsules.

Another specific modality of a team is a supplier designed to provide daily dose at a time for the purpose of its proposed use. Preferably, the supplier is equipped with a memory assistant, in order to further facilitate compliance with the regime. An example of such a memory aid is a mechanical counter, which indicates the number of daily doses that have been delivered. Another example of such a memory aid is a miero-chip memory with battery as a power source coupled with a liquid crystal display, or an audible reminder signal which, for example, reads the date of the last daily dose that has been taken and / or remember when the next dose will be taken. The kits of the present invention may also include, in addition to the KSP inhibitors, one or more additional pharmaceutically active compounds. Preferably, the additional compound is another KSP inhibitor or other useful compound in treatment for cancer. The additional compounds can be administered in the same dosage form as the KSP inhibitor or in different dosage forms. Similarly, additional compounds can be administered at the same time as the KSP inhibitor or at different times. The compositions of the present compounds can also be used in combination with other anticancer agents of similar spectrum to synergistically increase the treatment of cancer. The treatment may involve administering a composition which has both active agents or the administration of the inventive compounds followed by or preceded by administration of an additional active anticancer agent. While the compounds of the invention can be administered as the sole active pharmaceutical agent, they can also be used in combination with one or more other agents used in the treatment of cancer. Useful representative agents in combination with the compounds of the invention for the treatment of cancer include, for example, irinotecan, topotecan, gemcitabine, imatinib, trastuzumab, 5-fluorouracil, leucovorin, carboplatin, cisplatin, docetaxel, paclitaxel, tezacitaine, cyclophosphamide, vinca alkaloids, anthracyclines, rituximab, and trastuzumab, inhibitors of topoisomerase I, as well as other chemotherapeutic agents for cancer. The above compounds to be employed in combination with the compounds of the invention will be used in therapeutic amounts as indicated in the Physicians' Desk Reference (PDR) 47th edition (1993), which is incorporated herein by reference, or such amounts Therapeutically useful as may be known to one of ordinary skill in the art.

The compounds of the invention and the other anticancer agents can be administered at the maximum recommended clinical dose or at lower doses. The dose 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, severity of the disease and the response of the patient. The combination can be administered as separate compositions or as a single dose form which contains both agents. When administered as a combination, the therapeutic agents can be formulated as separate compositions, which are given at the same time or at different times, or the therapeutic agents, can be given as a simple composition. Antiestrogens, such as tamoxifen, inhibit the growth of breast cancer through the induction of cell cycle arrest, 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 in such a way that its inhibitory activity to stop the cell cycle is attenuated, thereby contributing to the resistance to antiestrogen antiestrogen (Donovan, et al., J. Biol. Chem. 276: 40888, 2001). As reported by Donovan et al., The inhibition of MAPK signaling through the Treatment with the MEK inhibitor changes the phosphorylation status of p27 in hormone refractory breast cancer cell lines and in doing so restores hormonal sensitivity. Accordingly, in one aspect, the compounds of formulas I-IV can be used in the treatment of hormone-dependent cancers, such as breast and prostate cancers, to reverse the hormone resistance commonly observed in these cancers with conventional anticancer agents. In hematologic cancers, such as chronic myelogenous leukemia (CML), chromosomal translocation is responsible for constitutively activated BCR-ABl tyrosine kinase. Some afflicted patients respond to gleevec, a molecule of the tyrosine kinase inhibitor, as a result of the inhibition of Abl kinase activity. However, many patients with advanced disease respond to gleevec initially, but then relapse later due to mutations that confer resistance in the Abl kinase domain. In vitro studies have shown that BCR-Avl uses the path of Raf kinase to produce its effects. In addition, inhibiting more than one kinase in the same path provides additional protection against mutations that confer resistance. Accordingly, in another aspect of the invention, the compounds of formulas I-IV 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. D. Methods for Making the Compounds of the Invention The present invention also provides methods for the manufacture of compounds of the formulas I-IV as described herein. The present invention also relates to processes for preparing the compounds of the invention and synthetic intermediates useful in such processes, as described in more detail below. The synthesis of representative compounds of the invention are described in Examples 1-3. One skilled in the art will appreciate that the compounds of the invention can be prepared by standard synthetic organic chemical methods. In some embodiments, the invention provides methods for making compounds of formulas I-IV as described in Examples 1-3. it is further contemplated that the present invention covers the intermediates as well as the corresponding methods of synthesis as described in Examples 1-3. A representative assay for determining the inhibitory activity of KSP is described in Example 4.

The present invention will be more readily understood with reference to the following examples, which are provided by the form of illustration and are not intended to be limiting of the present invention. EXAMPLES With reference to the following examples, the compounds of the present invention are synthesized using the methods described herein, or another method, which are well known in the art. The compounds and / or treatments are characterized by high performance liquid chromatography (HPLC) using a Waters Millenium chromatography system with a Separation Module 2690 (Milford, MA). The analytical columns are Alltima C-18 reverse phase, 4.6 x 250 mm Alltech (Deerfield, IL). An elution gradient is used, which typically starts with 5% acetonitrile / 95% water and progresses to 100% acetonitrile over a period of 40 minutes. All solvents contain 0.1% trifluoroacetic acid (TFA). The compounds are detected by ultraviolet (UV) light at an absorption of either 220 or 254 nm. The HPLC solvents are from Burdick and Jackson (Muskegan, MI), or Fisher Scientific (Pittsburg, PA). In some cases, purity is evaluated by thin layer chromatography (TLC) using silica gel plates reinforced with glass or plastic, such as, for example, flexible sheets Baker-Flex Silica Gel 1B2-F. The results of the TLC are easily detected visually under ultraviolet light, or by using well-known iodine vapor and various other staining techniques. Mass spectrometric analyzes are performed in one of two LCMS instruments: a Waters system (Alliance HT HPLC 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 0.4 ml / min, molecular weight range 150-850m, cone voltage 50V, temperature of column 30 ° C). All masses are reported as those of protonated progenitor ions. The GCMS analysis is performed on a Hewlett Packard instrument (gas chromatograph of the HP6890 series with a selective mass detector 5973, volume of the injector: 1 μL, initial column temperature: 50 ° C, final column temperature: 250 ° C, ramp time: 20 minutes: gas flow rate: 1 ml / min; column: 5% phenylmethylsiloxane, Model No. HP 190915-443, dimensions: 30.0 x 25 x 0.25 m). Nuclear magnetic resonance (NMR) analysis is performed on one of the compounds with a Varian 300 MHz NMR (Palo Alto, CA). The spectral reference is either TMS or the known chemical change of the solvent. Some samples of the compound are run in elevated temperatures (e.g., 75 ° C) to promote the solubility of the increased sample. The purity of some of the compounds of the invention is evaluated by elemental analysis (Desert Analytics, Tucson, AZ). The melting points are determined in a Laboratory Devices Mel-Temp (Holliston, MA). The preparative separations are carried out using a Flash 40 and KP-Sil, 60A chromatography system (Biotage, Charlottesville, VA) or by flash column chromatography using a silica gel packing material (230-400 mesh), or HPLC using an inverted phase C-18 column. Typical solvents used for the Biotage Flash 40 system and rapid column chromatography are dichloromethane, methanol, ethyl acetate, hexane, acetone, aqueous hydroxyamine and triethylamine. Typical solvents used for reverse phase HPLC are varying concentrations of acetonitrile and water with 0.1% trifluoroacetic acid. Unless stated otherwise, all temperatures are in degrees Celsius. Also, in these examples and in the description, the abbreviations have the following meanings: AcOH = acetic acid aq = aqueous ATP = adenosintri phosphate 9-BBN = 9-borabicyclo [3 .3. l] nonane Boc = tert-butoxycarbonyl Celite = filtering agent DAP or Dap = Diaminopropionate DCM = dichloromethane DEAD = diethylazodicarboxylate DIEA = diisopropylethylamine DMAP = 4-dimethylaminopyridine DME = 1,2-dimethoxyethane DMF = N, N-dimethylformamide DMS0 = dimethyl sulfoxide DPPA = diphenyl phosphoryl azide Et3N = triethylamine EDC = N- (3-dimethylaminopropyl-N'-ethylcarbodiimide EDCI = 1- (3-dimethylaminopropyl) 3-ethylcarbodiimide Et0Ac = ethyl acetate EtOH = ethanol Fmoc = 9-fluorenylmethoxycarbonyl Gly -OH = glycine HATU = O- (7-azabenzotriazol-l-yl) hexafluorophosphate -N, N, N'N '= tetramethyluronium HBTU = 2- (lH-benzotriazol-1-yl) -1,1 hexafluorophosphate, 3, 3-tetramethyluronium Hex = hexane HOBt = butyl alcohol HOBT = l-hydroxybenzotriazole HPLC = high pressure liquid chromatography NIS = N-iodosuccinimide ICso values = The concentration of an inhibitor that causes a 50% reduction in a measured activity. IPrOH = Isopropanol LC / MS = liquid chromatography / mass spectrometry LRMS = low resolution mass spectrometry MeOH = methanol NaOMe = sodium methoxide nm = nanometer NMP = N-methylpyrrolidone PPA = polyphosphoric acid PPh3 = triphenylphosphine PTFE = polytetrafluoroethylene RP- HPLC = reverse phase high pressure liquid chromatography RT = ambient temperature Sat = saturated TEA = triethylamine TFA = trifluoroacetic acid THF = tetrahydrofuran Thr = threonine TLC = Thin-layer chromatography Trt-Br = tert-butyl bromide The nomenclature for the example compounds is provided using the ACD Yam software version 5.07 (November 14, 2001) available from Advanced Chemistry Development, Inc. Some of the compounds and starting materials are named using the standard IUPAC nomenclature. It should be understood that the organic compounds according to the invention can exhibit the phenomenon of tautomerism. Since the chemical structures within this specification can represent only one of the possible possible tautomeric forms, it should be understood that the invention comprises any tautomeric forms of the drawn structure. It is understood that the invention is not limited to the modalities indicated herein for illustration, but comprises all forms thereof which are within the scope of the description mentioned above.

Example 1 N- (3-aminopropyl) -N- [1- (3-benzyl-4-o? O-67 / 8,9-tetrahydro-4 H -pyrido [1,2-a] pyrimidin-2-yl) -2-methylpropyl] -4-methylbenzamide; Stage 1 Stage 2 Step 1. 2- (Chloromethyl) -4H-pyrido [1,2- a] pyrimidine-4 -one 11 15 g (159.4 mmoles) of 2-aminopyridine are combined (10) with approximately 80 g of polyphosphoric acid and heated to 120 ° C to allow stirring. To the resulting solution, 30.5 ml (223.2 mmoles) of ethyl-4-chloroacetoacetate are added slowly and stirred at 120 ° C under nitrogen for two hours. The hot reaction mixture is then poured into 1500 ml of ice water and stirred vigorously. The aqueous layer is separated and extracted with methylene chloride (6X, approximately 6 1). The combined organic layers are washed with saturated NaHCO 3 and brine and dried on MgSO 4 and activated carbon. The solvent is removed in vacuo yielding 30.7 g (157.7 mmol, 99%) of 2- (chloromethyl) -4 H -pyrido [1,2-a] pyrimidin-4-one (11) as a white solid. Step 2. 2- (Chloromethyl) -3-iodo-4H-pyrido [1,2-a] pyrimidin-4-one A mixture of 21.9 g (112.5 mmol) of the product of Step 1 (11) and 38.9 g (168.8 mmol) of N-iodosuccinimide in 660 ml of acetonitrile at 80 ° C under stirring is stirred. nitrogen for 16 hours. The reaction mixture is then allowed to cool to room temperature and the acetonitrile is removed in vacuo. The resulting solid is washed with water, saturated Na203S2, saturated NaHCO3, and brine, and then filtered. Dry under reduced pressure at 40 ° C overnight yielding 29.8 g (92.9 mmol, 83%) of 2- (chloromethyl) -3-iodo-4H-pyrido [1,2-a] pyrimidin-4-one (12 ) as a light brown solid. Step 3. (3-iodo-4-oxo-4H-pyrido- [l, 2-a] pyrimidin-2-yl) acetate It shakes . a mixture of 20.0 g (62.4 mmol) of the product of Step 2 (12) and 9.2 g (93.6 mmol) of potassium acetate in 200 ml of DMF at 40 ° C under nitrogen for three hours. The reaction mixture is allowed to cool to room temperature and the addition of excess water to the reaction solution causes the product to precipitate out of the solution. The product is filtered, washed with water (3X) and dried under reduced pressure at 40 ° C overnight producing 19.4 g (56.4 mmoles, 90%) of (3-iodo-4-oxo-4H-pyrido [1,2- a] pyrimidin-2-yl) methyl acetate (13) as a white solid. Alternatively, the product of stage 2 (12) it may undergo hydrolysis to provide the corresponding alcohol (14). Stage . 2- (hydroxymethyl) -3-iodo-4H-pyrido [1,2- a] pyridimidin-4-one A mixture of 16.5 g (48.0 mmol) of the product from Step 3 (13) and 13.3 g (96.0 mmol) of potassium carbonate in 300 ml of methanol is stirred at room temperature for 3 hours. Excess water is added to the reaction mixture and the mixture is extracted using ethyl acetate (3X). The organic layers are combined, dried in MgSO4 and activated carbon, and the solvent is removed in vacuo yielding 12 g (39.7 mmol, 83%) of 2- (hydroxymethyl) -3-iodo-4H-pyrido [1, 2- a] pyrimidin-4-one (14) as a white solid Step 5. 3-Benzyl-3- (hydroxyethyl) -4H-pyrido [1,2-a] pyrimidin-4-one A mixture of 4.0 g (13.24 mmol) of the product from the Step 4 (14), 1.0 g (1.32 mmol) of dichloro [1, 1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloroethane adduct, and 8.4 g (39.72 mmol) of K3P04 in 30 ml of DMF were added. heat at 80 ° C. To The resulting solution is added dropwise to 40 ml (19.9 mmoles) of B-benzyl-9-BBN and stirred at 80 ° C under nitrogen for 12 hours. The reaction is then cooled to 0 ° C and an excess of 1N NaOH is added to the reaction mixture. The excess 30% H202 is then added to the mixture at 0 ° C which results in significant gas evolution. Stirring continues for at least one additional hour or until the gas emission ceases. The mixture is extracted with ethyl acetate (3X) and washed with saturated Na203S2 and brine. The organic layers are combined, dried in MgSO4 and activated carbon, and the solvent removed in vacuo. The resulting material is subjected to flash chromatography on a 10 cm column. Elution with a gradient of 100% hexanes, 20% ethyl acetate in hexanes, 33% ethyl acetate in hexanes, 43% ethyl acetate in hexanes, 50% ethyl acetate in hexanes, ethyl acetate 57% in hexanes, 67% ethyl acetate in hexanes, and 100% ethyl acetate yield 3.2 g (12.0 mmole, 91%) of 3-benzyl-2- (hydroxylmethyl) -4-pyrido [1,2]. -a] pyrimidin-4-one (15) as a pale yellow solid. Step 6: 3-benzyl-4-oxo-4H-pyrido [1,2-a] pyrimidine-2-carbaldehyde 26.5 ml (53.0 mmoles) of oxalyl chloride are cooled in 40 ml of dichloromethane at -78 ° C. It is added to the solution Resulting in a solution of 7.52 ml (105.9 mmol) of DMSO in 24 ml of dichloromethane and stirring at -78 ° C for one hour. Then a solution of 4.7 g (17.65 mmol) of the product of Step 5 (15) in 60 ml of dichloromethane is added and the resulting mixture is stirred at -78 ° C for one hour. Then 24.6 ml (176.5 mmol) of triethylamine are added and stirred at -78 ° C for one hour. The mixture is then allowed to warm to 0 ° C and is stirred for another hour. Finally, the mixture is allowed to warm to room temperature over the course of one hour. The excess water is added to the reaction mixture and the mixture is extracted (3X) using dichloromethane. The combined organic layers are dried over MgSO4 and activated carbon and the solvent is removed in vacuo. The resulting material is subjected to rapid chromatography on a 10 cm column. Elution with a gradient of 100% hexanes, 20% ethyl acetate in hexanes, 33% ethyl acetate in hexanes, 43% ethyl acetate in hexanes, and 50% ethyl acetate in hexanes yield 3.1 g. (11.7 mmol, 67%) of 3-benzyl-4-oxo-4H-pyrido [1,2-a] pyrimidine-2-carbaldehyde (16) as a yellow solid. Step 7. 3-Benzyl-2- (1-hydroxy-2-methylprop-2-enyl) -4 H -pyrido [1,2-a] pyrimidin-4-one A mixture of 500 mg (1.9 mmol) of the product of Step 6 (16) is cooled in 15 ml of THF at -78 ° C. 7.6 ml (3.8 mmoles) of isopropenylmagnesium bromide is added dropwise to the resulting mixture and stirred at -78 ° C for 2 hours. Quench the reaction with saturated NH4C1 and extract with ethyl acetate (2X). Dry the combined organic layers in MgSO4 and the solvent is removed in vacuo to yield 613 mg (2.0 mmol, 106%) of 3-benzyl-2- (1-hydroxy-2-methylprop-2-enyl) -4H-pyrido [1,2-a] pyrimidin-4-one (17) as a yellow solid pale. This is purified by flash chromatography.

Step 8. 3-Benzyl-2- (1-hydroxy-2-methylpropyl) -6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidin-4-one After the product of Step 7 (17) is purified, 100 mg (0.33 mmol) and 85 mg of Palladium on activated carbon is stirred in 5 ml of ethanol. The flask is equipped with a balloon containing hydrogen gas and the reaction mixture is stirred at room temperature overnight. The reaction mixture is then filtered through a PTFE filter and washed with ethyl acetate. The resulting product is concentrated yielding 90 mg (0.29 mmol, 88%) of 3-benzyl-2- (l-hydroxy-2-methylpropyl) -6,7,8,9-tetrahydro-4H-pyrido [l, 2-a] pyrimidin-4-one (18) as a clear oil. Step 9. 2- [l- (3-benzyl-4-oxo-6,7,8,8-tetrahydro-4H-pyrido [l, 2-a] pyrimidin-2-yl) -2-methylpropyl] -lH- isoindol-l / 3 (2H) -dione A previous batch of the product from Step 8 is combined (18) with the above and 150 mg (0.48 mmoles) of this unpurified material are dissolved in 3 ml of dry tetrahydrofuran then cooled to 0 ° C. Phthalimide 212 mg (1.4 mmol) is added to the cold solution followed by triphenylphosphine 189 mg (0.72 mmol) then DIAD 140 μl (0.72 mmol). The reaction mixture is stirred under nitrogen and allowed to warm to room temperature overnight. The solvent is evaporated and the solid is redissolved in ethyl acetate then washed with saturated NaHCO 3 and brine. The organic layer is then dried over MgSO 4 and the solvent is removed in vacuo resulting in 700 mg of unpurified material which is purified by flash chromatography to give 95 mg (0.22 mmol, 44%) of 2- [1- (3-benzyl) -4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2- a] pyrimidin-2-yl) -2-methylpropyl] -lH-isoindole-1,3 (2H) -dione ( 19) as a white solid.

Step 10. 2- (l-amino-2-methylpropyl) -3-benzyl-6,7 8 9-tetrahydro-4H-pyrido [1,2-a] pyrimidin-4-one The product of Step 9 (19), 95 mg (0.22 mmol) is dissolved in 3 ml of dry ethanol then 50 μl (1.6 mmol) hydrazine is added and the reaction is allowed to stir at room temperature for 1 hour after it is heated at 40 ° C for 2.5 hours. The precipitate is removed by filtration and washed with ethyl acetate and the solvent is evaporated resulting in 75 mg of 2- (l-amino-2-methylpropyl) -3-benzyl-6,7,8,9-tetrahydro-4H -py [l, 2-a] pyrimidin-4-one (20). This is purified on a silica column which yields 42 mg (0.13 mmol 63%) as a clear oil. Step 11. 2- (3-. {[[1- (3-benzyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [l / 2-a] pyrimidin-2-yl) - 2-methylpropyl] amino.}. Propyl) -1H-isoindol-1,3 (2H) -dione The product of Step 10 (20), 42 mg (0.13 mmol) is dissolved in anhydrous CH2C12 followed by the addition of 3-aminopropionaldehyde protected with phthalimide 33 mg (0.16 mmol) and 37 mg (0.18 mmol) of sodium acetoxyborohydride and finally 10 μl (0.18 mmoles) of acetic acid. The reaction is left stirring at room temperature for 2.5 hours. The solvent is evaporated and the product is redissolved in ethyl acetate and washed with saturated NaHCO 3 and brine. The organic layer is dried over MgSO, filtered and concentrated and dried under high vacuum in 63 mg (0.13 mmol, 94%) of 2- (3. {[1- (3-benzyl-4-oxo-) a] pyrimidin-2-yl) -2-methylpropyl] amino.}. propyl) -1H-isoindole-1,3 (2H) -dione (21) as a white solid. Step 12. N- [1- (3-Benzyl-4-oxo-6,7,8,9-tetrahydro-4 H -pyrido [1,2- a] pyrimidin-2-yl) -2-methylpropyl] -N - [3- (l, 3-dioxo-l, 3-dihydro-2H-isoindol-2-yl) propyl] -4-methylbenzamide The product of Step 11 (21), 63 mg (0.13 mmol) is dissolved in CHC12 followed by the addition of 33 μl (0.25 mmol) of 4-methylbenzoyl chloride and 53 μl (0.38 mmol) of triethylamine. The reaction is left to stir at room temperature environment for 2 hours. The ethyl acetate layer is washed with NaHCO 3 and brine. The organic layer is dried in MgSO, filtered and concentrated. The product is purified by flash chromatography resulting in 50 mg (0.08 mmol, 64%) of N- [1- (3-benzyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido] , 2-a] pyrimidin-2-yl) -2-methylpropyl] -N- [3- (1, 3-dioxo-l, 3-dihydro-2H-isoindol-2-yl) propyl] -4-methylbenzamide ( 22) as a white solid. Step 13: N- (3-aminopropyl) -N- [1- (3-benzyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2- a] pyrimidin-2-yl) ) -2-methylpropyl] -4-methylbenzamide The product of Step 12 (22), 50 mg (0.08) moles) is dissolved in 1 ml of anhydrous ethanol. Hydrazine 18 μl (0.57 mmol) is added and the reaction is stirred at room temperature for 2 hours. The precipitate is filtered through a PTFE filter and washed with ethyl acetate. The solvent is evaporated and the unpurified material is purified by reverse phase HPLC which results in 11 mg (0.023 mmole) of N- (3-aminopropyl) -N- [1- (3-benzyl-4-oxo-6 , 7, 8, 9- tetrahydro-4H-pyrido [1,2,2-a] pyrimidin-2-yl) -2-methylpropyl] -4-methylbenzamide (2) as the TFA salt. Example 2 N- (3-aminopropyl) -N- [1- (3-benzyl-4-oxo-6,7,8,9-tetrahydro-4 H -pyrido [1,2-a] pyrimidin-2-yl) propyl] -4-bromobenzamide Step 1. 2- (Chloromethyl) -4H-pyrido [1,2-a] pyrimidin-4-one g (159.4 mmoles) of 2-aminopyridine are combined (10) with approximately 80 g of polyphosphoric acid and heated to 120 ° C to allow stirring. To the resulting solution is slowly added 30.5 ml (223.2 mmol) of ethyl 4-chloroacetoacetate and stirred at 120 ° C under nitrogen for two hours. The hot reaction mixture is then poured into 1500 ml of ice water and stirred vigorously. The aqueous layer is separated and extracted with methylene chloride (6X, approximately 6 1). The combined organic layers are washed with saturated NaHCO3 and brine and dried in MgSO4 and activated carbon. The solvent is removed in vacuo producing . 7 g (157.7 mmol, 99%) of 2- (chloromethyl) -4 H -pyrido [1,2-a] pyrimidin-4-one (11) as a white solid. Step 2. 2- (Chloromethyl) -3-iodo-4H-pyrido [1,2-a] pyrimidin-4-one A mixture of 21.9 g (112.5 mmol) of the product is stirred from Step 1 (11) and 38.9 g (168.8 mmol) of N-iodosuccinimide in 660 ml of acetonitrile at 80 ° C under nitrogen for 16 hours. It is then allowed to cool the mixture of reaction at room temperature and the acetonitrile is removed in vacuo. The resulting solid is washed with water Na203S2 saturated, saturated NaHCO3, brine, and filtered. Dry under reduced pressure at 40 ° C overnight which produces 29.8 g (92.9 mmol, 83%) of 2- (chloromethyl) -3-iodo-4H-pyrido [1,2-a] pyrimidin-4-one (12) as a light brown solid. Step 3. (3-iodo-4-oxo-4H-pyrido [1, 2-a] pyrimidin-2-yl) -methyl acetate A mixture of 20.0 g (62.4 mmol) of the product from Step 2 (12) and 9.2 g (93.6 mmol) of potassium acetate in 200 ml of DMF is stirred at 40 ° C under nitrogen for three hours. The reaction mixture is allowed to cool to room temperature and the addition of excess water to the reaction solution causes the product to precipitate out of the solution. The product is filtered, washed with water (3X), and dried under reduced pressure at 40 ° C overnight yielding 19.4 g (56.4 mmoles, 90%) of (3-iodo-4-oxo-4H-) acetate. pyridofl, 2-a] pyrimidin-2-yl) methyl (13) as a white solid.

Step 4. 2- (Hydroxymethyl) -3-iodo-4-pyrido [1,2-a] pyrimidin-4-one A mixture of 16.5 g (48.0 mmol) of the product of Step 3 (13) and 13.3 g (96.0 mmol) of potassium carbonate in 300 ml of methanol is stirred at room temperature for 3 hours. Excess water is added to the reaction mixture and the mixture is extracted using ethyl acetate (3X) Combine the organic layers, dry in MgSO4 and activated carbon, and remove the solvent in vacuo to yield 12 g (39.7 mmol, 83%) of 2- (hydroxylmethyl) -3-iodo-4H-pyrido [1,2]. -a] pyrimidin-4-one as a white solid (14). Step 5. 3 ~ benzyl-2- (hydroxymethyl) -4H-pyrrolo [1,2-a] pyrimidin-4-one A mixture of 4.0 (13.24 mmol) of the product of Step 4 (14), 1.0 g of (1.32 mmol) of dichloromethane dichloro [1, 1-bis (diphenylphosphite) ferrocene] aladie (II) adduct is heated. and 8.4 g (39.72 mol) of K3P0 in 30 ml of DMF at 80 ° C. To the resulting solution, 40 ml (19.9 mmoles) of B-benzyl-9-BBN is added dropwise and stirred at 80 ° C under nitrogen for 12 hours. The reaction is then cooled to 0 ° C and the excess of IN NaOH is added to the reaction mixture. An excess of 30% H202 is then added to the mixture at 0 ° C resulting in significant gas emission. The mixture is extracted with ethyl acetate (3X) and washed with Na202S2 saturated and brine. The organic layers are combined, dried with MgSO4 and activated charcoal, and the solvent removed in vacuo. The resulting material is subjected to flash chromatography on a 10 cm column. Elution with a gradient of 100% hexanes, 20% ethyl acetate in hexanes, 33% ethyl acetate in hexanes, 43% ethyl acetate in hexanes, 50% ethyl acetate in hexanes, 57% ethyl acetate in hexanes, 67% ethyl acetate in hexane and 100% ethyl acetate yield 3.2 g (12.0 mol, 91%) of 3-benzyl-2- (hydroxymethyl) -4H-pyrido [l, 2- a] pyrimidin-4-one (15) as a pale yellow solid. Step 6: 3-benzyl-4-oxo-4H-pyrido [1,2-a] pyrimidine-2-carbaldehyde 26.5 ml (53.0 mmoles) of oxalyl chloride are cooled in 40 ml of dichloromethane at -78 ° C. A solution of 7.52 ml (105.9 mmol) of DMSO in 24 ml of dichloromethane is added to the resulting solution and stirred at -78 ° C for one hour. Then a solution of 4.7 g (17.65 mmol) of the product of Step 5 (15) in 60 ml of dichloromethane is added and the resulting mixture is stirred at -78 ° C for one hour. Then 24.6 ml (176.5 mmol) of triethylamine are added and stirred in -78 ° C for one hour. The mixture is then allowed to warm to 0 ° C and is stirred for another hour. Finally, the mixture is allowed to warm to room temperature over the course of one hour. The excess water is added to the reaction mixture and the mixture is extracted (3X) using dichloromethane. The combined organic layers are dried over MgSO4 and activated carbon and the solvent is removed in vacuo. The resulting material is subjected to rapid chromatography on a 10 cm column. Elution with a gradient of 100% hexanes, 20% ethyl acetate in hexanes, 33% ethyl acetate in hexanes, 43% ethyl acetate in hexanes, and 50% ethyl acetate in hexanes yield 3.1 g. (11.7 mmol, 67%) of 3-benzyl-4-oxo-4H-pyrido [1,2-a] pyrimidine-2-carbaldehyde (16) as a yellow solid. Step 7. 3-Benzyl-2- (1-hydroxyprop-2-enyl) -6,7,8,9-tetrahydro-4H- [1,2-a] pyrimidin-4-one A mixture of 2.5 g (9.5 mmol) of the product from Step 6 (16) is cooled in 35 ml of THF at -78 ° C. 11.4 ml (11.4 mmoles) of vinylmagnesium bromide is added dropwise to the resulting mixture and stirred at -78 ° C for 3 hours. HE stop the reaction with saturated NH4C1 and extract with ethyl acetate (4X). Dry the combined organic layers in MgSO4 and stir the solvent in vacuo to yield 2.95 g of 3-benzyl-2- (1-hydroxyprop-2-enyl) -6,7,8,9-tetrahydro-4H-pyrido [ 1, 2-a] pyrimidin-4-one (23) as a pale yellow solid. Step 8. 3-Benzyl-2- (1-hydroxypropyl) -6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidin-4-one A mixture of 0.097 g (0.33 mmol) of the product of Step 7 (23) and 0.02 g of Palladium in activated carbon in 5 ml of ethyl acetate is stirred. The flask is equipped with a balloon which contains the hydrogen gas and the reaction mixture is stirred at room temperature for 3 days. The reaction mixture is then filtered through celite and washed with ethyl acetate. The resulting organic mixture is concentrated yielding 0.084 g (0.28 mmol, 85%) of 3-benzyl-2- (1-hydroxypropyl) -6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine. -4-one (24) as a clear oil.

Step 9. l- (3-Benzyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1, 2-a] pyrimidin-2-yl) propyl methanesulfonate A mixture of 0.084 g (0.28 mmol) of the product (24) from Step 8 and 0.08 ml (0.56 mmol) of triethylamine in 2.5 ml of anhydrous DCM is cooled to 0 ° C. Then 0.03 ml (0.34 mol) of methanesulfonyl chloride is added dropwise and the mixture is allowed to warm. resulting at room temperature under nitrogen. The excess of DCM and wash the reaction mixture with water, saturated NaHCO3 and brine. The organic layer is then dried over MgSO 4 and the solvent is removed in vacuo to yield 0.106 g (0.28 mmol, 100%) of 1- (3-benzyl-4-oxo-6,7,8,8-tetrahydro) methanesulfonate. 4H-pyrido [1,2- a] pyrimidin-yl) propyl (25) as a dark oil. Stage 10. 3-. { [1- (3-benzyl-4-oxo-6,7,8,9-tetrahydro-4H-pyridofl, 2-a] pyrimidin-2-yl) propyl] amino} tert-butyl propylcarbamate A mixture of 0.106 g (0.28 mmol) of the product of Step 9 (25), 0.15 g (0.84 mmol) of tert-butyl 3-aminopropylcarbamate, and 0.005 g (0.03 mmol) of potassium iodide in 5 ml is stirred. of DMF at 60 ° C under nitrogen for 24 hours. The reaction is quenched with water, extracted with ethyl acetate (4X) and the combined organic layers are washed with saturated NaHCO3 and brine and dried in MgSO4. The solvent is removed in vacuo and the reaction mixture is subjected without purification to flash chromatography on a 7 cm column. Elution with a gradient of 50% ethyl acetate in hexanes, 100% ethyl acetate, 3% methanol and 0.1% ammonia in DCM, and 10% methanol and 0.1% ammonia in DCM produce 0.019 g (0.04 mmol, 15%) of 3-. { [1- (3-benzyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2- a] pyrimidin-2-yl) propyl] amino} tert-butyl propylcarbamate (26) as a clear oil. Step 11. 3 - [[1- (3-Benzyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2- a] pyrimidin-2-yl) propyl] (4-bromobenzoyl ) tert-butyl amino propylcarbamate) Cool 0.0005 g (0.004 mmol) of DMAP, and 0.02 ml (0.12 mmol) of triethylamine in 2 ml of anhydrous DCM at 0 ° C. 0.03 g (0.12 mmol) of 4-bromobenzoyl chloride is then added and the resulting mixture is allowed to warm to room temperature under nitrogen. After 3 hours, the solvent is removed in vacuo and the resulting mixture is subjected to flash chromatography on a 5 cm column. Elution with a gradient of 20% ethyl acetate in hexanes, 33% ethyl acetate in hexanes, 50% ethyl acetate in hexanes, 66% ethyl acetate in hexanes, and 100% ethyl acetate yield 0.023 g (0.02 mmol, 50%) of 3 - [[l- (3-benzyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2- a] pyrimidin-2-yl] ) propyl] (4-bromobenzoyl) amino] propylcarbamate tert-butyl (27) as a clear oil. Step 12. N- (3-aminopropyl) -N- [1- (3-benzyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidin-2-yl) ) propyl] -4-bromobenzamide 0.013 g (0.02 mmol) of the product of Step 11 (27) is stirred in 0.1 ml of trifluoroacetic acid and 1 ml of DCM at room temperature for 2 hours. The solvent is removed in vacuo yielding 0.0058 g (0.01, 50%) of N- (3-aminopropyl) -N- [1- (3-benzyl-4-oxo-6,7,8,8-tetrahydro-4H- pyridofl, 2-a] pyrimidin-2-yl) propyl] -4-bromobenzamide (1) as a white solid. Example 3 Synthesis of N- (3-methylaminopropyl) -N- [1- (3-benzyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidin-2- il) -2-methylpropyl] -4-methylbenzamide Compound 38 is synthesized using a protocol similar to the procedures detailed in step 11 of example 2. Flame-dried reaction vial is added. 0. 015 g (0.026 mmol) of compound 38, 0.002 ml (0.032 mmol) and 1 ml of DMF and cooled to 0 ° C. After 0.001 g (0.042 mmol) is added and the reaction is allowed to warm to room temperature under nitrogen for 1.5 hours. The reaction is then stopped with H20, extracted with CH2C12 (3X) and the combined organic layers washed with saturated NaHCO3 and brine, dried over MgSO4 and the solvent removed in vacuo. The resulting crude material is subjected to flash column chromatography and the product is eluted with a gradient of hexanes, 20% ethyl acetate in hexanes, 50% ethyl acetate in hexanes, and ethyl acetate yielding 0.01 g (0.017). mmoles, 65%) of compound 39 as a clear oil. The removal of the boc group is done by conventional means to produce the title product 7. The compounds in the following table are prepared using the methodology described in the previous examples. The starting materials used in the syntheses are recognizable to one skilled in the art and are commercially available or can be prepared using known methods. The compounds are named using the ACD / Name batch version 5.04 (Advanced Chemistry Development, Inc., Toronto Notary).

Example 4 KSP Activity Determination Assay This example provides a representative in vitro assay for determining the activity of KSP in vitro. Purified microtubules obtained from the bovine brain are purchased from Cytoskeleton Inc. (Denver, Colorado, USA). The motor domain of human KSP (Example 5, KNSL1) is cloned, expressed and purified at more than 95% homogeneity. The Biomol Green is purchased from Affinity Research Products Ltd. (Matford Court, Exter, Devon, Great Britain). Microtubules and motor protein KSP are diluted (ie, the KSP motor domain) in assay buffer (20 mM Tris-HCl (pH 7.5), 1 mM MgCl 2, 10 mM DTT, and 0.25 mg / ml BSA) at a final concentration of 35 μg / ml microtubules and 45 nM KSP . The microtubule / KSP mixture is then preincubated at 37 ° C for 10 minutes to promote the binding of KSP to the microtubules. To each well of the test plate (384-well plate) which contains 1.25 μl of the inhibitor or test compound in DMSO (or DMSO only in the case of controls) is added 25 μl of the microtubule / KSP solution described previously. Plates are incubated at room temperature for 1 hour. After the incubation, 65 μl of Biomol Green (a malachite green-based dye that detects the release of inorganic phosphate) is added to each well. The plates are incubated for an additional 5-10 minutes after the absorbance at 630 nm is determined using a Victor II plate reader. The amount of absorbance at 630 corresponds to the amount of KSP activity in the samples. The IC 50 of each inhibitor or test compounds is then determined based on the decrease in absorbance at 630 nm at each concentration, by means of non-linear regression using the data analysis software either XLFit for Excel or Prism from GraphPad Software Inc .

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (45)

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 I: or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof, wherein: R1 is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, halo, cyano, nitro, carboxy, hydroxy, alkoxy, aryloxy, heterocyclyloxy, aminocarbonyl, aminocarbonyloxy, alkylcarbonyloxy, arylcarbonyloxy, heterocyclycarbonyloxy, alkoxycarbonyl, aryloxycarbonyl, heterocyclyloxycarbonyl, amino, alkylcarbonylamino, arylcarbonylamino, heterocyclylcarbonylamino, alkoxycarbonylamino, aryloxycarbonylamino, heterocyclyloxycarbonylamino, alkylsulfonylamino, • arylsulfonylamino, heterocyclylsulfonylamino, aminosulfonyl, alkylsulfonyl, arylsulfonyl, and heterocyclylsulfonyl; R2 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, carboxy, alkoxycarbonyl, aryloxycarbonyl, heterocyclyloxycarbonyl and aminocarbonyl; R3 is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl and heterocyclyl, or R2 and R3, together with the carbon atom to which they are attached can form a carbocyclic or heterocyclic ring, which has from 3 to 8 atoms in the ring, wherein from 1 to 3 ring atoms, of the heterocyclic ring are selected from the group consisting of N, 0 and S; R 4 is selected from the group consisting of hydrogen, alkyl, aryl and heterocyclyl; R5 is selected from the group consisting of hydrogen, alkyl, aryl, heterocyclyl, alkoxycarbonyl, aryloxycarbonyl, heterocyclylcarbonyl, aminocarbonyl, alkylcarbonyl, arylcarbonyl, heterocyclylcarbonyl, alkylsulfonyl, aryisulfonyl and heterocyclylsulfonyl; R6 is selected from the group consisting of hydrogen, alkyl, aryl, heterocyclyl, hydroxy, alkoxy, aryloxy, heterocyclyloxy, amino, alkylsulfonyl, arylsulfonyl and heterocyclylsulfonyl, alkylcarbonyloxy, arylcarbonyloxy, heterocyclylcarbonyloxy, alkoxycarbonyl, aryloxycarbonyl, heterocyclyloxycarbonyl, alkoxycarbonylamino, aryloxycarbonylamino, heterocyclyloxycarbonylamino, alkylcarbonylamino, arylcarbonylamino, heterocyclylcarbonylamino, aminocarbonyloxy, alkylsulfonylamino, arylsulfonylamino, heterocyclylsulfonylamino, and aminosulfonyl; and R7 is selected from the group consisting of hydrogen, alkyl, aryl and heterocyclyl, or R6 and R7, can be taken together with the atoms to which they are attached to form a heterocyclic ring, which has 5 to 8 ring atoms , wherein from 1 to 3 ring atoms of the heterocyclic ring are selected from the group consisting of N, 0 and S.
2. 2. The compound according to claim 1, characterized in that the compound is of the formula II: or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof, wherein R1, R2, R3, R4 and R5 are as defined above; is 0, 1, 2, or 3; q is 1, 2, or 3; and and R8 is selected from the group consisting of alkyl, aryl, and heterocyclyl.
3. 3. The compound according to claim 1, characterized in that the compound has the formula III: Or a salt, stereoisomer, pharmaceutically acceptable prodrug thereof, wherein R1, R2, R3, R4, R5 are as defined above: m is 0, 1, 2, or 3; and R8 is selected from the group consisting of alkyl, aryl and heterocyclyl.
4. 4. The compound according to claim 1, characterized in that the compound has the formula IV: rv where A and B are independently selected of the group consisting of aryl, heteroaryl, heterocyclyl, cycloalkyl, all of which may be substituted with 1 to 4 substituents selected from the group consisting of alkyl, alkoxy, halo, hydroxy and nitro; n is 1, 2 or 3; m is 0, 1, 2, or 3; p is 1, 2, 3, or 4; R8 is selected from the group consisting of alkyl, aryl and heterocyclyl; R9 is C2 to C3 alkyl; R10 and R11 are independently selected from the group consisting of hydrogen and alguyl of Ci to C4.
5. 5. The compound according to claim 1, characterized in that R1 is alkyl.
6. 6. The compound in accordance with the claim 5, characterized in that R1 is alkyl substituted with aryl or heterocyclyl.
7. 7. The compound in accordance with the claim 6, characterized in that R1 is benzyl.
8. 8. The compound in accordance with the claim 1, characterized in that R2 is H.
9. 9. The compound according to claim 1, characterized in that R3 is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl or heterocyclyl.
10. 10. The compound according to claim 9, characterized in that R3 is selected from the group consisting of ethyl, or isopropyl, cyclopropyl, phenyl, thienyl or pyridinyl.
11. 11. The compound according to claim 10, characterized in that R3 is ethyl or isopropyl.
12. 12. The compound according to claim 1, characterized in that R4 is alkyl.
13. The compound according to claim 12, characterized in that R4 is selected from the group consisting of 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, 3- (methylamino) propyl, and 3- (ethylamino) propyl. 1 .
14. The compound according to claim 13, characterized in that R4 is selected from the group consisting of 3-aminopropyl, 3- (methylamino) propyl, and 3- (ethylamino) propyl.
15. 15. The compound according to claim 1, characterized in that R5 is arylcarbonyl or heterocyclylcarbonyl.
16. 16. The compound according to claim 15, characterized in that R5 is selected from the group consisting of benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-methylbenzoyl, 4-trifluoromethylbenzoyl, 3-fluoro-4-methylbenzoyl.
17. 17. The compound according to claim 16, characterized in that R5 is selected from the group consisting of 4-bromobenzoyl, 4-methylbromobenzoyl and 3-fluoro-4-methylbenzoyl.
18. 18. The compound according to claim 1, characterized in that R6 and R7, together with the pendant atoms therefor - form a heterocyclic ring.
19. 19. The compound according to claim 2, characterized in that R8 is alkyl.
20. 20. The compound according to claim 19, characterized in that R8 is methyl.
21. 21. The compound according to claim 2, characterized in that m is 0 or 1.
22. 22. The compound according to claim 2, characterized in that q is 2.
23. 23. The compound according to claim 4, characterized in that 3.
24. The compound according to claim 4, characterized in that n is 1.
25. 25. The compound according to claim 4, characterized in that R9 is selected from the group consisting of ethyl, isopropyl, cyclopropyl or propyl.
26. 26. The compound in accordance with claim 25, characterized in that R9 is selected from ethyl, or isopropyl.
27. 27. The compound according to claim 4, characterized in that A is aryl.
28. 28. The compound according to claim 27, characterized in that A is phenyl.
29. 29. The compound according to claim 4, characterized in that B is aryl.
30. 30. The compound according to claim 29, characterized in that B is aryl substituted with alkyl and / or halo.
31. 31. The compound according to claim 30, characterized in that B is phenyl substituted with methyl, fluorine and / or bromine.
32. 32. The compound according to claim 4, characterized in that R10 and R11 are hydrogen.
33. 33. The compound according to claim 32, characterized in that one of R10 or R11 is hydrogen and the other is alguil. .
34. 34. The compound according to claim 33, characterized in that one of R10 or R11 is hydrogen and the other is ethyl.
35. 35. A compound characterized in that it is selected from the group consisting of: N- (3-aminopropyl) -N- [1- (3-benzyl-4-oxo-6,7,8,9- tetrahydro-4H-pyrido [1,2- a] pyrimidin-2-yl) propyl] -4-bromobenzamide; N- (3-aminopropyl) -N- [l- (3-benzyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2- a] pyrimidin-2-yl) -2 -methylpropyl] -4- methylbenzamide; N- (3-aminopropyl) -N- [1- (3-benzyl-8-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2- a] pyrimidin-2-N- il) propyl] -4-methylbenzamy a; N- (3-aminopropyl) -N- [1- (3-benzyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2- a] pyrimidin-2-yl) -2 -methylpropyl] -3-fluoro-4-methylbenzamide; N- (3-ethylaminopropyl) -N- [1- (3-benzyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2- a] pyrimidin-2-yl) -2 -methylpropyl] -4-methylbenzamide; N- (3-ethylaminopropyl) -N- [1- (3-benzyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2- a] pyrimidin-2-yl) -2 -methylpropyl] -3-fluoro-4-methylbenzamide; and N- (3-methylaminopropyl) -N- [1- (3-benzyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2- a] pyrimidin-2-yl) - 2-methylpropyl] -4-methylbenzamide.
36. 36. A pharmaceutical composition characterized in that it comprises a therapeutically effective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier.
37. 37. The composition according to claim 36, characterized in that it also comprises at least one additional agent for the treatment of cancer.
38. 38. The composition according to claim 37, characterized in that the additional agent for the treatment of cancer is selected from the group consisting of irinotecan, topotecan, gemcitabine, imatinib, trastuzumab, 5-fluorouracil, leucovorin, carboplatin, cisplatin, docetaxel, paclitaxel, tezacitabine, cyclophosphamide, vincaalkaloids, anthracyclines, rituximab and trastuzumab.
39. 39. A method for the treatment of a disorder mediated, at least in part, by KSP in a mammalian patient characterized in that it comprises administering to a mammalian patient in need of such treatment a therapeutically effective amount of a composition according to claim 36
40. 40. The method of compliance with the claim 39, characterized in that the disorder is a cell proliferative disease.
41. 41. The method according to the claim 40, characterized in that the cell proliferative disease is cancer.
42. 42. The method according to claim 41, characterized in that the cancer is selected from the group that consists of pulmonary and bronchial; of the prostate; mammary, - pancreas: of the colon and rectum; of the thyroid; of the stomach; of the liver and intrahepatic bile duct; of kidney and renal 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 villous colon adenoma.
43. 43. The method according to the claim 39, characterized in that it further comprises administering to the mammalian patient an additional agent for the treatment of cancer.
44. 44. The method according to claim 43, characterized in that the additional agent for the treatment of cancer is selected from the group consisting of irinotecan, topotecan, gemcitabine, imatinib, trastuzumab, 5-fluorouracil, leucovorin, carboplatin, cisplatin, docetaxel, paclitaxel, tezacitabine, cyclophosphamide, vinca alkaloids, anthracyclines, rituximab and trastuzumab.
45. 45. The use of the composition according to claim 36, in the manufacture of a medicament for the treatment of cancer.