ES2361335T3 - PROCEDURE TO PREPARE SUBSTITUTE PYRIMIDINES. - Google Patents

Abstract

A method of preparing a compound of formula I: where: Q and T are each independently selected from oxygen, sulfur, or N (R); R x R and IN each R is independently selected from hydrogen or an optionally substituted (C1-C6) aliphatic group, where: two R bonded to the same nitrogen atom are optionally bonded together with the nitrogen to form a 3- monocyclic ring 7-membered optionally substituted, or an 8-10 membered, saturated, partially unsaturated, or fully unsaturated bicyclic ring containing 0-3 heteroatoms, in addition to the nitrogen attached to them, independently selected from nitrogen, oxygen, or sulfur; R x is U-R 5; R 5 is selected from halogen, NO2, CN, R, or Ar; each U independently is selected from a valence bond or a (C1-C4) alkylidene chain, where: up to two methylene units of U are optionally and independently replaced by -O-, -S-, -SO-, -SO2- , -N (R) SO2-, SO2N (R) -, -N (R) -, -C (O) -, -CO2-, -N (R) C (O) -, -N (R) C (O) O-, -N (R) CON (R) -, - N (R) SO2N (R) -, -N (R) N (R) -, -C (O) N (R) -, -OC (O) N (R) -, -C (R) = NN (R) -, or -C (R) = NO-; Each Ar is independently selected from an optionally substituted ring, selected from a 3-7 membered monocyclic ring, or an 8-10 membered bicyclic ring, saturated, partially unsaturated, or fully unsaturated, having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur; R y is -N (R 1) 2, -OR 1, or -SR 1; each R 1 is independently selected from R or a 3-8 membered monocyclic ring, an 8-10 membered bicyclic ring, or a saturated, partially unsaturated, or fully unsaturated 10-12 membered tricyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and where: T each R 1 is optionally and independently substituted with up to four substituents independently selected from R 2; Each R 2 is independently selected from -R 3, -OR 3, -SR 3, -CN, -NO2, oxo, halogen, -N (R 3) 2, -C (O) R 3, -OC (O) R 3, -CO2R 3, -SO2R 3, -SO2N (R 3) 2, -N (R 3) SO2R 3, -C (O) NR (R 3), -C (O) N (R 3) 2 , -OC (O) NR (R 3), - OC (O) N (R 3) 2, -NR 3 C (O) R 3, -NR 3 C (O) N (R 3) 2, or - NR 3 CO2 (R 3); each R 3 is independently selected from R or Ar; R z1 is selected from an aliphatic group (C1-C6) or a 3-8 membered monocyclic ring, an 8-10 membered bicyclic ring, or a 10-12 membered saturated, partially unsaturated, or fully unsaturated tricyclic ring , having 0-4 heteroatoms independently selected from oxygen, nitrogen or sulfur, where: R z2 R z1 is substituted with 0-4 independently selected R 2 groups; R z2 is an aliphatic group (C1-C6) or a 3-8 membered monocyclic or 8-10 membered bicyclic saturated, partially unsaturated, or fully unsaturated ring containing 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, where: R z2 is substituted with 0-4 substituents independently selected from oxo or UR 5; said process comprising: a first step of combining a compound of formula IV with a compound of formula R z2 -TH in a first suitable means to obtain a compound of formula III, after the first step, a second step of combining the compound of formula III with a compound of formula R z1 -QH in a second suitable means to obtain a compound of formula II, and after the second step, a third step of combining the compound of formula II with a compound of formula R and -H in a suitable third medium. ** Formula ** where the first suitable medium, the second suitable medium, and the third suitable medium independently comprise: i) a suitable solvent; and ii) optionally a suitable base, and L 3 where L 1, L 2 and L 3 independently is a suitable leaving group. Q N R z1 N L 3 independently is a suitable leaving group.

Description

The present invention provides an easy process for the preparation of substituted pyrimidines. The process is useful for preparing inhibitors of protein kinases, especially of FLT-3 kinase and of the Aurora family of kinases, serine / threonine protein kinases. The present invention also relates to inhibitors of FLT-3, Aurora-1, Aurora-2, and Aurora-3 protein kinases, and their compositions.

BACKGROUND OF THE INVENTION

The search for new therapeutic agents has been greatly supported in recent years by a better understanding of the structure of enzymes and other biomolecules associated with target diseases. An important class of enzymes that has been the subject of extensive study is that of protein kinases.

Protein kinases are involved in intracellular signal transduction. They do this by performing a phosphoryl group transfer from a nucleoside triphosphate to a protein acceptor that is involved in a signaling pathway. There are a number of kinases and pathways through which extracellular and other stimuli cause a variety of cellular responses to occur within the cell. Examples of such stimuli include environmental and chemical stress signals (eg, osmotic shock, heat shock, ultraviolet radiation, bacterial endotoxin, and H2O2), cytokines (eg, interleukin-1 (IL-1), and tumor necrosis factor alpha (TNF

�)), and growth factors (for example, granulocyte macrophage colony stimulating factor (GM-CSF) and fibroblast growth factor (FGF)). An extracellular stimulus can affect one or more cellular responses related to growth, migration, cell differentiation, hormone secretion, activation of transcription factors, muscle contraction, glucose metabolism, protein synthesis control, and cell cycle regulation.

Many diseases are associated with abnormal cellular responses triggered by events mediated by protein kinases. These diseases include autoimmune diseases, inflammatory diseases, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies and asthma, Alzheimer's disease, and hormone-related diseases. Consequently, there has been a substantial effort in medical chemistry to discover protein kinase inhibitors that are effective as therapeutic agents.

The Aurora family of serine / threonine kinases is essential for cell proliferation [Bischoff, J.R. & Plowman,

G.D. (The Aurora / Ip11p family of kinases: regulators of chromosome segregation and cytokinesis) Trends in Cell Biology 9, 454-459 (1999); Giet, R. and Prigent, C. (Kinases corresponding to Aurora / Ip11p, a new oncogenic family of mitotic serine-threonine kinases) Journal of Cell Science 112, 3591-3601 (1999); Nigg, E.A. (Mitotic kinases as cell division regulators and their controls) Nat. Rev. Mol. Cell Biol. 2, 21-32 (2001); Adams, R.R., Carmena, M., and Earnshaw, W.C. (Chromosomal Passengers and the ABCs (Aurora) of Mitosis) Trends in Cell Biology 11, 49-54 (2001)]. Thus, inhibitors of the Aurora kinase family have the ability to block the growth of all types of tumors.

The three known members of the mammalian family, Aurora-A ("1"), B ("2"), and C ("3") are highly homologous proteins responsible for chromosome segregation, mitotic wear function, and cytokinesis. Aurora expression is low and undetectable in resting cells, with maximum expression and activity during the G2 and mitotic phases of reproductive cells. In mammalian cells, the proposed substrates for Aurora include histone H3, a protein involved in chromosomal condensation, and CENP-A, myosin II regulatory light chain, protein phosphatase 1, TPX2, all of which are required for cell division.

Since its discovery in 1997, the mammalian Aurora kinase family has been closely linked to tumor formation. The most compelling evidence for this is that overexpression of Aurora-A transforms rodent fibroblasts (Bischoff, JR, et al. A homologue of Drosophila aurora kinase is oncogenic and is amplified in human colorectal cancers. EMBO J. 17 , 3052-3065 (1998)). Cells with elevated levels of this kinase contain multiple centrosomes and multipolar spindles, and they quickly become aneuploid. The oncogenic activity of Aurora kinases is likely linked to the generation of such genetic instability. Indeed, a correlation between amplification of the aurora-A locus and chromosomal instability has been observed in mammary and gastric tumors. (Miyoshi, Y., Iwao, K., Egawa, C., and Noguchi, S. Association of centrosomal kinase STK15 / BTAK. Association of the expression of centrosomal kinase STK15 / BTAK mRNA with chromosomal instability in human breast cancers Int. J. Cancer 92, 370-373 (2001). (Sakakura, C. et al. BTAK kinase amplified in tumors is amplified and overexpressed in gastric cancers with possible involvement in aneuploid formation. British Journal of Cancer 84 , 824-831 (2001)). Aurora kinases have been reported to be overexpressed in a wide range of human tumors. Elevated expression of Aurora-A has been detected in more than 50% of colorectal tumors (Bischoff, JR, et al. A homologue of Drosophila aurora kinase is oncogenic and amplifies in human colorectal cancers. EMBO J. 17, 3052-3065 (1998)) (Takahashi, T., et al. Centrosomal kinases, HsAIRk1 and HsAIRK3, se overexpressed in primary colorectal cancers. Jpn. J. Cancer Res. 91, 1007-1014 (2000)), of ova rio (Gritsko, T.M. et al. Activation and overexpression of centrosomal kinase BTAK / Aurora-A in human ovarian cancer. Clinical Cancer Research 9, 1420-1426 (2003)), and gastric (Sakakura, C. et al. BTAK kinase amplified in tumors is amplified and overexpressed in gastric cancers with possible involvement in aneuploid formation. British Journal of Cancer 84 , 824-831 (2001)), and in 94% of invasive ductal adenocarcinomas of the breast (Tanaka, T., et al. Centrosomal kinase AIK1 is overexpressed in invasive ductal carcinoma of the breast. Cancer Research. 59, 20412044 (1999 )). High levels of Aurora-A have also been described in renal, cervical, neuroblastoma, melanoma, lymphoma, pancreatic, and prostatic tumor cell lines. (Bischoff, JR, et al. A homolog of Drosophila aurora kinase is oncogenic and amplifies in human colorectal cancers. EMBO J. 17, 3052-3065 (1998)) (Kimura, M., Matsuda, Y., Yoshioka, T., and Okano, Y. Cell cycle-dependent expression and centrosome localization of a third human Aurora / Ip11-related protein kinase, AIK3. Journal of Biological Chemistry 274, 7334-7340 (1999)) (Zhou et al. STK15 / BTAK kinase amplified in tumors induces centrosomal amplification, aneuploidy, and transformation. Nature Genetics 20: 189-193 (1998)) (Li et al. Overexpression of STK15 / BTAK / Aurora-A oncogenic kinase in pancreatic cancer. Clin. Cancer Res. 9 (3): 991-7 (2003)). Amplification / overexpression of Aurora-A is observed in human bladder cancers and amplification of Aurora-A is associated with aneuploidy and aggressive clinical behavior (Sen S. et al. Amplification / overexpression of a mitotic kinase gene in human bladder cancer J Natl Cancer Inst. 94 (17): 1320-9 (2002)). Furthermore, amplification of the aurora-A locus (20q13) has a correlation with poor prognosis for patients with nodule-negative breast cancer (Isola, JJ, et al. Genetic aberrations detected by comparative genomic hybridization predict consequences in nodule-negative breast cancer American Journal of Pathology 147, 905-911 (1995)). Aurora-B is highly expressed in multiple human tumor cell lines, including leukemic cells (Katayama et al. Human AIM-1: cDNA cloning and reduced expression during endomytosis in megakaryocytic lineage cells. Gene 244: 1-7 )). Levels of this enzyme increase as a function of the Duke phase in primary colorectal cancers (Katayama, H. et al. Expression of mitotic kinases and progression of colorectal cancer. Journal of the National Cancer Institute 91, 1160-1162 (1999) ). Aurora-C, normally found only in germ cells, is also overexpressed in a high percentage of primary colorectal cancers and in a variety of tumor cell lines including cervical adenocarcinoma cells and breast carcinoma (Kimura, M., Matsuda, Y., Yoshioka, T., and Okano, Y. Cell cycle-dependent expression and centrosome localization of a third human protein kinase related to Aurora / Ip11, AIK3. Journal of Biological Chemistry 274, 7334-7340 (1999). (Takahashi , T., et al. Centrosomal kinases, HsAIRk1 and HsAIRK3, are overexpressed in primary colorectal cancers. Jpn. J. Cancer Res. 91, 1007-1014 (2000)).

Based on the known function of Aurora kinases, inhibition of their activity should interrupt mitosis leading to cell cycle arrest. Thus, in vivo, an Aurora inhibitor reduces tumor growth and induces regression.

Elevated levels of all members of the Aurora family are observed in a wide variety of tumor cell lines. Aurora kinases are overexpressed in many human tumors and this has been reported to be associated with chromosomal instability in mammary tumors (Miyoshi et al. 2001 92, 370-373).

Aurora-2 is highly expressed in multiple human tumor cell lines and levels increase as a function of Duke phase in primary colorectal cancers [Katayama, H. et al. (Expression of mitotic kinases and progression of colorectal cancer) Journal of the National Cancer Institute 91, 1160-1162 (1999)]. Aurora-2 plays a role in controlling the exact segregation of chromosomes during mitosis. Defective regulation of the cell cycle can lead to cell proliferation and other abnormalities. In human colon cancer tissue the Aurora-2 protein has been found to be overexpressed [Bischoff et al., EMBO J., 17, 3052-3065 (1998); Schumacher et al., J. Cell Biol., 143, 1635-1646 (1998); Kimura et al., J. Biol. Chem., 272, 13766-13771 (1997)]. Aurora-2 is overexpressed in most transformed cells. Bischoff et al. found high levels of Aurora-2 in 96% of cell lines derived from lung, colon, kidney, melanoma and breast tumors (Bischoff et al. EMBO J. 1998 17, 3052-3065). Two comprehensive studies show Aurora-2 elevated at 54% and 68% (Bischoff et al. EMBO J. 1998 17, 3052-3065) (Takahashi et al. 2000 Jpn. J. Cancer Res. 91, 1007-1014) of colorectal tumors and in 94% invasive ductal adenocarcinomas of the breast (Tanaka et al. 1999 59, 20412044).

Aurora-1 expression is elevated in cell lines derived from tumors of the colon, breast, lung, melanoma, kidney, ovary, pancreas, CNS, gastric tract, and leukemias (Tatsuka et al 1998 58, 4811-4816).

High levels of Aurora-3 have been detected in several tumor cell lines, although this is limited to testis in normal tissues (Kimura et al. 1999 274, 7334-7340). Aurora-3 overexpression in a high percentage (c. 50%) of colorectal cancers has also been documented (Takahashi et al. 2000 Jpn J Cancer Res. 91, 1007-1014). In contrast, the Aurora family is expressed at a low level in most normal tissues, the exceptions being tissues with a high proportion of dividing cells such as thymus and testis (Bischoff et al EMBO J. 1998 17, 3052-3065). .

For further review of the role that Aurora kinases play in proliferative disorders, see Bischoff, J.R. & Plowman, G.D. (The Aurora / Ip11p family of kinases: regulators of chromosome segregation and cytokinesis) Trends in Cell Biology 9, 454-459 (1999); Giet, R. and Prigent, C. (Kinases corresponding to Aurora / Ip11p, a new oncogenic family of mitotic serine-threonine kinases) Journal of Cell Science 112, 3591-3601 (1999);

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Nigg, E.A. (Mitotic kinases as cell division regulators and their controls) Nat. Rev. Mol. Cell Biol. 2, 21-32 (2001); Adams, R.R., Carmena, M., and Earnshaw, W.C. (Chromosomal passengers and the ABCs (aurora) of mitosis) Trends in Cell Biology 11, 49-54 (2001); and Dutertre, S., Descamps, S., & Prigent, P. (On the role of aurora-A in the function of centrosomes) Oncogene 21, 6175-6183 (2002).

The type III receptor tyrosine kinase, Flt3, plays an important role in the maintenance, growth and development of hematopoietic and non-hematopoietic cells [Scheijen, B, Griffin JD, Oncogene, 2002, 21, 3314-3333 and Reilly, JT, British Journal of Hematology, 2002, 116, 744-757]. FLT-3 regulates the maintenance of early progenitor / stem cell pools as well as the development of mature lymphoid and myeloid cells [Lyman, S, Jacobsen, S, Blood, 1998, 91, 1101-1134]. FLT-3 contains an intrinsic kinase domain that is activated by ligand-mediated receptor dimerization. By activation, the kinase domain induces receptor autophosphorylation as well as the phosphorylation of various cytoplasmic proteins that help propagate the activation signal conducive to growth, differentiation and survival. Some of the downstream regulators of FLT-3 receptor signaling include, PLC�-related kinases, PI3-kinase, Grb-2, SHIP, and Src [Scheijen, B, Griffin JD, Oncogene, 2002, 21, 3314-3333] . FLT-3 kinase plays a role in a variety of hematopoietic and non-hematopoietic malignancies. Mutations that induce ligand-independent activation of FLT-3 have been implicated in acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), mastocytosis, and gastrointestinal stromal tumor (GIST). These mutations include single amino acid changes in the kinase domain or internal tandem duplications, point mutations, or deletions in the skeleton of the juxtamembrane region of the receptors. In addition to activating mutations, ligand-dependent stimulation (autocrine or paracrine) of overexpressed wild-type FLT-3 contributes to the malignant phenotype [Scheijen, B, Griffin JD, Oncogene, 2002, 21 33143333]. See also Sawyer, C.I. (Finding the next Gleevec: FLT3-targeted kinase inhibitory therapy for acute myeloid leukemia) Cancer Cell. 1, 413-415 (2002).

Tri- or tetra-substituted pyrimidine derivatives useful as kinase inhibitors are known in the art. Typically, these pyrimidine derivatives are 2,4,6- or 2,4,5,6-substituted, as shown below:

image 1

2,4,6-substituted pyrimidine 2,4,5,6-substituted pyrimidine

Known methods for preparing such pyrimidine derivatives have many synthetic drawbacks such as lacking the ability to regioselectively introduce substituents at the 2-, 4- or 6-position in high yields. See M. Botta, Nucleosides and Nucleotides, 13, 8, 1994, 1769-78; M. Ban, Bioorg. Med. Chem., 6, 7, 1998, 1057-68; Y. Fellahi, Eur. J. Med. Chem. Chim. Ther., 31, 1, 1996, 77-82; T.J. Delia, J. Het. Chem., 35, 2, 1998, 269-74; H. Uchel, Tetrahedron Lett., 36, 52, 1995, 9457-60; and Y. Nezu, Pestic. Sci., 47, 2, 1996, 115-24.

WO 02/057259 relates to pyrazole compounds useful as protein kinase inhibitors, such as Aurora-2 and GSK-3.

There is a need for a synthetic process that can be easily used to prepare tri- or tetra-substituted pyrimidine derivatives on a large scale. There is also a need for a process that uses minimal steps and uses readily available starting materials and simple reaction media. Ideally, such a procedure will be easy to scale up, if necessary, and will be inexpensive. There is also a need for a process that does not lead to mixtures of regioisomeric intermediates that must be separated by, for example, chromatographic methods. Such separations reduce overall yields.

It would be desirable to have a synthetic process for producing tri- or tetra-substituted pyrimidine derivatives that possesses the above advantages and thereby improves on currently available processes.

SUMMARY OF THE INVENTION

The present invention provides a process for preparing a compound of formula I:

image2

I

where:

Q and T are each independently selected from oxygen, sulfur, or N (R);

each R independently is selected from hydrogen or an optionally substituted C1-C6 aliphatic group,

5 where:

two R's bonded to the same nitrogen atom are optionally bonded together with the nitrogen to form an optionally substituted 3-7 membered monocyclic ring, or an 8-10 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring containing 0 -3 heteroatoms, in addition to the nitrogen attached to them, independently selected from nitrogen, oxygen or sulfur;

Rx is U-R5;

R5 is selected from halogen, NO2, CN, R, or Ar;

each U independently is selected from a valence bond or a (C1-C4) alkylidene chain, where:

up to two methylene units of U are optionally and independently replaced by -O-, -S-, -SO-, -SO2-, -N (R) SO2-, SO2N (R) -, -N (R) -, - C (O) -, -CO2-, -N (R) C (O) -, -N (R) C (O) O-, -N (R) CON (R) -,

-N (R) SO2N (R) -, -N (R) N (R) -, -C (O) N (R) -, -OC (O) N (R) -, -C (R) = NN (R) -, or -C (R) = NO-;

Each Ar is independently selected from an optionally substituted ring, selected from a 3-7 membered monocyclic ring, or an 8-10 membered bicyclic ring, saturated, partially unsaturated, or fully unsaturated, having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur;

Ry is -N (R1) 2, -OR1, or -SR1;

Each R1 is independently selected from R or a 3-8 membered monocyclic ring, an 8-10 membered bicyclic ring, or a saturated, partially unsaturated, or fully unsaturated 10-12 membered tricyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and where:

Each R1 is optionally and independently substituted with up to four substituents independently selected from R2;

each R2 is independently selected from -R3, -OR3, -SR3, -CN, -NO2, oxo, halogen, -N (R3) 2, -C (O) R3, -OC (O) R3, -CO2R3, - SO2R3, -SO2N (R3) 2, -N (R3) SO2R3, -C (O) NR (R3), -C (O) N (R3) 2, -OC (O) NR (R3), OC (O ) N (R3) 2, -NR3C (O) R3, -NR3C (O) N (R3) 2, or -NR3CO2 (R3);

Each R3 is independently selected from R or Ar;

Rz1 is selected from an aliphatic group (C1-C6) or a 3-8 membered monocyclic ring, an 8-10 membered bicyclic ring, or a 10-12 membered, saturated, partially unsaturated, or fully unsaturated tricyclic ring, having 0-4 heteroatoms independently selected from oxygen, nitrogen or sulfur, where:

Rz1 is substituted with 0-4 independently selected R2 groups;

35 Rz2 is an aliphatic (C1-C6) group or a 3-8 membered monocyclic or 8-10 membered bicyclic saturated, partially unsaturated, or fully unsaturated ring containing 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, where:

image3

Rz2 is substituted with 0-4 substituents independently selected from oxo or U-R5;

said process comprising the step of combining a compound of formula II and a compound of formula Ry-H in a suitable medium:

Ry H

Rz2

T

II

5 where:

said suitable medium comprises: i) a suitable solvent; and ii) optionally, a suitable base; and

L3 is a suitable leaving group; 10 and where compounds of formula II are prepared from compounds of formula III and compounds of formula III are prepared from compounds of formula IV. Formulas III and IV are defined on the following pages. DESCRIPTION OF THE INVENTION

The present invention provides a process for preparing a compound of formula I: where:

image2

I

fifteen

Q and T are each independently selected from oxygen, sulfur, or N (R);

each R is independently selected from hydrogen or an optionally substituted (C1-C6) aliphatic group, where:

two R's bonded to the same nitrogen atom are optionally bonded together with the nitrogen to

20 form an optionally substituted 3-7 membered monocyclic ring, or a saturated, partially unsaturated, or fully unsaturated 8-10 membered bicyclic ring containing 0-3 heteroatoms, in addition to the nitrogen attached to them, independently selected from nitrogen, oxygen or sulfur;

Rx is U-R5;

R5 is selected from halogen, NO2, CN, R, or Ar;

Each U is independently selected from a valence bond or a (C1-C4) alkylidene chain, where:

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twenty

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up to two methylene units of U are optionally and independently replaced by -O-, -S-, -SO-, SO2-, -N (R) SO2-, SO2N (R) -, -N (R) -, -C (O) -, -CO2-, -N (R) C (O) -, -N (R) C (O) O-, -N (R) CON (R) -, N (R) SO2N (R ) -, -N (R) N (R) -, -C (O) N (R) -, -OC (O) N (R) -, -C (R) = NN (R) -, or - C (R) = NO-;

Each Ar is independently selected from an optionally substituted ring, selected from a 3-7 membered monocyclic ring, or an 8-10 membered bicyclic ring, saturated, partially unsaturated, or fully unsaturated, having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur;

Ry is -N (R1) 2, -OR1, or -SR1;

Each R1 is independently selected from R or a 3-8 membered monocyclic ring, an 8-10 membered bicyclic ring, or a saturated, partially unsaturated, or fully unsaturated 10-12 membered tricyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and where:

each R1 is optionally and independently substituted with up to four substituents independently selected from R2;

each R2 is independently selected from -R3, -OR3, -SR3, -CN, -NO2, oxo, halogen, -N (R3) 2, -C (O) R3, -OC (O) R3, -CO2R3, - SO2R3, -SO2N (R3) 2, -N (R3) SO2R3, -C (O) NR (R3), -C (O) N (R3) 2, -OC (O) NR (R3), OC (O ) N (R3) 2, -NR3C (O) R3, -NR3C (O) N (R3) 2, or -NR3CO2 (R3);

each R3 is independently selected from R or Ar;

Rz1 is selected from an aliphatic group (C1-C6) or a 3-8 membered monocyclic ring, an 8-10 membered bicyclic ring, or a 10-12 membered tricyclic ring, saturated, partially unsaturated, or completely unsaturated, having 0-4 heteroatoms independently selected from oxygen, nitrogen or sulfur, where:

Rz1 is substituted with 0-4 independently selected R2 groups;

Rz2 is a saturated, partially unsaturated, or fully unsaturated aliphatic (C1-C6) group or 3-8 membered monocyclic or 8-10 membered bicyclic ring containing 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, where :

Rz2 is substituted with 0-4 substituents independently selected from oxo or U-R5;

said process comprising the step of combining a compound of formula II and a compound of formula Ry-H in a suitable medium:

Ry H

Rz2

T

II

where: said suitable medium comprises: i) a suitable solvent; and ii) optionally, a suitable base; and L3 is a suitable leaving group;

where the compound of formula II is prepared by combining a compound of formula III with a compound of formula

Rz1-Q-H in a suitable medium:

image3

2

L

R image4 x N z1

R QH 3

z2

LNTR

III

where:

said suitable medium comprises: i) a suitable solvent; and ii) optionally, a suitable base; and

L2 is a suitable leaving group, and where the compound of formula III is prepared by combining a compound of formula IV with a compound of formula Rz2-T-H in a suitable medium:

2

L

image5

z2 R TH

1

IV

10 where:

said suitable medium comprises:

i) a suitable solvent; and

ii) optionally, a suitable base; and

L1 is a suitable removable group.

A suitable solvent is a solvent or a mixture of solvents which, in combination with the combined compounds, can facilitate the progress of the reaction between them. The suitable solvent can solubilize one or more of the reaction components, or, alternatively, the suitable solvent can facilitate stirring of a suspension of one or more of the reaction components. Examples of suitable solvents useful in the present invention are a protic solvent, a halogenated hydrocarbon, an ether, an aromatic hydrocarbon, a

20 polar or non-polar aprotic solvent, or any of their mixtures. These and other suitable solvents are well known in the art, for example see "Advanced Organic Chemistry", Jerry March, 4th edition, John Wiley and Sons, N.Y. (1992).

Preferably the suitable solvent is a linear or branched (C1-C7) alkyl alcohol, ether, or a polar or non-polar aprotic solvent.

For the reaction between a compound of formula II and a compound Ry-H, a more preferred suitable solvent is selected from ethanol, isopropanol, t-butanol, n-butanol or tetrahydrofuran.

For the reaction between a compound of formula III and a compound Rz1-Q-H, a more preferred suitable solvent is selected from ethanol, isopropanol, t-butanol, n-butanol, N, N-dimethylformamide, dimethylsulfoxide, or tetrahydrofuran.

For the reaction between a compound of formula IV and a compound Rz2-T-H, a more preferred suitable solvent is selected from N, N-dimethylformamide, dimethylsulfoxide, or tetrahydrofuran.

According to an alternative embodiment, the suitable solvent is Ry-H. Thus, in one such embodiment, the reacting compound Ry-H acts, in part, as a suitable solvent in combination with a compound of formula II, and also acts, in part, as a reacting compound and reacts with the compound of formula II. to produce compound of formula I.

According to another alternative embodiment, the suitable solvent is Rz1-Q-H. Thus, in one such embodiment, the reactant Rz1-QH acts, in part, as a suitable solvent in combination with a compound of formula III, and also acts, in part, as a reactant and reacts with the compound of formula III. to produce compound of formula II.

According to another alternative embodiment, the suitable solvent is Rz2-T-H. Thus, in one such embodiment, the reacting compound Rz2-TH acts, in part, as a suitable solvent in combination with a compound of formula IV, and also acts, in part, as a reactant compound and reacts with the compound of formula IV. to produce compound of formula III.

A suitable base is a chemical entity that has the ability to be a proton acceptor. Examples include organic amines, alkaline earth metal carbonates, alkaline earth metal hydrides, and alkaline earth metal hydroxides. These and other suitable bases are well known in the art, for example see "Advanced Organic Chemistry", Jerry March, 4th Ed., Pp. 248-253, John Wiley and Sons, N.Y. (1992). Preferred suitable bases include trialkylamines, sodium carbonate, potassium carbonate, sodium hydride, potassium hydride, sodium hydroxide, or potassium hydroxide. Most preferably, the suitable base is diisopropylethylamine or triethylamine.

A suitable leaving group is a chemical group that is easily displaced by an incoming chemical moiety. Thus, the choice of a suitable specific leaving group is based on its ability to be easily displaced by the incoming chemical moiety Ry in Ry-H, Rz1-Q in Rz1-Q-H, or Rz2-T in Rz2-T-H. Suitable releasing groups are well known in the art, see for example "Advanced Organic Chemistry", Jerry March, 4th Ed., Pp. 351-357, John Wiley and Sons, N.Y. (1992). Such removable groups include, but are not limited to, halogen, alkoxy, sulfonyloxy, optionally substituted alkylsulfonyl, optionally substituted alkenylsulfonyl, optionally substituted arylsulfonyl, and diazonium moieties. Examples of suitable leaving groups include chlorine, iodine, bromine, fluoro, methanesulfonyl (mesyl), tosyl, triflate, nitrophenylsulfonyl (nosyl), and bromophenylsulfonyl (brosyl).

For example, in the process of preparing a compound of formula I, L3 is displaced by the incoming moiety Ry of Ry-H. Thus, if Ry-H is for example a piperazine, then L3 is a removable group that is easily displaced by the NH residue on the piperazine.

L3

Preferred leaving groups are selected from halogen, optionally substituted arylsulfonyl, or optionally substituted alkylsulfonyl. For example, L3 can be fluoro, chloro, bromine, iodine, paratoluenesulfonyl, methanesulfonyl, paranitrophenylsulfonyl, parabromophenylsulfonyl, or trifluoromethanesulfonate. More preferably, L3 is chlorine, iodine, or methanesulfonyl. Most preferably L3 is chlorine.

For example, in the process of preparing a compound of formula II, L2 is displaced by the incoming moiety Rz1 Q of Rz1-Q-H. Thus, if Rz1-Q-H is, for example, 3-aminopyrazole, then L2 is a removable group that is easily displaced by 3-aminopyrazole.

Preferred L2 releasing groups are selected from halogen, optionally substituted arylsulfonyl, or L2 alkylsulfonyl

optionally substituted. For example, it can be fluoro, chlorine, bromine, iodine, paratoluenesulfonate, methanesulfonate, paranitrophenylsulfonyl, parabromophenylsulfonyl, or trifluoromethanesulfonate. More preferably, L2 is chlorine, iodine, or fluoro. Most preferably L2 is chlorine.

For example, in the process of preparing a compound of formula III, L1 is displaced by the incoming moiety Rz2-T of Rz2-T-H. Thus, if Rz2-T is for example an optionally substituted arylthiol, then L1 is a removable group that is easily displaced by the thio group in the optionally substituted arylthiol.

Preferred removable groups L1 are selected from halogen, optionally substituted arylsulfonyl, or optionally substituted alkylsulfonyl. More preferably, L1 is chlorine, iodine, or methanesulfonyl. Most preferably, L1 is methanesulfonyl.

According to an alternative embodiment, the suitable removable group can be generated in situ within the reaction medium. For example, L3 in a compound of formula II can be generated in situ from a precursor of that compound of formula II where said precursor contains a group easily replaced by L3 in situ. In a specific illustration of such a substitution, said precursor of a compound of formula II contains a group (eg, a chloro group or hydroxyl group) that is replaced in situ by L3, such as an iodine group. The source of the iodine group can be, for example, sodium iodide. Consequently, L2 and L1 can also be formed in situ in an analogous manner. Such in situ generation of a suitable removable group is well known in the art, see for example "Advanced Organic Chemistry", Jerry March, pp. 430-431, 4th Ed., John Wiley and Sons, N.Y. (1992).

According to another alternative embodiment, an anion of either Ry in Ry-H, Rz1-Q in Rz1-Q-H, or Rz2-T in Rz2-T-H can be formed prior to addition to the reaction medium. The preparation of said anion is well known to those skilled in the art. For example, when T is oxygen, the anion of Rz2-T-H is easily formed by treating Rz2-T-H with a base such as sodium hydride. This oxygenated anion can then combine with the compound of formula IV to form a compound of formula III.

According to another embodiment, the reactions described in this document are carried out at a temperature lower than or equal to the reflux temperature of the reaction medium. According to another embodiment, said reaction medium has a temperature lower than the boiling point of said suitable solvent or at a temperature reached by refluxing said suitable solvent in said reaction medium. In another embodiment, said reaction medium has a temperature between about 0 ° C and about 190 ° C. According to a further embodiment, said reaction medium has a temperature between about 40 ° C and about 120 ° C. According to another aspect of the present invention, said reaction medium has a temperature between approximately 70 ° C and approximately 115 ° C.

When used herein, the following definitions apply unless otherwise indicated.

The term "Aurora" refers to any isoform of the Aurora family of protein kinases, which includes Aurora-1, Aurora-2, and Aurora-3. The term "Aurora" also refers to isoforms of the Aurora family of protein kinases known as Aurora-A, Aurora-B, and Aurora-C.

The phrase "optionally substituted" is used interchangeably with the phrase "substituted or unsubstituted." Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position in the group, and each substitution is independent of the other.

The term "aliphatic" or "aliphatic group" when used herein means a straight or branched (C1-C8) hydrocarbon chain that is fully saturated or contains one or more unsaturation units, or a (C3-C8) hydrocarbon ) monocyclic or a bicyclic (C8-C12) hydrocarbon that is fully saturated or contains one or more units of unsaturation, but is not aromatic (also referred to herein as "carbocycle" or "cycloalkyl"), which has a single point of attachment to the rest of the molecule where any single ring in said bicyclic ring system has 3-7 members. For example, suitable aliphatic groups include, but are not limited to, linear or branched alkyl, alkenyl, alkynyl groups, and their hybrids such as (cycloalkyl) alkyl, (cycloalkenyl) alkyl, or (cycloalkyl) alkenyl.

The terms "alkyl", "alkoxy", "hydroxyalkyl", "alkoxyalkyl", and "alkoxycarbonyl", used alone or as part of a larger moiety include both straight and branched chains containing one to twelve carbon atoms.

The term "heteroatom" means nitrogen, oxygen, or sulfur and includes any oxidized form of nitrogen and sulfur, and the quaternary form of any basic nitrogen. Also the term "nitrogen" includes a substitutable nitrogen from a heterocyclic ring. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur, or nitrogen, the nitrogen can be N (as in 3,4-dihydro-2Hpyrrolyl), NH (as in pyrrolidinyl), or NR + (as in N-substituted pyrrolidinyl).

The term "aryl" or "aryl ring" refers to a monocyclic, bicyclic, or tricyclic ring system that has a total of five to fourteen ring carbon atoms, where at least one ring is aromatic and where each ring in the system contains three to seven ring members. The term "aryl" can be used interchangeably with the term "aryl ring". Examples include phenyl, indanyl, 1-naphthyl, 2-naphthyl, 1-anthracyl, 2-anthracyl, and bicyclo [2.2.2] oct-3-yl.

More preferred ring sizes for aryl rings are set forth below for various preferred embodiments of compounds of formula I.

The term "aryl" used alone or as part of a larger moiety as in "aralkyl", "aralkoxy", or "aryloxyalkyl", refers to monocyclic, bicyclic, and tricyclic ring systems having a total of five to fourteen members in ring, where at least one ring of the system is aromatic and where each ring of the system contains 3 to 7 ring members. The term "aryl" can be used interchangeably with the term "aryl ring". The term "aryl" also refers to heteroaryl ring systems as defined hereinafter.

The term "heterocycle", "heterocyclyl", or "heterocyclic" when used herein means non-aromatic, monocyclic, bicyclic, or tricyclic ring systems having five to fourteen ring members, wherein one or more ring members ring are a heteroatom, where each ring of the system contains 3 to 7 ring members.

The term "heteroaryl", used alone or as part of a larger moiety as in "heteroalkyl" or "heteroarylalkoxy", refers to monocyclic, bicyclic, and tricyclic ring systems having a total of five to fourteen ring members, where at least one ring of the system is aromatic, at least one ring of the system contains one or more heteroatoms, and where each ring of the system contains 3 to 7 ring members. The term "heteroaryl" can be used interchangeably with the term "heteroaryl ring" or the term "heteroaromatic."

An aryl group (including aralkyl, aralkoxy, aryloxyalkyl, and the like) or heteroaryl (including heteroaralkyl and heteroarylalkoxy, and the like) may contain one or more substituents. Suitable substituents on the unsaturated carbon atom of an aryl, heteroaryl, aralkyl, or heteroaralkyl group are selected from halogen, -Ro, -ORo, -SRo, 1,2-methylenedioxy, 1,2-ethylenedioxy, optionally substituted phenyl (Ph) with Ro, -O (Ph) optionally substituted with Ro, -CH2 (Ph) optionally substituted with Ro, -CH2-CH2 (Ph), optionally substituted with Ro, -NO2, -CN, -N (Ro) 2, - NRoC (O) Ro, -NRoC (O) N (Ro) 2, -NRoCO2Ro, -NRoNRoC (O) Ro, -NRoNRoC (O) N (Ro) 2, -NRoNRoCO2Ro, -C (O) C (O) Ro, -C (O) CH2C (O) Ro, -CO2Ro, -C (O) Ro, -C (O) N (Ro) 2, -OC (O) N (Ro) 2, -S (O) 2Ro, -SO2N (Ro) 2, -S (O) Ro, -NRoSO2N (Ro) 2, -NRoSO2Ro, -C (= S) N (Ro) 2, -C (= NH) -N (Ro) 2 , or - (CH2) andNHC (O) Ro, where each Ro is independently selected from hydrogen, aliphatic group (C1-C6), an unsubstituted 5-6 membered heteroaryl or heterocyclic ring, phenyl, -O (Ph), or -CH2 (Ph). Optional substituents on the aliphatic group of Ro are selected from NH2, NH (C1-C4 aliphatic), N (C1-C4 aliphatic) 2, halogen, (C1-C4) aliphatic, OH, O (C1-C4 aliphatic), NO2, CN, CO2H, CO2 (C1-C4 aliphatic), O (halo (C1-C4 aliphatic)), or halo (C1-C4 aliphatic).

An aliphatic group or a non-aromatic heterocyclic ring can contain one or more substituents. Suitable substituents on saturated carbon of an aliphatic group or of a non-aromatic heterocyclic ring are selected from those included above for unsaturated carbon of an aryl or heteroaryl group and the following: = O, = S, = NNHR *, = NN (R * ) 2, = NNHC (O) R *, = NNHCO2 (alkyl), = NNHSO2 (alkyl), or = NR *, where each R * is independently selected from hydrogen or an optionally substituted (C1-C6) aliphatic group. Optional substituents on the aliphatic group of R * are selected from NH2, NH (C1-C4 aliphatic), N (C1-C4 aliphatic) 2, halogen, (C1-C4) aliphatic, OH, O (C1-C4 aliphatic), NO2, CN, CO2H, CO2 (C1-C4 aliphatic), O (halo (C1-C4 aliphatic)), or halo (C1-C4 aliphatic).

Optional substituents on the nitrogen of a non-aromatic heterocyclic ring are selected from -R +, -N (R +) 2, -C (O) R +, -CO2R +, -C (O) C (O) R +, -C (O) CH2C (O) R +, -SO2R +, -SO2N (R +) 2, -C (= S) N (R +) 2, -C (= NH) -N (R +) 2, or -NR + SO2R +; where R + is hydrogen, an optionally substituted (C1-C6) aliphatic group, optionally substituted phenyl, optionally substituted -O (Ph), optionally substituted -CH2 (Ph), -CH2CH2 (Ph), or a heteroaryl ring

or unsubstituted 5-6 membered heterocyclic. Optional substituents on the aliphatic group or phenyl ring of R + are selected from NH2, NH (C1-C4 aliphatic), N (C1-C4 aliphatic) 2, halogen, (C1-C4) aliphatic, OH, O (C1-C4 aliphatic), NO2, CN, CO2H, CO2 (C1-C4 aliphatic), O (halo (C1-C4 aliphatic)), or halo (C1-C4 aliphatic).

The term "alkylidene chain" refers to a straight or branched carbon chain that can be fully saturated or have one or more units of unsaturation and has two points of attachment to the rest of the molecule.

A combination of substituents or variables is permissible only if such combination results in a stable or chemically feasible compound. A stable compound or chemically feasible compound is one that is not substantially altered when kept at a temperature of 40 ° C or less, in the absence of moisture or other chemically reactive conditions, for at least one week.

It will be apparent to those skilled in the art that certain compounds of this invention may exist in tautomeric forms, all such tautomeric forms of the compounds being within the scope of the invention.

Unless otherwise indicated, the structures depicted herein are also meant to include all stereochemical forms of the structure; that is, the R and S configurations for each asymmetric center. Thus, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the invention. Unless otherwise indicated, the structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except the substitution of a hydrogen for a deuterium or tritium, or the substitution of a carbon for a carbon enriched in 13C or 14C, are within the scope of this invention. Such compounds are useful, for example, as analytical tools or probes in biological assays.

According to another embodiment, Q of formula I is NH, oxygen, or sulfur.

According to a preferred embodiment, Q of formula I is NR. More preferably, Q of formula I is NH.

According to another preferred embodiment, T of formula I is oxygen or sulfur. More preferably, T of formula I is sulfur.

According to another embodiment, T of formula I is oxygen and the anion of Rz2-T-H is formed prior to combining with a compound of formula IV to form a compound of formula III.

According to another embodiment, Rx of formula I is U-R5, where U is a valence bond, -O-, or -NR-, and R5 is R or Ar.

According to another preferred embodiment, Rx of formula I is selected from R, Ar, or -N (R) 2. More preferably, Rx of formula I is hydrogen.

According to another preferred embodiment, Ry of formula I is selected from -OR1 or -N (R1) 2.

According to another embodiment, Ry of formula I is selected from N (R1) 2 where each R1 is independently selected from R or a saturated, partially unsaturated, or completely 3-7 membered monocyclic or 8-10 membered bicyclic ring unsaturated having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Preferred R1 substituents are selected from -OR3, -SR3, -CN, -NO2, oxo, halogen, -N (R3) 2, -C (O) R3, or a 3-6 membered aromatic or non-aromatic ring having zero to two heteroatoms independently selected from nitrogen, oxygen, or sulfur. More preferred substituents on R1 are 5-6 membered non-aromatic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. The most preferred substituents on the R1 aliphatic (C1-C4) group are NH (CH3), NH2, OH, OCH3, morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl, and thiomorpholinyl.

According to another preferred embodiment, Ry of formula I is selected from N (R1) 2, where each R1 is R such that the two R groups join together to form an optionally substituted 4-7 membered non-aromatic ring having up to two additional heteroatoms independently selected from nitrogen, oxygen, or sulfur. Preferred substituents on said ring are selected from -R3, -OR3, -SR3, -CN, -NO2, oxo, halogen, -N (R3) 2, -C (O) R3, -CO2R3, -SO2R3, or a ring 3-6 membered aromatic or non-aromatic having zero to two heteroatoms independently selected from nitrogen, oxygen, or sulfur. More preferred substituents on said ring are selected from optionally substituted (C1-C4) aliphatic, NH2, NH (C1-C4 aliphatic), N (C1-C4 aliphatic) 2, optionally substituted phenyl, CO2 (C1-C4 aliphatic), or SO2 (C1-C4 aliphatic). The most preferred substituents on said ring are selected from methyl, ethyl, methylsulfonyl, (CH3) 2SO2CH3, cyclopropyl, CH2cyclopropyl, (CH2) 2OH, CO2t-butyl, CH2phenyl, phenyl, NH2, NH (CH3), N (CH3) 2 , (CH2) 2NH2, (CH2) 2morpholin-4-yl, (CH2) 2N (CH3) 2, isopropyl, propyl, t-butyl, (CH2) 2CN, or (CH2) 2C (O) morpholin-4-yl .

Most preferably, Ry of formula I is pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, piperazin-1yl, diazepanyl, or tetrahydroisoquinolinyl, where each ring is optionally substituted with one or two groups independently selected from methyl, ethyl, methylsulfonyl, (CH2) 2SO2CH3, cyclopropyl, CH2cyclopropyl, (CH2) 2OH, CO2t-butyl, CH2phenyl, phenyl, NH2, NH (CH3), N (CH3) 2, (CH2) 2NH2, (CH2) 2morpholin-4-yl, (CH2) 2N (CH3) 2, isopropyl, propyl, t-butyl, (CH2) 2CN, or (CH2) 2C (O) morpholin-4-yl.

According to another embodiment, Rz1 of formula I is a 3-7 membered monocyclic or 8-10 membered bicyclic, saturated, partially unsaturated, or fully unsaturated ring having 0-4 heteroatoms independently selected from oxygen, nitrogen or sulfur , where said ring is optionally and independently substituted with up to three substituents selected from -R3, -OR3, -SR3, -CN, -NO2, oxo, halogen, -N (R3) 2, -C (O) R3, -OC (O) R3, -CO2R3, -SO2R3, -SO2N (R3) 2, -N (R3) SO2R3, -C (O) NR (R3), -C (O) N (R3) 2, -OC (O ) NR (R3), -OC (O) N (R3) 2, -NR3C (O) R3, -NR3C (O) N (R3) 2, or -NR3CO2R3.

According to another embodiment, Rz1 of formula I is a saturated, partially unsaturated, or fully unsaturated 5-6 membered monocyclic or 8-10 membered bicyclic ring having 1-4 heteroatoms independently selected from oxygen, nitrogen or sulfur , where said ring is optionally and independently substituted with up to three substituents selected from -R3, -OR3, -SR3, -CN, -NO2, oxo, halogen, -N (R3) 2, -C (O) R3, -OC (O) R3, -CO2R3, -SO2R3, -SO2N (R3) 2, -N (R3) SO2R3, -C (O) NR (R3), -C (O) N (R3) 2, -OC (O ) NR (R3), -OC (O) N (R3) 2, -NR3C (O) R3, -NR3C (O) N (R3) 2, or -NR3CO2R3.

According to a more preferred embodiment, Rz1 of formula I is a fully unsaturated five or six membered ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is optionally and independently substituted with up to three substituents selected from -R3, -OR3, -SR3, -CN, -NO2, oxo, halogen, -N (R3) 2, -C (O) R3, -OC (O) R3, -CO2R3, -SO2R3, -SO2N (R3) 2, -N (R3) SO2R3, -C (O) NR (R3), -C (O) N (R3) 2, -OC (O) NR (R3), -OC (O) N (R3) 2, -NR3C (O) R3, -NR3C (O) N (R3) 2, or -NR3CO2R3.

Preferred Rz1 rings of formula I are optionally substituted rings selected from pyrazole or any of the following 5-6 membered rings:

N NN N N

N

NN N H

N NN S

O N S

OR

N N NO NS

NNS O

NN ON SNN

N N NO Y

H OS NN

N NN

N

N

N H

Most preferably, Rz1 of formula I is a pyrazole ring having up to three substituents as defined above.

According to another preferred embodiment, Rz1 of formula I has up to two substituents, where said 5 substituents are as described above. More preferably, Rz1 of formula I has a substituent, where said substituent is as described above.

Preferred substituents on the Rz1 moiety of formula I are -N (R3) 2, -OR3, Ar, or an optionally substituted (C1-C4) aliphatic group, where Ar is a partially saturated optionally substituted 5-6 membered ring unsaturated, or fully unsaturated having 0-4 heteroatoms independently selected from

10 nitrogen, oxygen, or sulfur. An even more preferred substituent on the Rz1 moiety of formula I is a (C1-C4) aliphatic group. The most preferred substituents on the Rz1 moiety of formula I are selected from methyl, ethyl, propyl, isopropyl, t-butyl, cyclopropyl, or phenyl.

According to another embodiment, Rz1 of formula I is a (C1-C6) aliphatic group substituted with 0-4 R2 groups. Preferably, Rz1 is substituted with 0-3 R2 groups, where each R2 is independently selected from R3, oxo, halogen, N (R3) 2, CN, or CO2R3.

According to a preferred embodiment, Rz2 of formula I is a saturated, partially unsaturated, or fully unsaturated 5-6 membered monocyclic or 8-10 membered bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur , wherein said ring is optionally substituted with up to three substituents independently selected from -R3, -OR3, -SR3, -CN, -NO2, oxo, halogen,

-N (R3) 2, -C (O) R3, -OC (O) R3, -CO2R3, -SO2R3, -SO2N (R3) 2, -N (R3) SO2R3, -C (O) NR (R3 ), -C (O) N (R3) 2, -OC (O) NR (R3), -OC (O) N (R3) 2, -NR3C (O) R3, -NR3C (O) N (R3) 2, or -NR3CO2R3.

More preferably, Rz2 of formula I is selected from an optionally substituted ring selected from a saturated, partially unsaturated, or fully unsaturated 5-6 membered monocyclic or 9-10 membered bicyclic ring having 0-4 heteroatoms independently selected from nitrogen. , oxygen or sulfur; wherein said ring is optionally substituted with up to three independently selected substituents as described above. Most preferably, Rz2 of formula I is selected from phenyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrazinyl, naphthyl, tetrahydronaphthyl, benzimidazolyl, benzothiazolyl, quinolinyl, quinazolinyl, benzodioxynyl, isobenzofuran, indanyl, or indoldazolyl, indolinyl, indoldazolyl,

5

10

fifteen

twenty

25

30

35

40

where the Rz2 moiety of formula I is optionally and independently substituted with up to three substituents as described above.

Preferred substituents on Rz2 of formula I, when present, are independently selected from halogen, -CN, -NO2, -C (O) R3, -CO2R3, -C (O) NR (R3), -NR3C (O) R3, -N (R3) 2, -N (R3) SO2R3, -NR3C (O) N (R3) 2, or -NR3CO2R3. More preferred substituents on the Rz2 moiety of formula I are independently selected from -Cl, -Br, -F, -CN, -CF3, -COOH, -CONHMe, -CONHEt, -NH2, -NHAc, -NHSO2Me, -NHSO2Et , -NHSO2 (n-propyl), -NHSO2 (isopropyl), -NHCOEt, -NHCOCH2NHCH3, -NHCOCH2N (CO2t-Bu) CH3, -NHCOCH2N (CH3) 2, -NHCOCH2CH2N (CH3) 2, -NHCOCH2CH3CH2N , -NHCO (cyclopropyl), -NHCO (isopropyl), -NHCO (isobutyl), -NHCOCH2 (morpholin-4-yl), -NHCOCH2CH2 (morpholin-4-yl), -NHCOCH2CH2CH2 (morpholin-4-yl), - NHCO2 (t-butyl), -NH (cyclohexyl), -NHMe, -NMe2, -OH, -OMe, methyl, ethyl, cyclopropyl, isopropyl, or t-butyl.

According to another preferred embodiment, Rz2 of formula I has up to two substituents, where said substituents are as described above. More preferably, Rz2 of formula I has a substituent, where said substituent is as described above. Most preferably, Rz2 of formula I has a substituent selected from -NR3C (O) R3, where each R3 is independently selected from R or Ar and where R is hydrogen or an optionally substituted (C1-C4) aliphatic group.

According to another embodiment, Rz2 of formula I is an aliphatic group (C1-C6) substituted with 0-3 groups independently selected from halogen, oxo, -CN, -NO2, -C (O) R3, -CO2R3, - C (O) NR (R3), -NR3C (O) R3, -N (R3) 2, -N (R3) SO2R3, -NR3C (O) N (R3) 2, or -NR3CO2R3. More preferably, Rz2 of formula I is a (C1-C4) aliphatic group substituted with 0-3 groups independently selected from halogen, -CN, -NO2, -C (O) R3, -CO2R3, -N (R3) 2 , or -NR3CO2R3.

Preferred embodiments of Rx, T, Q, Rz1, and Rz2 in formula II are as described for these moieties in formula I.

Preferred embodiments of the Ry moiety of Ry-H are as described for the group Ry in formula I.

Preferred embodiments of Rx, L3, T and Rz2 in formula III are as described for these moieties in formula

I.

Preferred embodiments of the Q and Rz1 residues of Rz1-Q-H are as described for these residues in the formula

I.

Preferred embodiments of Rx, L3, L2, and Q in formula IV are as described for these moieties in formula

I.

Preferred embodiments of Rz2 and T in Rz2-T-H are as described for these moieties in formula I.

Preferably Rx in the process of the present invention is other than a suitable leaving group:

Preferred compounds of formula I, prepared using the process of the present invention, have formula I ':

3

R

image6

HN

H

image4 NR 3C (O) R3

image4 N Rx

1

R image4 NNS

1

R

I '

or a pharmaceutically acceptable derivative or salt thereof, where R1 and R3 are as defined above.

Preferred groups R1 of formula I 'are independently selected from R, where R is hydrogen or an optionally substituted (C1-C4) aliphatic group. Preferred substituents on the aliphatic group (C1-C4) of the residue R1 of formula I 'are selected from -OR3, -SR3, -CN, -NO2, oxo, halogen, -N (R3) 2, -C (O) R3, or a 3-6 membered aromatic or non-aromatic ring having zero to two heteroatoms independently selected from nitrogen, oxygen, or sulfur. More preferred substituents on the aliphatic group (C1-C4) of the R1 residue of formula I 'are rings

5

10

fifteen

twenty

25

30

35

5-6 membered non-aromatics having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. The most preferred substituents on the aliphatic group (C1-C4) R1 of the residue R1 of formula I 'are NH (CH3), NH2, OH, OCH3, morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl, and thiomorpholinyl.

According to another preferred embodiment, each R1 of formula I 'is R such that the two R groups join together to form an optionally substituted 4-7 membered non-aromatic ring having up to two additional heteroatoms independently selected from nitrogen, oxygen and sulfur. Preferred substituents on said ring are selected from -R3, -OR3, -SR3, -CN, -NO2, oxo, halogen, -N (R3) 2, -C (O) R3, -CO2R3, -SO2R3, or a ring 3-6 membered aromatic or non-aromatic having zero to two heteroatoms independently selected from nitrogen, oxygen, or sulfur. More preferred substituents on said ring are selected from optionally substituted (C1-C4) aliphatic group, NH2, NH (C1-C4 aliphatic), N (C1-C4 aliphatic) 2, optionally substituted phenyl, CO2 (C1-C4 aliphatic), or SO2 (C1-C4 aliphatic). The most preferred substituents on said ring are selected from methyl, ethyl, methylsulfonyl, (CH2) 2SO2CH3, cyclopropyl, CH2cyclopropyl, (CH2) 2OH, CO2t-butyl, CH2phenyl, phenyl, NH2, NH (CH3), N (CH3) 2 , (CH2) 2NH2, (CH2) 2morpholin-4-yl, (CH2) 2N (CH3) 2, isopropyl, propyl, t-butyl, (CH2) 2CN, or (CH2) 2C (O) morpholin-4-yl .

More preferably, the ring formed by N (R1) 2 of formula I 'is pyrrolidinyl, piperidinyl, morpholin-4-yl, thiomorpholin-4-yl, piperazin-1-yl, diazepanyl, or tetrahydroisoquinolinyl, where each ring is substituted optionally with one or more groups independently selected from methyl, ethyl, methylsulfonyl, (CH2) 2SO2CH3, cyclopropyl, CH2cyclopropyl, (CH2) 2OH, CO2t-butyl, CH2phenyl, phenyl, NH2, NH (CH3), N (CH3) 2, (CH2) 2NH2, (CH2) 2-morpholin-4-yl, (CH2) 2N (CH3) 2, isopropyl, propyl, t-butyl, (CH2) 2CN, or (CH2) 2C (O) morpholin-4-yl.

More preferred compounds within the compounds of formula I prepared using the process of the present invention have the formula V:

image7

V

or a pharmaceutically acceptable derivative or salt thereof, where: R5 is selected from hydrogen or (C1-C4) aliphatic group; R6 is selected from the group (C1-C3) aliphatic; and R7 is selected from the group (C1-C4) aliphatic.

Preferred R5 groups of formula V are selected from halogen, methyl, ethyl, t-butyl, propyl, cyclopropyl, cyclopropylmethyl, or isopropyl. More preferred R5 groups of formula V are selected from hydrogen or methyl. Most preferably, R5 of formula V is methyl.

Preferred R6 groups of formula V are selected from methyl, ethyl, or cyclopropyl. Most preferred R6 groups of the

Formula V are methyl or cyclopropyl. Most preferably, R6 of formula V is methyl. Preferred R7 groups of formula V are selected from methyl, ethyl, t-butyl, or cyclopropyl. R7 groups plus Preferred formula V are selected from ethyl or cyclopropyl. Most preferably, R7 of formula V is cyclopropyl.

According to another embodiment, the present invention describes compounds of formula V:

R6

image8

V

or a pharmaceutically acceptable derivative or salt thereof. R5 is selected from hydrogen or aliphatic (C1-C4) group; R6 is selected from the group (C1-C3) aliphatic; and

R7 is selected from the group (C1-C4) aliphatic; provided that said compound is other than N- {4- [4- (4-methyl

piperazin-1-yl) -6- (5-methyl-2H-pyrazol-3-ylamino) -pyrimidin-2-ylsulfanyl] -phenyl} -propionamide. Preferred R5 groups of formula V are selected from hydrogen, methyl, ethyl, t-butyl, or isopropyl. More preferred R5 groups of formula V are selected from hydrogen or methyl. Most preferably, R5 of formula V is methyl.

Preferred R6 groups of formula V are selected from methyl, ethyl, or cyclopropyl. Most preferred R6 groups of the

Formula V are methyl or cyclopropyl. Most preferably, R6 of formula V is methyl. Preferred R7 groups of formula V are selected from methyl, ethyl, t-butyl, or cyclopropyl. More preferred R7 groups of formula V are selected from ethyl or cyclopropyl. Most preferably, R7 of formula V is cyclopropyl.

Compounds of formula V fall within the genus of compounds described in PCT publication WO

15 02/057259. However, Applicants have discovered that the present compounds have surprisingly and unexpectedly increased their ability as inhibitors of Aurora protein kinase and / or FLT-3 protein kinase.

Exemplary structures of formula V are listed below in Table 1. Table 1

Nov-

Structure Nov- Structure

1

image4 2

3

4

5

6

7

8

9

10

eleven

12 image4

CH3

N

N H

N H

13

H N 14

N

image4

OR

NN

S

NCH3

image4

fifteen

16

17

image4 18

19

image4

Other exemplary compounds of formula I prepared in accordance with the processes of the present invention are described in Table 2 below.

Table 2. Exemplary Compounds of Formula I.

image9

image4

I-2

image4

I-4

I-3

image10

I-8

I-9

I-12

I-13

I-14

image11

I-15

image12

I-23 I-24

image13

I-30

I-29

image14

image4

I-32

I-34

image4

I-35

I-36

image15

image4

I-38

image4

I-39

I-40

image4

I-41

image16

image17

I-44

image18

I-47

I-48

image19

image4

I-55 I-56

image20

I-61

Preferably the processes of the present invention are used to prepare a compound selected from Tables 1 and 2. More preferably, the processes of the present invention are used to prepare a compound selected from Table 1.

According to an alternative embodiment, the present invention discloses a compound of formula II, formula III, or formula IV:

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z1

image4 R 2

image4 Q image4 L2 image4 L

RxRx

Rx N

NN

3 13 Rz2 3 z2

LNLLNT LNTR

II III IV

or a pharmaceutically acceptable salt thereof, where Rx, Ry, L1, L2, L3, T, Rz2, and Q, and their preferred embodiments, are as defined above.

According to a preferred embodiment, the present invention discloses an intermediate of formula II.

According to another preferred embodiment, the present invention discloses an intermediate of formula III.

In accordance with yet another preferred embodiment, the present invention discloses an intermediate of formula IV.

In accordance with another embodiment, the invention discloses a composition comprising a compound of this invention or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable excipient, adjuvant, or vehicle. The amount of compound in the compositions of this invention is such that it is effective to detectably inhibit a protein kinase, particularly Aurora and / or FLT-3 kinase, in a biological sample or in a patient. Preferably the composition of this invention is formulated for administration to a patient in need of such a composition. Most preferably, the composition of this invention is formulated for oral administration to a patient.

The term "patient", when used herein, means an animal, preferably a mammal, and most preferably a human.

The term "pharmaceutically acceptable excipient, adjuvant, or vehicle" refers to a non-toxic excipient, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable excipients, adjuvants or carriers that can be used in the compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine , sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, poly ( vinylpyrrolidone), cellulose-based substances, poly (ethylene glycol), sodium carboxymethyl cellulose, polyacrylates, waxes, poly (ethylene) -poly (oxypropylene) block polymers, poly (ethylene glycol) and wool grease.

The term "detectably inhibit" when used herein means a measurable change in protein kinase activity between a sample comprising said composition and protein kinase and an equivalent sample comprising protein kinase in the absence of said composition.

A "pharmaceutically acceptable salt or derivative" means any non-toxic salt, ester, salt of an ester or other derivative of a compound of this invention which upon administration to a recipient is capable of directly or indirectly providing a compound of this invention or an inhibitory active metabolite or residue thereof. When used herein, the term "inhibitory active metabolite or residue thereof" means that a metabolite or residue thereof is also an Aurora and / or FLT-3 protein kinase inhibitor.

According to another embodiment, the present invention provides processes for preparing a pharmaceutically acceptable salt of compound of formula I, I ', or V comprising the step of converting a compound of formula I, I', or V, prepared according to the methods of the present invention, in the desired pharmaceutically acceptable salt. Such conversions are well known in the art. See generally "Advanced Organic Chemistry", Jerry March, 4th Ed., John Wiley and Sons, N.Y. (1992).

Pharmaceutically acceptable salts of the compounds of this invention include those derived from pharmaceutically acceptable inorganic and organic acids and bases. Examples of suitable acid salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphor sulfonate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucohephophthane sulfate, hemisulfonate, glycerophthane, glycerophthane , hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, propionate, salicylate, salicylate , succinate, sulfate, tartrate, thiocyanate, tosylate, and undecanoate. Other acids, such as oxalic, although they are not themselves pharmaceutically acceptable, can be used in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts.

Salts derived from appropriate bases include alkali metal (eg sodium and potassium), alkaline earth metal (eg magnesium), ammonium and N + ((C1-C4) alkyl) salts. This invention also provides for the quaternization of any basic nitrogen-containing groups disclosed herein. By such quaternization, products soluble or dispersible in water or oil can be obtained.

Table 3 below includes representative salts of compounds of formula V of the present invention.

10 Table 3. Representative Salts of Compounds of Formula V

image4

OR

V-1 i

N N N N N H HH V-1 ii N N N N H HH S O OH

N

OR

N N S

OR

N N S

N

N

H Cl

V-1 iii

N N N N N H HH S OO HO OH V-1 iv N N N N N H HH HO OH OO

N N N S O

N N N S O

V-1 v

N N N H HH OH O HO O V-1 vi N N N N H HH OH HO O O

N N N N S N O

N N N N S O

O O

OH H CO2H

V-1 vii

N N N N H HH OH HO V-1 viii N N N H HH CO2H HHO

N N N N S O

N N N N S N O

V-1 ix

N N N N S N N N N O H HH HO2C S OH OO V-1 x N N N N S N N N N O H HH OH HO2C OH HO2C O

V-1 xi

N NH N N H N H P O HO OH HO V-20 i NH N N N H N H

N

N N S OR N N N S HCl salt OR

image4

N

V-20 ii

N NH N H N H

image4

N N S OR

N

image4 OR

H3C salt

S OH

OR

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The compositions of the compounds prepared according to the method of the present invention can be administered orally, parenterally, by inhalation aerosol, topically, rectally, nasal, buccal, vaginal,

or via an implanted reservoir. The term "parenteral" when used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, instrastemal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally, or intravenously. Sterile injectable forms of the compositions of this invention can be aqueous or oleaginous suspensions. These suspensions can be formulated according to procedures known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or a suspension in a diluent.

or a parenterally acceptable non-toxic solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be used are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally used as a solvent or suspending medium.

To this end, any mild fixed oil can be used that includes synthetic mono- or di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are the pharmaceutically acceptable natural oils such as olive oil or castor oil, especially in their polyoxyethylated versions. These oily solutions or suspensions may also contain a long chain alcoholic diluent or dispersant, such as carboxymethylcellulose or similar dispersing agents that are commonly used in formulating pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans, and other emulsifying agents

or bioavailability amplifiers that are commonly used in the manufacture of solid, liquid or other pharmaceutically acceptable dosage forms can also be used for formulation purposes.

The pharmaceutically acceptable compositions of this invention can be administered orally in any orally acceptable dosage form including, but not limited to, capsules, tablets, suspensions, or aqueous solutions. In the case of tablets for oral use, commonly used carriers include lactose and cornstarch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring agents can also be added.

or colorants.

Alternatively, the pharmaceutically acceptable compositions of this invention can be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature, but liquid at rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter, beeswax, and polyethylene glycols.

The pharmaceutically acceptable compositions of this invention can also be administered topically, especially when the treatment target includes areas or organs readily accessible by topical application, including diseases of the eye, skin, or lower intestinal tract. Topical formulations suitable for each of these areas or organs are readily prepared.

For the lower intestinal tract, topical application of a rectal suppository formulation (see above) or in a suitable enema formulation can be performed. Topically transdermal patches can also be used.

For topical applications, the pharmaceutically acceptable compositions can be formulated into a suitable ointment containing the active component suspended or dissolved in one or more carriers. Vehicles for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petroleum jelly, propylene glycol, poly (oxyethylene), poly (oxypropylene) compound, emulsifying wax, and water. Alternatively, the pharmaceutically acceptable compositions can be formulated into a suitable cream or lotion containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

For ophthalmic use, the pharmaceutically acceptable compositions may be formulated as micronized suspensions in pH-adjusted sterile isotonic saline, or, preferably, as solutions in pH-adjusted sterile isotonic saline, with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutically acceptable compositions can be formulated in an ointment such as petroleum jelly.

The pharmaceutically acceptable compositions of this invention can also be administered by nasal spray or inhalation. Such compositions are prepared according to procedures well known in the pharmaceutical formulation art and can be prepared as solutions in saline, using benzyl alcohol or other suitable preservatives, absorption promoters to amplify bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

Most preferably, the pharmaceutically acceptable compositions of this invention are formulated for oral administration.

The amount of the compounds of the present invention that can be combined with the carrier materials to produce a composition in a single dosage form will vary depending on the host treated, the particular mode of administration. Preferably, the compositions should be formulated so that a dosage of between 0.01-100 mg / kg body weight / day of the inhibitor can be administered to a patient receiving these compositions.

It should also be understood that a specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the specific compound used, age, body weight, general health, gender, diet, time of administration, cadence. excretion, drug combination, and the judgment of the treating physician and the severity of the specific disease being treated. The amount of a compound of the present invention in the composition will also depend on the particular compound in the composition.

Depending on the particular condition or disease to be treated or prevented, additional therapeutic agents that are normally administered to treat or prevent that disease may also be present in the compositions of this invention. When used herein, additional therapeutic agents that are normally administered to treat or prevent a particular disease or condition are known to be "appropriate for the disease or condition being treated.

For example, chemotherapeutic or other anti-proliferative agents can be combined with the compounds of this invention to treat proliferative diseases and cancer. Examples of known chemotherapeutic agents include, but are not limited to, Gleevec ™, adriamycin, dexamethasone, vincristine, cyclophosphamide, fluorouracil, topotecan, taxol, interferons, and platinum derivatives. Other examples of agents with which the inhibitors of this invention can be combined also include, without limitation: treatments for Alzheimer's Disease such as Aricept¡ and Excelon¡; treatments for Parkinson's disease such as LDOPA / carbidopa, entacapone, ropinrole, pramipexole, bromocriptine, pergidol, trihexephenyl, and amantadine; agents to treat Multiple Sclerosis such as beta interferon (eg, Avonex¡, and Rebif¡), Copaxone¡, and mitoxantrone; asthma treatments such as albuterol and Singulair¡; agents to treat schizophrenia such as zyprexa, risperdal, seroquel, and halopyiredol; anti-inflammatory agents such as corticosteroids, TNF blockers, IL-1 RA, azathioprine, cyclophosphamide, and sulfasalazine; immunomodulatory and immunosuppressive agents such as cyclosporine, tacrolimus, rapamycin, mycophenolate mofetil, interferons, corticosteroids, cyclophosphamide, azathioprine, and sulfasalazine; neurotrophic factors such as acetyl cholinesterase inhibitors, MAO inhibitors, interferons, anti-convulsants, ion channel blockers, riluzole, and anti-Parkinsonian agents; agents for treating cardiovascular disease such as beta-blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers, and statins; agents for treating liver disease such as corticosteroids, cholestyramine, interferons, and antiviral agents; agents for treating blood disorders such as corticosteroids, anti-leukemic agents, and growth factors; and agents for treating immunodeficiency disorders such as gamma globulin.

Other examples of chemotherapeutic agents or other anti-proliferative agents that can be combined with the compounds of the present invention to treat proliferative diseases and cancer include, but are not limited to, For example, other anti-cancer therapies or agents that can be used in combination. The anticancer agents of the present invention include surgery, radiation therapy (in, except for a few examples, gamma radiation, neutron beam radiation therapy, electron beam radiation therapy, proton therapy, brachytherapy, and systemic radioactive isotopes, to name a few), endocrine therapy. , biological response modifiers (interferons, interleukins, and tumor necrosis factor (TNF) to name a few), hyperthermia or cryotherapy, agents to mitigate any adverse effects (eg, antiemetics), and other approved chemotherapeutic drugs, including, but are not limited to, alkylating drugs, (mechlorethamine, chlorambucil or, Cyclophosphamide, Melphalan, Ifosfamide), antimetabolites (Methotrexate), puric antagonists and pyrimidine antagonists (6-Mercaptopurine, 5-Fluorouracil, Cytarabine, Gemcitabine), achromatic spindle poisons (Vinblastine, Vintoxytoxyclobistine) , Irinotecan, Topotecan), antibiotics (Doxorubicin, Bleomycin, Mitomycin), nitrosoureas (Carmustine, Lomustine), inorganic ions (Cisplatin, Carboplatin), enzymes (Asparaginase), and hormones (Tamoxifen, Leuprolide, Flutamide), Glee MegestrolTM, and Glee MegestrolTM adriamycin, dexamethasone, and cyclophosphamide. For a more comprehensive discussion of updated cancer therapies, see http://www.nci.nih.gov/, a list of FDA-approved cancer drugs at http://www.fda.gov/cder/cancer/ druglistframe.htm, and The Merck Manual, 17th Ed. 1999, the entire contents of which are incorporated herein by reference.

The amount of additional therapeutic agent present in the compositions of this invention will be no more than the amount that would be administered in a composition comprising that therapeutic agent as the only active agent. Preferably, the amount of additional therapeutic agent in presently disclosed compositions will range from about 50% to 100% of the amount normally present in a composition comprising that agent as the sole therapeutically active agent.

According to another embodiment, the invention relates to a method of inhibiting the activity of Aurora-1, Aurora-2, Aurora-3 and / or FLT-3 kinases, in a biological sample, comprising the step of contacting said biological sample with a compound of formula V, or a composition comprising said compound.

The term "biological sample" when used herein includes without limitation cell cultures or extracts thereof; biopsy material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other bodily fluids or their extracts.

Inhibition of Aurora-1, Aurora-2, Aurora-3, and / or FLT-3 kinase activity in a biological sample is useful for a variety of purposes that are known to the practitioner. Examples of such purposes include, but are not limited to, blood transfusion, organ transplantation, storage of biological samples, and biological assays.

According to another embodiment the invention relates to a method for inhibiting Aurora-1 kinase activity in a patient, comprising the step of administering to said patient a compound of formula V, or a composition comprising said compound.

According to another embodiment the invention relates to a method for inhibiting Aurora-2 kinase activity in a patient, comprising the step of administering to said patient a compound of formula V, or a composition comprising said compound.

According to another embodiment the invention relates to a method for inhibiting Aurora-3 kinase activity in a patient, comprising the step of administering to said patient a compound of formula V, or a composition comprising said compound.

According to another embodiment the invention relates to a method for inhibiting FLT3 kinase activity in a patient, comprising the step of administering to said patient a compound of formula V, or a composition comprising said compound.

According to another embodiment the invention relates to a method for inhibiting the kinase activity Aurora-1, Aurora-2, Aurora3 and FLT3 in a patient, comprising the step of administering to said patient a compound of formula V, or a composition comprising said compound.

According to another embodiment, the invention provides a method of treating or reducing the severity of an Aurora-mediated disease or condition in a patient, comprising the step of administering to said patient a compound of formula V, or a composition comprising said compound.

The term "Aurora-mediated disease", when used herein, means any disease or other deleterious condition in which an Aurora family protein kinase is known to play a role. Such diseases or conditions include, without limitation, melanoma, leukemia, or a selected colon, breast, gastric, ovarian, cervical, melanoma, kidney, prostate, lymphoma, neuroblastoma, pancreatic, leukemia, and bladder cancer.

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According to another embodiment, the present invention relates to a method for treating cancer in a patient, comprising the step of administering to said patient a compound of formula V or composition thereof.

According to another embodiment, the present invention relates to a method of treating melanoma, lymphoma, neuroblastoma, leukemia, or a selected cancer of the colon, breast, lung, kidney, ovary, pancreatic, renal, CNS, cervical, prostate, or gastric tract cancer in a patient, comprising the step of administering to said patient a compound of formula V or composition thereof.

According to another embodiment, the present invention relates to a method for treating acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), mastocytosis or gastrointestinal stromal tumor (GIST), comprising the step of administering to said patient a compound of formula V or composition thereof.

Another aspect of the present invention relates to the disruption of cancer cell mitosis in a patient, comprising the step of administering to said patient a compound of formula V or composition thereof.

According to another embodiment, the present invention relates to a method for treating or reducing the severity of a cancer in a patient, comprising the step of disturbing the mitosis of cancer cells by inhibiting Aurora-1, Aurora-2, and / or Aurora-3 with a compound of formula V or composition thereof.

In an alternative embodiment, the methods of this invention using compositions that do not contain an additional therapeutic agent comprise the additional step of separately administering an additional therapeutic agent to said patient. When these additional therapeutic agents are administered separately they can be administered to the patient prior to, sequentially with, or after administration of the compositions of this invention.

The following examples are described in order that the invention described herein may be more fully understood. It should be understood that these examples are for illustrative purposes only and should not be construed as limiting this invention in any way.

Examples

General Scheme:

Cl Cl

H H

image4 N image4 N (a)

+

image4 N image21 I

OR

OCl HS Cl NS O

CA B

I image22 I

V-1 D

Example 1

4,6-Dichloropyrimidine-2-methylsulfone (A): Prepared by methods substantially similar to those described in Koppell et al, JOC, 26, 1961, 792, as follows. To a stirred solution of 4,6-dichloro-2 (methylthio) pyrimidine (50 g, 0.26 mol) in dichloromethane (1 L) at 0 ° C was added meta-chloroperoxybenzoic acid (143.6 g, 0.64 mol) for a period of 20 minutes. The solution was allowed to warm to room temperature and stirred for 4 hours. The mixture was diluted with dichloromethane (1.5 L) and then treated sequentially with 50% Na2S2O3 / NaHCO3 solution (2 x 200 mL), saturated NaHCO3 solution (4 x 300 mL), and brine (200 mL) , then dried (MgSO4). The solvent was removed in vacuo to provide an off-white solid which was redissolved in EtOAc (1 L) and treated sequentially with saturated NaHCO3 solution (3 x 300 mL), and brine (100 mL), then dried (MgSO4). The solvent was removed in vacuo to provide the title compound (A) as a white solid (55.6 g, 96% yield). 1H NMR CDCl3 * 3.40 (3H, s CH3), 7.75 (1H s. ArH).

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Example 2

Cyclopropanecarboxylic acid [4- (4,6-dichloro-pyrimidin-2-ylsulfanyl) -phenyl] amide (C): A suspension of compound A (10 g, 44.04 mmol) and cyclopropanecarboxylic acid (4- mecapto-phenyl) amide (B, 8.51 g, 44.04 mmol) in t-butanol (300 ml), then nitrogen flow. The mixture was stirred at 90 ° C under nitrogen atmosphere for 1 hour, then the solvent was removed in vacuo. The residue was dissolved in ethyl acetate (600 ml) and washed with an aqueous solution of potassium carbonate and sodium chloride. The organic extract was dried over magnesium sulfate, concentrated to a small volume, and allowed to crystallize. Product C was collected as colorless crystals, (11.15 g, 74%). 1H NMR DMSO-d6, � 0.82-0.89 (4H, m), 1.80-1.88 (1H, m), 7.55 (2H, d), 7.70-7.76 ( 3H, m), 10.49 (1H, s); M + H, 340.

Example 3

Cyclopropanecarboxylic acid {4- [4-chloro-6- (5-methyl-2H-pyrazol-3-ylamino) -pyrimidin-2-ylsulfanyl] -phenyl} amide (D): A mixture of compound C (1.0 g , 2.94 mmol) and 3-amino-5-methylpyrazole (314 mg, 3.23 mmol) in dimethylformamide (6 ml) was treated with diisopropylethylamine (0.614 ml, 3.53 mmol) and sodium iodide (530 mg, 3 , 53 mmol). The mixture was stirred under nitrogen at 85 ° C for 4 hours, cooled to room temperature, and diluted with ethyl acetate. The solution was washed with water (x 4), dried over magnesium sulfate and concentrated to 5 ml to provide the title compound D (920 mg, 78%) by crystallization and collection of colorless crystals. 1H-NMR DMSO-d6 � 0.80-0.87 (4H, m), 1.77-1.85 (1H, m), 1.92 (1H, s), 5.24 (1H, br s ), 6.47 (1H, br s), 7.55 (2H, d), 7.70-7.80 (2H, m), 10.24 (1H, s), 10.47 (1H, s ), 11.92 (1H, s).

Example 4

Cyclopropanecarboxylic acid {4- [4- (4-methyl-piperazin-1-yl) -6- (5-methyl) -2H-pyrazol-3-ylamino) -pyrimidine-2ylsulfanyl] -phenyl} -amide (V-1 ): Compound D (2.373 g, 5.92 mmol) was treated with N-methylpiperazine (10 ml) and the mixture was stirred at 110 ° C for 2 hours. The excess N-methylpiperazine was removed in vacuo, then the residue was dissolved in ethyl acetate, washed with aqueous sodium bicarbonate solution, dried over magnesium sulfate, and concentrated. The residue was recrystallized from methanol to give colorless crystals of the desired product V-1 (1.82 g, 66%), 1H-NMR DMSO-d6, � 0.81 (4H, d), 1.79 (1H, m ), 2.01 (3H, s), 2.18 (3H, s), 2.30 (4H, m), 3.35 (masked signal), 5.42 (1H, s), 6.02 ( 1H, br s), 7.47 (2H, d), 7.69 (2H, d), 9.22 (1H, s), 10.39 (1H, s), 11.69 (1H, s) .

Example 5

image23

V-5

N- {4- [4- (5-Methyl-2H-pyrazol-3-ylmethyl) -6- (4-propyl-piperazin-1-yl) -pyrimidin-2-ylsulfanyl] -phenyl} -propionamide (V- 5):

Ethanecarboxylic acid {4- [4-chloro-6- (5-methyl-2H-pyrazol-3-ylamino) -pyrimidin-2-ylsulfanyl] -phenyl} amide (119 mg, 0.306 mmol, prepared by methods analogous to those described in Examples 1, 2 and 3) in n-BuOH (5 mL) were treated with N-propylpiperazine hydrobromide (887 mg, 3.06 mmol) followed by diisopropylethylamine (1.066 mL, 6.12 mmol). The resulting mixture was stirred at 110 ° C for 20 hours. The solvent was removed under reduced pressure, and the residue was purified using preparative HPLC to provide the title compound. 1H-NMR (DMSO): � 1.10 (3H, t), 2.05 (3H, s), 2.35 (2H, d), 3.30 (4H, s), 3.70 (4H, s), 5.45 (1H, s), 6.05 (1H, br s), 7.45 (2H, d), 7.70 (2H, d), 9.20 (1H, s), 11 , 7o (1H, br s).

Example 6

image24

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N- [4- (4,6-Dichloro-pyrimidin-2-yloxy) -phenyl] -acetamide: A solution of 4-acetamidophenol (666 mg, 4.40 mmol) in anhydrous THF (40 ml), stirring at temperature ambient, treated with a 60% dispersion of sodium hydride in mineral oil (176 mg, 4.40 mmol). The reaction mixture was then allowed to stir for 30 minutes at room temperature before adding 4,6-dichloro-2-methanesulfonyl-pyrimidine (1.0 g, 4.40 mmol). The reaction was then allowed to stir for an additional 3 hours, before diluting the reaction with saturated aqueous NH4Cl and EtOAc. The organic layer was separated, washed with saturated aqueous NaCl, and dried over sodium sulfate, then concentrated in vacuo. The residue was purified by column chromatography (Silica Gel, MeOH: CH2Cl2, 5:95), afforded the title compound 1.25 g (95%) as a solid. 1H-NMR (400 MHz, DMSO-d6): � 2.06 (3H, s), 7.18 (2H, d, J = 8.5 Hz), 7.62 (2H, d, J = 8, 5Hz), 10.05 (1H, s), LC.MS: ES + = 298.16, ES- = 296.18).

Example 7

Cyclopropanecarboxylic acid {4- [4- (4-methyl-4-oxy-piperazin-1-yl) -6- (5-methyl-2H-pyrazol-3-ylamino) -pyrimidin-2ylsulfanyl] -phenyl} -amide ( V-19): Compound (V-1) (1 g, 2.1 mmol) was suspended in dichloromethane (20 mL), cooled to 0 ° C and treated with a dichloromethane solution of mCPBA in 10 aliquots at intervals of 10 minutes (each aliquot consisting of 100 mg, 0.44 mmol in 1 ml of DCM). Each time an aliquot was added the solution turned brown and gradually returned to a yellow color as the mCPBA was consumed. Once all the starting material had been consumed, the solvent was removed in vacuo and the resulting orange oil was purified by preparative HPLC to give the title compound as an off-white solid (69 mg, 7%); 1H-NMR (DMSO-d6): 0.85-0.91 (4H, m), 1.90 (1H, m), 2.10 (3H, s), 3.10-3.17 (2H, m), 3.25 (3H, s), 3.50-3.66 (4H, m), 3.98 (2H, d), 5.50 (1H, s), 6.11 (1H, br s), 7.56 (2H, d), 7.80 (2H, d), 9.42 (1H, s), 10.50 (1H, s), 11.82 (1H, br s).

Example 8

Cyclopropanecarboxylic acid {4- [4- (4-methyl-piperazin-1-yl) -6- (5-methyl-2H-pyrazol-3-ylamino) -pyrimidine-2ylsulfanyl] -phenyl} -amide methanesulfonate (V-1 ii): Compound V-1 (515 mg, 1.11 mmol) was suspended in ethanol (80 mL) and heated under reflux. Methanesulfonic acid (106 mg, 1.11 mmol) was added to the clear solution and the reaction mixture was refluxed for a further 10 minutes. The mixture was allowed to cool to room temperature and the solvent was evaporated until a precipitate began to form. The mixture was then allowed to cool to 0 ° C and the resulting precipitate was collected by filtration before drying in vacuo to provide the title compound as a white solid (290 mg, 47%); 1H-NMR (400 MHz, DMSO-d6) 0.81-0.82 (4H, d), 1.82 (1H, m), 2.36 (6H, s), 2.83 (3H, d) , 3.03-3.12 (4H, m), 3.40-3.47 (2H, m), 3.79 (br s, OH), 4.14-4.18 (2H, m), 5.50 (1H, s), 6.05 (1H, s), 7.49 (2H, d), 7.72 (2H, d), 9.61 (1H, s), 10.41 (1H , brs), 10.80 (1H, s).

Example 9

The following compounds listed below in Table 4 were prepared in accordance with the procedures of the present invention and by methods substantially similar to those described in Examples 1-8 above. Characterization data for these compounds is summarized in Table 4 below and includes 1H-NMR, melting point (m.p.) and mass spectra (MS) data.

Unless otherwise indicated, each 1H-NMR spectrum discussed, included in Table 4, was obtained at 400 MHz in deuterated dimethylsulfoxide (dmso-d6).

Table 4. Characterization Data for Representative Compounds

No.

Structure m.p. 1H-NMR Mass Spectrum

V-2

- 1.09 (3H, t), 2.00 (3H, s), 2.34 (2H, q), 2.72 (4H, m), 3.3 (masked signal), 5.42 (1H, s), 5.98 (1H, s), 7.47 (2H, d), 7.69 (2H, d), 9.20 (1H, s), 10.07 (1H, s), 11, 69 (1H, s) ES + 439.4 ES-437.4

V-3

178181ºC 1.24 (9H, s), 1.98 (3H, s), 2.68-2.70 (4H, m), 3.31 (4H, masked signal), 5.35 (1H, s), 5.96 (1H, br s), 7.47 (2H, d), 7.79 (2H, d), 9.20 (1H, s), 9.33 (1H, s), 11.66 ( 1H, s) ES + 467.35 ES-465.38

No.

Structure m.p. 1H-NMR Mass Spectrum

V-4

- 0.97 (6H, d), 1.10 (3H, t), 2.00 (3H, s), 2.35 (2H, q), 2.45 (4H, br s), 2.65 ( 1H, br s), 3.35 (4H, br s), 5.40 (1H, s), 6.00 (1H, br s), 7.50 (2H, d), 7.70 (2H, d), 9.20 (1H, s), 10.10 (1H, s), 11.70 (1H, br s) ES + 481.4

V-6

- 1.01 (3H, t), 1.09 (3H, t), 2.00 (3H, s), 2.31-2.37 (8H, m), 3.35 (masked signal), 5, 42 (1H, s), 6.01 (1H, brs), 7.47 (2H, d), 7.70 (2H, d), 9.22 (1H, s), 10.07 (1H, s ), 11.69 (1H, s) ES + 467.3 ES-465.4

V-7

- 0.80-0.82 (4H, m), 1.81 (1H, m), 2.01 (3H, s), 2.68 (4H, m), 3.1-3.5 (5H, m), 5.43 (1H, s), 5.99 (1H, br s), 7.47 (2H, d), 7.69 (2H, d), 9.21 (1H, s), 10 , 40 (1H, s), 11.70 (1H, s) ES + 451.3 ES-449.4

V-8

image4 - 0.08 (2H, m), 0.46 (2H, m), 0.84 (1H, m), 1.09 (3H, t), 2.00 (3H, s), 2.19 ( 2H, d), 2.34 (2H, q), 2.44 (4H, m), 3.35 (masked signal), 5.41 (1H, s), 6.00 (1H, br s), 7.47 (2H, d), 7.70 (2H, d), 9.23 (1H, s), 10.08 (1H, s), 11.66 (1H, s) ES + 493.4 ES- 491.4

V-9

- 0.33 (2H, m), 0.42 (2H, m), 1.09 (3H, t), 1.62 (1H, m), 2.00 (3H, s), 2.34 (2H , q), 2.53 (4H, m), 3.32 (masked signal), 5.42 (1H, s), 6.00 (1H, br s), 7.47 (2H, d), 7 , 70 (2H, d), 9.22 (1H, s), 10.07 (1H, s), 11.69 (1H, s) ES + 479.4 ES-477.4

V-10

161-163 1.01 (9H, s), 1.09 (3H, t), 2.00 (3H, s), 2.34 (2H, q), 2.5 (masked signal), 3.36 (masked signal ), 5.42 (1H, s), 5.98 (1H, br s), 7.47 (2H, d), 7.70 (2H, d), 9.21 (1H, s), 10, 08 (1H, s), 11.69 (1H, s) ES + 495.4 ES-493.4

No.

Structure m.p. 1H-NMR Mass Spectrum

0.80-0.82 (4H, m), 1.01 (3H, t),

1.81 (1H, m), 2.01 (3H, s), 2.32

V-11

- 2.37 (6H, m), 3.35 (masked signal), 5.43 (1H, s), 6.01 (1H, br s), 7.47 (2H, d), 7.69 (2H , ES + 479.3 ES-477.4

d), 9.23 (1H, s), 10.40 (1H, s),

11.69 (1H, s)

0.48-0.59 (2H, m), 1.75-1.87 (2H,

m), 1.08 (3H, t, J = 7.5 Hz), 1.61

V-12

- 1.75 (1H, m), 2.32 (2H, q, J = 7.5 Hz), 2.61-2.71 (4H, m), 3.20-3.30 (4H, m) , 5.47 (1H, s), 6.10 (1H, br ES + 465.34 ES-463.37

s), 7.47 (2H, d, J = 8.4 Hz), 7.70

(2H, d, J = 8.4 Hz), 9.20 (1H, br s),

10.13 (1H, s), 11.74 (1H, br s)

V-13

N N H N N H CH3 N H - 0.81-0.82 (4H, m), 1.01 (3H, t), 1.05 (3H, t), 1.81 (1H, m), 2.262.38 (8H, m), 3 , 35 (signal masked), 5.44 (1H, s), 6.03 (1H, br s), 7.47 (2H, d), 7.70 (2H, ES + 493.4 ES-491.4

image4

OR d), 9.25 (1H, s), 10.39 (1H, s),

N SN

11.74 (1H, s)

NCH3

image4

V-14

- 0.54 (2H, m), 0.79-0.82 (6H, m), 1.01 (3H, t), 1.69 (1H, m), 1.82 (1H, m), 2 , 32-2.36 (6H, m) 3.35 (masked signal), 5.45 (1H, s), 6.07 (1H, br s), 7.47 (2H, d), 7.70 (2H, d), 9.23 (1H, s), 10.38 (1H, s), 11.70 (1H, s) ES + 505.4 ES-503.4

V-15

- 0.49-0.59 (2H, m), 0.76-0.85 (2H, m), 1.08 (3H, t, J = 7.5 Hz), 1.631.72 (1H, m) , 2.19 (3H, s), 2.232.38 (6H, m), 3.30-3.43 (4H, m), 5.50 (1H, s), 6.15 (1H, br s), 7 , 48 (2H, d, J = 8.6 Hz), 7.70 (2H, d, J = 8.6 Hz), 9.23 (1H, br s), 10.04 (1H, s), 11.71 (1H, br s) ES + 479.34 ES-477.37

V-16

- 2.02 (3H, s), 2.07 (3H, s), 2.18 (3H, s), 2.30 (4H, m), 3.35 (masked signal), 5.44 (1H, s), 6.03 (1H, br s), 7.47 (2H, d), 7.67 (2H, d), 9.23 (1H, s), 10.14 (1H, s), 11 , 71 (1H, s) ES + 439.3 ES-437.4

No.

Structure m.p. 1H-NMR Mass Spectrum

V-17

image4 1.23 (9H, s), 1.97 (3H, s), 2.20 (3H, s), 2.30-2.33 (4H, m), 3.31 (4H, masked signal), 5.37 (1H, s), 5.96 (1H, br s), 7.47 (2H, d), 7.79 (2H, d), 9.24 (1H, s), 9.38 ( 1H, s), 11.67 (1H br s) ES + 481.4 ES-479.4

V-18

0.76-0.91 (4H, m), 1.00-1.18 (3H, m), 1.76-1.86 (1H, m), 2.18 (3H, s), 2, 22-2.43 (6H, m), 3.3-3.4 (4H, confused), 5.46 (1H, s), 6.08 (1H, br s), 7.49 (2H, d ), 7.72 (2H, d), 9.30 (1H, s), 10.40 (1H, s), 11.72 (1H, s) ES + 479.3 ES-477.3

I-1

238-239 1.10 (3H, t), 2.00 (3H, s), 2.45 (2H, q), 3.65 (4H, s), 5.45 (1H, s), 6.05 (1H , br s), 7.50 (2H, d), 7.80 (2H, d), 9.25 (1H, s), 10.05 (1H, s), 11.70 (1H, br s) MS 440.3 (M + H) +

I-2

- 1.09 (3H, t), 2.00 (3H, s), 2.34 (2H, q), 2.59 (2H, m), 3.04 (2H, m), 3.3 (signal masked), 5.39 (1H, s), 5.77 (1H, br s), 6.85 (1H, s), 7.47 (2H, d), 7.69 (2H, d), 9 .07 (1H, s), 10.07 (1H, s), 11.63 (1H, br s) ES + 413.3 ES-411.4

I-3

- 1.09 (3H, t), 1.35-1.37 (2H, m), 1.44-1.46 (4H, m), 2.03 (3H, s), 2.26 (6H, m), 2.33 (2H, q), 3.13 (2H, m), 5.45 (1H, s), 5.84 (1H, br s), 6.75 (1H, br s), 7.46 (2H, d), 7.68 (2H, d), 9.05 (1H, s), 10.05 (1H, s), 11.65 (1H, br s) ES + 538.3 ES-536.4

I-4

- 2.01 (3H, s), 2.07 (3H, s), 2.34-2.44 (12H, m), 3.3 (masked signal), 3.55 (4H, m), 5, 43 (1H, s), 6.02 (1H, br s), 7.47 (2H, d), 7.67 (2H, d), 9.22 (1H, s), 10.14 (1H, s), 11.70 (1H, s) ES + 538.3 ES-536.4

No.

Structure m.p. 1H-NMR Mass Spectrum

I-5

image4 - 1.06 (3H, t), 1.98 (3H, s), 2.20 (3H, s), 2.31 (2H, q), 2.50 (masked signal), 2.84 (3H , s), 3.38 (2H, m), 5.42 (1H, s), 5.77 (1H, s), 7.45 (2H, d), 7.65 (2H, d), 9 0.00 (1H, s), 10.18 (1H, s), 11.68 (1H, br s) ES + 441.3 ES-439.4

I-6

- 1.10 (3H, t), 1.45 (4H, s), 1.60 (2H, s), 2.00 (3H, s), 2.35 (2H, q), 3.35 (4H , s), 5.40 (1H, s), 6.05 (1H br s), 7.50 (2H, d), 7.70 (2H, d), 9.15 (1H, s), 10 .05 (1H, s), 11.80 (1H, br s) ES + 438.3

I-7

- 1.10 (3H, t), 1.70 (2H, s), 2.05 (3H, s), 2.35 (2H, q), 2.70 (2H, s), 2.75 (2H , s), 3.45 (2H, s), 5.50 (1H, s), 6.00 (1H, br s), 7.50 (2H, d), 7.70 (2H, d), 9.15 (1H, s), 10.10 (1H, s), 11.70 (1H, br s) ES + 453.3

I-8

image4 - 1.10 (3H, t), 2.05 (3H, s), 2.15 (6H, s), 2.3-2.4 (4H, m), 3.15 (2H, s), 5.40 (1H, s), 5.85 (1H, br s), 6.75 (1H, br s), 7.45 (2H, d), 7.70 (2H, d), 9.05 (1H, br s), 10.10 (1H, s), 11.65 (1H, br s) ES + 441.3

I-9

- 1.09 (3H, t), 1.78 (2H, m), 2.03 (3H, s), 2.22 (3H, s), 2.33 (2H, q), 2.41 (4H , m), 3.3 (masked signal), 3.50 (2H, m), 5.48 (1H, s), 5.97 (1H, br s), 7.46 (2H, d), 7 , 68 (2H, d), 9.14 (1H, s), 10.06 (1H, s), 11.70 (1H, s) ES + 467.4 ES-465.4

I-10

image4 - 1.09 (3H, t), 1.94 (3H, s), 2.20 (3H, s), 2.30-2.38 (6H, m), 3.42 (4H, m), 6.94 (1H, s), 7.49 (2H, d), 7.69 (2H, d), 7.95 (1H, s), 9.27 (1H, s), 10.07 (1H , s), ES + 470.2 ES-468.3

No.

Structure m.p. 1H-NMR Mass Spectrum

I-11

- 1.10 (3H, t), 2.05 (3H, s), 2.35 (2H, d), 3.30 (4H, s), 3.70 (4H, s), 5.45 (1H , s), 6.05 (1H, br s), 7.45 (2H, d), 7.70 (2H, d), 9.20 (1H, s), 10.05 (1H, s), 11.70 (1H, br s) ES + 456.2

I-12

- 1.09 (3H, t), 2.00 (3H, s), 2.25-241 (8H, m), 3.35 (partially masked signal), 3.51 (2H, m), 4.45 (1H, m), 5.42 (1H, s), 6.00 (1H, br s), 7.47 (2H, d), 7.70 (2H, d), 9.22 (1H, s ), 10.08 (1H, s), 11.70 (1H, s) ES + 483.4 ES-481.4

I-13

- 1.10 (3H, t), 1.23 (2H, q), 1.37 (9H, s), 1.70 (2H, d), 2.00 (3H, s), 2.35 (2H , q), 2.83 (2H, t), 3.47 (1H, m), 3.95 (2H, d), 5.45 (1H, s), 6.05 (1H, br s), 6.85 (1H, d), 7.50 (2H, d), 7.70 (2H, d), 9.20 (1H, s), 10.10 (1H, s), 11.70 (1H , br s) ES + 553.4

I-14

- 0.46-0.58 (2H, m), 0.78-0.89 (2H, m), 1.08 (3H, t, J = 7.5 Hz), 1.621.72 (1H, m) , 2.21-2.43 (6H, m), 3.23-3.40 (4H, m), 3.50 (2H, s), 5.48 (1H, s), 6.10 (1H , br s), 7.197.36 (5H, m), 7.46 (2H, d, J = 8.5 Hz), 7.68 (2H, d, J = 8.5 Hz), 9.21 ( 1H, s), 10.03 (1H, s), 11.70 (1H, br s) ES + 555.34 ES-553.40

I-15

- 1.07 (3H, t), 1.12-1.22 (2H, m), 1.70 (2H, d), 2.02 (3H, s), 2.35 (2H, q), 2 , 80-2.90 (3H, m), 3.95 (2H, d), 5.45 (1H, s), 6.00 (1H, br s), 7.45 (2H, d), 7 , 70 (2H, d), 9.20 (1H, s), 10.15 (1H, s), 11.75 (1H, br s) ES + 453.3

I-16

- 1.00 (3H, d), 1.08 (3H, t), 2.00 (3H, s), 2.35 (2H, q), 2.55-2.90 (3H, m), 3 , 65-4.25 (5H, m), 5.45 (1H, s), 6.00 (1H, br s), 7.45 (2H, d), 7.70 (2H, d), 9 , 25 (1H, br s), 10.20 (1H, s), 11.70 (1H, br s) ES + 453.3

No.

Structure m.p. 1H-NMR Mass Spectrum

I-17

- 0.47-0.55 (2H, m), 0.72-0.81 (2H, m), 1.08 (3H, t, J = 7.5 Hz), 1.41 (9H, s) , 1.62-1.73 (1H, m), 2.32 (2H, q, J = 7.5Hz), 3.30-3.41 (8H, m), 5.48 (1H, s ), 6.10 (1H, br s), 7.47 (2H, d, J = 8.5 Hz), 7.70 (2H, d, J = 8.5 Hz), 9.29 (1H, br s), 10.05 (1H, s), 11.74 (1H, br s) ES + 565.33 ES-563.36

I-18

- 1.10 (3H, t), 2.01 (3H, s), 2.35 (2H, q), 3.16-3.18 (4H, m), 3.52-3.54 (4H, m), 5.43 (1H, s), 6.08 (1H, br s), 6.891 (1H, t), 6.97 (2H, d), 7.23 (2H, t), 7.49 (2H, d), 7.71 (2H, d), 9.28 (1H, s), 10.09 (1H, s), 11.72 (1H, s) ES + 515.3 ES-513.4

I-19

151-152 0.95 (6H, s), 1.10 (3H, t), 2.05 (3H, s), 2.20 (2H, t), 2.35 (2H, q), 2.60 (2H , br s), 3.80 (2H, br s), 5.50 (1H, s), 6.05 (1H, br s), 7.50 (2H, d), 7.70 (2H, d ), 9.15 (1H, s), 10.05 (1H, s), 11.70 (1H, br s) ES + 467.3

I-20

159-160 1.10 (3H, t), 1.75 (1H, br s), 2.00 (3H, s), 2.30-2.40 (3H, m), 2.65 (1H, m), 3.25-3.45 (3H, m), 3.60 (1H, br s), 5.45 (1H, s), 5.80 (1H, br s), 7.50 (2H, d) , 7.70 (2H, d), 9.15 (1H, br s), 10.05 (1H, s), 11.70 (1H, br s) ES + 439.3

I-21

- 0.50-0.58 (2H, m), 0.78-0.85 (2H, m), 0.90 (3H, d, J = 6.1 Hz), 0.951.05 (2H, m) , 1.09 (3H, t, J = 7.6Hz), 1.51-1.64 (3H, m), 1.66-1.75 (1H, m), 2.32 (2H, q , J = 7.5 Hz), 2.66-2.78 (2H, m), 3.96-4.08 (2H, m), 5.48 (1H, s), 6.16 (1H, br s), 7.48 (2H, q, J = 8.6 Hz), 7.69 (2H, d, J = 8.6 Hz), 9.18 (1H, br s), 10.04 ( 1H, s), 11.74 (1H, br s) ES + 478.37 ES-476.39

0.80-0.81 (4H, m), 1.23-1.38 (6H,

m), 1.82 (1H, m), 2.04 (3H, s), 2.34

(6H, m), 3.17 (2H, m), 5.47 (1H, s),

I-22

- 5.86 (1H, br s), 6.80 (1H, br s), 7.46 (2H, d), 7.69 (2H, d), 9.07 (1H, ES + 493.4 ES-491.4

s), 10.41 (1H, s), 11.65 (1H, br s)

No.

Structure m.p. 1H-NMR Mass Spectrum

I-23

image4 - 0.80-0.82 (4H, m), 1.81 (1H, m), 2.04 (3H, s), 2.28 (6H, m), 3.15 (2H, m), 3.53 (4H, m), 5.48 (1H, s), 5.89 (1H, br s), 6.81 (1H, br s), 7.46 (2H, d), 7.68 (2H, d), 9.06 (1H, s), 10.38 (1H, s), 11.66 (1H, br s) ES + 495.4 ES-493.4

I-24

- 1.10 (3H, t), 1.47 (2H, q), 1.90 (2H, d), 2.03 (3H, s), 2.35 (2H, q), 2.85 (2H , br s), 3.23 (2H, d), 5.45 (1H, s), 5.90 (1H, br s), 7.05 (1H, d), 7.50 (2H, d) , 7.70 (2H, d), 8.30 (1H, br s), 8.55 (1H, br s), 9.10 (1H, s), 10.10 (1H, s), 11, 70 (1H, br s) ES + 453.3

I-25

image4 - 0.83 (4H, m), 1.82 (1H, m), 2.22 (3H, s), 2.89 (4H, m), 3.33 (4H, m) (masked), 5 , 81 (1H, s), 6.24 (1H, br s), 7.36 (1H, s), 7.48 (2H, d), 7.65 (2H, d), 9.32 (1H , br s), 10.35 (1H, s), 12.10 (1H, br s) ES-449.4 ES + 451.3

I-26

- 0.81-0.83 (4H, m), 1.81 (1H, m), 3.29-3.31 (4H, m), 3.59-3.61 (4H, m), 5, 82 (1H, s), 6.22 (1H, br s), 7.36 (1H, s), 7.48 (2H, d), 7.64 (2H, d), 9.38 (1H, s), 10.37 (1H, s), 12.10 (1H, s) ES + 438.3 ES-436.4

I-27

image4 - 0.81-0.83 (4H, m), 1.81 (1H, m), 2.37-2.41 (6H, m), 3.3 (masked signal), 3.50 (2H, m), 4.44 (1H, s), 5.81 (1H, s), 6.23 (1H, br s), 7.36 (1H, s), 7.47 (2H, d), 7 , 65 (2H, d), 9.32 (1H, s), 10.38 (1H, s), 12.10 (1H, s) ES + 481.3 ES-479.4

I-28

- 0.81-0.83 (4H, m), 0.96 (6H, d), 1.81 (1H, m), 2.41-2.43 (4H, m), 2.65 (1H, m), 3.3 (signal masked), 5.82 (1H, s), 6.24 (1H, br s), 7.36 (1H, s), 7.47 (2H, d), 7, 65 (2H, d), 9.31 (1H, s), 10.37 (1H, s), 12.10 (1H, s) ES + 479.3 ES-477.4

No.

Structure m.p. 1H-NMR Mass Spectrum

I-29

220-222 - M + H 479

I-30

image4 - 0.77-0.88 (4H, m), 1.28-1.55 (6H, m), 1.76-1.88 (1H, m), 2.12-2.43 (6H, m), 3.05-3.17 (2H, m), 5.81 (1H, br s), 6.04 (1H, br s), 6.84 (1H, br s), 7.39 ( 1H, br s), 7.47 (2H, d, J = 8.6 Hz), 9.12 (1H, br s), 10.33 (1H, s), 12.06 (1H br s) ES + 479.35 ES-477.41

I-31

- 0.78-0.89 (4H, m), 1.59-1.86 (3H, m), 2.18-2.26 (3H, m), 2.38-2.52 (2H, m ), 2.70-2.83 (2H, m), 3.283.55 (4H, m), 5.88 (1H, s), 6.15 (1H, br s), 7.39 (1H, s ), 7.47 (2H, d, J = 8.6 Hz), 7.63 (2H, d, J = 8.6 Hz), 9.25 (1H, br s), 10.35 (1H, s), 12.11 (1H, br s) ES + 465.34 ES-463.41

I-32

- 0.72-0.90 (4H, m), 1.31-1.54 (3H, m), 2.20-2.35 (2H, m), 2.57-2.75 (3H, m ), 3.12-3.50 (2H, m), 5.80 (1H, s), 6.22 (1H, br s), 7.38 (1H, br s), 7.47 (2H, d, J = 8.6 Hz), 7.64 (2H, d, J = 8.6 Hz), 9.29 (1H, s), 10.36 (1H, s), 12.08 (1H, br s) ES + 437.3 ES-435.37

I-33

- 1.15 (3H, t, J = 7.5Hz), 2.19 (3H, s), 2.25-2.40 (6H, m), 3.30-3.40 (4H, m) , 5.80 (1H, s), 6.25 (1H, br s), 7.38 (1H, s), 7.48 (2H, d, J = 8.6 Hz), 7.66 (2H , d, J = 8.6 Hz), 9.32 (1H, s), 10.06 (1H, s), 12.12 (1H, br s). ES + 439.34 ES-437.39

I-34

- 1.10 (3H, t, J = 7.5 Hz), 2.36 (2H, q, J = 7.5 Hz), 3.25-3.40 (4H, m), 3.55-3 , 69 (4H, m), 5.80 (1H, s), 6.21 (1H, br s), 7.32 (1H, br s), 7.47 (2H, d, J = 8.6 Hz), 7.65 (2H, d, J = 8.6 Hz), 9.38 (1H, s), 10.04 (1H, s), 12.10 (1H, br s) ES + 426.29 ES-424.38

I-35

image4 Shrinks 140 ° C Melts 280282 ° C 0.81-0.82 (4H, m), 1.81 (1H, m), 2.08 (6H, s), 2.33 (2H, br s), 3.103.12 ( 2H, m), 5.81 (1H, s), 6.03 (1H, br s), 6.79 (1H, br s), 7.38 (1H, s), 7.47 (2H, d ), 7.64 (2H, d), 9.12 (1H, br s), 10.34 (1H, s), 12.05 (1H, br s) ES + 439.40 ES-437.24

No.

Structure m.p. 1H-NMR Mass Spectrum

I-36

image4 Shrinks 130 ° C Melts 209212 ° C 0.81-0.82 (4H, m), 1.80 (1H, m), 2.24 (6H, m), 3.10-3.15 (2H, m), 3 , 51-3.53 (4H, m), 5.84 (1H, br s), 6.05 (1H, br s), 6.87 (1H, br s), 7.41 (1H, s) , 7.48 (2H, d), 7.66 (2H, d), 9.13 (1H, br s), 10.35 (1H, s), 12.07 (1H, br s) ES + 481, 34 ES-479.39

I-37

131-132 0.80-0.85 (4H, m), 1.82 (1H, quin), 2.40-2.45 (4H, m), 2.58 (2H, t), 2.70 (2H, t), 3.33-3.38 (4H, m), 5.85 (1H, s), 6.30 (1H, br s), 7.40 (1H, s), 7.50 (2H, d), 7.70 (2H, d), 9.35 (1H, s), 10.40 (1H, s), 12.10 (1H, br s) ES + 490.3

I-38

image4 Shrinks 220 ° C mp greater than 340 ° C 0.80-0.82 (4H, m), 1.63 (4H, m), 1.63 (1H, m), 2.33 (6H, m), 3,103.13 ( 2H, m), 5.82 (1H, s), 5.99 (1H, br s), 6.87 (1H, br s), 7.38 (1H, s), 7.46 (2H, d ), 7.65 (2H, d), 9.17 (1H, br s), 10.37 (1H, s), 12.07 (1H, br s) ES + 465.39 ES-463.31

I-39

- 0.80-0.83 (4H, m), 1.15-2.02 (5H, m), 2.22-2.47 (1H, 2m), 2.63-2.79 (1H, 2m ), 2.91-3.62 (6H, m), 4.034.53 (1H, 2m), 5.80 (1H, s), 6.15 and 6.24 (1H, br s), 7.35 (1H, s), 7.464.49 (2H, d), 7.65-7.69 (2H, 2d), 9.32 and 9.37 (1H, 2s), 10.48 and 10.49 (1H , 2s), 12.09 (1H, br s) ES + 477.3 ES-475.4

I-40

- 0.80-0.83 (4H, m), 1.15-2.02 (5H, m), 2.22-2.47 (1H, 2m), 2.63-2.79 (1H, 2m ), 2.91-3.62 (6H, m), 4.034.53 (1H, 2m), 5.80 (1H, s), 6.15 and 6.24 (1H, 2br s), 7.35 (1H, s), 7.467.49 (2H, d), 7.65-7.69 (2H, 2d), 9.32 and 9.37 (1H, 2s), 10.48 and 10.49 (1H , 2s), 12.09 (1H, br s) ES + 477.3 ES-475.4

I-41

- 0.70-0.89 (4H, m), 1.80-1.89 (1H, m), 2.65-2.73 (1H, m), 2.90-2.99 (1H, m ), 4.49 (2H, s), 5.86 (1H, br s), 6.30 (1H, br s), 6.95-7.20 (4H, m), 7.40 (1H, s), 7.50 (2H, d, J = 8.6 Hz), 7.69 (2H, d, J = 8.6 Hz), 9.36 (1H, s), 10.40 (1H, s), 12.15 (1H, br s) ES + 484.36 ES-482.37

I-42

168-169 0.80-0.88 (4H, m), 1.82 (1H, m), 2.88 (3H, s), 3.13 (4H, br s), 3.48 (4H, br s) , 5.82 (1H, s), 6.27 (1H, br s), 7.40 (1H, s), 7.50 (2H, d), 7.68 (2H, d), 9.41 (1H, s), 10.40 (1H, s), 12.15 (1H, br s) ES + 515.3

No.

Structure m.p. 1H-NMR Mass Spectrum

I-43

image4 - 0.86 (7H, m), 1.43 (2H, m), 1.80 (1H, m), 2.23 (2H, t), 2.33 (4H, m), 3.31 ( 4H, m) (masked), 5.81 (1H, s), 6.23 (1H, br s), 7.36 (1H, s), 7.48 (2H, d), 7.65 (2H , d), 9.31 (1H, s), 10.35 (1H, s), 12.15 (1H, br s) ES-463.4 ES + 465.3

I-44

image4 - 0.83 (4H, m), 1.82 (1H, m), 2.22 (3H, s), 2.89 (4H, m), 3.33 (4H, m) (masked), 5 , 81 (1H, s), 6.24 (1H, br s), 7.36 (1H, s), 7.48 (2H, d), 7.65 (2H, d), 9.32 (1H , br s), 10.35 (1H, s), 12.10 (1H, br s) ES-477.5 ES + 479.4

I-45

154-155 0.80-0.84 (4H, m), 1.80 (1H, quin), 2.40-2.43 (4H, m), 2.72 (2H, t), 3.03 (3H, s), 3.28-3.35 (6H, m), 5.80 (1H, s), 6.25 (1H, br s), 7.40 (1H, s), 7.50 (2H, d), 7.65 (2H, d), 9.36 (1H, s), 10.40 (1H, s), 12.10 (1H, br s) ES + 543.3

I-46

160-161 0.80-0.85 (4H, m), 1.06 (3H, d), 1.80 (1H, quin), 2.67 (1H, br s), 3.65 (1H, m), 4.05 (1H, br s), 5.85 (1H, s), 6.25 (1H, br s), 7.40 (1H, s), 7.50 (2H, d), 7.65 (2H, d), 9.30 (1H, br s), 10.35 (1H, s), 12.10 (1H, br s) ES + 451.3

I-47

image4 158-159 0.80-0.85 (4H, m), 1.82 (1H, quin), 2.35-2.45 (4H, m), 3.17 (2H, br s), 3, 22-3.26 (2H, m), 3.42-3.45 (2H, m), 3.50-3.58 (6H, m), 5.85 (1H, s), 6.25 ( 1H, brs), 7.40 (1H, s), 7.50 (2H, d), 7.70 (2H, d), 9.35 (1H, brs), 10.40 (1H, s ), 12.10 (1H, br s) ES + 564.3

I-48

image4 - 0.70-0.82 (4H, m), 1.79 (1H, m), 2.36 (4H, m), 3.3 (masked signal), 3.48 (2H, s), 5 , 81 (1H, s), 6.19 (1H, br s), 7.24-7.35 (6H, m), 7.47 (2H, d), 7.63 (2H, d), 9 , 33 (1H, s), 10.34 (1H, s), 12.09 (1H, s) ES + 527.4 ES-525.4

No.

Structure m.p. 1H-NMR Mass Spectrum

I-49

image4 - 0.80-0.81 (4H, m), 1.80 (1H, m), 2.00 (3H, s), 2.36-2.38 (4H, m), 3.3 (signal masked), 3.49 (2H, s), 5.42 (1H, s), 5.99 (1H, br s), 7.257.35 (5H, m), 7.47 (2H, d), 7 , 69 (2H, d), 9.23 (1H, s), 10.39 (1H, s), 11.69 (1H, s). ES + 541.4 ES-539.4

I-50

- 0.80 (4H, m), 0.93 (6H, d), 1.82 (1H, m), 2.20 (2H, t), 2.58 (2H, m), 3.79 (2H , m), 5.87 (1H, s), 6.23 (1H, br s), 7.40 (1H, s), 7.47 (2H, d), 7.74 (2H, d), 9.27 (1H, br s), 10.35 (1H, s), 12.11 (1H, br s) ES-463.5 ES + 465.4

I-51

- 1.10 (£ h, t, J = 7.5 Hz), 2.36 (2H, q, J = 7.5 Hz), 3.32 (3H, s), 5.80 (1H, br s ), 6.05 (1H, br s), 7.12-7.45 (6H, m), 7.49 (2H, d, J = 8.6 Hz), 7.71 (2H, d, J = 8.6 Hz), 9.48 (1H, br s), 10.11 (1H, s), 12.05 (1H, br s) ES + 446.31 ES-444.34

I-52

image4 - 0.75-0.89 (4H, m), 0.89-1.03 (6H, m), 1.74-1.88 (1H, m), 3.153.29 (4H, m), 5.89 (1H, br s), 6.18 (1H, br s), 7.42 (1H, br s), 7.47 (2H, d, J = 8.6 Hz), 7.63 (2H, d , J = 8.6 Hz), 9.19 (1H, br s), 10.34 (1H, s), 12.10 (1H, br s) ES + 424.34 ES-422.35

I-53

167-169 0.81-0.83 (4H, m), 1.00 (9H, s), 1.81 (1H, m), 2.47 (4H, m), 3.14 (4H, m), 5 , 82 (1H, s), 6.20 (1H, br s), 7.36 (1H, s), 7.47 (2H, d), 7.65 (2H, d), 9.32 (1H , s), 10.37 (1H, s), 12.09 (1H, s) ES + 493.4 ES-491.4

I-54

image4 - 2.21 (3H, s), 2.27-2.40 (4H, m), 3.31-3.50 (4H, m), 5.90 (1H, s), 6.31 (1H , br s), 7.10-7.25 (3H, m), 7.35-7.50 (3H, m), 9.38 (1H, s), 12.14 (1H, br s) ES + 352.28 ES-350.32

No.

Structure m.p. 1H-NMR Mass Spectrum

I-55

- 2.05 (3H, s), 2.19 (3H, s), 2.26-2.39 (4H, m), 3.36-3.46 (4H, m), 5.95 (1H, br s), 6.37 (1H, br s), 7.06 (2H, d, J = 8.9 Hz), 7.45 (1H, br s), 7.56 (2H, d, J = 8.9 Hz), 9.30 (1H, br s), 9.95 (1H, s), 12.12 (1H, s) ES + 409.31 ES-407.37

I-56

Darkens 250 277-9 ES + 485.3

I-57

- 1.34 (3H, t, J = 7.1 Hz), 3.33-3.42 (4H, m), 3.59-3.68 (4H, m), 4.32 (2H, q, J = 7.1 Hz), 5.94 (1H, s), 6.40 (1H, br s), 7.29 (2H, d, J = 8.7 Hz), 7.49 (1H, br s), 7.99 (2H, d, J = 8.7Hz), 9.50 (1H, s), 12.20 (1H, br s). ES + 411.30 ES-409.37

I-58

- 3.30-3.39 (4H, m), 3.60-3.65 (4H, m), 5.89 (1H, s), 6.25 (1H, br s), 7.15-7 , 50 (9H, m), 9.40 9 [mu] H, br s), 12.12 (1H, s). ES + 415.32 ES-413.37

I-59

- 2.05 (3H, s), 3.25-3.45 (4H, m), 3.59-3.70 (4H, m), 5.94 (1H, s), 6.35 (1H, br s), 7.07 (2H, d, J = 8.9 Hz), 7.46 (1H, br s), 7.58 (2H, d, J = 8.9 Hz), 9.40 ( 1H, s), 9.98 (1H, s), 12.13 (1H, br s). ES + 396.32 ES-394.38

I-60

- 0.38-0.48 (2H, m), 0.79-0.89 (2H, m), 1.64-1.73 (1H, m), 2.04 (3H, s), 3, 34-3.40 (4H, m), 3.61-3.69 (4H, m), 5.46 (1H, s), 6.10 (1H, br s), 7.05 (2H, d , J = 8.9 Hz), 7.61 (2H, d, J = 8.9 Hz), 9.34 (1H, s), 9.99 (1H, s), 11.85 (1H, br s). ES + 436.36 ES-434.41

No.

Structure m.p. 1H-NMR Mass Spectrum

0.85 (4H, s), 1.80 (1H, m), 2.00

(3H, s), 3.35 (4H, s), 3.60 (4H, s),

5.43 (1H, s), 6.00 (1H, br s), 7.50

(2H, d), 7.70 (2H, d), 9.30 (1H, s),

I-61

238-239 10.40 (1H, s), 11.70 (1H, br s) ES + 452.2

image4

0.81 (4H, d), 1.83 (1H, m), 2.20

N

(3H, s), 2.77 (3H, s), 2.90-3.17 (4H,

V-1 i

N N N S N N N O H HH - m), 4.09-4.33 (4H, m), 5.46 (1H, s), 6.06 (1H, s), 7.47 (2H, d), 7.72 (2H, d ), 9.35 (1H, s), 1.45 (1H, s), 10.62 (1H, s), 11.72 (1H, s) -

N

H Cl

OO

0.81-0.83 (4H, d), 1.81 (1H, m),

V-1 iii

N N N N N H HH S HO OH - 2.04 (3H, s), 2.82-2.83 (3H, m), 3.08-3.11 (4H, m), 3.42-3.47 (4H, m), 4, 14-4.17 (br m, OH), 5.49 (1H, s), 6.04 (1H, s), 7.48 (2H, d), 7.71 -

OR

(2H, d), 9.53 (1H, s), 9.64 (1H, s),

N N S

10.39 (1H, s)

N

V-1 iv

N N N N S N N N N O H HH HO OH OO - 0.82 (4H, d), 1.80 (1H, m), 2.02 (3H, s), 2.45 (3H, s), 2.69 (br s, OH), 3.01 ( 2H, s), 3.38-3.47 (8H, m), 5.45 (1H, s), 6.05 (1H, s), 7.47 (2H, d), 7.70 (2H , d), 9.25 (1H, s), 10.36 (1H, s) -

OR

0.80-0.82 (4H, m), 1.81 (1H, m),

HO

2.02 (3H, s), 2.21 (3H, s), 2.34-2.36

image4

(4H, m), 3.36-3.38 (signal masks

V-1 v

N N N N H HH OH O - 4H + OH), 5.45 (1H, s), 6.04 (1H, s), 6.61 (1H, s), 7.47 (2H, d), -

N

7.69 (2H, d), 9.18 (1H, s), 10.36

N N S O

(1H, s)

N

V-1 vi

N N N N S N N N N O H HH OH HO O O - 0.80-0.82 (4H, d), 1.81 (1H, m), 2.02 (3, s), 2.21 (3H, s), 2.33-2.36 (4H, m), 2.41 (4H, s), 3.30-3.45 (signal masked, 4H, m), 4.19 (1H, br s), 5.45 (1H, s), 6.03 (1H, br s), 7.47 (2H, d), 7.69 (2H, d), 9.18 (1H, s), 10.35 (1H, s), 11.70 (1H, br s) -

No.

Structure m.p. 1H-NMR Mass Spectrum

O O

0.81-0.83 (4H, d), 1.81 (1H, m),

image4

2.02 (3H, s), 2.80 (3H, s), 3.11-3.45

N OH HO

(masked signal, 8H, m), 5.45

V-1 vii

N N N H HH - (1H, s), 6.07 (3H, s), 7.48 (2H, d), 7.71 (2H, d), 9.36 (1H, s), 10.38 -

N N N N S O

(1H, s), 11.75 (1H, br s)

CO2H

0.81-0.82 (4H, d), 1.81 (1H, m),

OH H

2.02 (3H, s), 2.27 (3H, s), 2.43 (4H,

HHO

m), 3.38-3.47 (masked signal,

V-1 viii

N N N N H HH CO2H - 4H, m), 4.20 (2H, s), 5.45 (1H, s), 6.04 (1H, br s), 7.47 (2H, d), 7.69 -

N N N N S O

(2H, d), 9.20 (1H, s), 10.36 (1H, s),

V-1 ix

N N N N S N N N N O H HH HO2C S OH OO - 0.81-0.83 (4H, d), 1.81 (1H, m), 2.02 (3H, s), 2.82 (3H, s), 3.03-3.13 (4H, m), 3.36-3.75 (masked signal, 6H, m), 4.12-4.15 (2H, m), 5.45 (1H, s), 6.05 (1H, s), 7.48 (2H, d), 7.71 (2H, d), 9.37 (1H, s), 9.61 (1H, br s), 10.38 (1H, s) -

V-1 x

N N N N S N N N N O H HH OH HO2C OH HO2C O - 0.81-0.82 (4H, d), 1.81 (1H, m), 2.02 (3H, s), 2.40 (3H, s), 2.54-2.68 (8H, m), 3.40-3.45 (signal masked, 4H, m), 4.32 (1H, br s), 5.45 (1H, s), 6.05 (1H, br s), 7, 47 (2H, d), 7.69 (2H, d), 9.24 (1H, s), 10.36 (1H, s) -

v-1 xi

N N N N S N N N N O H HH P O HO OH HO - 0.80-0.82 (4H, d), 1.80 (1H, m), 2.02 (3H, s), 2.31 (3H, s), 2.50 (signal masked, 4H), 3,363.47 (4H, m), 4.88 (br m, OH), 5.45 (1H, s), 6.04 (1H, s), 7.47 (2H, d), 7.69 ( 2H, d), 9.22 (1H, s), 10.36 (1H, s) -

V-20 i

N N N N S N N N N O H HH HCl salt 1.09 (3H, t), 2.00 (3H, s), 2.38 (2H, q), 2.77 (3H, s), 3.00 (2H, m), 3.18 (2H , m), 3.40 (2H, d), 4.10 (2H, d), 5.41 (1H, s), 6.06 (1H, br s), 7.48 (2H, d), 7.73 (2H, d), 9.42 (1H, s), 10.15 (1H, s), 10.64 (1H, br s), 11.77 (1H, br s) ES-451.4 ES + 453.4 (M + H) +

No.

Structure m.p. 1H-NMR Mass Spectrum

image4

1.09 (3H, t), 2.0 (3H, s), 2.35 (5H,

V-20 ii

N N N N S N N N H H O N O H m), 2.81 (3H, s), 3.09 (4H, m), 3.44 (2H, d), 4.12 (2H, d), 5.41 (1H s), 6.02 (1H, br s), 7.48 (2H, d), 7.73 (2H, d), 9.44 (1H, s), 9.70 (1H, br s), 10.10 (1H, s), 11.80 (1H, br s) ES-451.4 ES + 453.4 (M + H) +

H3C S OH salt

OR

5

10

fifteen

twenty

25

30

35

40

BIOLOGICAL TESTS

The activity of the compounds of this invention as kinase inhibitors can be tested in vitro, in vivo, or in a cell line. In vitro assays include assays that determine the inhibition of kinase activity

or ATPase activity of activated Aurora and / or FLT-3 enzymes. Alternative in vitro assays quantify the ability of the inhibitor to bind Aurora and / or FLT-3 and can be measured by radioactively labeling the inhibitor prior to binding, isolating the inhibitor / Aurora and / or inhibitor / FLT-3 complex, and determining the amount of bound radioactive label, or by conducting a competition experiment where new compounds are incubated with Aurora and / or FLT-3 bound to known radioligands. Any type of Aurora isoform can be used, depending on which type or isoform of Aurora is to be inhibited. The details of the conditions used for enzymatic assays are described in the examples mentioned below.

Example 10

Determination of Ki for Inhibition of Aurora

Compounds were screened as follows, for their ability to inhibit Aurora using a standard coupled enzyme assay (Fox et al (1998) Protein Sci 7, 2249). To a stock assay buffer solution containing 7.5 0.1 M HEPES, 10 mM MgCl2, 1 mM DTT, 25 mM NaCl, 2.5 mM phosphoenolpyruvate, 300 mM NADH, 30 mg / ml pyrivate kinase, 10 mg / ml lactate dehydrogenase, 40mM ATP, and 800 µM peptide (LRRASLG, American Peptide, Sunnyvale, CA), a DMSO solution of a compound of the present invention was added to a final concentration of 30 µM. The resulting mixture was incubated at 30 ° C for 10 minutes. The reaction was started by the addition of 10 µL of Aurora stock solution to give a final concentration of 70 nM in the assay. Reaction percentages were obtained by monitoring absorbance at 340 nm for a 5 minute read time at 30 ° C using a BioRad Ultramark plate reader (Hercules, CA). Ki values were determined from percentage data as a function of inhibitor concentration.

The compounds of formula V of the present invention were found to be inhibitors of Aurora-1, Aurora-2, and Aurora-3.

Example 11

Determination of Ki for Inhibition of FLT-3

Compounds were screened for their ability to inhibit FLT-3 activity using a radiometric filter binding assay. This assay monitors the incorporation of 33P into a 4: 1 poly (Glu, Tyr) substrate (pE4Y). The reactions were carried out in a solution containing 100 mM HEPES (pH 7.5), 10 mM MgCl2, 25 mM NaCl, 1 mM DTT, 0.01% BSA and 2.5% DMSO. Final substrate concentrations in the assay were 90 µM ATP and 0.5 mg / ml pE4Y (both from Sigma Chemicals, St Louis, MO). The final concentration of a compound of the present invention is generally between 0.01 and 5 µM. Typically, a 12 point titration was performed by preparing dilutions of test compound in 10 mM DMSO stock. Reactions were carried out at room temperature.

Two test solutions were prepared. Solution 1 contains 100 mM HEPES (pH 7.5), 10 mM MgCl2, 25 mM NaCl, 1 mg / ml pE4Y, and 180 µM ATP (containing 0.3 µCi [�-33P] ATP for each reaction) . Solution 2 contains 100 mM HEPES (pH 7.5), 10 mM MgCl2, 25 mM NaCl, 2 mM DTT, 0.02% BSA, and 3 nM FLT-3. The assay was performed on a 96-well plate mixing 50 µl of Solution 1 and 2.5 ml of the compounds of the present invention. The reaction was started with Solution 2. After incubation for 20 minutes at room temperature, the reaction was stopped with 50 µl of 20% TCA containing 0.4 mM ATP. The entire reaction volume was transferred to a filter plate and washed with 5% TCA by a Harvester 9600 from TOMTEC (Hamden, CT). The amount of 33P incorporated into pE4y was analyzed by means of a Packard Top Count Microplate Scintillation Counter (Meridem, CT). The data was adjusted using a Prism computer program to obtain an IC50 or Ki.

The compounds of formula V of the present invention were found to be inhibitors of FLT-3.

Example 12

Determination of IC50 for Aurora Inhibition in a Colo205 Cell Assay

Compounds were also tested for inhibition of cell proliferation. In this assay, complete medium was prepared by adding 10% fetal calf serum, L-glutamine solution, and penicillin / streptomycin to medium.

5 RPMI 1640 (Sigma). Colon cancer cells (COLO-205 cell line) were added to a 96-well plate at a seeding density of 1.25 x 104 cells / well / 150 µL. A compound solution in complete medium was prepared by serial dilution, the test compound solution (50 µL) was added to each well.

Each plate contained a series of wells in which only complete medium (200 µL) was added to form a control group in order to measure maximum proliferation. A control vehicle group was also added to each plate.

The plates were incubated at 37 ° C for 2 days. A 3H-thymidine stock solution (1 mCi / mL, Amersham, Pharmacia UK) was diluted to 20 µCi / mL in RPMI medium, then 25 µL of this solution was added to each well. Plates were further incubated at 37 ° C for 3 hours, then collected and analyzed for 3H-thymidine uptake using a liquid scintillation counter.

The compounds of formula V of the present invention were found to be inhibitors of the proliferation of Colo205 cancer cells.

Example 13

Measurement of Cell Proliferation in a Panel of Normal and Tumor Cell Types: 3H-Thymidine Incorporation Assay

The 3H-thymidine incorporation assay was chosen as a well characterized method to determine the

20 cell proliferation. Cells from normal tissues and from a wide variety of different tumor types were chosen for analysis. Many of the tumor cells were selected because they express high levels of Aurora proteins (for example, MCF-7, PC3, A375, A549) (See section 5.3.5 and Bischoff et al EMBO J. 1998 17, 3052-3065) and / or are capable of forming tumors in nude mice or rats (for example HCT116, MCF-7 and MDA-MB-231)

Logarithmically growing cells were incubated with compound for 96 hours. To measure cell proliferation,

3 hours before the end of the experiment, 0.5 µCi of 3H-thymidine was added to each well. Cells were harvested, washed, and incorporated radioactivity was counted in a Wallac microplate beta counter. To determine inhibition of proliferation, cpm were plotted against compound concentration, and IC50 was determined logarithmically.

Table 5 below includes the cell lines used in the cell proliferation assay above.

30 described. For each cell line, the inhibition of cell proliferation and the incorporation of 3Hthymidine were determined.

Table 5. Cell Lines

Origin

Cellphone line

Colorectal acenocarcinoma

HCT-116

Colorectal adenocarcinoma

LS174T

Leukemia

HL60

Adenocarcinoma of the mammary glands

MDA-MB-231

Adenocarcinoma of the mammary glands

ZR-75-1

Adenocarcinoma of the mammary glands

MCF-7

Prostate adenocarcinoma

PC3

Pancreatic

MIA-Pa-Ca-2

Melanoma

A375

PHA stimulated human primary lymphocytes

PHA blasts

Although a number of embodiments of this invention have been described, it is apparent that the basic examples can be changed to provide other embodiments using the compounds and methods of this invention. By

48

Therefore, it will be understood that the scope of this invention is to be defined by the appended claims rather than by the specific embodiments which have been represented by way of example.

Claims (30)

1. A method of preparing a compound of formula I: image 1 I where: Q and T are each independently selected from oxygen, sulfur, or N (R); each R independently is selected from hydrogen or an optionally substituted (C1-C6) aliphatic group, where: two R's bonded to the same nitrogen atom are optionally bonded together with the nitrogen to form an optionally substituted 3-7 membered monocyclic ring, or an 8-10 membered, saturated, partially unsaturated, or fully unsaturated bicyclic ring containing 0-3 heteroatoms, in addition to the nitrogen attached to them, independently selected from nitrogen, oxygen or sulfur; Rx is U-R5; R5 is selected from halogen, NO2, CN, R, or Ar; each U independently is selected from a valence bond or a (C1-C4) alkylidene chain, where: Up to two methylene units of U are optionally and independently replaced by -O-, -S-, -SO-, SO2-, -N (R) SO2-, SO2N (R) -, -N (R) -, - C (O) -, -CO2-, -N (R) C (O) -, -N (R) C (O) O-, -N (R) CON (R) -, N (R) SO2N ( R) -, -N (R) N (R) -, -C (O) N (R) -, -OC (O) N (R) -, -C (R) = NN (R) -, or -C (R) = NO-; each Ar is independently selected from an optionally substituted ring, selected from a 3-7 membered monocyclic ring, or an 8-10 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring, having 0-4 independently selected heteroatoms nitrogen, oxygen or sulfur; Ry is -N (R1) 2, -OR1, or -SR1; each R1 is independently selected from R or a 3-8 membered monocyclic ring, an 8-10 membered bicyclic ring, or a saturated, partially unsaturated, or fully unsaturated 10-12 membered tricyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and where: each R1 is optionally and independently substituted with up to four substituents independently selected from R2; each R2 is independently selected from -R3, -OR3, -SR3, -CN, -NO2, oxo, halogen, -N (R3) 2, -C (O) R3, -OC (O) R3, -CO2R3, -SO2R3, -SO2N (R3) 2, -N (R3) SO2R3, -C (O) NR (R3), -C (O) N (R3) 2, -OC (O) NR (R3), OC ( O) N (R3) 2, -NR3C (O) R3, -NR3C (O) N (R3) 2, or -NR3CO2 (R3); each R3 is independently selected from R or Ar; Rz1 is selected from an aliphatic group (C1-C6) or a 3-8 membered monocyclic ring, an 810 membered bicyclic ring, or a saturated, partially unsaturated, or fully unsaturated 10-12 membered tricyclic ring, which has 0-4 heteroatoms independently selected from oxygen, nitrogen or sulfur, where: Rz1 is substituted with 0-4 independently selected R2 groups; Rz2 is a saturated, partially unsaturated, or fully unsaturated aliphatic (C1-C6) group or 3-8 membered monocyclic or 8-10 membered bicyclic ring containing 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, where : Rz2 is substituted with 0-4 substituents independently selected from oxo or U-R5; 5 comprising said procedure: a first step of combining a compound of formula IV with a compound of formula Rz2-T-H in a suitable first medium to obtain a compound of formula III, after the first step, a second step of combining the compound of formula III with a compound of formula Rz1-Q-H in a second suitable medium to obtain a compound of formula II, and After the second step, a third step of combining the compound of formula II with a compound of formula Ry-H in a third suitable medium. 2 L Rz2 TH 1 IV 2 L image2 R image3 x N z1 R QH 3 z2 LNTR III Ry H Rz2 T II Wherein the first suitable medium, the second suitable medium, and the third suitable medium independently comprise: i) a suitable solvent; and ii) optionally, a suitable base, and where L1, L2 and L3 independently is a suitable leaving group. L3 The method according to claim 1, wherein it is selected from halogen, optionally substituted arylsulfonyl, or optionally substituted alkylsulfonyl. image4

3.

The method according to claim 2, wherein L3 is fluoro, chloro, bromo iodo, paratoluenesulfonyl, methanesulfonyl, paranitrophenylsulfonyl, parabromophenylsulfonyl, or trifluoromethanesulfonate.

Four.

The method according to claim 3, wherein L3 is chlorine or iodine.

5.

The method according to claim 1, wherein L2 is halogen, optionally substituted arylsulfonyl,

or optionally substituted alkylsulfonyl.

6.

The method according to claim 5, wherein L2 is fluoro, chloro, bromine, iodine, paratoluenesulfonate, methanesulfonate, paranitrophenylsulfonyl, parabromophenylsulfonyl, or trifluoromethanesulfonate.

7.

The method according to claim 6, wherein L2 is chlorine or iodine.

8.

The method according to claim 1, wherein L1 is halogen, optionally substituted arylsulfonyl,

or optionally substituted alkylsulfonyl.

9.

The method according to claim 8, wherein L1 is optionally substituted alkylsulfonyl.

10.

The method according to claim 9, wherein L1 is methanesulfonyl.

eleven.

The method according to claim 1, where Q is N (R).

12.

The method according to claim 1, wherein T is oxygen or sulfur.

13.

The method according to claim 12, wherein T is sulfur.

14.

The method according to claim 1, wherein Ry is –OR1 or –N (R1) 2.

fifteen.

The method according to claim 14, where Ry is –N (R1) 2, and where: R1

is selected from R or a saturated 3-7 membered monocyclic or 8-10 membered bicyclic ring, partially unsaturated, or fully unsaturated, having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or: each R1 is R such that the two R's on the same nitrogen atom join together to form an optionally substituted 4-7 membered saturated ring having up to two additional heteroatoms independently selected from nitrogen, oxygen, or sulfur, and where : each R1 is optionally and independently substituted with up to four substituents selected from -R3, -OR3, -SR3, -CN, -NO2, oxo, halogen, -N (R3) 2, -C (O) R3, -OC (O ) R3, -CO2R3, -SO2R3, SO2N (R3) 2, -N (R3) SO2R3, -C (O) NR (R3), -C (O) N (R3) 2, -OC (O) NR ( R3), -OC (O) N (R3) 2, NR3C (O) R3, -NR3C (O) N (R3) 2, or -NR3CO2 (R3).

16.

The method according to claim 15, where Ry is N (R1) 2, where: R1

each independently is selected from R, where R is hydrogen or an optionally substituted (C1-C4) aliphatic group.

17.

The method according to claim 15, where Ry is N (R1) 2, where:

each R1 is R such that the two R groups join together to form an optionally substituted 4-7 membered saturated ring, having up to two additional heteroatoms independently selected from nitrogen, oxygen, or sulfur.

18.

The method according to claim 17, wherein Ry is selected from pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, piperazin-1-yl, diazepanyl, or tetrahydroisoquinolinyl, where each ring is optionally substituted with one or two groups independently selected from methyl, ethyl, methylsulfonyl, (CH2) 2SO2CH3, cyclopropyl, CH2cyclopropyl, (CH2) 2OH, CO2t-butyl, CH2phenyl, phenyl, NH2, NH (CH3), N ( CH3) 2, (CH2) 2NH2, (CH2) 2morpholin-4-yl, (CH2) 2N (CH3) 2, isopropyl, propyl, t-butyl, (CH2) 2CN, or (CH2) 2C (O) morpholin- 4-yl.

19.

The method according to claim 1, wherein Rz1 is a 3-7 membered monocyclic or 8-10 membered bicyclic ring, saturated, partially unsaturated, or fully unsaturated, having 0-4 heteroatoms independently selected from oxygen, nitrogen or sulfur, where said ring is optionally and independently substituted with up to three substituents selected from -R3, -OR3, -SR3, -CN, -NO2, oxo, halogen, -N (R3) 2, -C (O) R3, - OC (O) R3, -CO2R3, -SO2R3, -SO2N (R3) 2, -N (R3) SO2R3, -C (O) NR (R3), -C (O) N (R3) 2, -OC ( O) NR (R3), -OC (O) N (R3) 2, -NR3C (O) R3, -NR3C (O) N (R3) 2, or -NR3CO2 (R3).

twenty.

The method according to claim 19, wherein Rz1 is a fully unsaturated 5-6 membered ring, having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is optionally and independently substituted with up to three substituents selected from –R3, -OR3,

-SR3, -CN, -NO2, oxo, halogen, -N (R3) 2, -C (O) R3, -OC (O) R3, -CO2R3, -SO2R3, -SO2N (R3) 2, -N ( R3) SO2R3, -C (O) NR (R3), -C (O) N (R3) 2, -OC (O) NR (R3), -OC (O) N (R3) 2, -NR3C (O ) R3, -NR3C (O) N (R3) 2, or -NR3CO2 (R3).

twenty-one.

The method according to claim 20, wherein Rz1 is an optionally substituted ring selected from pyrazole or any of the following 5-6 membered rings:

22.

The method according to claim 21, wherein Rz1 is a pyrazole ring having up to two substituents independently selected from -N (R3) 2, -OR3, or an aliphatic group (C1-C4).

2. 3.

The method according to claim 22, wherein Rz1 is a pyrazole optionally substituted with a substituent selected from methyl, ethyl, propyl, isopropyl, t-butyl, cyclopropyl, or phenyl.

image5 image6 image7 image8 5 24. The method according to claim 1, wherein Rz2 is an optionally substituted ring selected from a saturated, partially unsaturated, or fully unsaturated 5-6 membered monocyclic or 8-10 membered bicyclic ring, having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, wherein said ring is optionally substituted with up to three substituents independently selected from halogen, -CN, -NO2, -C (O) R3, -CO2R3, -C (O) NR (R3) , -NR3C (O) R3, -N (R3) 2, -N (R3) SO2R3, -NR3C (O) N (R3) 2, or -NR3CO2 (R3). 25. The method according to claim 24, wherein: Rz1 is selected from phenyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrazinyl, naphthyl, tetrahydronaphthyl, benzimidazolyl, benzothiazolyl, quinolinyl, quinazolinyl, benzodioxynyl, isobenzofuran, indanyl, indolyl, indolinyl, indazolyl, or isoquinolinyl, 20 where: Rz2 is optionally substituted with up to three substituents independently selected from -Cl, -Br, -F, CN, -CF3, -COOH, -CONHMe, -CONHEt, -NH2, -NHAc, -NHSO2Me, -NHSO2Et, -NHSO2 (n -propyl), NHSO2 (isopropyl), -NHCOEt, -NHCOCH2NHCH3, -NHCOCH2N (CO2t-Bu) CH3, -NHCOCH2N (CH3) 2, NHCOCH2CH2N (CH3) 2, -NHCOCH2CH2CH2N (CH3) 2, -NHCO (cyclo) -NHCO (isopropyl), -NHCO (isobutyl), -NHCOCH2 (morpholin-4-yl), -NHCOCH2CH2 (morpholin-4-yl), -NHCOCH2CH2CH2 (morpholin-4-yl), -NHCO2 (t-butyl), NH (cyclohexyl), -NHMe, -NMe2, -OH, -OMe, methyl, ethyl, cyclopropyl, isopropyl, or t-butyl. 26. The method according to claim 25, wherein Rz2 has a substituent selected from NR3C (O) R3, where: each R3 is independently selected from R or Ar, and where: R is hydrogen or an optionally substituted (C1-C4) aliphatic group. 27. The method according to claim 1, wherein said suitable solvent is a protic solvent, a halogenated hydrocarbon, an ether, an aromatic hydrocarbon, a polar or non-polar aprotic solvent, or any of their mixtures. 28. The method according to claim 27, wherein said solvent is a linear or branched (C1-C5) alkyl alcohol, ether, or a polar or non-polar aprotic solvent.

29.

The method according to claim 1, wherein said suitable base is selected from an organic amine, an alkaline earth metal carbonate, an alkaline earth metal hydride, or an alkaline earth metal hydroxide.

30.

The method according to claim 29, wherein said suitable base is selected from a

10 trialkylamine, sodium carbonate, potassium carbonate, sodium hydride, potassium hydride, sodium hydroxide, or potassium hydroxide. 31. The method according to claim 1, wherein said method is used to prepare a compound selected from the following compounds from Table 1 and Table 2: Table 1

Nov-

Structure Nov- Structure

1

2

3

4

5

6

7

8

9

10 image3

eleven

12

13

CH3 14

N

N H

N H

H

N

N

image3

OR

NN

S

NCH3

image3

fifteen

16

17

18

19

Table 2. image9 image3 I-2 image3 I-4 I-3 image10 I-8 I-9 image11 image3 I-12 image3 I-13 I-14 image12 I-15 image13 image14 I-20 image15 image3 I-22 image3 I-23 I-24 image16 I-30 I-29 image17 image3 I-32 I-34 image3 I-35 I-36 image18 image3 I-38 image3 I-39 I-40 image3 I-41 image19 image20 I-44 image21 I-47 I-48 image3 image22 I-49 image23 image3 I-52 I-54 image3 I-55 I-56 image24 image3 I-61 32. The method according to claim 31, wherein said method is used to prepare a compound of formula V-1.