• 专利附录
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    • 专利摘要:
    2-amino-1,3-thiazole derivatives of the formula I or formula II or pharmaceutically acceptable salts thereof of the present invention are, for example, cancer, cell proliferative diseases, Alzheimer's disease, viral infections, autoimmune diseases Or for the treatment of neurodegenerative diseases. Formula I Formula II In Formula I and Formula II above, R, R 1 , R 2 and R 3 are as defined herein.
    公开号:KR20020060159A
    申请号:KR1020027001844
    申请日:2000-08-11
    公开日:2002-07-16
    发明作者:페바렐로파올로；아미치라파엘라；빌라마누엘라；살롬바르바라；불펫티안나；바라시마리오
    申请人:파마시아 이탈리아 에스.피.에이.；
    IPC主号:
    专利说明:

    Arylmethyl-carbonylamino-thiazole derivatives and their use as antitumor agents}
    [1] Field of invention
    [2] The present invention relates to arylmethyl-carbonylaminothiazole derivatives, and more particularly, to 2- (arylmethyl-carbonylamino) -1,3-thiazole derivatives, a preparation method thereof, and a pharmaceutical composition containing the same. And their use as therapeutic agents, in particular in the treatment of cancer and cell proliferative diseases.
    [3] Background of the Invention
    [4] Several cytotoxic drugs, such as fluorouracil (5-FU), doxorubicin and camptothecin, cause DNA damage or affect cellular metabolic pathways, which in many cases indirectly block the cell cycle. Thus, these agents cause inevitable damage to normal cells and tumor cells, resulting in significant toxicity and side effects.
    [5] In this regard, there is a need for compounds that can be highly specific anti-tumor agents by selectively inducing tumor cell arrest and apoptosis, whose efficacy is comparable to currently available drugs but with less toxicity.
    [6] Progression through the cell cycle is known to be governed by a series of checkpoint controls (referred to as running limitations) that are regulated by a class of enzymes known as cyclin dependent kinases (cdk).
    [7] On the other hand, cdk itself is regulated at various levels, for example, binding to cyclin.
    [8] Coordinated activation and inactivation of different cyclin / cdk complexes is essential for normal progression through the cell cycle. Important G1-S and G2-M transitions are all controlled by activation of different cyclin / cdk activities. For G1, cyclin D / cdk4 and cyclin E / cdk2 are thought to mediate the initiation of the S-phase. Progression through the S-phase requires the activity of cyclin A / cdk2, while activation of cyclin A / cdc2 (cdk1) and cyclin B / cdc2 is required for the onset of medium term. General discussion of cyclin and cyclin dependent kinases is described, for example, in Kevin R. Webster et al., Exp. Opin. Invest. Drugs, 1998, Vol. 7 (6), 865-887.
    [9] Checkpoint control is incomplete in tumor cells, in part due to unregulation of cdk activity. For example, changes in the expression of cyclin E and cdk are observed in tumor cells, and deletion of the cdk inhibitor p27 KIP gene in mice has been shown to increase the incidence of cancer.
    [10] There is increasing evidence to support the view that cdk is a rate limiting enzyme in cell cycle progression and is itself a molecular target for therapeutic intervention. In particular, direct inhibition of cdk / cyclin kinase activity should help to limit unregulated tumor cell proliferation.
    [11] Summary of the Invention
    [12] It is an object of the present invention to provide compounds useful for treating cell proliferative diseases associated with changes in cell dependent kinase activity. Another object is to provide compounds having cdk / cyclin kinase inhibitory activity.
    [13] It is another object of the present invention to provide compounds which are useful for treatment as anti-tumor agents and are free from the drawbacks associated with the currently available anti-tumor drugs mentioned above in terms of toxicity and side effects.
    [14] The inventors have described above in which 2-amino-1,3-thiazole derivatives provide cdk / cycline kinase inhibitory activity, and thus are useful for treatment as antitumor agents and related to antitumor drugs currently available in terms of toxicity and side effects. No defects were found.
    [15] More specifically, the compounds of the present invention include, but are not limited to, carcinoma (eg, bladder cancer, breast cancer, colon cancer, kidney cancer, liver cancer, lung cancer including small cell lung cancer, esophageal cancer, gallbladder cancer, ovarian cancer, pancreatic cancer, gastric cancer, Skin cancer including uterine cancer, thyroid cancer, prostate cancer and squamous cell carcinoma); Hematopoietic tumors of the lymphatic system (eg leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodkin's lymphoma, non-Hodkin's lymphoma, hairy cell lymphoma and Burkitt's lymphoma); Hematopoietic tumors of the myeloid system (eg, acute and chronic myeloid leukemia, myelodysplastic syndromes and promyelocytic leukemia); Tumors of mesenchymal origin (eg fibrosarcoma and rhabdomyosarcoma); Tumors of the central and peripheral nervous system (eg, astrocytoma, neuroblastoma, glioma and Schwannocytoma); It is useful for the treatment of a variety of cancers including other tumors such as melanoma, normal carcinoma, teratoma, osteosarcoma, pigmentary dry skin disease, keratinocytes, thyroid follicular cancer and Kaposi's sarcoma.
    [16] Due to the major role of cdk in the regulation of cell proliferation, 2-amino-1,3-thiazole derivatives are also used in various proliferative diseases, such as benign prostatic hyperplasia, familial adenomatous polyps, neurofibromatosis, psoriasis It is useful for the treatment of smooth muscle cell proliferation, pulmonary fibrosis, arthritis, glomerulonephritis and postoperative stenosis and restenosis associated with atherosclerosis.
    [17] The compounds of the present invention may be useful for the treatment of Alzheimer's disease, as suggested by the fact that cdk5 is involved in phosphorylation of tau proteins (J. Biochem., 117, 741-749, 1995). .
    [18] The compounds of the present invention may be useful as modulators of apoptosis in the prevention of the development of ADIS, autoimmune diseases and neurodegenerative diseases in cancer, viral infections, HIV infected individuals.
    [19] Compounds of the invention may also be useful for inhibiting tumor angiogenesis and metastasis.
    [20] Compounds of the invention may also act as inhibitors of other protein kinases, such as protein kinase C, her2, raf1, MEK1, MAP kinase, EGF receptor, PDGF receptor, IGF receptor, PI3 kinase, weel kinase, Scr and Abl. And thus may be effective in the treatment of diseases associated with other protein kinases.
    [21] Accordingly, the present invention relates to a cell proliferative disorder associated with a change in cell dependent kinase activity, comprising administering an effective amount of a compound of Formula I or Formula II or a pharmaceutically acceptable salt thereof to a mammal in need thereof. Provides a treatment method.
    [22]
    [23]
    [24] In Formula Ia and Formula II above,
    [25] L is a 5 or 6 membered aromatic heterocycle having at least one hetero atom selected from a phenyl group or a group consisting of nitrogen, oxygen and sulfur,
    [26] R is a halogen atom, nitro group, or pyrrolidino, morpholino, piperazino, N-alkyl piperazino, N-aryl-piperazino, N-arylalkylpiperazino, piperidino and azabai Group (i) selected from the group consisting of cyclone [3.2.2] nonane,
    [27] A group consisting of unsubstituted, identical or different alkyl, aryl, arylalkyl, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, alkylcarbonyl, arylcarbonyl and arylalkylcarbonyl, wherein the alkyl moiety is substituted Amino group (ii), or further substituted with one or more groups selected from one or more hydroxy or amino groups),
    [28] C 3 -C 6 cycloalkyl (iii) unsubstituted or substituted with straight or branched C 1 -C 6 alkyl groups,
    [29] Unsubstituted, halogen, cyano, carboxy, hydroxy, nitro, alkylthio, alkoxy, straight or branched C 1 -C 6 alkyl, arylthio, aryloxy, amino, alkylamino, dialkylamino, arylamino, Arylalkylamino, hydroxyaminocarbonyl, alkoxyaminocarbonyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 6 cycloalkyl, alkyl-C 3 -C 6 cycloalkyl, alkyl Carbonyl, arylcarbonyl, arylalkylcarbonyl, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylcarbonylamino, arylalkylcarbonylamino , Arylaminosulfonyl, arylalkylaminosulfonyl, arylcarbonylamino, alkylsulfonylamino, arylsulfonylamino, arylalkylsulfonylamino, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, alkylaminocarbonyl , Arylaminocarbonyl, dialkylaminocarbonyl, a Alkylaminocarbonyl, pyrrolidino, morpholino, piperazino, N-alkylpiperazino, N-aryl-piperazino, N-arylalkyl-piperazino, piperidino and azabicyclo [3.2 .2] a straight or branched C 1 -C 6 alkyl group or arylalkyl group (iv) substituted with one or more substituents selected from the group consisting of nonanes or
    [30] Unsubstituted, halogen, cyano, carboxy, hydroxy, nitro, alkylthio, alkoxy, straight or branched C 1 -C 6 alkyl, arylthio, aryloxy, amino, alkylamino, dialkylamino, arylamino, Arylalkylamino, hydroxyaminocarbonyl, alkoxyaminocarbonyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 6 cycloalkyl, alkyl-C 3 -C 6 cycloalkyl, alkyl Carbonyl, arylcarbonyl, arylalkylcarbonyl, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylcarbonylamino, arylalkylcarbonylamino , Arylaminosulfonyl, arylalkylaminosulfonyl, arylcarbonylamino, alkylsulfonylamino, arylsulfonylamino, arylalkylsulfonylamino, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, alkylaminocarbonyl , Arylaminocarbonyl, dialkylaminocarbonyl, aryl Alkylaminocarbonyl, pyrrolidino, morpholino, piperazino, N-alkylpiperazino, N-aryl-piperazino, N-arylalkyl-piperazino, piperidino and azabicyclo [3.2 .2] an aryl group (v) substituted with one or more substituents selected from the group consisting of nonan,
    [31] R 1 is a hydrogen atom or a straight or branched C 1 -C 4 alkyl group which is unsubstituted or substituted with one or more hydroxy, alcoholic, amino, alkylamino or dialkylamino groups,
    [32] R 2 and R 3 may be the same or different and are a hydrogen atom, a cycloalkyl group, a straight or branched C 1 -C 6 alkyl group or an aryl group which is unsubstituted or substituted as described above for R, or
    [33] R 2 and R 3 together with the nitrogen atom to which they are attached are 4-morpholinyl, 1-piperazinyl, N-alkyl-piperazinyl, N-aryl-piperazinyl, N-arylalkyl-piperazinyl , Piperidinyl, pyrrolidinyl, 2-oxo-1-pyrrolidinyl, imidazolyl or 3-azabicyclo [3.2.2] nonyl ring,
    [34] R 4 is a carboxy, perfluorinated alkyl group, C 2 -C 4 alkynyl group, 2-oxo-pyrrolidinyl, piperidinyl, or straight or branched chain C which is unsubstituted or substituted as described above for R 1- C 6 alkyl group or aryl group.
    [35] In a preferred embodiment of the invention, the cell proliferative disease is selected from the group consisting of cancer, Alzheimer's disease, viral infections, autoimmune diseases and neurodegenerative diseases.
    [36] Specific types of cancer that can be treated include carcinomas, squamous cell carcinomas, hematopoietic tumors of the myeloid or lymphatic system, tumors of the mesenchymal origin, tumors of the central and peripheral nervous system, melanoma, normal carcinoma, teratoma, osteosarcoma, pigment Sex dry skin, keratinocytes, thyroid follicular cancer and Kaposi's sarcoma.
    [37] In another preferred embodiment of the method described above, the cell proliferative disease is benign prostatic hyperplasia, familial adenomatous polyposis, neurofibromatosis, psoriasis, smooth muscle cell proliferation associated with atherosclerosis, pulmonary fibrosis, arthritis, glomerulonephritis and postoperative stenosis And restenosis.
    [38] In addition, the methods of the present invention may provide methods for inhibiting tumor angiogenesis and metastasis. The methods of the invention can also provide methods for cell cycle inhibition or cdk / cyclin dependency inhibition.
    [39] The present invention provides 2-amino-1,3-thiazole derivatives of formula (I) or formula (II) or pharmaceutically acceptable salts thereof.
    [40] Formula I
    [41]
    [42] Formula II
    [43]
    [44] In Formula I and Formula II above,
    [45] L is a 5 or 6 membered aromatic heterocycle having at least one hetero atom selected from a phenyl group or a group consisting of nitrogen, oxygen and sulfur,
    [46] R is a halogen atom, nitro group, or pyrrolidino, morpholino, piperazino, N-alkyl piperazino, N-aryl-piperazino, N-arylalkylpiperazino, piperidino and azabai Group (i) selected from the group consisting of cyclone [3.2.2] nonane,
    [47] A group consisting of unsubstituted, identical or different alkyl, aryl, arylalkyl, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, alkylcarbonyl, arylcarbonyl and arylalkylcarbonyl, wherein the alkyl moiety is substituted Amino group (ii), or further substituted with one or more groups selected from one or more hydroxy or amino groups),
    [48] C 3 -C 6 cycloalkyl (iii) unsubstituted or substituted with straight or branched C 1 -C 6 alkyl groups,
    [49] Unsubstituted, one or more halogen, cyano, carboxy, hydroxy, nitro, alkylthio, alkoxy, straight or branched C 1 -C 6 alkyl, arylthio, aryloxy, amino, alkylamino, dialkylamino, aryl Amino, arylalkylamino, hydroxyaminocarbonyl, alkoxyaminocarbonyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 6 cycloalkyl, alkyl-C 3 -C 6 cycloalkyl , Alkylcarbonyl, arylcarbonyl, arylalkylcarbonyl, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, arylaminosulfonyl, dialkylaminosulfonyl, alkylcarbonyl Amino, arylalkylaminosulfonyl, arylcarbonylamino, arylalkylcarbonylamino, alkylsulfonylamino, arylsulfonylamino, arylalkylsulfonylamino, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, alkylamino Carbonyl, Dialkylaminocarbonyl, Arylami Carbonyl, arylalkylaminocarbonyl, pyrrolidino, morpholino, piperazino, N-alkylpiperazino, N-aryl-piperazino, N-arylalkyl-piperazino, piperidino or aza Straight or branched C 1 -C 6 alkyl group or arylalkyl group (iv) substituted with a bicyclo [3.2.2] nonane substituent or
    [50] Unsubstituted, halogen, cyano, carboxy, hydroxy, nitro, alkylthio, alkoxy, straight or branched C 1 -C 6 alkyl, arylthio, aryloxy, amino, alkylamino, dialkylamino, arylamino, Arylalkylamino, hydroxyaminocarbonyl, alkoxyaminocarbonyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 6 cycloalkyl, alkyl-C 3 -C 6 cycloalkyl, alkyl Carbonyl, arylcarbonyl, arylalkylcarbonyl, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, arylaminosulfonyl, dialkylaminosulfonyl, alkylcarbonylamino, Arylalkylaminosulfonyl, arylcarbonylamino, arylalkylcarbonylamino, alkylsulfonylamino, arylsulfonylamino, arylalkylsulfonylamino, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, alkylaminocarbonyl , Dialkylaminocarbonyl, arylaminocarbonyl, aryl Alkylaminocarbonyl, pyrrolidino, morpholino, piperazino, N-alkylpiperazino, N-aryl-piperazino, N-arylalkyl-piperazino, piperidino and azabicyclo [3.2 .2] an aryl group (v) substituted with one or more substituents selected from the group consisting of nonan,
    [51] R 1 is a hydrogen atom or a straight or branched C 1 -C 4 alkyl group which is unsubstituted or substituted with one or more hydroxy, alcoholic, amino, alkylamino or dialkylamino groups,
    [52] R 2 and R 3 may be the same or different and are a hydrogen atom, a cycloalkyl group, a straight or branched C 1 -C 6 alkyl group or an aryl group which is unsubstituted or substituted as described above for R, or
    [53] R 2 and R 3 together with the nitrogen atom to which they are attached are 4-morpholinyl, 1-piperazinyl, N-alkyl-piperazinyl, N-aryl-piperazinyl, N-arylalkyl-piperazinyl , Piperidinyl, pyrrolidinyl, 2-oxo-1-pyrrolidinyl, imidazolyl or 3-azabicyclo [3.2.2] nonyl ring,
    [54] R 4 is carboxy, perfluorinated alkyl group, C 2 -C 4 alkenyl group, C 2 -C 4 alkynyl group, 2-oxo-pyrrolidinyl, piperidinyl, or unsubstituted or described above for R Substituted or straight chain or branched C 1 -C 6 alkyl group or aryl group.
    [55] In addition, the present invention reacts a compound of formula III with a compound of formula IV so that the 2-amino-1,3-thiazole derivative of formula I wherein R, L, R 1 , R 2 and R 3 are To a 2-amino-1,3-thiazole derivative as described above or a pharmaceutically acceptable salt thereof.
    [56]
    [57]
    [58] In Formula III and Formula IV above,
    [59] R, L, R 1 , R 2 and R 3 are as defined above,
    [60] Z is hydroxy or a suitable leaving group.
    [61] In addition, the present invention is to react the compound of formula (Ia) with a compound of formula (V) wherein 2-amino-1,3-thiazole derivatives of formula (II, wherein R, L, R 1 , R 2 and R 3 To a 2-amino-1,3-thiazole derivative as described above or a pharmaceutically acceptable salt thereof.
    [62]
    [63]
    [64] In the above formulas (Ia) and (V),
    [65] R, R 1 , L and R 4 are as defined above,
    [66] X is hydroxy or a suitable leaving group such as chlorine or bromine.
    [67] The present invention also relates to the reaction of 2-amino-1,3-thiazole derivatives of formula (I, wherein at least one of R 2 and R 3 is a hydrogen atom) with a compound of formula (VI) to 1,3-thiazole derivatives, wherein at least one of R 2 and R 3 is not hydrogen, and optionally, 2-amino-1,3-thiazole derivatives of Formula I or Of the 2-amino-1,3-thiazole derivatives described above, or pharmaceutically acceptable salts thereof, including the conversion to another 2-amino-1,3-thiazole derivative of Formula II and / or salts thereof It provides a manufacturing method.
    [68]
    [69] In Formula VI above,
    [70] R 'has the meaning of R 2 or R 3 but is not hydrogen,
    [71] Y is a suitable leaving group.
    [72] The present invention also provides a pharmaceutical composition comprising the 2-amino-1, 3-thiazole derivative described above and one or more pharmaceutically acceptable carriers and / or diluents.
    [73] A more detailed understanding of the present invention and many of its advantages will be readily obtained as the present invention is better understood with reference to the following detailed description.
    [74] Some 2-amino-1,3-thiazoles are known as herbicides, synthetic intermediates or therapeutic agents. Among them, for example, 2-benzamido-1,3-thiazole is known as an antiallergic agent (European Patent Publication No. 261 503 of Valeas SPA). , 5-alkyl-2-phenylalkylcarbonylamino-1,3-thiazole is known as a protein kinase C inhibitor (WO 98/04536 by Otsuka Pharmaceutical Co.). 5-arylthio-2-acylamino-1,3-thiazole is known from antitumor agents (European Patent Publication No. 412 404 by Fujisawa Pharm. Co.). 4-amino-2-carbonylamino-1,3-thiazole is a cyclin dependent kinase inhibitor (International Publication No. WO 99/21845 of Agouron Pharmaceuticals Inc.). Known.
    [75] As used herein, the term halogen atom means a fluorine, chlorine, bromine or iodine atom unless otherwise specified.
    [76] As used herein, the terms alkyl and alkoxy include C 1 -C 6 alkyl and C 1 -C 6 alkoxy groups unless otherwise specified. The term straight or branched chain is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary-butyl, tert-butyl, n-pentyl, n-hexyl, methoxy, ethoxy, n- C 1 -C 6 alkyl or C 1 -C 6 alkoxy selected from propoxy, isopropoxy, n-butoxy and the like.
    [77] Likewise, the terms N-alkyl-piperazinyl, alkylsulfonyl, alkylcarbonyl, alkylthio, dialkylamino, alkoxyamino, arylalkyl, alkylamino, alkyl-cycloalkyl, alkoxycarbonyl, alkoxycarbonylamino and the like Alkyl and alkoxy moieties include the groups mentioned above having, for example, C 1 -C 6 alkyl or alkoxy groups.
    [78] Unless otherwise specified, the term cycloalkyl refers to C 3 -C 6 cycloalkyl groups (e.g. cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl) and cycloalkyl and crosslinked cycloalkyl groups of up to 10 carbon atoms (e.g. Just a burnt group).
    [79] The term aryl includes mono-, bi- or poly-carbocyclic or heterocyclic hydrocarbons having 1 to 4 ring residues, wherein at least one ring is an aromatic group and is fused or linked to each other by a single bond. Therefore, these groups may have 5 to 20 carbon atoms, preferably 6 to 20 carbon atoms.
    [80] Thus, the term heterocycle including heteroaromatic rings includes saturated or unsaturated 5- or 6-membered carbocycles, wherein one or more carbon atoms are replaced by one or more atoms selected from nitrogen, oxygen, and sulfur.
    [81] Examples of preferred aryl groups are phenyl, 1-naphthyl, 2-naphthyl, indanyl, indenyl, biphenyl, benzocycloalkyl (e.g. bicyclo [4.2.0] octa-1,3,5-triene ), Benzoheterocyclyl (e.g. benzodioxolyl), quinoxalyl, indolyl, optionally benzo condensed pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isoxazolyl, tetra Zolyl, pyridyl, pyrazinyl, pyrimidyl and the like.
    [82] The term C 2 -C 4 alkenyl or alkynyl is selected from vinyl, allyl, 1-propenyl, isopropenyl, 1-butanol, 2-butenyl, 3-butenyl, ethynyl, propynyl, butynyl, and the like. Include a group.
    [83] The terms perfluorinated alkyl and alkoxy groups are C 1 -C 4 alkyl or alkoxy groups further substituted by one or more fluorine atoms, for example trifluoromethyl, 2,2,2-trifluoroethyl, 1, 1,2,2,2-pentafluoroethyl, trifluoromethoxy, etc. are meant.
    [84] Pharmaceutically acceptable salts of compounds of formula I or formula II include inorganic or organic acids such as nitric acid, hydrochloric acid, bromic acid, sulfuric acid, perchloric acid, phosphoric acid, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, lactic acid, oxalic acid, Acid addition salts with malonic acid, malic acid, maleic acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, isethionic acid and salicylic acid, as well as inorganic bases or organic bases such as alkali or alkaline earth metals. , In particular sodium hydroxide, potassium hydroxide, calcium hydroxide or magnesium hydroxide, sodium carbonate, potassium carbonate, calcium carbonate or magnesium carbonate, sodium bicarbonate, potassium bicarbonate, calcium bicarbonate, magnesium bicarbonate, bicyclic amines or cyclic amines, preferably methylamine , Ethylamine, diethylamine, triethylamine or piperidine).
    [85] The compounds of formula (I) or formula (II) may comprise asymmetric carbon atoms and thus may exist as racemic mixtures or as individual optical isomers.
    [86] Accordingly, the use of all possible isomers of compounds of formula (I) or formula (II) and mixtures thereof and metabolites and pharmaceutically acceptable bioprecursors (called running pro-drugs) as antitumor agents is also within the scope of the present invention. do.
    [87] Preferred compounds of the invention of formula (I) or formula (II) are those wherein L is phenyl, thiazole, imidazole, oxazole, pyrazole, isoxazole, thiophene, pyridine or pyrimidine,
    [88] Group (ii) wherein R is selected from the group consisting of halogen atoms (i), arylamino, alkylamino and dialkylamino, wherein the alkyl moiety may be unsubstituted or further substituted with one or more hydroxy or amino groups A C 3 -C 6 cycloalkyl group (iii) unsubstituted or substituted with an alkyl group, a straight or branched C 1 -C 4 alkyl or arylalkyl group (iv) or a substitution unsubstituted or substituted as described above Unsubstituted or substituted aryl group (v),
    [89] R 1 is hydrogen or a C 1 -C 4 alkyl group which is unsubstituted or substituted with a hydroxy or amino group.
    [90] Within this class, more preferred compounds are
    [91] L is phenyl or thiazole,
    [92] R is alkylamino or dialkylamino, wherein the alkyl moiety may be further substituted with one or more hydroxy groups or amino groups, C 3 -C 6 cycloalkyl, straight chain unsubstituted or substituted with one or more hydroxy Or branched C 1 -C 4 alkyl, amino, alkylamino, dialkylamino, pyrrolidino, morpholino, N-alkylpiperazino and azabicyclo [3.2.2.] Nonane ,
    [93] R 1 is hydrogen,
    [94] Straight or branched C 1 -C 6 alkyl, alkoxy, amino, alkylamino, dialkylamino, p, wherein R 2 and R 3 are the same or different and are hydrogen, adamantyl, unsubstituted or substituted with one or more hydroxy; Lolidino, morpholino, N-alkyl-piperazino, imidazole, 3-azabicyclo [3.2.2] nonane, aminocarbonyl or dialkylaminocarbonyl, or
    [95] R 2 and R 3 together with the nitrogen atom to which they are attached are 4-morpholinyl, N-alkyl-piperazinyl, pyrrolidinyl, 2-oxo-1-pyrrolidinyl, imidazolyl or 3-azabi To form a cyclo [3.2.2] nonyl ring,
    [96] R 4 is carboxy, perfluorinated alkyl, C 2 -C 4 -alkenyl, C 2 -C 4 alkynyl, 2-oxopyrrolidinyl, piperidinyl; Aryl unsubstituted or substituted with halogen, dialkylamino, aminosulfonyl, aminocarbonyl, alkoxy, hydroxy, alkylcarbonylamino, amino, pyrrolidino, N-alkyl-piperazino or morpholino, or
    [97] R 4 is unsubstituted or halogen, hydroxy, alkoxy, alkylthio, arylthio, C 3 -C 6 cycloalkyl, cyano, carboxy, amino, alkylamino, dialkylamino, pyrrolidino, morpholino, N-alkylpiperazino, azabicyclo [3.2.2] nonane, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aryl unsubstituted or substituted with halogen, dialkylamino, aminosulfonyl, amino Formula I or a straight or branched chain C 1 -C 6 alkyl group substituted with carbonyl, alkoxy, hydroxy, alkylcarbonylamino, amino, alkylamino, pyrrolidino, N-alkyl-piperazino or morpholino Compound of formula (II).
    [98] Examples of preferred compounds of formula (I) or formula (II) of the present invention that may be present in pharmaceutically acceptable salts, eg, hydrobromide or hydrochloride forms, include:
    [99] N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) acrylamide,
    [100] N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -2-methyl Propanamide,
    [101] N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -2-na FTamide,
    [102] N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) benzamide,
    [103] N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -2-phenyl Acetamide,
    [104] N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -2- ( 3-pyridinyl) acetamide,
    [105] 2,2,3,3,3-pentafluoro-N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1 , 3-thiazol-2-yl) propanamide,
    [106] 2-[(4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) amino]- 2-oxoacetic acid,
    [107] 2-fluoro-N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl Acetamide,
    [108] 2-chloro-N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) Acetamide,
    [109] 2-cyano-N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl Acetamide,
    [110] N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -3-oxo Beta-alanine,
    [111] N'1 '-(4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) malon amides,
    [112] 4-[(4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -4- Oxobutanoic Acid,
    [113] 2- [2- (glycloylamino) -1,3-thiazol-4-yl] -N- (5-isopropyl-1,3-thiazol-2-yl) acetamide,
    [114] 3-hydroxy-N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl Propanamide,
    [115] 3-amino-N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) Propanamide,
    [116] 2-amino-N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) Acetamide,
    [117] 4-hydroxy-N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl Butanamide,
    [118] 4-amino-N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) Butanamide,
    [119] N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -2- ( 4-methyl-1-piperazinyl) acetamide,
    [120] 2- (4-benzyl-1-piperazinyl) -N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1 , 3-thiazol-2-yl) acetamide,
    [121] N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -2- ( 1-piperidinyl) acetamide,
    [122] N- (5-isopropyl-1,3-thiazol-2-yl) -2- [2- (2-oxo-1-pyrrolidinyl) -1,3-thiazol-4-yl] acetamide ,
    [123] 2- [4- (dimethylamino) phenyl) -N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3 -Thiazol-2-yl) acetamide,
    [124] N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -2- ( 1H-1,2,3,4-tetrazol-1-yl) acetamide,
    [125] N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -5-oxo -2-pyrrolidinecarboxamide,
    [126] N'1 '-(4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) succinate amides,
    [127] 3- (1H-benzimidazol-2-yl) -N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1 , 3-thiazol-2-yl) propanamide,
    [128] 1-acetyl-N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -4-piperidinecarboxamide,
    [129] 2- [2- (acetylamino) -1,3-thiazol-4-yl] -N- (5-isopropyl-1,3-thiazol-2-yl) acetamide,
    [130] 4-chloro-N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) Butanamide,
    [131] N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -2-meth Oxyacetamide,
    [132] 3,3,3-trifluoro-N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thia Zol-2-yl) propanamide,
    [133] 2- (dimethylamino) -N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazole-2 Acetamide,
    [134] N- (5-isopropyl-1,3-thiazol-2-yl) -2- (2-{[2- (4-methyl-1-piperazinyl) ethyl] amino} -1,3-thia Zol-4-yl) acetamide,
    [135] N- (5-isopropyl-1,3-thiazol-2-yl) -2- (2- {methyl [2- (4-methyl-1-piperazinyl) ethyl] amino} -1,3- Thiazol-4-yl) acetamide,
    [136] N- (5-isopropyl-1,3-thiazol-2-yl) -2- (2-{[2- (4-morpholinyl) ethyl] amino} -1,3-thiazole-4- Acetamide,
    [137] N- (5-isopropyl-1,3-thiazol-2-yl) -2- (2- {methyl [2- (4-morpholinyl) ethyl] amino} -1,3-thiazole-4 Acetamide,
    [138] 2- {2-[(2,3-dihydroxypropyl) amino] -1,3-thiazol-4-yl} -N- (5-isopropyl-1,3-thiazol-2-yl) Acetamide,
    [139] 2- {2-[(2,3-dihydroxypropyl) (methyl) amino] -1,3-thiazol-4-yl} -N- (5-isopropyl-1,3-thiazole-2 Acetamide,
    [140] 2- (2-{[3- (dimethylamino) -2-hydroxypropyl] amino} -1,3-thiazol-4-yl) -N- (5-isopropyl-1,3-thiazole- 2-yl) acetamide,
    [141] 2- {2-[(2-amino-2-oxoethyl) amino] -1,3-thiazol-4-yl} -N- (5-isopropyl-1,3-thiazol-2-yl) Acetamide,
    [142] 2- (2-{[2- (dimethylamino) -2-oxoethyl] amino} -1,3-thiazol-4-yl) -N- (5-isopropyl-1,3-thiazole-2 -Yl) -acetamide,
    [143] 2- [2- (adamantylamino) -1,3-thiazol-4-yl] -N- (5-isopropyl-1,3-thiazol-2-yl) acetamide,
    [144] 2- [4- (dimethylamino) phenyl] -N- (5-isopropyl-1,3-thiazol-2-yl) acetamide,
    [145] N- (5-isopropyl-1,3-thiazol-2-yl) -2- [4- (4-methyl-1-piperazinyl) phenyl] acetamide,
    [146] N- (5-isopropyl-1,3-thiazol-2-yl) -2- [4- (4-morpholinyl) phenyl] acetamide,
    [147] N- (5-isopropyl-1,3-thiazol-2-yl) -2- [4- (1-pyrrolidinyl) phenyl] acetamide,
    [148] N- [5-isopropyl-1,3-thiazol-2-yl) -2- (4-{[2- (4-methyl-1-piperazinyl) ethyl] amino} phenyl) acetamide,
    [149] N- (5-isopropyl-1,3-thiazol-2-yl) -2- (4- {methyl [2- (4-methyl-1-piperazinyl) ethyl] amino} phenyl) acetamide,
    [150] N- (5-isopropyl-1,3-thiazol-2-yl) -2- (4-{[2- (4-morpholinyl) ethyl] amino} phenyl) acetamide,
    [151] N- (5-isopropyl-1,3-thiazol-2-yl) -2- (4- {methyl [2- (4-morpholinyl) ethyl] amino} phenyl) acetamide,
    [152] 2- {4-[(2,3-dihydroxypropyl) amino] phenyl} -N- (5-isopropyl-1,3-thiazol-2-yl) acetamide,
    [153] 2- {4-[(2,3-dihydroxypropyl) (methyl) amino] phenyl} -N- (5-isopropyl-1,3-thiazol-2-yl) acetamide,
    [154] 2- (4-{[3- (dimethylamino) -2-hydroxypropyl] amino} phenyl) -N- (5-isopropyl-1,3-thiazol-2-yl) acetamide,
    [155] 2- [4- (1-adamantylamino) phenyl) -N- (5-isopropyl-1,3-thiazol-2-yl) acetamide,
    [156] 2- {4-[(2-amino-2-oxoethyl) amino] phenyl} -N- (5-isopropyl-1,3-thiazol-2-yl) acetamide,
    [157] 2- (4-{[2- (dimethylamino) -2-oxoethyl] amino} phenyl) -N- (5-isopropyl-1,3-thiazol-2-yl) acetamide,
    [158] 2- [4- (acetylamino) phenyl] -N- (5-isopropyl-1,3-thiazol-2-yl) acetamide,
    [159] N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) nicotinamide,
    [160] N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) -5-methyl-2-thiophencarboxamide,
    [161] N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl-5-methyl-2-pyrazinecarboxamide,
    [162] N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) -5-methyl-4-isooxazolecarboxamide,
    [163] N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) -3,5-dimethyl-4-isooxazolecarboxamide ,
    [164] (Dimethylamino) -N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) benzamide,
    [165] 4- (acetylamino) -N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) benzamide,
    [166] 4- (dimethylamino) -N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) benzamide,
    [167] N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) -1,3-benzodioxol-5-carboxamide ,
    [168] 4- (aminosulfonyl) -N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) benzamide,
    [169] 2-chloro-2,2-difluoro-N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) acetamide ,
    [170] 2-cyano-N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) acetamide,
    [171] 1-acetyl-N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) -4-piperidinecarboxamide,
    [172] N'1 '-(4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) succinamide,
    [173] N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) -2-methoxyacetamide,
    [174] 3,3,3-trifluoro-N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) propanamide,
    [175] N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) -2-phenylacetamide,
    [176] N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) -2-methoxy-2-phenylacetamide,
    [177] 2- [4- (dimethylamino) phenyl] -N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) acetamide ,
    [178] N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) -2- (3-pyridinyl) acetamide,
    [179] N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) -2- (3-thienyl) acetamide,
    [180] N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) -2- [5- (1-pyrrolidinyl)- 2H-1,2,3,4-tetraazol-2-yl] acetamide,
    [181] 2-cyclopropyl-N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl Acetamide,
    [182] N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -5-methyl -2-pyrazinecarboxamide,
    [183] N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -2-propyl amides,
    [184] N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -5-methyl -1,3-oxazole-4-carboxamide,
    [185] N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -3,3 Dimethylbutanamide,
    [186] N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -3-methyl -2-butenamide,
    [187] 3-cyclopentyl-N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl Propanamide,
    [188] N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -2- ( 3-thienyl) acetamide,
    [189] N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -2- ( 3-pyridinyl) acetamide,
    [190] 2,2,2-trifluoro-N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thia Zol-2-yl) acetamide,
    [191] N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -3- ( 2-thienyl) propanamide,
    [192] N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -2- ( 4-pyridinylsulfanyl) acetamide,
    [193] N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -2- ( 3-pyridinyl) -1,3-thiazole-4-carboxamide,
    [194] 2- [2- (acetylamino) -1,3-thiazol-4-yl] -N- (5-cyclopropyl-1,3-thiazol-2-yl) acetamide,
    [195] 2- [2- (acetylamino) -1,3-thiazol-4-yl] -N- {5-[(3-hydroxypropyl) (methyl) amino] -1,3-thiazole-2- Acetamide,
    [196] 2- [2- (acetylamino) -1,3-thiazol-4-yl] -N- {5-[(2-hydroxyethyl) (methyl) amino] -1,3-thiazole-2- Acetamide,
    [197] 2- [4- (dimethylamino) phenyl] -N- {5-[(2-hydroxyethyl) (methyl) amino] -1,3-thiazol-2-yl} acetamide,
    [198] 2- [4- (dimethylamino) phenyl] -N- {5-[(3-hydroxypropyl) (methyl) amino] -1,3-thiazol-2-yl] acetamide and
    [199] N- (5-cyclopropyl-1,3-thiazol-2-yl) -2- [4- (dimethylamino) phenyl] acetamide.
    [200] Compounds of formula (I) or formula (II) and salts thereof can be prepared by reacting, for example, compounds of formula (III) with compounds of formula (IV), wherein R, L, R 1 , R 2 and R 3 (A) as defined above, or
    [201] Reacting a compound of Formula Ia with a compound of Formula V to yield a compound of Formula II wherein R, L, R 1 , R 2 and R 3 are as defined above, or (b)
    [202] Compounds of formula I, wherein at least one of R 1 and R 2 are hydrogen atoms, are reacted with compounds of formula VI to yield compounds of formula I, wherein at least one of R 2 and R 3 is not hydrogen And, optionally, a method comprising converting a compound of formula (I) or formula (II) to another compound of formula (I) or formula (II) and / or salts thereof.
    [203] Formula Ia
    [204]
    [205] Formula III
    [206]
    [207] Formula IV
    [208]
    [209] Formula V
    [210]
    [211] Formula VI
    [212]
    [213] In the above formulas (Ia), (III) to (VI),
    [214] R, L, R 1 , R 2 and R 3 are as defined above,
    [215] Z is hydroxy or a suitable leaving group,
    [216] X is hydroxy or a suitable leaving group,
    [217] R 'has the meaning of R 2 or R 3 but is not hydrogen,
    [218] Y is a suitable leaving group.
    [219] As will be readily appreciated by those skilled in the art, when a compound of formula (I) or formula (II) prepared according to the above process is obtained as a mixture of isomers, single isomers of formula (I) or Furnace separation is also included within the scope of the present invention. Likewise, the conversion of the corresponding salts to the free compounds (I or II) according to processes known in the art is also within the scope of the present invention.
    [220] The processes of (a), (b) and (c) above are similar processes that can be carried out according to methods known in the art.
    [221] Reaction of a compound of formula III according to process (a) with a compound of formula IV, wherein Z is a hydroxy group, or a compound of formula I according to process (b), wherein R 2 and R 3 are both Reaction of a carboxylic acid of formula V, wherein X is a hydroxy group, with a coupling agent (e.g., carbodiimide, ie 1,3-dicyclohexylcarbodiimide, 1,3-diisopropyl) In the presence of carbodiimide or 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide) or in a suitable solvent such as dichloromethane, chloroform, tetrahydrofuran, diethyl ether, 1,4-dioxane At about −10 ° C. to reflux using polymer supported carbodiimide (eg, N-cyclohexylcarbodiimide) and N′-methyl polystyrene in acetonitrile, toluene or N, N-dimethylformamide For a suitable time, ie, from about 30 minutes to about 8 days .
    [222] In addition, the reaction of a compound of formula III with a compound of formula IV, wherein Z is hydroxy, or a compound of formula I, wherein R 2 and R 3 are hydrogen atoms, and a compound of formula V, wherein Hydroxy) reactions can be carried out in a mixed anhydride method using, for example, alkyl chloroformates (e.g. ethyl, isobutyl or isopropyl chloroformate), tertiary bases (e.g. triethylamine, N, Suitable solvents in the presence of N-diisopropylethylamine or pyridine), such as toluene, dichloromethane, chloroform, tetrahydrofuran, acetonitrile, diethyl ether, 1,4-dioxane or N, N-dimethylformamide ) At about -30 ° C to room temperature.
    [223] Reaction of a compound of formula III according to process (a) with a carboxylic acid derivative of formula IV, wherein Z is a suitable leaving group or a compound of formula I according to process (b), wherein R 2 and R 3 are both Reaction of a carboxylic acid derivative of formula V, wherein X is a suitable leaving group, is a suitable solvent in the presence of a tertiary base such as triethylamine, N, N-diisopropylethylamine or pyridine (For example, toluene, dichloromethane, chloroform, diethyl ether, tetrahydrofuran, acetonitrile or N, N-dimethylformamide).
    [224] The reaction of the compound of formula (I) according to process (c) with a compound of formula (VI), wherein Y is a suitable leaving group, is carried out in a suitable base (e.g. Pyridine) in the presence of a suitable solvent such as ethanol, acetonitrile, N, N-dimethylformamide, 1,4-dioxane or tetrahydrofuran.
    [225] The reaction of the compound of formula (I) and the compound of formula (VI) according to step (c), wherein Y is hydroxy, is suitable in the presence of triphenylphosphine and diethylazidodicarboxylate under Mitsunobu conditions. It can be carried out at 0 ° C. to room temperature in a solvent such as tetrahydrofuran.
    [226] The reaction of the compound of formula (I) with the compound of formula (VI), wherein Y is CHO, according to process (c) is carried out by conventional reducing agents such as sodium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride. Ride) in the presence of a suitable solvent such as methanol or ethanol.
    [227] In addition, any conversion of a compound of Formula (I) or Formula (II) to another compound of Formula (I) or Formula (II) can be carried out according to known methods.
    [228] For example, step (c) above can be regarded as a possible conversion of a compound of the present invention to another compound of the present invention.
    [229] Any saponification process of the compounds of formula (I) or formula (II) or the conversion of salts to free compounds or the separation of isomer mixtures into single isomers can be carried out in conventional manner.
    [230] The compounds of the formula (III), (IV), (V) and (VI) according to the process of the invention are known compounds or can be obtained according to known methods.
    [231] Compounds of formula IV or compounds of formula V, wherein Z or X are leaving groups as defined above, are formulated from the corresponding carboxylic acids of formula IV or formula V, wherein Z or X are hydroxy Can be obtained accordingly.
    [232] Compounds of formula III, wherein R is as defined above, can be prepared by, for example, the compounds of formula VII in room temperature in a suitable solvent such as methanol, ethanol, tetrahydrofuran, 1,4-dioxane or toluene. It can be obtained by reacting with thiourea for a suitable time (about 1 hour to about 24 hours) at the reflux temperature.
    [233]
    [234] In Formula VII above,
    [235] R is as defined above,
    [236] W is bromine or chlorine.
    [237] The compounds of the formulas (IV) to (VII), in some cases, are commercially available or can be prepared by methods known in the art.
    [238] When preparing the compounds of formula (I) according to the process of the invention, any functional groups in the starting material or intermediates thereof, which can give rise to undesired side reactions, must be suitably protected according to conventional techniques.
    [239] In addition, the conversion of these protected compounds to free deprotected compounds can also be carried out according to known processes.
    [240] Pharmacology
    [241] Compounds of formula (I) or formula (II) are active as cdk / cycline inhibitors because they give positive results when tested according to the following process.
    [242] The inhibitory activity of putative cdk / cycline inhibitors and the efficacy of the selected compounds are determined by assay methods based on the use of Multiscreen-PH 96 well plates (Millipore), where phosphocellulose filter paper is washed / filtered. After the step is placed at the bottom of each well to bind the positively charged substrate.
    [243] If the radioactively labeled phosphate residues are transferred to the filter paper bound histones by ser / threo kinase, luminescence is measured with a scintillation counter.
    [244] Inhibition assay of cdk2 / cyclin A activity is carried out according to the following protocol:
    [245] Kinase reaction: 10 M in 1.5 M histone HI substrate, 25 M ATP (0.5 μCi P33g-ATP), 100 ng cyclin A / cdk2 complex and final volume 100 μL buffer (Tris HCl 10 mM pH 7.5, MgCl 2 10 mM, 7.5 mM DTT) Inhibitor is added to each well of a 96U lower well plate. After incubation at 37 ° C. for 10 minutes, the reaction is stopped with 20 μl of 120 mM EDTA.
    [246] Capture: Transfer 100 L from each well to a multiscreen plate to bind the substrate to phosphocellulose filter paper. The plates are then washed three times with 150 pi of Ca ++ / Mg ++ free PBS per well and filtered through a multiscreen filtration system.
    [247] Detection: The filtrate is dried at 37 ° C., 100 L of Scintillant is added per well, and then 33P labeled histone H1 is detected by radioactivity count in a Top-counting device.
    [248] Results: Data is analyzed and expressed as% inhibition against total enzyme activity (= 100%).
    [249] All compounds with inhibition above 50% are further analyzed to study and define the kinetics profile of the inhibitor via Ki calculation.
    [250] The protocol used is the same as described above except for ATP and substrate concentration. The concentrations of ATP and histone H1 substrates vary: 4, 8, 12, 24, 48AM for ATP (relatively diluted P33g-ATP) and 0.4, 0.8, 1.2, 2.4, 4.8AM for histones. It is used in the presence and absence of two different inhibitor concentrates.
    [251] The experimental data is analyzed with the computer program "SigmaPlot" for Ki measurement using a random double reactant system equation.
    [252]
    [253] In Equation 1 above,
    [254] A is ATP and B is histone H1.
    [255] For example, a compound of the invention, represented by an IC 50 value, namely 2- [2- (acetylamino) -1,3-thiazol-4-yl] -N- (5-isopropyl-1,3 Inhibitory activity of -thiazol-2-yl) acetamide [0.5 (M)] against the CDk2 / cyclin A complex is reported.
    [256] In addition, the inhibitory activity of putative cdk / cycline inhibitors and the efficacy of the selected compounds are determined by an assay method based on the use of a SPA (Scintilation-like assay) 96 well plate assay. This assay is based on the ability of streptavidin coated SPA beads to capture biotinylated peptides derived from the phosphorylation site of histones.
    [257] If the radioactively labeled phosphate residue is transferred to the biotinylated histone peptide by ser / threo kinase, luminescence is measured with a scintillation counter.
    [258] Inhibition assay of cdk5 / p25 activity is performed according to the following protocol:
    [259] Kinase Activity: 0-100 M inhibitor in 1.0 M biotinylated histone peptide substrate, 0.25 μCi P33g-ATP, 4 nM cdk2 / p25 complex, and final volume 100 μL buffer [Herpes 20 mM pH 7.5, MgCl 2 15 mM, 1 mM DTT] Is added to each well of a 96U lower well plate. After incubation at 37 ° C. for 10 minutes, the reaction is stopped by adding 500 μg of SPA beads in phosphate buffered saline containing 0.1% Triton X-100, 50 μM ATP and 5 mM EDTA. Beads were immobilized and the radioactivity introduced into the 33P labeled peptide was detected with a Top count scintillation counter.
    [260] Results: The data is analyzed and expressed as percent inhibition using Equation 2 below.
    [261]
    [262] IC 50 values are calculated using the logarithmic equation variance of four variables.
    [263]
    [264] In Equation 3 above,
    [265] X is log (μM) and Y is percent inhibition.
    [266] Thus, the compounds of formula (I) or formula (II) are useful for inhibiting uncontrolled proliferation of tumor cells, and thus are useful for various tumors, such as carcinomas such as breast cancer, lung cancer, bladder cancer, colon cancer, ovarian cancer and endometrial cancer. ), Sarcomas (eg soft tissue and bone sarcoma) and hematologic malignancies (eg leukemia).
    [267] In addition, the compounds of formula (I) or formula (II) are useful for the treatment of vascular smooth muscle proliferation and post stenosis and restenosis associated with other cell proliferative diseases such as psoriasis, atherosclerosis, and for the treatment of Alzheimer's disease.
    [268] Compounds of formula (I) or formula (II) of the invention suitable for administration to a mammal, such as a human, may be administered by conventional routes, with dosage levels dependent on age, weight, patient's condition and route of administration. .
    [269] For example, a suitable dosage to be employed for oral administration of a compound of formula (I) or formula (II) may range from about 10 to about 500 mg per administration once to five times per day.
    [270] Compounds of the present invention may be administered as a single agent or may be a cytostatic or cytotoxic agent, an antibiotic type agent, an alkylating agent, an antimetabolic agent, a hormonal agent, an immunological agent, an agent of the interferon type, a cyclooxygenase inhibitor ( Examples: COX-2 inhibitors), metallomatrix protease inhibitors, telomerase inhibitors, tyrosine kinase inhibitors, anti growth factor receptor preparations, anti-HER preparations, anti-EGFR preparations, anti-angiogenic agents, farnesyl transferase inhibitors known anticancer therapies, such as radiation therapy or chemotherapy, in combination with ras-raf signal hemolytic pathway inhibitors, cell cycle inhibitors, other cdk inhibitors, tubulin binding agents, topoisomerase I inhibitors, topoisomerase II inhibitors, and the like. It can be administered together with.
    [271] For example, the compounds of the present invention may contain one or more chemotherapeutic agents in any of their liposome formulations, such as taxanes, taxane derivatives, encapsulated taxanes, CPT-11, camptothecin derivatives, anthracycline glycosides (eg doxorubicin, In combination with idarubicin, epirubicin, etoposide, nabelbin, vinblastine, carboplatin, cisplatin, esturamustine, celecoxib, sugen SU-5416, sugen SU-6668, herceptin, etc.) Can be.
    [272] When formulated at fixed dosages, these combination products use the compounds of the invention within the dosage ranges described above and other pharmaceutical actives within the approved dosage ranges.
    [273] The compounds of formula (I) can be used sequentially with known anticancer agents if the formulation is inappropriate.
    [274] The compounds of the present invention can be administered orally in a variety of dosage forms, eg, in the form of tablets, capsules, sugars or film coated tablets, solutions or suspensions; Administered rectally in the form of suppositories; Parenterally, for example, intramuscularly; Administration may be by intravenous and / or intradural and / or intrathecal injection or infusion.
    [275] The present invention also includes pharmaceutical compositions comprising a compound of Formula I or Formula II or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable excipient, which may be a carrier or diluent.
    [276] Pharmaceutical compositions containing a compound of the present invention are generally prepared according to conventional methods and administered in a pharmaceutically suitable form.
    [277] For example, solid oral forms may contain diluents (e.g. lactose, dextrose, saccharose, sucrose, cellulose, corn starch or potato starch), lubricants (e.g. silica, talc, stearic acid, magnesium) with the active compound Or calcium stearate and / or polyethylene glycol), binders (e.g. starch, gum arabic, gelatin, methylcellulose, carboxymethylcellulose or polyvinyl pyrrolidone), disintegrants (e.g. starch, alginic acid, alginate or sodium starch) Glycolates), foaming mixtures, dyes, sweeteners, wetting agents (e.g. lecithin, polysorbates, laurylsulfate) and generally nontoxic pharmacologically active substances used in pharmaceutical formulations. Pharmaceutical formulations can be prepared by known methods such as mixing, granulating, sugar coating or film coating processes. Liquid dispersants for oral dosage forms for tableting can be, for example, syrups, emulsions and suspensions.
    [278] The syrup may contain, for example, saccharose as a carrier, or saccharose with glycerin and / or mannitol and / or sorbitol.
    [279] Suspending agents and emulsions may contain, for example, natural gums, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose or polyvinyl alcohol as carriers.
    [280] Suspensions or solutions for intramuscular injection, together with the active compounds, include pharmaceutically acceptable carriers such as sterile water, olive oil, ethyl oleate, glycols (such as propylene glycol) and, optionally, suitable amounts of lidocaine It may contain hydrochloride. Solutions for intravenous injection or infusion may, for example, contain sterile water as a carrier, or they may preferably be sterile, aqueous, isotonic saline solutions or contain propylene glycol as a carrier.
    [281] Suppositories may contain pharmaceutically acceptable carriers such as cocoa butter, polyethylene glycols, polyoxyethylene sorbitan fatty acid ester surfactants or lecithin with the active compound.
    [282] The following examples are for illustrative purposes and do not limit the invention.
    [283] Although the present invention has been described in general, it will be further understood with reference to specific examples which are provided herein for purposes of illustration and not limitation, unless otherwise specified.
    [284] Example 1
    [285] Preparation of 2-amino-5-isopropyl-1,3-thiazole
    [286] 2 ml (18.6 mmol) of 3-methylbutyraldehyde are dissolved in 15 ml of 1,4-dioxane. 40.4 ml (18.6 mmol) of a 2% (v / v) solution of bromine in 1,4-dioxane are added dropwise at 0 ° C. The mixture is kept at room temperature for 2 hours with stirring, then 2.83 g (37.2 mmol) thiourea and 5 ml of ethanol are added.
    [287] After 6 h at rt, the solution is evaporated to dryness, the residue is dissolved in CH 2 Cl 2 , the product is extracted with 1M hydrochloric acid, the aqueous layer is basified with 30% ammonium hydrate and extracted again with CH 2 Cl 2 . The organic phase is dried over sodium sulfate and evaporated in vacuo. The residue is chromatographed on a silica gel column eluting with cyclohexane-ethyl acetate to give 1.1 g (42% yield) of the title compound.
    [288] 1 H-NMR (DMSO-d 6 ) ppm: 6.6 (s, 2H, NH 2 ); 6.58 (s, 1 H, thiazole CH); 2.9 (m, 1 H, CHMe 2 ); 1.18 (s, 3 H, MeCHMe); 1.17 (s, 3 H, MeCHMe).
    [289] Similarly, the following products can be prepared starting from the corresponding aldehydes: 2-amino-5-cyclopropyl-1,3-thiazole.
    [290] Example 2
    [291] Preparation of tert-butyl 4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-ylcarbamate
    [292] EDCI (20.6 g, 107 mmol) solution of 2- {2 [(tert-butoxycarbonyl) amino] -1,3-thiazol-4-yl} acetic acid (25 g, 97 mmol) in CHCl 3 (200 ml) It is added under ice cooling.
    [293] After stirring for 1 hour, a solution of 2-amino-5-isopropyl-1,3-thiazole (13.7 g, 97 mmol) in CHCl 3 (150 ml) was added dropwise and the entire mixture was added at 0 ° C. for 1 hour and It is then kept at room temperature overnight.
    [294] The solution is washed with water, 5% citric acid, water, saturated sodium bicarbonate and brine.
    [295] Drying with sodium sulfate and evaporation gave a solid, which was chromatographed with silica gel using CH 2 Cl 2 : MeOH (95: 5) as eluent to afford the title compound as a colorless solid (22 g; 59%).
    [296] Melting point: 196-197 ° C
    [297] 1 H-NMR (DMSO-d 6 ) ppm: 12 (s, broad, 1H, NH); 11.4 (s, broad, NHBoc); 7.14 (s, 1H, H 4 -thiazole); 6.9 (s, 1H, H 5 -thiazole); 3.7 (s, 2H, CH 2 ); 3.08 (m, 1 H, CHMe 2 ); 1.42 (s, 9 H, t-Bu); 1.22 (d, 6H, CHMe 2 ).
    [298] Similarly, starting from the corresponding carboxylic acid, the following product is prepared:
    [299] Tert-butyl 4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenylcarbamate
    [300] Melting Point: 179 to 180 ° C
    [301] 1 H-NMR (DMSO-d 6 ) ppm: 12.1 (s, broad, 1H, NH); 9.22 (s, broad, 1H, NHBoc); 7.35 (d, 2 H, Ph); 7.19 (s, 1 H, H 4 -thiazole); 7.15 (d, 2 H, Ph); 3.6 (s, 2H, CH 2 ); 3.08 (m, 1 H, CHMe 2 ); 1.43 (s, 9 H, t-Bu); 1.11 (d, 6H, CHMe 2 ).
    [302] Example 3
    [303] Preparation of 2- (2-amino-1,3-thiazol-4-yl) -N- (5-isopropyl-1,3-thiazol-2-yl) acetamide
    [304] Trifluoroacetic acid (168 ml) was tert-butyl 4- {2-[(5-isopropyl-1,3-thiazole-2) in CH 2 Cl 2 (750 ml) and anisole (9.33 ml, 86.27 mmol). -Yl) amino] -2-oxoethyl} -1,3-thiazol-2-ylcarbamate (22 g, 57.51 mmol) was added under ice-cooling.
    [305] After stirring at 0 ° C. for 2 hours, the solution is kept at room temperature overnight and then evaporated. The residue is dissolved in CH 2 Cl 2 and the solvent is evaporated (500 ml × 3).
    [306] The residue is then partitioned between CH 2 Cl 2 and water. The organic layer is further washed with water, saturated sodium bicarbonate and brine.
    [307] Drying with sodium sulfate and evaporation gave a solid, which was triturated with isopropyl ether / cyclohexane to afford the title compound as a beige solid (13 g; 81%).
    [308] Melting point: 201 to 203 캜.
    [309] 1 H-NMR (DMSO-d 6 ) ppm: 11.98 (s, broad, 1H, NH); 7.13 (s, broad, 1H, NHBoc); 7-6.6 (m, 4, Ph); 5.9 (s, broad, 2H, NH 2 ); 3.55 (s, 2 H, CH 2 ); 3.08 (m, 1 H, CHMe 2 ); 1.12 (d, 6H, CHMe 2 ).
    [310] Similarly, the following products can be prepared:
    [311] 2- (4-aminophenyl) -N- (5-isopropyl-1,3-thiazol-2-yl) acetamide
    [312] Melting Point: 165 to 166 ° C
    [313] 1 H-NMR (DMSO-d 6 ) ppm: 11.98 (s, broad, 1H, NH); 7.13 (s, 1H, H 4 -thiazole); 7-6.6 (m, 4 H, Ph); 5.9 (s, broad, 2H, NH 2 ); 3.55 (s, 2 H, CH 2 ); 3.08 (m, 1 H, CHMe 2 ); 1.12 (d, 6H, CHMe 2 );
    [314] 4-amino-N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) Butanamide;
    [315] 3-amino-N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) Propanamide and
    [316] 2-amino-N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) Acetamide.
    [317] Example 4
    [318] 2-chloro-N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) Preparation of Acetamide
    [319] EDCI (0.49 g, 2.54 mmol) was added to a solution of 2-chloroacetic acid (0.24 g, 2.54 mmol) in CHCl 3 (10 ml) under ice cooling.
    [320] After stirring at 0 ° C. for 1 hour, 2- (2-amino-1,3-thiazol-4-yl) -N- (5-isopropyl-1,3-thiazole- in CHCl 3 (10 ml) A solution of 2-yl) acetamide (0.6 g, 2.12 mmol) is added dropwise and the entire mixture is kept at 0 ° C. for 1 hour and then at room temperature overnight.
    [321] The solution is washed with water, 5% citric acid, water, saturated sodium bicarbonate and brine.
    [322] Drying with sodium sulfate and evaporation gave a solid which was chromatographed with silica gel using CH 2 Cl 2 and then CH 2 Cl 2 : MeOH (99: 1) as eluent to give the title compound a colorless solid (0.49 g; 65%). Obtained as
    [323] Melting point: 176-178 ° C
    [324] 1 H-NMR (CDCl 3 ) ppm: 11 (s, broad, 2H, 2NH); 7.01 (s, 1H, H 4 -thiazole); 6.63 (s, 1H, H 5 -thiazole); 4.23 (s, 2H, CH 2 Cl); 3.83 (s, 2 H, CH 2 CO); 3.1 (m, 1 H, CHMe 2 ); 1.35 (d, 6H, CHMe 2 ).
    [325] Similarly, the following products can be prepared:
    [326] 2- [2- (acetylamino) -1,3-thiazol-4-yl] -N- (5-isopropyl-1,3-thiazol-2-yl) acetamide
    [327] Melting Point: 174-176 deg.
    [328] 1 H-NMR (DMSO-d 6 ) ppm: 12.1 (2s, broad, 2H, 2NH); 7.15 (s, 1H, H 4 -thiazole); 6.93 (s, 1 H, H 5 -thiazole); 3.77 (s, 2 H, CH 2 ); 3.3 (s, 3H, CH 3 ); 3.1 (m, 1 H, CHMe 2 ); 1.22 (d, 6H, CHMe 2 );
    [329] 4-chloro-N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) Butanamide
    [330] Melting Point: 170-172 ° C
    [331] 1 H-NMR (DMSO-d 6 ) ppm: 12.15 (s, broad, 1H, NH); 12.05 (s, broad, 1H, NH); 7.12 (s, 1 H, H 4 -thiazole); 6.95 (s, 1 H, H 5 -thiazole); 3.76 (s, 2 H, CH 2 CO); 3.62 (t, 2H, CH 2 CH 2 CH 2 Cl); 3.08 (m, 1 H, CHMe 2 ); 2.55 (t, 2H, CH 2 CH 2 CH 2 Cl); 2 (tt, 2H, CH 2 CH 2 CH 2 Cl); 1.1 (d, 6H, CHMe 2 ).
    [332] N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -2-meth Oxyacetamide
    [333] Melting Point: 147-149 ° C
    [334] 1 H-NMR (DMSO-d 6 ) ppm: 12.03 (s, broad, 1H, NH); 7.11 (s, 1H, H 4 -thiazole); 6.98 (s, 1 H, H 5 -thiazole); 4.09 (s, 3 H, OMe); 3.79 (s, 2 H, CH 2 ); 3.1 (m, 1 H, CHMe 2 ); 1.21 (d, 6H, CHMe 2 );
    [335] 3,3,3-trifluoro-N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thia Zol-2-yl) propanamide
    [336] Melting Point: 214-216 ° C
    [337] 1 H-NMR (DMSO-d 6 ) ppm: 12.5 (s, broad, 1H, NH); 12.1 (s, broad, 1H, NH); 7.15 (s, 1H, H 4 -thiazole); 7.02 (s, 1 H, H 5 -thiazole); 3.79 (s, 2 H, CH 2 ); 3.6 (q, 2H, CH 2 CF 3 ); 3.1 (m, 1 H, CHMe 2 ); 1.11 (d, 6H, CHMe 2 );
    [338] 2- [4- (dimethylamino) phenyl] -N- (5-isopropyl-1,3-thiazol-2-yl) -acetamide
    [339] Melting Point: 136-137 ° C
    [340] 1 H-NMR 1 H-NMR (DMSO-d 6 ) ppm: 12 (s, broad, 1H, NH); 7.11 (s, 1H, H 4 -thiazole); 7.1 (d, 2H, Ph); 6.65 (d, 2 H, Ph); 3.55 (s, 2 H, CH 2 ); 3.1 (m, 1 H, CHMe 2 ); 2.82 (s, 6 H, NMe 2 ); 1.21 (d, 6H, CHMe 2 );
    [341] 2- [4- (acetylamino) phenyl] -N- (5-isopropyl-1,3-thiazol-2-yl) -acetamide
    [342] Melting point: 186 ~ 187 ° C
    [343] 1 H-NMR (DMSO-d 6 ) ppm: 12.09 (s, broad, 1H, NH); 9.9 (s, broad, 1H, NH); 7.6-7.2 (m, 4H, Ph); 7.15 (s, 1H, H 4 -thiazole); 3.62 (s, 2H, CH 2 ); 3.08 (m, 1 H, CHMe 2 ); 2- (s, 3H, CH 3 ); 1.21 (d, 6H, CHMe 2 );
    [344] Tert-butyl 2-[(4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl ) Amino] -2-oxoethylcarbamate;
    [345] Tert-butyl 3-[(4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl ) Amino] -3-oxopropylcarbamate and
    [346] Tert-butyl 4-[(4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl ) Amino] -4-oxobutylcarbamate;
    [347] 2- [4- (dimethylamino) phenyl] -N- (5-nitro-1,3-thiazol-2-yl) acetamide;
    [348] 2- [2- (acetylamino) -1,3-thiazol-4-yl] -N- (5-nitro-1,3-thiazol-2-yl) acetamide and
    [349] N- (5-cyclopropyl-1,3-thiazol-2-yl) -2- [4- (dimethylamino) phenyl] acetamide.
    [350] Example 5
    [351] N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -2-methyl Preparation of Propanamide
    [352] N-cyclohexylcarbodiimide, N'-methyl polystyrene (0.4 g, 2 mmol / g dropwise, 0.798 mmol), N-hydroxy to a solution of isobutyric acid (49 ml, 0.53 mmol) in CH 2 Cl 2 (1.5 ml) 2- (2-amino-1, 3-thiazol-4-yl) -N- (5-iso in benzotriazole (0.072 g, 0.53 mmol) and CH 2 Cl 2 / DMF (0.4 ml / 0.6 ml) A solution of propyl-1,3-thiazol-2-yl) acetamide (0.075 g, 0.266 mmol) is added. The reaction mixture is kept at room temperature for about 8 days under stirring. Then, PS-trisamine (0.44 g, 3.62 mmol / g dropwise, 1.596 mmol) is added and stirring is continued for about 6 hours, and then the mixture is filtered. The resin is washed with CH 2 Cl 2 (1 ml × 5), the organic layers are combined, evaporated to dryness and triturated with diisopropyl ether to afford the title compound.
    [353] Similarly, the following compounds can be prepared starting from the corresponding carboxylic acid:
    [354] N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) acrylamide;
    [355] N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -2-na Ftamide;
    [356] N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) benzamide;
    [357] N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -2-phenyl Acetamide;
    [358] N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -2- ( 3-pyridinyl) acetamide;
    [359] 2,2,3,3,3-pentafluoro-N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1 , 3-thiazol-2-yl) propanamide;
    [360] 2-fluoro-N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl Acetamide;
    [361] 2-cyano-N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl Acetamide;
    [362] N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -2- ( 4-methyl-1-piperazinyl) acetamide;
    [363] 2- (4-benzyl-1-piperazinyl) -N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1 , 3-thiazol-2-yl) acetamide;
    [364] N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -2- ( 1-piperidinyl) acetamide;
    [365] 2- [4- (dimethylamino) phenyl) -N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3 -Thiazol-2-yl) acetamide;
    [366] N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -2- ( 1H-1,2,3,4-tetrazol-1-yl) acetamide;
    [367] N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -5-oxo -2-pyrrolidinecarboxamide;
    [368] N'1 '-(4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) malon amides;
    [369] N'1 '-(4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) succinate amides;
    [370] 3- (1H-benzimidazol-2-yl) -N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1 , 3-thiazol-2-yl) propanamide and
    [371] 1-acetyl-N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -4-piperidinecarboxamide;
    [372] 2-cyclopropyl-N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl Acetamide;
    [373] N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -5-methyl -2-pyrazinecarboxamide;
    [374] N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -2-pro Pinamide;
    [375] N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -5-methyl -1,3-oxazole-4-carboxamide;
    [376] N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -3,3 Dimethylbutanamide;
    [377] N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -3-methyl 2-butenamide;
    [378] 3-cyclopentyl-N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl Propanamide;
    [379] N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -2- ( 3-thienyl) acetamide;
    [380] N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -2- ( 3-pyridinyl) acetamide;
    [381] 2,2,2-trifluoro-N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thia Zol-2-yl) acetamide;
    [382] N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -3- ( 2-thienyl) propanamide;
    [383] N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -2- ( 4-pyridinylsulfanyl) acetamide;
    [384] N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -2- ( 3-pyridinyl) -1,3-thiazole-4-carboxamide and
    [385] 2- [2- (acetylamino) -1,3-thiazol-4-yl] -N- (5-cyclopropyl-1,3-thiazol-2-yl) acetamide.
    [386] Example 6
    [387] Ethyl 2-[(4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) amino] -2-Oxoacetate Preparation
    [388] A solution of ethyl oxalyl chloride (1.2 ml, 10.6 mmol) in CHCl 3 (3 ml) was cooled to 0 ° C. with 2- (2-amino-1,3-thiazole-4 in CHCl 3 / DMF (50 ml / 15 ml) -Yl) -N- (5-isopropyl-1,3-thiazol-2-yl) acetamide (2.5 g, 8.85 mmol) and triethylamine (1.85 ml, 13.28 mmol) are added dropwise. The reaction mixture is stirred at 0 ° C. and room temperature overnight for about 1 hour, washed with water, 5% citric acid, saturated sodium bicarbonate and brine and then dried over sodium sulfate and evaporated to dryness to afford the title compound, without further purification. Use (1.2 g).
    [389] Similarly, starting from the corresponding acid chlorides, the following compounds can be prepared and used as crudes:
    [390] Ethyl 3-[(4- {2-[(5-isopropyl-1,3-thiazol-2-yl) -amino] -2-oxoethyl} -1,3-thiazol-2-yl) amino ] -3-oxopropanoate and
    [391] Ethyl 4-[(4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) amino] 4-oxobutanoate.
    [392] Example 7
    [393] 2-[(4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) amino]- Preparation of 2-oxoacetic acid
    [394] The crude material (0.5 g; 1.31 mmol) obtained in Example 6 was dissolved in 1,4-dioxane / methanol (10 ml / 5 ml) and treated with 1N NaOH (1.5 ml, 1.5 mmol) at temperature for about 48 hours. do. The product is filtered by treatment with 1N HCl (1.5 ml) cooling in an ice bath, washed with methanol and dried to afford the title compound as a colorless solid (0.25 g, 54%).
    [395] Melting Point: 214-215 ° C
    [396] 1 H-NMR (DMSO-d 6 ) ppm: 12.65 (s, broad, 1H, NH); 12.1 (s, broad, 1H, NH); 7.15 (s, 1H, H 4 -thiazole); 7.1 (s, 1H, H 5 -thiazole); 4.8 (s, 2H, CH 2 ); 3.1 (m, 1 H, CHMe 2 ); 1.21 (d, 6H, CHMe 2 );
    [397] Similarly, the following compounds can be prepared:
    [398] N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -3-oxo -Beta-alanine
    [399] Melting point: 186 ~ 188 ° C
    [400] 1 H-NMR (DMSO-d 6 ) ppm: 12.77 (s, broad, 1H, COOH); 12.22 (s, broad, 1H, NH); 12.05 (s, broad, 1H, NH); 7.25 (s, 1 H, H 4 -thiazole); 6.98 (s, 1 H, H 5 -thiazole); 3.8 (s, 2 H, CH 2 COOH); 3.42 (s, 2 H, CH 2 ); 3.2 (m, 1 H, CHMe 2 ); 1.22 (d, 6H, CHMe 2 ) and
    [401] 4-[(4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) amino]- 4-oxobutanoic acid.
    [402] Example 8
    [403] Preparation of 2- [2- (Glycloylamino) -1,3-thiazol-4-yl] -N- (5-isopropyl-1,3-thiazol-2-yl) acetamide
    [404] The crude material (0.7 g, 1.8 mmol) obtained in Example 6 was partially dissolved in diethyl ether / tetrahydrofuran (65 ml / 30 ml), methanol (0.13 ml, 3.15 mmol) and LiBH 4 (0.07 g, 3.15 mmol). The reaction mixture is stirred at 45 ° C. for about 20 minutes, tetrahydrofuran (20 ml) is added and after 1 hour an additional amount of methanol (0.03 ml) and LiBH 4 (0.018 g) are added. Stirring continued for 1 hour, the suspension is quenched with 1N HCl, diluted with water and extracted with CH 2 Cl 2 . The organic layer is washed with 1N HCl and brine, dried and evaporated. The residue was triturated with diisopropyl ether and then silica gel chromatography using CHCl 3 : MeOH: 30% NH 4 OH (97: 3: 0.3) as eluent to afford the title compound as a colorless solid (0.154 g, 28%). Obtained as
    [405] Melting Point: 173-175 캜
    [406] 1 H-NMR (CDCl 3 ) ppm: 6.95 (s, 1H, H 4 -thiazole); 6.7 (s, 1 H, H 5 -thiazole); 4.26 (s, 2 H, CH 2 OH); 3.8 (s, 2 H, CH 2 ); 3.1 (m, 1 H, CHMe 2 ); 1.21 (d, 6H, CHMe 2 );
    [407] Similarly, the following compounds can be prepared starting from the corresponding ester derivatives:
    [408] 3-hydroxy-N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl Propanamide and
    [409] 4-hydroxy-N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl ) Butanamide.
    [410] Example 9
    [411] 2- (dimethylamino) -N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazole-2 Preparation of Acetamide
    [412] 2-chloro-N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) A mixture of acetamide (0.5 g, 1.4 mmol), 2M dimethylamine in methanol (3.5 ml, 7 mmol) and potassium iodide (0.116 g, 0.7 mmol) is refluxed for about 6 hours. After cooling, the solution is diluted with water, acidified with 1N HCl and then extracted with diethyl ether to remove unreacted product. The aqueous solution is then basified with 1N NaOH and extracted with diethyl ether. The organic layer is dried over sodium sulfate and evaporated. The residue is purified by silica gel chromatography using CH 2 Cl 2 : MeOH (97: 3 and then 95: 5) as eluent. The title compound is obtained in 20% yield (0.1 g) as a pale yellow solid.
    [413] Melting point: 70-71 ° C
    [414] 1 H-NMR (DMSO-d 6 ) ppm: 12.1 (s, broad, 1H, NH); 11.8 (s, broad, 1H, NH); 7.17 (s, 1H, H 4 -thiazole); 6.95 (s, 1 H, H 5 -thiazole); 3.75 (s, 2 H, CH 2 NMe 2 ); 3.17 (s, 2 H, CH 2 ); 3.1 (m, 1 H, CHMe 2 ); 2.12 (s, 6H, NMe 2 ); 1.22 (d, 6H, CHMe 2 );
    [415] Example 10
    [416] 2- (2-{[2- (dimethylamino) -2-oxoethylamino} -1,3-thiazol-4-yl) -N- (5-isopropyl-1,3-thiazole-2- I) Preparation of Acetamide
    [417] 2- (2-amino-1,3-thiazol-4-yl) -N- (5-isopropyl-1,3-thiazol-2-yl) acetamide (0.6 g, 2.12 mmol), 2- A mixture of chloro-N, N-dimethylacetamide (0.27 ml, 1.96 mmol) and anhydrous potassium carbonate (0.54 g, 3.92 mmol) in anhydrous DMF (5 ml) is stirred at 60 ° C. for about 4 hours. After cooling, the solution is diluted with water and extracted with CHCl 3 . The organic layer is washed with brine, dried and evaporated. The residue is purified by silica gel chromatography using CH 2 Cl 2 and then CH 2 Cl 2 : MeOH (95: 5) as eluent. The title compound is obtained as a colorless solid in 62% yield (0.5 g).
    [418] Melting Point: 211-213 ° C
    [419] 1 H-NMR (DMSO-d 6 ) ppm: 7.02 (s, 1H, H 4 -thiazole); 6.75 (s, 1 H, H 5 -thiazole); 5 (s, 2H, NHCH 2 ); 3.43 (s, 2H, NHCOCH 2 ); 3.55 (s, 2 H, CH 2 ); 3.1 (s, 3H, NMe); 2.98 (m, 1 H, CHMe 2 ); 2.82 (s, 3 H, NMe); 1.2 (d, 6H, CHMe 2 );
    [420] Similarly, the following products can be prepared starting from the corresponding alkyl halides:
    [421] 2- {2- [2-amino-2-oxoethyl) amino] -1,3-thiazol-4-yl} -N- (5-isopropyl-1,3-thiazol-2-yl) acet amides
    [422] Melting Point: 172-174 캜
    [423] 1 H-NMR (DMSO-d 6 ) ppm: 7.6 (s, broad, 1H, NHCO); 7.2 (s, broad, 1 H, NH); 7.09 (s, 1 H, H 4 -thiazole); 6.72 (s, 1 H, H 5 -thiazole); 4.7 (s, 2H, NHCH 2 ); 3.45 (s, 2H, NHCOCH 2 ); 2.95 (m, 1 H, CHMe 2 ); 1.2 (d, 6H, CHMe 2 );
    [424] N- (5-isopropyl-1,3-thiazol-2-yl) -2- (2-{[2- (4-morpholinyl) ethyl] amino} -1,3-thiazole-4- I) acetamide;
    [425] 2- {2-[(2,3-dihydroxypropyl) amino] -1,3-thiazol-4-yl} -N- (5-isopropyl-1,3-thiazol-2-yl) Acetamide;
    [426] 2- [2- (1-adamantylamino) -1,3-thiazol-4-yl] -N- (5-isopropyl-1,3-thiazol-2-yl) acetamide;
    [427] N- (5-isopropyl-1,3-thiazol-2-yl) -2- (2-{[2- (4-methyl-1-piperazinyl) ethyl] amino} -1,3-thia Zol-4-yl) acetamide;
    [428] 2- (2-{[3- (dimethylamino) -2-hydroxypropyl] amino} -1,3-thiazol-4-yl) -N- (5-isopropyl-1,3-thiazole- 2-yl) acetamide;
    [429] N- (5-isopropyl-1,3-thiazol-2-yl) -2- [4- (4-methyl-1-piperazinyl) phenyl] acetamide;
    [430] N- (5-isopropyl-1,3-thiazol-2-yl) -2- [4- (4-morpholinyl) phenyl] acetamide;
    [431] N- (5-isopropyl-1,3-thiazol-2-yl) -2- [4- (1-pyrrolidinyl) phenyl] acetamide;
    [432] N- (5-isopropyl-1,3-thiazol-2-yl) -2- (4-{[2- (4-methyl-1-piperazinyl) ethyl] amino} phenyl) acetamide;
    [433] N- (5-isopropyl-1,3-thiazol-2-yl) -2- (4-{[2- (4-morpholinyl) ethyl] amino} phenyl) acetamide;
    [434] 2- {4-[(2,3-dihydroxypropyl) amino] phenyl} -N- (5-isopropyl-1,3-thiazol-2-yl) acetamide;
    [435] 2- (4-{[3- (dimethylamino) -2-hydroxypropyl] amino} phenyl) -N- (5-isopropyl-1,3-thiazol-2-yl) acetamide;
    [436] 2- [4- (1-adamantylamino) phenyl) -N- (5-isopropyl-1,3-thiazol-2-yl) acetamide;
    [437] 2- {4-[(2-amino-2-oxoethyl) amino] phenyl} -N- (5-isopropyl-1,3-thiazol-2-yl) acetamide and
    [438] 2- (4-{[2- (dimethylamino) -2-oxoethyl] amino} phenyl) -N- (5-isopropyl-1,3-thiazol-2-yl) acetamide.
    [439] Example 11
    [440] N- (5-isopropyl-1,3-thiazol-2-yl) -2- (2- {methyl- [2- (4-methyl-1-piperazinyl) ethyl] amino} -1,3 Preparation of -thiazol-4-yl) acetamide
    [441] N- (5-isopropyl-1,3-thiazol-2-yl) -2- (2-{[2- (4-methyl-1-piperazinyl) ethyl] amino} -1,3-thia Zol-4-yl) acetamide (1 g, 2.45 mmol) and 40% formaldehyde in water (0.17 ml, 2.45 mmol) were mixed in CHCl 3 (10 ml), followed by sodium triacetoxyborohydride (0.727 g, 3.43 mmol). The mixture is stirred at room temperature under nitrogen atmosphere for 5 hours. Aqueous saturated sodium bicarbonate is added to quench the reaction mixture and the product is extracted with CHCl 3 . The organic layer is washed with brine, dried and evaporated. The title compound is obtained after purification by chromatography in 75% yield.
    [442] Similarly, the following products can be prepared:
    [443] 2- {2-[(2,3-dihydroxypropyl) (methyl) amino] -1,3-thiazol-4-yl} -N- (5-isopropyl-1,3-thiazole-2 -Yl) acetamide;
    [444] N- (5-isopropyl-1,3-thiazol-2-yl) -2- (2- {methyl [2- (4-morpholinyl) ethyl] amino} -1,3-thiazole-4 -Yl) acetamide;
    [445] N- (5-isopropyl-1,3-thiazol-2-yl) -2- (4- {methyl [2- (4-morpholinyl) ethyl] amino} phenyl) acetamide;
    [446] N- (5-isopropyl-1,3-thiazol-2-yl) -2- (4- {methyl-1-piperazinyl) ethyl] amino} phenyl) acetamide;
    [447] 2- {4-[(2,3-dihydroxypropyl) (methyl) amino] phenyl} -N- (5-isopropyl-1,3-thiazol-2-yl) acetamide;
    [448] 3-[[2-({2- [4- (dimethylamino) phenyl] acetyl} amino) -1,3-thiazol-5-yl] (methyl) amino] propyl acetate;
    [449] 2-[[2-({2- [4- (dimethylamino) phenyl] acetyl} amino) -1,3-thiazol-5-yl] (methyl) amino] ethyl acetate;
    [450] 2-[[2-({2- [2- (acetylamino) -1,3-thiazol-4-yl] acetyl} amino) -1,3-thiazol-5-yl] (methyl) amino] Ethyl acetate and
    [451] 3-[[2-({2- [2- (acetylamino) -1,3-thiazol-4-yl] acetyl} amino) -1,3-thiazol-5-yl] (methyl) amino] Propyl acetate.
    [452] Example 12
    [453] Preparation of N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) -2-methoxyacetamide
    [454] N'-cyclohexylcarbodiimide, N'-methyl polystyrene, previously treated with a solution of 2-methoxyacetic acid (41 μl, 0.53 mmol) in CH 2 Cl 2 (1.5 mL), CH 2 Cl 2 (5 mL × 3) (0.53 g, 2 mmol / g dropping, 1.064 mmol), 2- (4-aminophenyl) -N- (in 4-DMAP (0.032 g, 0.266 mmol) and CH 2 Cl 2 / DMF (0.4 ml / 0.6 ml) A solution of 5-isopropyl-1,3-thiazol-2-yl) acetamide (0.076 g, 0.266 mmol) is added. The reaction mixture is kept at room temperature for about 72 hours under stirring. The resin is filtered, washed with CH 2 Cl 2 (10 ml × 3), the combined filtrates are washed with water, 5% hydrochloric acid, water, saturated sodium bicarbonate and water, then dried and evaporated.
    [455] Similarly, starting from the corresponding carboxylic acid, the following compounds can be prepared:
    [456] N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) nicotinamide;
    [457] N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) -5-methyl-2-thiophencarboxamide;
    [458] N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) -5-methyl-2-pyrazinecarboxamide;
    [459] N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) -5-methyl-4-isooxazolecarboxamide;
    [460] N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) -3,5-dimethyl-4-isooxazolecarboxamide ;
    [461] (Dimethylamino) -N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) benzamide;
    [462] 4- (acetylamino) -N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) benzamide;
    [463] 4- (dimethylamino) -N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) benzamide;
    [464] N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) -1,3-benzodioxol-5-carboxamide ;
    [465] 4- (aminosulfonyl) -N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) benzamide;
    [466] 2-chloro-2,2-difluoro-N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) acetamide ;
    [467] 2-cyano-N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) acetamide;
    [468] 1-acetyl-N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) -4-piperidinecarboxamide;
    [469] N'1 '-(4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) succinamide;
    [470] 3,3,3-trifluoro-N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) propanamide;
    [471] N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) -2-phenylacetamide;
    [472] N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) -2-methoxy-2-phenylacetamide;
    [473] 2- [4- (dimethylamino) phenyl] -N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl] phenyl) acetamide ;
    [474] N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) -2- (3-pyridinyl) acetamide;
    [475] N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) -2- (3-thienyl) acetamide;
    [476] N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) -2- [5- (1-pyrrolidinyl)- 2H-1,2,3,4-tetrazol-2-yl] acetamide.
    [477] Example 13
    [478] N- (5-isopropyl-1,3-thiazol-2-yl) -2- [2- (2-oxo-1-pyrrolidinyl) -1,3-thiazol-4-yl] acetamide Manufacture
    [479] 2.8 g (0.01 mol) of 2- (2-amino-1, 3-thiazol-4-yl) -N- (5-isopropyl-1,3-thiazol-2-yl) acetamide in 50 ml of absolute ethanol , A mixture of 4.84 g (0.02 mol) of ethyl-iodobutyrate and 2.76 g (0.02 mmol) of potassium carbonate is stirred under reflux for 5 hours. The mixture is cooled to filtration and the salts are washed with two 20 ml fractions of ethanol. Ethanol is removed under reduced pressure and the residue is dissolved in 100 ml of CH 2 Cl 2 . The solution is washed with 30 ml of water, dried and the solvent is evaporated. The residue is purified by silica gel chromatography using CH 2 Cl 2 : MeOH (95: 5) as eluent to afford the title compound in 30% yield (1.05 g).
    [480] Example 14
    [481] Preparation of 1- (2,2-diethoxyethyl) cyclopropane
    [482] Diazomethane (6.17 g, 147 mmol) was added dropwise to 3.02 g (21 mmol) of 3-butenal diethyl acetal in 10 ml of anhydrous ether with vigorous stirring at 0 ° C. Then 70 mg (0.312 mmol) of palladium (II) acetate in 50 ml of anhydrous ether are added all at once. Stirring is continued at 0 ° C. until evaporation of N 2 is stopped (10 min). The ether is distilled off to reduce the reaction mixture to about 10 ml volume. The precipitate is filtered through a fritted glass funnel and the filtrate is evaporated. The crude product (2.57 g) contains 97% of the title compound (GC) and is used without further purification.
    [483] Example 15
    [484] Preparation of 2-cyclopropylacetaldehyde
    [485] 1- (2,2-diethoxyethyl) cyclopropane (2.57 g, 16 mmol) was suspended in aqueous HCl (0.1 M, 120 ml), stirred at room temperature for 30 hours, and then checked by TLC to give a turbid solution. It was found to be completely converted to the resulting product. The reaction mixture is then extracted with ether. The ethereal solution is washed with water, dried and the solvent is evaporated. The residue is purified by silica gel chromatography using petroleum ether: ethyl acetate (95: 5) as eluent to afford the title compound as an oil (1.07 g, 80%).
    [486] Example 16
    [487] Preparation of 2- [2- (acetylamino) -1,3-thiazol-4-yl] -N- (5-amino-1,3-thiazol-2-yl) acetamide
    [488] 2- [2- (acetylamino) -1,3-thiazol-4-yl] -N- (5-nitro-1,3-thiazol-2-yl) acetamide (1 g, in ethanol (150 ml) 3.23 mmol) of the solution is hydrogenated in the presence of 10% Pd / C (0.1 g, 10% w / w) at room temperature for about 5 hours. The reaction mixture is filtered and evaporated. The residue is triturated with diisopropyl ether to afford the title compound in 89% yield (0.8 g).
    [489] Similarly, the following compounds can be prepared starting from the corresponding nitro derivatives:
    [490] 2- [4- (dimethylamino) phenyl] -N- (5-amino-1, 3-thiazol-2-yl) acetamide.
    [491] Example 17
    [492] 3-{[2-({2- [2- (acetylamino) -1,3-thiazol-4-yl] acetyl} amino) -1,3-thiazol-5-yl] amino} propyl acetate Produce
    [493] 2- [2- (acetylamino) -1,3-thiazol-4-yl] -N- (5-amino-1,3-thiazol-2-yl) acetamide (0.5 g in DMF (10 ml) , 1.79 mmol), 3-bromopropyl acetate (0.4 g, 2.15 mmol) and 2,6-lutidine (0.25 ml, 2.15 mmol) are heated at 70 ° C. for about 72 hours. The reaction mixture is diluted with water, acidified with 0.5N HCl and extracted with CH 2 Cl 2 . The aqueous layer is adjusted to pH 7/8 with 0.5N NaOH and extracted with CH 2 Cl 2 . The organic layer is washed with brine, dried and evaporated. The residue was purified by silica gel chromatography using CH 2 Cl 2 : MeOH (95: 5) as eluent to afford the title compound in 45% yield.
    [494] Similarly, the following compounds can be prepared:
    [495] 2-{[2-({2- [2- (acetylamino) -1,3-thiazol-4-yl] acetyl} amino) -1,3-thiazol-5-yl] amino} ethyl acetate;
    [496] 2-{[2-({2- [4- (dimethylamino) phenyl] acetyl} amino) -1,3-thiazol-5-yl] amino} ethyl acetate and
    [497] 2-{[2-({2- [4- (dimethylamino) phenyl] acetyl} amino) -1,3-thiazol-5-yl] amino} propyl acetate.
    [498] Example 18
    [499] 2- [2- (acetylamino) -1,3-thiazol-4-yl] -N- {5-[(3-hydroxypropyl) (methyl) amino] -1,3-thiazole-2- Preparation of Acetamide
    [500] 3-[[2-({2- [2- (acetylamino) -1,3-thiazol-4-yl] acetyl} amino-1,3-thiazol-5-yl] (methyl) amino] propyl Acetate (0.5 g, 1.27 mmol) is dissolved in methanol (50 ml) and treated with 1N NaOH (1.4 ml, 1.4 mmol) for about 24 hours at 0 ° C. The solvent is evaporated and the residue is CH 2 Cl 2 / water. The organic layer is washed with water and brine, dried and evaporated The residue is purified by silica gel chromatography using CH 2 Cl 2 : MeOH (95: 5) as eluent to give the title compound in 40% yield. do.
    [501] Similarly, the following compounds can be prepared:
    [502] 2- [2- (acetylamino) -1,3-thiazol-4-yl] -N- {5-[(3-hydroxypropyl) amino] -1,3-thiazol-2-yl} acet amides;
    [503] 2- [2- (acetylamino) -1,3-thiazol-4-yl] -N- {5-[(2-hydroxyethyl) (methyl) amino] -1,3-thiazole-2- Acetamide;
    [504] 2- [2- (acetylamino) -1,3-thiazol-4-yl] -N- {5-[(2-hydroxyethyl) amino] -1,3-thiazol-2-yl} acet Amides and
    [505] 2- [4- (dimethylamino) phenyl] -N- {5-[(2-hydroxyethyl) amino] -1,3-thiazol-2-yl} acetamide;
    [506] 2- [4- (dimethylamino) phenyl] -N- {5-[(2-hydroxyethyl) (methyl) amino] -1,3-thiazol-2-yl} acetamide;
    [507] 2- [4- (dimethylamino) phenyl] -N- {5-[(3-hydroxypropyl) (methyl) amino] -1,3-thiazol-2-yl} acetamide and
    [508] 2- [4- (dimethylamino) phenyl] -N- {5-[(3-hydroxypropyl) amino] -1,3-thiazol-2-yl} acetamide.
    [509] Obviously, many modifications and variations of the present invention can be made in light of the above teachings. It is, therefore, to be understood that within the scope of the appended claims, the invention may be practiced otherwise than as specifically described herein.
    权利要求:
    Claims (21)
    [1" claim-type="Currently amended] A method of treating a cell proliferative disorder associated with a change in cell dependent kinase activity, comprising administering an effective amount of a compound of Formula I or Formula II or a pharmaceutically acceptable salt thereof to a mammal in need thereof.
    Formula I

    Formula II

    In Formula I and Formula II above,
    L is a 5 or 6 membered aromatic heterocycle having at least one hetero atom selected from a phenyl group or a group consisting of nitrogen, oxygen and sulfur,
    R is a halogen atom, nitro group, or pyrrolidino, morpholino, piperazino, N-alkyl piperazino, N-aryl-piperazino, N-arylalkylpiperazino, piperidino and azabai Group (i) selected from the group consisting of cyclone [3.2.2] nonane,
    A group consisting of unsubstituted, identical or different alkyl, aryl, arylalkyl, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, alkylcarbonyl, arylcarbonyl and arylalkylcarbonyl, wherein the alkyl moiety is substituted Amino group (ii), or further substituted with one or more groups selected from one or more hydroxy or amino groups),
    C 3 -C 6 cycloalkyl (iii) unsubstituted or substituted with straight or branched C 1 -C 6 alkyl groups,
    Unsubstituted, halogen, cyano, carboxy, hydroxy, nitro, alkylthio, alkoxy, straight or branched C 1 -C 6 alkyl, arylthio, aryloxy, amino, alkylamino, dialkylamino, arylamino, Arylalkylamino, hydroxyaminocarbonyl, alkoxyaminocarbonyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 6 cycloalkyl, alkyl-C 3 -C 6 cycloalkyl, alkyl Carbonyl, arylcarbonyl, arylalkylcarbonyl, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylcarbonylamino, arylalkylcarbonylamino , Arylaminosulfonyl, arylalkylaminosulfonyl, arylcarbonylamino, alkylsulfonylamino, arylsulfonylamino, arylalkylsulfonylamino, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, alkylaminocarbonyl , Arylaminocarbonyl, dialkylaminocarbonyl, a Alkylaminocarbonyl, pyrrolidino, morpholino, piperazino, N-alkylpiperazino, N-aryl-piperazino, N-arylalkyl-piperazino, piperidino and azabicyclo [3.2 .2] a straight or branched C 1 -C 6 alkyl group or arylalkyl group (iv) substituted with one or more substituents selected from the group consisting of nonanes or
    Unsubstituted, halogen, cyano, carboxy, hydroxy, nitro, alkylthio, alkoxy, straight or branched C 1 -C 6 alkyl, arylthio, aryloxy, amino, alkylamino, dialkylamino, arylamino, Arylalkylamino, hydroxyaminocarbonyl, alkoxyaminocarbonyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 6 cycloalkyl, alkyl-C 3 -C 6 cycloalkyl, alkyl Carbonyl, arylcarbonyl, arylalkylcarbonyl, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylcarbonylamino, arylalkylcarbonylamino , Arylaminosulfonyl, arylalkylaminosulfonyl, arylcarbonylamino, alkylsulfonylamino, arylsulfonylamino, arylalkylsulfonylamino, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, alkylaminocarbonyl , Arylaminocarbonyl, dialkylaminocarbonyl, aryl Alkylaminocarbonyl, pyrrolidino, morpholino, piperazino, N-alkylpiperazino, N-aryl-piperazino, N-arylalkyl-piperazino, piperidino and azabicyclo [3.2 .2] an aryl group (v) substituted with one or more substituents selected from the group consisting of nonan,
    R 1 is a hydrogen atom or a straight or branched C 1 -C 4 alkyl group which is unsubstituted or substituted with one or more hydroxy, alcoholic, amino, alkylamino or dialkylamino groups,
    R 2 and R 3 may be the same or different and are a hydrogen atom, a cycloalkyl group, a straight or branched C 1 -C 6 alkyl group or an aryl group which is unsubstituted or substituted as described above for R, or
    R 2 and R 3 together with the nitrogen atom to which they are attached are 4-morpholinyl, 1-piperazinyl, N-alkyl-piperazinyl, N-aryl-piperazinyl, N-arylalkyl-piperazinyl , Piperidinyl, pyrrolidinyl, 2-oxo-1-pyrrolidinyl, imidazolyl or 3-azabicyclo [3.2.2] nonyl ring,
    R 4 is a carboxy, perfluorinated alkyl group, C 2 -C 4 alkynyl group, 2-oxo-pyrrolidinyl, piperidinyl, or straight or branched chain C which is unsubstituted or substituted as described above for R 1- C 6 alkyl group or aryl group.
    [2" claim-type="Currently amended] The method of claim 1, wherein the cell proliferative disease is selected from the group consisting of cancer, Alzheimer's disease, viral infection, autoimmune disease and neurodegenerative disease.
    [3" claim-type="Currently amended] The method of claim 2, wherein the cancer is carcinoma, squamous cell carcinoma, hematopoietic tumor of myeloid or lymphatic system, tumor of mesenchymal origin, tumor of central and peripheral nervous system, melanoma, normal carcinoma, teratoma, osteosarcoma, pigmentary Dry skin, keratinocytes, thyroid follicular cancer and Kaposi's sarcoma.
    [4" claim-type="Currently amended] The method of claim 1, wherein the cell proliferative disease is due to benign prostatic hyperplasia, familial adenomatous polyposis, neurofibromatosis, psoriasis, smooth muscle cell proliferation associated with atherosclerosis, pulmonary fibrosis, arthritis, glomerulonephritis and postoperative stenosis and restenosis. Method selected from the group consisting of:
    [5" claim-type="Currently amended] The method of claim 1, which provides tumor angiogenesis and metastasis inhibition.
    [6" claim-type="Currently amended] The method of claim 1, which provides cell cycle inhibition or cdk / cycline dependency inhibition.
    [7" claim-type="Currently amended] The method of claim 1, wherein the mammal in need of treatment for a cell proliferative disease is further treated with radiation therapy or chemotherapy with one or more cytostatic or cytotoxic agents.
    [8" claim-type="Currently amended] The method of claim 1 wherein the compound is a compound of Formula (I).
    [9" claim-type="Currently amended] The method of claim 1 wherein the compound is a compound of Formula II.
    [10" claim-type="Currently amended] The compound of claim 1 wherein L is selected from the group consisting of phenyl, thiazole, imidazole, oxazole, pyrazole, isoxazole, thiophene, pyridine and pyrimidine,
    Group (ii) wherein R is selected from the group consisting of halogen atoms (i), arylamino, alkylamino and dialkylamino, wherein the alkyl moiety may be unsubstituted or further substituted with one or more hydroxy or amino groups A C 3 -C 6 cycloalkyl group (iii) unsubstituted or substituted with an alkyl group, a straight or branched C 1 -C 4 alkyl or arylalkyl group (iv) or a substituted or unsubstituted as described above Unsubstituted or substituted aryl group (v),
    R 1 is hydrogen or a C 1 -C 4 alkyl group unsubstituted or substituted with a hydroxy or amino group.
    [11" claim-type="Currently amended] The compound of claim 1 wherein the compound is
    N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) acrylamide,
    N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -2-methyl Propanamide,
    N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -2-na FTamide,
    N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) benzamide,
    N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -2-phenyl Acetamide,
    N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -2- ( 3-pyridinyl) acetamide,
    2,2,3,3,3-pentafluoro-N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1 , 3-thiazol-2-yl) propanamide,
    2-[(4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) amino]- 2-oxoacetic acid,
    2-fluoro-N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl Acetamide,
    2-chloro-N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) Acetamide,
    2-cyano-N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl Acetamide,
    N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -3-oxo Beta-alanine,
    N'1 '-(4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) malon amides,
    4-[(4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -4- Oxobutanoic Acid,
    2- [2- (glycloylamino) -1,3-thiazol-4-yl] -N- (5-isopropyl-1,3-thiazol-2-yl) acetamide,
    3-hydroxy-N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl Propanamide,
    3-amino-N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) Propanamide,
    2-amino-N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) Acetamide,
    4-hydroxy-N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl Butanamide,
    4-amino-N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) Butanamide,
    N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -2- ( 4-methyl-1-piperazinyl) acetamide,
    2- (4-benzyl-1-piperazinyl) -N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1 , 3-thiazol-2-yl) acetamide,
    N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -2- ( 1-piperidinyl) acetamide,
    N- (5-isopropyl-1,3-thiazol-2-yl) -2- [2- (2-oxo-1-pyrrolidinyl) -1,3-thiazol-4-yl] acetamide ,
    2- [4- (dimethylamino) phenyl) -N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3 -Thiazol-2-yl) acetamide,
    N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -2- ( 1H-1,2,3,4-tetrazol-1-yl) acetamide,
    N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -5-oxo -2-pyrrolidinecarboxamide,
    N'1 '-(4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) succinate amides,
    3- (1H-benzimidazol-2-yl) -N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1 , 3-thiazol-2-yl) propanamide,
    1-acetyl-N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -4-piperidinecarboxamide,
    2- [2- (acetylamino) -1,3-thiazol-4-yl] -N- (5-isopropyl-1,3-thiazol-2-yl) acetamide,
    4-chloro-N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) Butanamide,
    N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -2-meth Oxyacetamide,
    3,3,3-trifluoro-N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thia Zol-2-yl) propanamide,
    2- (dimethylamino) -N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazole-2 Acetamide,
    N- (5-isopropyl-1,3-thiazol-2-yl) -2- (2-{[2- (4-methyl-1-piperazinyl) ethyl] amino} -1,3-thia Zol-4-yl) acetamide,
    N- (5-isopropyl-1,3-thiazol-2-yl) -2- (2- {methyl [2- (4-methyl-1-piperazinyl) ethyl] amino} -1,3- Thiazol-4-yl) acetamide,
    N- (5-isopropyl-1,3-thiazol-2-yl) -2- (2-{[2- (4-morpholinyl) ethyl] amino} -1,3-thiazole-4- Acetamide,
    N- (5-isopropyl-1,3-thiazol-2-yl) -2- (2- {methyl [2- (4-morpholinyl) ethyl] amino} -1,3-thiazole-4 Acetamide,
    2- {2-[(2,3-dihydroxypropyl) amino] -1,3-thiazol-4-yl} -N- (5-isopropyl-1,3-thiazol-2-yl) Acetamide,
    2- {2-[(2,3-dihydroxypropyl) (methyl) amino] -1,3-thiazol-4-yl} -N- (5-isopropyl-1,3-thiazole-2 Acetamide,
    2- (2-{[3- (dimethylamino) -2-hydroxypropyl] amino} -1,3-thiazol-4-yl) -N- (5-isopropyl-1,3-thiazole- 2-yl) acetamide,
    2- {2-[(2-amino-2-oxoethyl) amino] -1,3-thiazol-4-yl} -N- (5-isopropyl-1,3-thiazol-2-yl) Acetamide,
    2- (2-{[2- (dimethylamino) -2-oxoethyl] amino} -1,3-thiazol-4-yl) -N- (5-isopropyl-1,3-thiazole-2 -Yl) -acetamide,
    2- [2- (adamantylamino) -1,3-thiazol-4-yl] -N- (5-isopropyl-1,3-thiazol-2-yl) acetamide,
    2- [4- (dimethylamino) phenyl] -N- (5-isopropyl-1,3-thiazol-2-yl) acetamide,
    N- (5-isopropyl-1,3-thiazol-2-yl) -2- [4- (4-methyl-1-piperazinyl) phenyl] acetamide,
    N- (5-isopropyl-1,3-thiazol-2-yl) -2- [4- (4-morpholinyl) phenyl] acetamide,
    N- (5-isopropyl-1,3-thiazol-2-yl) -2- [4- (1-pyrrolidinyl) phenyl] acetamide,
    N- [5-isopropyl-1,3-thiazol-2-yl) -2- (4-{[2- (4-methyl-1-piperazinyl) ethyl] amino} phenyl) acetamide,
    N- (5-isopropyl-1,3-thiazol-2-yl) -2- (4- {methyl [2- (4-methyl-1-piperazinyl) ethyl] amino} phenyl) acetamide,
    N- (5-isopropyl-1,3-thiazol-2-yl) -2- (4-{[2- (4-morpholinyl) ethyl] amino} phenyl) acetamide,
    N- (5-isopropyl-1,3-thiazol-2-yl) -2- (4- {methyl [2- (4-morpholinyl) ethyl] amino} phenyl) acetamide,
    2- {4-[(2,3-dihydroxypropyl) amino] phenyl} -N- (5-isopropyl-1,3-thiazol-2-yl) acetamide,
    2- {4-[(2,3-dihydroxypropyl) (methyl) amino] phenyl} -N- (5-isopropyl-1,3-thiazol-2-yl) acetamide,
    2- (4-{[3- (dimethylamino) -2-hydroxypropyl] amino} phenyl) -N- (5-isopropyl-1,3-thiazol-2-yl) acetamide,
    2- [4- (1-adamantylamino) phenyl) -N- (5-isopropyl-1,3-thiazol-2-yl) acetamide,
    2- {4-[(2-amino-2-oxoethyl) amino] phenyl} -N- (5-isopropyl-1,3-thiazol-2-yl) acetamide,
    2- (4-{[2- (dimethylamino) -2-oxoethyl] amino} phenyl) -N- (5-isopropyl-1,3-thiazol-2-yl) acetamide,
    2- [4- (acetylamino) phenyl] -N- (5-isopropyl-1,3-thiazol-2-yl) acetamide,
    N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) nicotinamide,
    N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) -5-methyl-2-thiophencarboxamide,
    N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl-5-methyl-2-pyrazinecarboxamide,
    N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) -5-methyl-4-isooxazolecarboxamide,
    N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) -3,5-dimethyl-4-isooxazolecarboxamide ,
    (Dimethylamino) -N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) benzamide,
    4- (acetylamino) -N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) benzamide,
    4- (dimethylamino) -N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) benzamide,
    N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) -1,3-benzodioxol-5-carboxamide ,
    4- (aminosulfonyl) -N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) benzamide,
    2-chloro-2,2-difluoro-N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) acetamide ,
    2-cyano-N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) acetamide,
    1-acetyl-N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) -4-piperidinecarboxamide,
    N'1 '-(4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) succinamide,
    N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) -2-methoxyacetamide,
    3,3,3-trifluoro-N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) propanamide,
    N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) -2-phenylacetamide,
    N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) -2-methoxy-2-phenylacetamide,
    2- [4- (dimethylamino) phenyl] -N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) acetamide ,
    N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) -2- (3-pyridinyl) acetamide,
    N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) -2- (3-thienyl) acetamide,
    N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) -2- [5- (1-pyrrolidinyl)- 2H-1,2,3,4-tetraazol-2-yl] acetamide,
    2-cyclopropyl-N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl Acetamide,
    N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -5-methyl -2-pyrazinecarboxamide,
    N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -2-propyl amides,
    N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -5-methyl -1,3-oxazole-4-carboxamide,
    N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -3,3 Dimethylbutanamide,
    N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -3-methyl -2-butenamide,
    3-cyclopentyl-N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl Propanamide,
    N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -2- ( 3-thienyl) acetamide,
    N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -2- ( 3-pyridinyl) acetamide,
    2,2,2-trifluoro-N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thia Zol-2-yl) acetamide,
    N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -3- ( 2-thienyl) propanamide,
    N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -2- ( 4-pyridinylsulfanyl) acetamide,
    N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -2- ( 3-pyridinyl) -1,3-thiazole-4-carboxamide,
    2- [2- (acetylamino) -1,3-thiazol-4-yl] -N- (5-cyclopropyl-1,3-thiazol-2-yl) acetamide,
    2- [2- (acetylamino) -1,3-thiazol-4-yl] -N- {5-[(3-hydroxypropyl) (methyl) amino] -1,3-thiazole-2- Acetamide,
    2- [2- (acetylamino) -1,3-thiazol-4-yl] -N- {5-[(2-hydroxyethyl) (methyl) amino] -1,3-thiazole-2- Acetamide,
    2- [4- (dimethylamino) phenyl] -N- {5-[(2-hydroxyethyl) (methyl) amino] -1,3-thiazol-2-yl} acetamide,
    2- [4- (dimethylamino) phenyl] -N- {5-[(3-hydroxypropyl) (methyl) amino] -1,3-thiazol-2-yl] acetamide,
    N- (5-cyclopropyl-1,3-thiazol-2-yl) -2- [4- (dimethylamino) phenyl] acetamide and pharmaceutically acceptable salts thereof.
    [12" claim-type="Currently amended] The method of claim 1, wherein the mammal is a human.
    [13" claim-type="Currently amended] 2-amino-1,3-thiazole derivatives of formula (I) or formula (II) or pharmaceutically acceptable salts thereof.
    Formula I

    Formula II

    In Formula I and Formula II above,
    L is a 5 or 6 membered aromatic heterocycle having at least one hetero atom selected from a phenyl group or a group consisting of nitrogen, oxygen and sulfur,
    R is a halogen atom, nitro group, or pyrrolidino, morpholino, piperazino, N-alkyl piperazino, N-aryl-piperazino, N-arylalkylpiperazino, piperidino and azabai Group (i) selected from the group consisting of cyclone [3.2.2] nonane,
    A group consisting of unsubstituted, identical or different alkyl, aryl, arylalkyl, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, alkylcarbonyl, arylcarbonyl and arylalkylcarbonyl, wherein the alkyl moiety is substituted Amino group (ii), or further substituted with one or more groups selected from one or more hydroxy or amino groups),
    C 3 -C 6 cycloalkyl (iii) unsubstituted or substituted with straight or branched C 1 -C 6 alkyl groups,
    Unsubstituted, one or more halogen, cyano, carboxy, hydroxy, nitro, alkylthio, alkoxy, straight or branched C 1 -C 6 alkyl, arylthio, aryloxy, amino, alkylamino, dialkylamino, aryl Amino, arylalkylamino, hydroxyaminocarbonyl, alkoxyaminocarbonyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 6 cycloalkyl, alkyl-C 3 -C 6 cycloalkyl , Alkylcarbonyl, arylcarbonyl, arylalkylcarbonyl, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, arylaminosulfonyl, dialkylaminosulfonyl, alkylcarbonyl Amino, arylalkylaminosulfonyl, arylcarbonylamino, arylalkylcarbonylamino, alkylsulfonylamino, arylsulfonylamino, arylalkylsulfonylamino, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, alkylamino Carbonyl, Dialkylaminocarbonyl, Arylami Carbonyl, arylalkylaminocarbonyl, pyrrolidino, morpholino, piperazino, N-alkylpiperazino, N-aryl-piperazino, N-arylalkyl-piperazino, piperidino or aza Straight or branched C 1 -C 6 alkyl group or arylalkyl group (iv) substituted with a bicyclo [3.2.2] nonane substituent or
    Unsubstituted, halogen, cyano, carboxy, hydroxy, nitro, alkylthio, alkoxy, straight or branched C 1 -C 6 alkyl, arylthio, aryloxy, amino, alkylamino, dialkylamino, arylamino, Arylalkylamino, hydroxyaminocarbonyl, alkoxyaminocarbonyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 6 cycloalkyl, alkyl-C 3 -C 6 cycloalkyl, alkyl Carbonyl, arylcarbonyl, arylalkylcarbonyl, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, arylaminosulfonyl, dialkylaminosulfonyl, alkylcarbonylamino, Arylalkylaminosulfonyl, arylcarbonylamino, arylalkylcarbonylamino, alkylsulfonylamino, arylsulfonylamino, arylalkylsulfonylamino, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, alkylaminocarbonyl , Dialkylaminocarbonyl, arylaminocarbonyl, a Alkylaminocarbonyl, pyrrolidino, morpholino, piperazino, N-alkylpiperazino, N-aryl-piperazino, N-arylalkyl-piperazino, piperidino and azabicyclo [3.2 .2] an aryl group (v) substituted with one or more substituents selected from the group consisting of nonan,
    R 1 is a hydrogen atom or a straight or branched C 1 -C 4 alkyl group which is unsubstituted or substituted with one or more hydroxy, alcoholic, amino, alkylamino or dialkylamino groups,
    R 2 and R 3 may be the same or different and are a hydrogen atom, a cycloalkyl group, a straight or branched C 1 -C 6 alkyl group or an aryl group which is unsubstituted or substituted as described above for R, or
    R 2 and R 3 together with the nitrogen atom to which they are attached are 4-morpholinyl, 1-piperazinyl, N-alkyl-piperazinyl, N-aryl-piperazinyl, N-arylalkyl-piperazinyl , Piperidinyl, pyrrolidinyl, 2-oxo-1-pyrrolidinyl, imidazolyl or 3-azabicyclo [3.2.2] nonyl ring,
    R 4 is carboxy, perfluorinated alkyl group, C 2 -C 4 alkenyl group, C 2 -C 4 alkynyl group, 2-oxo-pyrrolidinyl, piperidinyl, or unsubstituted or described above for R Substituted or straight chain or branched C 1 -C 6 alkyl group or aryl group.
    [14" claim-type="Currently amended] The 2-amino-1,3-thiazole derivative of formula I according to claim 13.
    [15" claim-type="Currently amended] The 2-amino-1, 3-thiazole derivative of claim 13.
    [16" claim-type="Currently amended] The compound of claim 13, wherein L is selected from the group consisting of phenyl, thiazole, imidazole, oxazole, pyrazole, isoxazole, thiophene, pyridine and pyrimidine,
    Group (ii) wherein R is selected from the group consisting of halogen atoms (i), arylamino, alkylamino and dialkylamino, wherein the alkyl moiety may be unsubstituted or further substituted with one or more hydroxy or amino groups , A C 3 -C 6 cycloalkyl group (iii) unsubstituted or substituted with an alkyl group, a straight or branched C 1 -C 4 alkyl or arylalkyl group (iv) or a substituted or unsubstituted as described above Unsubstituted or substituted aryl group (v),
    2-amino-1,3-thiazole derivative or a pharmaceutically acceptable salt thereof, wherein R 1 is hydrogen or a C 1 -C 4 alkyl group unsubstituted or substituted with a hydroxy or amino group.
    [17" claim-type="Currently amended] The method of claim 13,
    N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) acrylamide,
    N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -2-methyl Propanamide,
    N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -2-na FTamide,
    N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) benzamide,
    N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -2-phenyl Acetamide,
    N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -2- ( 3-pyridinyl) acetamide,
    2,2,3,3,3-pentafluoro-N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1 , 3-thiazol-2-yl) propanamide,
    2-[(4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) amino]- 2-oxoacetic acid,
    2-fluoro-N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl Acetamide,
    2-chloro-N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) Acetamide,
    2-cyano-N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl Acetamide,
    N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -3-oxo Beta-alanine,
    N'1 '-(4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) malon amides,
    4-[(4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -4- Oxobutanoic Acid,
    2- [2- (glycloylamino) -1,3-thiazol-4-yl] -N- (5-isopropyl-1,3-thiazol-2-yl) acetamide,
    3-hydroxy-N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl Propanamide,
    3-amino-N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) Propanamide,
    2-amino-N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) Acetamide,
    4-hydroxy-N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl Butanamide,
    4-amino-N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) Butanamide,
    N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -2- ( 4-methyl-1-piperazinyl) acetamide,
    2- (4-benzyl-1-piperazinyl) -N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1 , 3-thiazol-2-yl) acetamide,
    N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -2- ( 1-piperidinyl) acetamide,
    N- (5-isopropyl-1,3-thiazol-2-yl) -2- [2- (2-oxo-1-pyrrolidinyl) -1,3-thiazol-4-yl] acetamide ,
    2- [4- (dimethylamino) phenyl) -N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3 -Thiazol-2-yl) acetamide,
    N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -2- ( 1H-1,2,3,4-tetrazol-1-yl) acetamide,
    N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -5-oxo -2-pyrrolidinecarboxamide,
    N'1 '-(4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) succinate amides,
    3- (1H-benzimidazol-2-yl) -N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1 , 3-thiazol-2-yl) propanamide,
    1-acetyl-N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -4-piperidinecarboxamide,
    2- [2- (acetylamino) -1,3-thiazol-4-yl] -N- (5-isopropyl-1,3-thiazol-2-yl) acetamide,
    4-chloro-N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) Butanamide,
    N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -2-meth Oxyacetamide,
    3,3,3-trifluoro-N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thia Zol-2-yl) propanamide,
    2- (dimethylamino) -N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazole-2 Acetamide,
    N- (5-isopropyl-1,3-thiazol-2-yl) -2- (2-{[2- (4-methyl-1-piperazinyl) ethyl] amino} -1,3-thia Zol-4-yl) acetamide,
    N- (5-isopropyl-1,3-thiazol-2-yl) -2- (2- {methyl [2- (4-methyl-1-piperazinyl) ethyl] amino} -1,3- Thiazol-4-yl) acetamide,
    N- (5-isopropyl-1,3-thiazol-2-yl) -2- (2-{[2- (4-morpholinyl) ethyl] amino} -1,3-thiazole-4- Acetamide,
    N- (5-isopropyl-1,3-thiazol-2-yl) -2- (2- {methyl [2- (4-morpholinyl) ethyl] amino} -1,3-thiazole-4 Acetamide,
    2- {2-[(2,3-dihydroxypropyl) amino] -1,3-thiazol-4-yl} -N- (5-isopropyl-1,3-thiazol-2-yl) Acetamide,
    2- {2-[(2,3-dihydroxypropyl) (methyl) amino] -1,3-thiazol-4-yl} -N- (5-isopropyl-1,3-thiazole-2 Acetamide,
    2- (2-{[3- (dimethylamino) -2-hydroxypropyl] amino} -1,3-thiazol-4-yl) -N- (5-isopropyl-1,3-thiazole- 2-yl) acetamide,
    2- {2-[(2-amino-2-oxoethyl) amino] -1,3-thiazol-4-yl} -N- (5-isopropyl-1,3-thiazol-2-yl) Acetamide,
    2- (2-{[2- (dimethylamino) -2-oxoethyl] amino} -1,3-thiazol-4-yl) -N- (5-isopropyl-1,3-thiazole-2 -Yl) -acetamide,
    2- [2- (adamantylamino) -1,3-thiazol-4-yl] -N- (5-isopropyl-1,3-thiazol-2-yl) acetamide,
    2- [4- (dimethylamino) phenyl] -N- (5-isopropyl-1,3-thiazol-2-yl) acetamide,
    N- (5-isopropyl-1,3-thiazol-2-yl) -2- [4- (4-methyl-1-piperazinyl) phenyl] acetamide,
    N- (5-isopropyl-1,3-thiazol-2-yl) -2- [4- (4-morpholinyl) phenyl] acetamide,
    N- (5-isopropyl-1,3-thiazol-2-yl) -2- [4- (1-pyrrolidinyl) phenyl] acetamide,
    N- [5-isopropyl-1,3-thiazol-2-yl) -2- (4-{[2- (4-methyl-1-piperazinyl) ethyl] amino} phenyl) acetamide,
    N- (5-isopropyl-1,3-thiazol-2-yl) -2- (4- {methyl [2- (4-methyl-1-piperazinyl) ethyl] amino} phenyl) acetamide,
    N- (5-isopropyl-1,3-thiazol-2-yl) -2- (4-{[2- (4-morpholinyl) ethyl] amino} phenyl) acetamide,
    N- (5-isopropyl-1,3-thiazol-2-yl) -2- (4- {methyl [2- (4-morpholinyl) ethyl] amino} phenyl) acetamide,
    2- {4-[(2,3-dihydroxypropyl) amino] phenyl} -N- (5-isopropyl-1,3-thiazol-2-yl) acetamide,
    2- {4-[(2,3-dihydroxypropyl) (methyl) amino] phenyl} -N- (5-isopropyl-1,3-thiazol-2-yl) acetamide,
    2- (4-{[3- (dimethylamino) -2-hydroxypropyl] amino} phenyl) -N- (5-isopropyl-1,3-thiazol-2-yl) acetamide,
    2- [4- (1-adamantylamino) phenyl) -N- (5-isopropyl-1,3-thiazol-2-yl) acetamide,
    2- {4-[(2-amino-2-oxoethyl) amino] phenyl} -N- (5-isopropyl-1,3-thiazol-2-yl) acetamide,
    2- (4-{[2- (dimethylamino) -2-oxoethyl] amino} phenyl) -N- (5-isopropyl-1,3-thiazol-2-yl) acetamide,
    2- [4- (acetylamino) phenyl] -N- (5-isopropyl-1,3-thiazol-2-yl) acetamide,
    N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) nicotinamide,
    N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) -5-methyl-2-thiophencarboxamide,
    N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl-5-methyl-2-pyrazinecarboxamide,
    N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) -5-methyl-4-isooxazolecarboxamide,
    N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) -3,5-dimethyl-4-isooxazolecarboxamide ,
    (Dimethylamino) -N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) benzamide,
    4- (acetylamino) -N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) benzamide,
    4- (dimethylamino) -N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) benzamide,
    N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) -1,3-benzodioxol-5-carboxamide ,
    4- (aminosulfonyl) -N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) benzamide,
    2-chloro-2,2-difluoro-N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) acetamide ,
    2-cyano-N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) acetamide,
    1-acetyl-N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) -4-piperidinecarboxamide,
    N'1 '-(4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) succinamide,
    N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) -2-methoxyacetamide,
    3,3,3-trifluoro-N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) propanamide,
    N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) -2-phenylacetamide,
    N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) -2-methoxy-2-phenylacetamide,
    2- [4- (dimethylamino) phenyl] -N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) acetamide ,
    N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) -2- (3-pyridinyl) acetamide,
    N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) -2- (3-thienyl) acetamide,
    N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) -2- [5- (1-pyrrolidinyl)- 2H-1,2,3,4-tetraazol-2-yl] acetamide,
    2-cyclopropyl-N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl Acetamide,
    N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -5-methyl -2-pyrazinecarboxamide,
    N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -2-propyl amides,
    N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -5-methyl -1,3-oxazole-4-carboxamide,
    N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -3,3 Dimethylbutanamide,
    N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -3-methyl -2-butenamide,
    3-cyclopentyl-N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl Propanamide,
    N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -2- ( 3-thienyl) acetamide,
    N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -2- ( 3-pyridinyl) acetamide,
    2,2,2-trifluoro-N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thia Zol-2-yl) acetamide,
    N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -3- ( 2-thienyl) propanamide,
    N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -2- ( 4-pyridinylsulfanyl) acetamide,
    N- (4- {2-[(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -2- ( 3-pyridinyl) -1,3-thiazole-4-carboxamide,
    2- [2- (acetylamino) -1,3-thiazol-4-yl] -N- (5-cyclopropyl-1,3-thiazol-2-yl) acetamide,
    2- [2- (acetylamino) -1,3-thiazol-4-yl] -N- {5-[(3-hydroxypropyl) (methyl) amino] -1,3-thiazole-2- Acetamide,
    2- [2- (acetylamino) -1,3-thiazol-4-yl] -N- {5-[(2-hydroxyethyl) (methyl) amino] -1,3-thiazole-2- Acetamide,
    2- [4- (dimethylamino) phenyl] -N- {5-[(2-hydroxyethyl) (methyl) amino] -1,3-thiazol-2-yl} acetamide,
    2- [4- (dimethylamino) phenyl] -N- {5-[(3-hydroxypropyl) (methyl) amino] -1,3-thiazol-2-yl] acetamide,
    2-amino-1 from the group consisting of N- (5-cyclopropyl-1,3-thiazol-2-yl) -2- [4- (dimethylamino) phenyl] acetamide and pharmaceutically acceptable salts thereof , 3-thiazole derivatives.
    [18" claim-type="Currently amended] A 2-amino-1,3-thiazole derivative or pharmaceutical composition of claim 13 comprising reacting a compound of Formula III with a compound of Formula IV to produce a 2-amino-1,3-thiazole derivative of Formula I Method for preparing a salt thereof is acceptable.
    Formula III

    Formula IV

    In Formula III and Formula IV above,
    R, L, R 1 , R 2 and R 3 are as defined in claim 13,
    Z is hydroxy or a suitable leaving group.
    [19" claim-type="Currently amended] A 2-amino-1,3-thiazole derivative or pharmaceutical composition of claim 13 comprising reacting a compound of Formula Ia with a compound of Formula V to produce a 2-amino-1,3-thiazole derivative of Formula II Method for preparing a salt thereof is acceptable.
    Formula Ia

    Formula V

    In the above formulas (Ia) and (V),
    R, R 1 , L and R 4 are as defined in claim 13,
    X is hydroxy or a suitable leaving group.
    [20" claim-type="Currently amended] 2-amino-1,3-thiazole derivative of formula (I, wherein at least one of R 2 and R 3 is a hydrogen atom) is reacted with a compound of formula (VI) to react 2-amino-1,3-thia Preparing a sol derivative, wherein at least one of R 2 and R 3 is not hydrogen, and optionally, a 2-amino-1,3-thiazole derivative of Formula I or Formula II is further A process for preparing the 2-amino-1,3-thiazole derivative of claim 13 or a pharmaceutically acceptable salt thereof, comprising converting to a 2-amino-1,3-thiazole derivative and / or a salt thereof.
    Formula VI

    In Formula VI above,
    R 'has the meaning of R 2 or R 3 of claim 13 but is not hydrogen,
    Y is a suitable leaving group.
    [21" claim-type="Currently amended] A pharmaceutical composition comprising the 2-amino-1, 3-thiazole derivative of claim 13 and one or more pharmaceutically acceptable carriers and / or diluents.
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    CZ2002486A3|2002-11-13|
    US6114365A|2000-09-05|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    1999-08-12|Priority to US09/372,832
    1999-08-12|Priority to US09/372,832
    2000-08-11|Application filed by 파마시아 이탈리아 에스.피.에이.
    2002-07-16|Publication of KR20020060159A
    2007-11-09|Application granted
    2007-11-09|Publication of KR100773709B1
    优先权:
    申请号 | 申请日 | 专利标题
    US09/372,832|1999-08-12|
    US09/372,832|US6114365A|1999-08-12|1999-08-12|Arylmethyl-carbonylamino-thiazole derivatives, process for their preparation, and their use as antitumor agents|
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