• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    (1) A compound of formula (1) and a pharmaceutically acceptable salt thereof. Throughout this specification, the symbols used in formula (1) have the following meanings: R 1 and R 2 are independently hydrogen, fluorine or alkyl; R 3 is aryl or heteroaryl. The compounds of formula (1) are inhibitors of protein kinases and are useful for the treatment and inhibition of proliferative diseases such as cancer, inflammation and arthritis.
    公开号:KR20010031896A
    申请号:KR1020007004995
    申请日:1998-11-02
    公开日:2001-04-16
    发明作者:김경에스.；킴볼에스.데이비드；포스마이클에이.；미스라라지엔.；카이첸-웨이；롤린스데이비드비.；웹스터케빈；헌트존티.；한웬-칭
    申请人:말라테스티닉 니콜라스 피.；브리스톨-마이어즈 스퀴브 컴페니；
    IPC主号:
    专利说明:

    [0001] AMINOTHIAZOLE INHIBITORS OF CYCLIN DEPENDENT KINASES OF CYCLINE-DEPENDENT KINASE [0002]
    The present invention relates to a compound represented by the formula (1)
    And pharmaceutically acceptable salts thereof. Throughout this specification, the symbols used in formula (1) have the following meanings:
    R 1 and R 2 are independently hydrogen, fluorine or alkyl;
    R < 3 > is aryl or heteroaryl
    R 4 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, cycloalkylalkyl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl; or
    CO-alkyl, heteroaryl, CO-heterocycloalkyl, CO-alkyl-heterocyclo Alkyl; or
    CONH-alkyl, CONH-cycloalkyl, CONH-aryl, CONH-alkyl-cycloalkyl, CONH-alkyl-aryl, CONH-heteroaryl, CONH-alkyl- heteroaryl, CONH-heterocycloalkyl, CONH-alkyl-heterocyclo Alkyl; or
    Alkyl-COO-alkyl, COO-cycloalkyl, COO-aryl, COO-alkyl-cycloalkyl, COO-alkyl-aryl, COO-heteroaryl, Alkyl; or
    SO 2 -alkyl, SO 2 -alkyl, SO 2 -cycloalkyl, SO 2 -aryl, SO 2 -alkyl-cycloalkyl, SO 2 -alkyl-aryl, SO 2 -heteroaryl, SO 2 -alkyl-heteroaryl, SO 2 -heterocyclo alkyl, SO 2 - alkyl-heterocycloalkyl; or
    C (NCN) NH-alkyl, C (NCN) NH-cycloalkyl, C (NCN) NH- C (NCN) NH-alkyl-heteroaryl, C (NCN) NH-heterocycloalkyl, C (NCN) NH-alkyl-heterocycloalkyl; or
    C (NNO 2) NH- alkyl, C (NNO 2) NH- cycloalkyl, C (NNO 2) NH- aryl, C (NNO 2) NH- alkyl-cycloalkyl, C (NNO 2) NH- alkyl-aryl C (NNO 2 ) NH -heteroaryl, C (NNO 2 ) NH-alkyl-heteroaryl, C (NNO 2 ) NH -heterocycloalkyl, C (NNO 2 ) NH-alkyl-heterocycloalkyl; or
    C (NH) NH-alkyl, C (NH) NH-alkyl, C (NH) NH-Cycloalkyl, Heteroaryl, C (NH) NH-alkyl-heteroaryl, C (NH) NH -heterocycloalkyl, C (NH) NH-alkyl-heterocycloalkyl; or
    C (NH) NHCO-alkyl, C (NH) NHCO-cycloalkyl, C (NH) NHCO- Heteroaryl, C (NH) NHCO-alkyl-heteroaryl, C (NH) NHCO-heterocycloalkyl, C (NH) NHCO-alkyl-heterocycloalkyl; or
    C (NOR 6) NH- alkyl, C (NOR 6) NH- cycloalkyl, C (NOR 6) NH- aryl, C (NOR 6) NH- alkyl-cycloalkyl, C (NOR 6) NH- alkyl-aryl C (NOR 6 ) NH -heteroaryl, C (NOR 6 ) NH -alkyl-heteroaryl, C (NOR 6 ) NH -heterocycloalkyl, C (NOR 6 ) NH -alkyl-heterocycloalkyl;
    R < 5 > is hydrogen or alkyl;
    R 6 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, cycloalkylalkyl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl;
    m is an integer from 0 to 2; And
    n is an integer from 1 to 3;
    The compounds of formula (I) are inhibitors of protein kinases and are useful for the treatment and prevention of proliferative diseases such as cancer, inflammation and arthritis. It is also useful for the treatment of neurodegenerative diseases such as Alzheimer's disease, cardiovascular diseases, viral diseases and fungal diseases.
    The present invention provides a compound of formula (I), a pharmaceutical composition using such a compound, and a method of using the compound.
    The following is a definition of various terms used to describe the compounds of the present invention. This definition applies to terms used throughout this specification whether they are individual or part of a larger group (unless they are otherwise limited in certain instances).
    Any heteroatom that does not satisfy the valence must be assumed to have a hydrogen atom to satisfy that valence.
    The carboxylate anion represents a negatively charged -COO - group.
    &Quot; Alkyl " or " alk ", unless otherwise defined, is a monovalent alkane (hydrocarbon) derived radical comprising 1 to 12 carbon atoms. Optionally, the alkyl group is a substituted straight, branched or cyclic saturated hydrocarbon group. When substituted, the alkyl group may substitute up to four substituents defined by R at their possible attachment sites. When the alkyl group is substituted by an alkyl group, it may be referred to as a " branched alkyl group ". Typical examples of such unsubstituted groups are methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, , 4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, and the like. Typical substituents include but are not limited to one or more of the following groups: halo (F, Cl, Br, I), haloalkyl (CCl 3 or CF 3 ), alkoxy, alkylthio, hydroxy, carboxy (-COOH) , Alkyloxycarbonyl (-C (O) R), alkylcarbonyloxy (-OCOR), amino (-NH 2 ), carbamoyl (-NHCOOR- or OCONHR-), urea (-NHCONHR-) (-SH). The defined alkyl groups may also consist of one or more double bonds of carbon and carbon or triple bonds of one or more carbon and carbon.
    &Quot; Alkenyl " is a straight, branched or cyclic hydrocarbon radical containing from 2 to 12 carbon atoms and at least one double bond of carbon and carbon.
    &Quot; Alkynyl " is a straight, branched or cyclic hydrocarbon radical containing from 2 to 12 carbon atoms and at least one triple bond of carbon and carbon.
    Cycloalkyl is an alkyl species containing from 3 to 15 carbon atoms and is free of cross or resonant double bonds between carbon atoms. It may contain from 1 to 4 rings. Typical examples of such unsubstituted groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, and the like. Typical substituents are one or more of the following groups: halogen, alkyl, alkoxy, alkylhydroxy, amino, nitro, cyano, thiol and / or alkylthio.
    &Quot; Alkoxy " or " alkylthio " as used herein refers to an alkyl group as defined above bound through an oxygen linkage (-O-) or a sulfur linkage (-S-), respectively.
    &Quot; Alkyloxycarbonyl " refers to an alkoxy group bonded through a carbonyl group. Representative formulas of alkoxycarbonyl radicals are: -C (O) OR, wherein the R group is a linear or branched C 1-6 alkyl group.
    &Quot; Alkylcarbonyl " means an alkenyl group bonded through a carbonyl group.
    As used herein, " alkylcarbonyloxy " refers to an alkylcarbonyl group bonded through an oxygen linkage.
    &Quot; Arylalkyl " is an aromatic ring bonded to an alkyl group as described above.
    &Quot; Aryl " includes fused groups such as, for example, naphthyl, phenanthrenyl and the like, as well as monocyclic or bicyclic aromatic rings such as phenyl, substituted phenyl, and the like. The aryl group therefore comprises at least one ring having at least 6 atoms and such rings can be up to 5 and contain 22 atoms therein. May have a cross (resonance) double bond between adjacent carbon atoms or a suitable heteroatom. The aryl group may be optionally substituted with one or more groups such as halogen, alkyl, alkoxy, hydroxy, carboxy, carbamoyl, alkyloxycarbonyl, nitro, trifluoromethyl, amino, cycloalkyl, cyano, (m = 0, 1, 2) or thiol.
    &Quot; Heteroaryl " is a monocyclic aromatic hydrocarbyl group having 5 or 6 ring atoms containing one or more heteroatoms O, S, or N, or a bicyclic aromatic group having 8 to 10 atoms, Location. In which one or two additional carbon atoms are optionally replaced by a heteroatom selected from O or S and three additional carbon atoms in each case are optionally replaced by a heteroatom nitrogen. The heteroaryl group is optionally substituted as described herein. Typical heteroaryl groups are: thienyl, furyl, pyrrolyl, pyridinyl, imidazolyl, pyrrolidinyl, piperidinyl, thiazolyl, oxazolyl, triazolyl, pyrazolyl, isoxazolyl, isothiazolyl , Pyrazinyl, pyridazinyl, pyrimidinyl, triazinylazepinyl, indolyl, isoindolyl, quinolinyl, isoquinolinyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzoxadia ≪ / RTI > benzofurazanyl, and tetrahydropyranyl. Typical substituents are one or more of the following groups: halogen, alkyl, alkoxy, hydroxy, carboxy, carbamoyl, alkyloxycarbonyl, trifluoromethyl, cycloalkyl, nitro, cyano, ) m (m = 0, 1, 2) or a thiol.
    &Quot; Heteroarylium " means a heteroaryl group having a fourth nitrogen atom and is thus positively charged.
    &Quot; Heterocycloalkyl " is a cycloalkyl group (non-aromatic) in which one carbon atom present in the ring is replaced by a heteroatom selected from O, S or N and additionally up to three carbon atoms can be replaced by said heteroatom .
    &Quot; Nitrogen in the fourth period " means a nitrogen atom charged in the amount of the fourth valence, and includes, for example, a nitrogen charged in a tetraalkylammonium group (for example, tetramethylammonium, N-methylpyridinium) (E.g., N-methyl-morpholine-N-oxide, pyridine-N-nitropyridine, Oxide) and nitrogen charged in an amount in the N-amino-ammonium group (e.g., N-aminopyridinium).
    &Quot; Heteroatom " means O, S or N, selected on an independent basis.
    &Quot; Halogen " or " halo " denotes chlorine, bromine, fluorine or isodine.
    When a functional group is referred to as " protected ", this means that the functional group is present in a modified form in advance to prevent undesirable side effects at the protected site. Suitable protecting groups for the compounds of the present invention will be known from applications taking into account the current state of the art, and can be found in standard texts such as: Green, T. W. et al., Protective Groups in Organic Synthesis, Wiley, N. Y. (1991).
    Specific examples of suitable compound salts according to the present invention, including inorganic or organic acids, include hydrochloride, hydrobromide, sulfate and phosphate. They are also unsuitable for pharmacological use, for example salts which can be used for the isolation or purification of the free compounds 1, or their pharmacologically acceptable salts.
    All stereoisomers of the compounds according to the invention are believed to be mixtures or pure or generally pure forms. The definition of the compounds of the present invention includes all possible stereoisomers and mixtures thereof. More particularly, separate optically isomers having a racemic form and a specific activity. Racemic forms can be resolved by physical methods, for example, partial crystallization, separation or crystallization of diastereomeric derivatives or separation by chiral column chromatography. The individual optical isomers can be obtained from the racemate by conventional methods, for example, crystallizing the optically active acid to form a salt.
    It is to be understood that solvates (e.g., hydrates) of the compounds of Formula 1 are also within the scope of the present invention. The solvation method uses a general method known in the art. Thus, the compounds of the present invention will be present in the free or hydrate form and can be obtained by the method of the following reaction scheme.
    As shown in Reaction Scheme 1, a compound of Formula 1 (wherein X is S) is prepared. The 2-aminothiazole (2) is reacted with bromine in the presence of sodium or potassium thiocyanate to obtain thiocyanatized aminothiazole, more specifically, 5-thiocyanatoaminothiazole (3). Compound 3 is then reacted with R 4 -L (where L is a leaving group such as halogen) in the presence of a base such as triethylamine to produce the 5-thiocyanatothiazole intermediate 4 (R 4 is As defined herein). The intermediate (4) is reduced to thiol (5) using dithiothreitol (DTT), sodium borohydride, zinc or other known reducing agents. Reacting compound (5) with an alkyl, aryl, or heteroaryl halide such as R 3 (CR 1 R 2 ) nL (wherein L is a leaving group such as halogen) in the presence of a base such as potassium carbonate, 1 < / RTI > The step of reducing the thiocyanothiazole intermediate product 4 to the thiol 5 and reacting the reduced thiol 5 to produce the compound of formula 1 wherein X is S proceed continuously without purification.
    In Scheme 2, the structure 6 2,5-thio-acetyl-2-acetylamino-thiazol the alkoxide and the resulting thiols such as a sol as potassium t- butoxide in alcohol or THF solvent of the formula R 3 (CR 1 R 2) n L wherein L is a leaving group such as halogen, such as 2-halomethyloxazole (7), to obtain a compound of formula 8 wherein R 1 and R 2 are hydrogen and R 6 is acetyl . The 2-halomethyloxazole compounds of formula (7) can be prepared via several synthetic routes known in the art. Chem. Pharm. Bull. 30, 1865 (1982); Bull. Chem. Soc. Comprehensive Heterocyclic Chemistry, Vol. 6, 177, A. Katritzky and CWRees, Pergamon Press (1984), JCS Chem. Comm. 322 (1981);
    The compound of formula 8 (R < 4 > in formula I is acetyl and X is S) is hydrogenated in the presence of a base such as sodium hydroxide to produce the compound of formula 9. The compound of formula 9 is then reacted with R 4 -L (wherein L is a leaving group such as halogen) in the presence of a base such as triethylamine to produce a compound of formula 1 wherein X is S. Thus, treatment of a compound of formula 9 (R < 4 > in a compound of formula 1 with hydrogen) with a drug such as isothiocyanate, halide, acyl halide, chloroformate, isocyanate, or sulfonyl chloride provides thiourea, Amines, amides, carbamates, ureas or sulfonamides. The method of Scheme 2 more specifically describes the methyloxazole group but is for the R 3 (CR 1 R 2 ) n-group generally embodied by Formula (1).
    Alternatively, the compound of formula 7 (wherein L is bromine) can be prepared by halogenating 2-methyloxazole with N-bromosuccinimide in the presence of dibenzoyl peroxide.
    Scheme 3 describes a method for the selective preparation of compound 7, i.e., formula R 3 (CR 1 R 2 ) nL, wherein L is chlorine and n is an integer 1. In the scheme, compound 7 is prepared as follows. Compounds of formula (10) and (11) are reacted in the presence of a base such as triethylamine to produce the compound of formula (12). Compound 12 is oxidized by an oxidizing agent such as oxalyl chloride / DMSO in the presence of a base such as triethylamine to produce the compound of formula 13. Which is cyclized by a chemical agent such as phosphorous oxychloride to provide a compound of formula 7 wherein L is chlorine. Alternatively, the compound of formula (13) can be prepared by reacting an amino ketone corresponding to 10 with an acid chloride such as 11.
    In Scheme 4, the diazo ketone depicted in Formula 14 and the chloronitrile of Formula 15 can be reacted in the presence of BF 3 etherate to provide a compound of Formula 7 wherein L is chlorine.

    In Scheme 5, starting compound 16 is Merrifield (Merrifield) resin used in the solid phase synthesis resin obtained from the labeled-benzyl alcohol support and the 2-methoxy-4-hydroxybenzaldehyde combination, which is reduced using a reducing agent such as NaBH 4. In step 1, starting material 16 is treated with tripsogen and triphenylphosphine (PPh 3 ) in dichloromethane to give the chlorobenzyl resin of formula 17. In step 2, thiocyanatotrifluoroacetamide (18) is alkylated with resin-bound benzyl chloride (17) in the presence of diisopropylethylamine (DIPEA). The product obtained is a resin-bound thiocyanate (19). The thiocyanatotrifluoroacetamide compound of formula (17) can be prepared by reacting 5-thiocyanatoaminothiazole of formula (3) with trifluoroacetic anhydride using a base such as 2,6- And the like.
    The resin-bound thiocyanate (19) is then reduced to the resin-bound thiol (20) using tetrahydrofuran (THF) and a reducing agent such as dithiothreitol under methanol in step 3. The resulting resin-bound thiol of 20 to 80 ℃ in dimethylformamide (DMF), 1,8- diazabicyclo [5.4.0] undec-7-ene in the presence of a base, such as R 3 (DBU) ( CR 1 R 2 ) nL, wherein L is a leaving group, to form a compound of formula (21) (step 4). In step 5, the trifluoroacetyl group of compound 21 is protected using sodium borohydride to produce the compound of formula 22. In step 6, the protected compound 22 is reacted with R 6 X (wherein X is a leaving group) in the presence of a base such as diisopropylethylamine to give the compound of formula 23. The product is then separated from the solid phase resin using trifluoroacetic acid (TFA) in step 7 to yield a compound of formula 1 wherein X is S. The compound of formula (1) wherein X is S (O) m and m is 1 or 2 can be obtained by reacting a compound of formula (1) wherein m is 0 with an oxidizing agent such as sodium peridodate, metachloroperbenzoic acid or oxone And then oxidizing the resultant.
    The starting materials of Schemes 1-5 are either commercially available or can be prepared by conventional methods known in the art.
    All compounds of formula (I) can be prepared by modifying the methods described herein.
    Preferred compounds of formula (1) are:
    R 1 and R 2 are independently hydrogen, fluorine or alkyl;
    R 3 is
    (Wherein Y is oxygen, sulfur or NR < 9 >);
    R 4 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, cycloalkylalkyl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl; or
    CO-alkyl, heteroaryl, CO-heterocycloalkyl, CO-alkyl-heterocyclo Alkyl; or
    CONH-alkyl, CONH-cycloalkyl, CONH-aryl, CONH-alkyl-cycloalkyl, CONH-alkyl-aryl, CONH-heteroaryl, CONH-alkyl- heteroaryl, CONH-heterocycloalkyl, CONH-alkyl-heterocyclo Alkyl; or
    Alkyl-COO-alkyl, COO-cycloalkyl, COO-aryl, COO-alkyl-cycloalkyl, COO-alkyl-aryl, COO-heteroaryl, Alkyl; or
    SO 2 -alkyl, SO 2 -alkyl, SO 2 -cycloalkyl, SO 2 -aryl, SO 2 -alkyl-cycloalkyl, SO 2 -alkyl-aryl, SO 2 -heteroaryl, SO 2 -alkyl-heteroaryl, SO 2 -heterocyclo alkyl, SO 2 - alkyl-heterocycloalkyl; or
    C (NCN) NH-alkyl, C (NCN) NH-cycloalkyl, C (NCN) NH- C (NCN) NH-alkyl-heteroaryl, C (NCN) NH-heterocycloalkyl, C (NCN) NH-alkyl-heterocycloalkyl; or
    C (NNO 2) NH- alkyl, C (NNO 2) NH- cycloalkyl, C (NNO 2) NH- aryl, C (NNO 2) NH- alkyl-cycloalkyl, C (NNO 2) NH- alkyl-aryl C (NNO 2 ) NH -heteroaryl, C (NNO 2 ) NH-alkyl-heteroaryl, C (NNO 2 ) NH -heterocycloalkyl, C (NNO 2 ) NH-alkyl-heterocycloalkyl; or
    C (NH) NH-alkyl, C (NH) NH-alkyl, C (NH) NH-Cycloalkyl, Heteroaryl, C (NH) NH-alkyl-heteroaryl, C (NH) NH -heterocycloalkyl, C (NH) NH-alkyl-heterocycloalkyl; or
    C (NH) NHCO-alkyl, C (NH) NHCO-cycloalkyl, C (NH) NHCO- Heteroaryl, C (NH) NHCO-alkyl-heteroaryl, C (NH) NHCO-heterocycloalkyl, C (NH) NHCO-alkyl-heterocycloalkyl; or
    C (NOR 6) NH- alkyl, C (NOR 6) NH- cycloalkyl, C (NOR 6) NH- aryl, C (NOR 6) NH- alkyl-cycloalkyl, C (NOR 6) NH- alkyl-aryl C (NOR 6 ) NH -heteroaryl, C (NOR 6 ) NH -alkyl-heteroaryl, C (NOR 6 ) NH -heterocycloalkyl, C (NOR 6 ) NH -alkyl-heterocycloalkyl;
    R 5 is hydrogen; And
    R 6 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, cycloalkylalkyl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl;
    R 7 and R 8 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, alkylcycloalkyl, alkylaryl, heteroaryl, alkylheteroaryl, heterocycloalkyl, alkylheterocycloalkyl or halogen;
    R < 9 > is H or alkyl;
    m is an integer 0; And
    n is an integer 1.
    Most preferred compounds of formula (1) are:
    R 1 is hydrogen;
    R 2 is hydrogen, fluorine or alkyl;
    R 3 is a substituted oxazole having the following structure:

    R 4 is CO-alkyl, CO-alkyl-aryl, CO-cycloalkyl, CONH-cycloalkyl or CONH-alkyl-heterocycloalkyl;
    R 5 is hydrogen;
    R 7 is hydrogen;
    R 8 is an alkyl group such as tert-butyl;
    m is an integer 0; And
    n is an integer of 1;
    The compounds of the present invention have pharmacological properties; More specifically, compounds of formula (I) are inhibitors of protein kinases such as cyclin dependent kinases (cdks) such as cdc2 (cdk1), cdk2 and cdk4. The novel compounds of formula (I) are expected to be useful in the treatment of proliferative diseases such as cancer, autoimmune diseases, viral diseases, fungal diseases, neurodegenerative diseases and cardiovascular diseases.
    More specifically, the compounds of formula (I) are useful in the treatment of a variety of cancers, including, but not limited to:
    Includes lung, esophagus, gallbladder, ovary, pancreas, stomach, uterus, thyroid, prostate and skin carcinoma, squamous cell carcinoma, including bladder, breast, colon, kidney, liver and small cell lung cancer;
    Lymphoma hematopoietic tumors such as leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, biopsy cell lymphoma and Burkett's lymphoma;
    - Bone marrow-derived hematopoietic tumors including acute and chronic myelogenous leukemia, spinal dysplasia syndrome and promyelocytic lymphoma
    - mesenchymal tumors such as fibrosarcoma and rhabdomyoma
    - tumors of the central nervous system and peripheral nervous system, including astrocytomas, neuroblastomas, gliomas and schwannomas
    - Other tumors, including melanoma, carcinoma, teratoma, osteosarcoma, parasitic species, pigmentosum, keratinocyte, thyroid follicular cancer and Kaposi's sarcoma.
    Since the role of cdks in regulating cell proliferation is generally important, the inhibitor may be any disease characterized by abnormal cell proliferation, such as benign prostatic hypertrophy, familial adenomatous polyposis, neurofibromatosis, atherosclerosis, pulmonary fibrosis, arthritis , Any reversible cell proliferation useful for treating progression of psoriasis, glomerulonephritis, restenosis following angioplasty or vascular surgery, proliferative scar formation, inflammatory bowel disease, graft rejection, endotoxic shock, and fungal infection Lt; / RTI >
    Compounds of formula 1 are also useful in the treatment of Alzheimer's disease as suggested by recent studies suggesting that cdk5 is involved in the phosphorylation of tau proteins (J. Biochem, 117, 741-749 (1995)).
    The compounds of formula (I) can induce or inhibit apoptosis. Various human diseases make apoptosis reaction abnormal. As modulators of apoptosis, the compounds of formula (I) may be used in the treatment of cancer (including, but not limited to, those mentioned above), viral infections (such as herpes virus, poxvirus, Epstein- Viruses and adenoviruses), prevention of the development of AIDS in HIV-infected individuals, autoimmune diseases (autoimmune, rheumatic arthritis, psoriasis, inflammatory bowel disease and autoimmune diabetes mellitus mediated by systemic lupus, But are not limited to, disorders of neurodegeneration, including Alzheimer ' s disease, AIDS-related dementia, Parkinson's disease, amyotrophic lateral sclerosis, retinitis pigmentosa, caustic myotonia, and cerebellar degeneration ), Spinal dysplasia, ischemic anemia, ischemia associated with myocardial infarction, stroke and reperfusion injury, arrhythmia, (Including, but not limited to, thrombotic atherosclerosis, toxic-induced or alcohol-related liver disease, blood diseases (including, but not limited to, chronic anemia and anemia), degenerative diseases of the musculoskeletal system including osteoporosis and arthritis ), Aspirin-sensitive non-sinusitis, bladder fibrosis, multiple sclerosis, kidney disease and cancer pain.
    As inhibitors of cdks, the compounds of formula (I) can modulate cellular RNA and DNA synthesis levels. Therefore, these drugs are useful for the treatment of viral infections (HIV, human papilloma virus, herpes virus, poxvirus, Epstein-Barr virus, Sindbis virus and adenovirus).
    The compounds of formula (I) are also useful for the chemical prophylaxis of cancer. The definition of chemical prophylaxis is to prevent the initiation of mutations or to inhibit the development of invasive cancer by inhibiting the progress of pre-malignant cells that have already been damaged, or to inhibit recurrence of the disease.
    The compounds of formula (I) are also useful for inhibiting angiogenesis and metastasis of tumors.
    The compound of formula I can act as an inhibitor of other protein kinases such as protein kinase C, her2, raf1, MEK1, MAP kinase, EGF receptor, PDGF receptor, IGF receptor, PI3 kinase, wee1 kinase, Src, Can be effective in the treatment of diseases related to kinase.
    The compounds of the present invention may also be used in combination with known chemotherapeutic agents such as radiotherapy or DNA interactions such as cell proliferation inhibitors or cytotoxic agents such as cisplatin or doxorubicin; Topoisomerase II inhibitors such as etoposide; Topoisomerase I inhibitors such as CPT-11 or topotecan; Tubulin interactors such as paracetaxel, docetaxel or epothilones; Hormones such as tamoxifen; Thymidylate synthase inhibitors such as 5-fluorouracil; (Both administered together or sequentially) with anti-metabolites such as, for example, methotrexate, and methotrexate.
    When compounded at a fixed dose, such a mixture will include the compound of the invention within the dosage range described below and include other pharmacologically active agents or agents within the approved dosage range. For example, the cdc2 inhibitor olomycin is known to act synergistically with known cytotoxic agents in inducing apoptosis (J. Cell Sci., 108, 2897 (1995)). It is also possible to administer the compound of formula (1) continuously when it is inadequate to blend with already known anticancer drugs or cytotoxic agents. The order of administration in the present invention is not limited; The compound of formula (1) may be used before or after administration of known anticancer drugs or cytotoxic agents. For example, the inhibitor of cyclin-dependent kinase, flavopiridol, is affected by the order of administration of anticancer drugs. Cancer Research, 57, 3375 (1997).
    The pharmacological properties of the compounds according to the invention can be confirmed by numerous drug analyzes. Good examples of drug analysis performed on the compounds and salts thereof according to the present invention are described below. The compounds of Examples 1 to 8 exhibited cdc2 / Cyclin B1 kinase activity with an IC 50 value of 50 μM or less. The compounds of Examples 1 to 8 exhibited cdk2 / Cyclin E kinase activity with IC 50 values of 50 μM or less. The compounds of Examples 1 to 8 exhibited cdk4 / Cyclin D1 kinase activity with an IC 50 value of 50 μM or less.
    cdc2 / Cyclin B1 kinase assay
    The cdc2 / cyclin B1 kinase activity was measured by monitoring the binding of 32 P to histone H1. The reaction mixture contained 50 ng baculovirus expressing GST-cdc2, 75 ng baculovirus expressing GST-cyclin B1, 1 ug histone HI (50 ng / ml) in the kinase buffer (50 mM Tris, pH 8.0, 10 mM MgCl 2 , 1 mM EGTA, 0.5 mM DTT) (Boehringer Mannheim, Boehringer Mannheim), 0.2 mCi of 32 P g-ATP and 25 mM ATP. The reaction was incubated at 30 ° C for 30 minutes and incubation was stopped by adding cold trichloroacetic acid (TCA) to a final concentration of 15%. Then, it was incubated on ice for 20 minutes. Reactions were harvested on GF / C uni-filter plates (Packard) using a Packard Filtermate Universal harvester. The filters were then counted on a Packard TopCount 96-well liquid scintillation counter (Marshak, DR, Vanderberg, MT, Bae, YS, Yu, IJ, Cellular Biochemistry, J., 45, 391-400 (1991) Incorporated herein by reference).
    Analysis of cdk2 / Cyclin E kinase
    The cdk2 / cyclin E kinase activity was determined by monitoring the binding of 32 P with the retinoblastoma protein. The reactants with kinase buffer (50mM HEPES, pH 8.0, 10mM MgCl 2, 5mM EGTA, 2mM DTT) with 500ng GST- produced by viruses, bacteria 2.5ng of baculovirus GST-cdk2 / cyclin E expressed in the retinal cell tumor protein ( aa 776-928), 0.2 mCi of 32 P g-ATP, and 25 mM ATP. The reaction was incubated at 30 ° C for 30 minutes and incubation was stopped by adding cold trichloroacetic acid (TCA) to a final concentration of 15%. Then, it was incubated on ice for 20 minutes. Reactions were harvested on GF / C uni-filter plates (Packard) using a Packard Filtermate Universal harvester. The filters were then counted on a Packard TopCount 96-well liquid scintillation counter.
    cdk4 / cyclin D1 kinase activity
    for cdk4 / cyclin D1 kinase activity was determined by monitoring the binding of 32 P with the retinoblastoma protein. The reactants were prepared from bacterial-produced 282 ng of bacteria with 165 ng baculovirus, S-tag Cyclin D1 of GST-cdk4 expression in kinase buffer (50 mM HEPES, pH 8.0, 10 mM MgCl 2 , 5 mM EGTA, 2 mM DTT) 500ng GST-retinoblastoma protein (aa 776-928), 0.2 μCi of 32 P γ-ATP and 25 μM ATP. The reaction was incubated at 30 DEG C for 1 hour and incubation was stopped by adding cold trichloroacetic acid (TCA) to a final concentration of 15%. Then, it was incubated on ice for 20 minutes. Reactions were harvested on GF / C uni-filter plates (Packard) using a Packard Filtermate Universal harvester. The filters were then counted on a Packard Topcount 96-well liquid scintillation counter (Coleman, KG, Wautlet, BS, Morrisey, D, Mulheron, JG, Sedman, S., Brinkley, P., Price, (1997). Identification of the CDK4 sequence and p16 binding contained in Cyclin D. J. Biol. Chem. 272, 30: 18869-18874, incorporated herein by reference).
    In addition, the present invention relates to the use of the above-described medicament having the function of controlling cancer, inflammation and arthritis and comprising at least one compound of formula (I) as defined above or at least one pharmaceutically acceptable acid addition salt thereof. The invention also relates to the use of a compound of formula 1 as defined above for the manufacture of a medicament having activity against proliferative diseases, as described above, acting against cancer, inflammation and / or arthritis.
    The following examples and preparations illustrate means and methods for carrying out and using the present invention and are intended to be more specific than the present invention. It is to be understood that other embodiments within the spirit and scope of the invention as defined in the claims herein are possible.
    Example 1
    N- [5 - [[(5-ethyl-2-oxazolyl) methyl] thio] -2-thiazolyl] acetamide
    A. Preparation of 1-benzyloxycarbonylamino-2-butanol
    A solution of 1-amino-2-butanol (5.5 g, 61.8 mmol), benzyl chloroformate (11.5 g, 676.6 mmol) and sodium carbonate (7.16 g, 67.7 mmol) in water (50 mL) Lt; / RTI > Water (50 mL) was added to the reaction mixture and the product was extracted with methylene chloride (3 x 20 mL). The methylene chloride extract was dried over Na 2 SO 4 and concentrated. The residue was passed through a short column (SiO2, hexane: ethyl acetate / 10: 1, and ethyl acetate) to give 1-benzyloxycarbonylamino-2-butanol (13.9 g, 100%) as a liquid.
    1 H NMR (CDCl 3) δ 7.30 (m, 5H), 5.45 (s, 1H), 5.06 (s, 2H), 3.57 (s, 1H), 3.31 (m, 1H), 3.04 (m, 1H), 2.91 (m, 1H), 1.43 (m, 2H), 0.91 (t, J = 7.6 Hz, 3H).
    B. Preparation of 1-benzyloxycarbonylamino-2-butanone
    Oxalyl chloride (37 mL of a 2 M solution in methylene chloride, 74 mmol) was added to methylene chloride (60 mL) under argon at -78 [deg.] C followed by DMSO (7.8 g, 100 mmol). The mixture was stirred at -78 [deg.] C for 20 minutes and thereto was added a solution of 1-benzyloxycarbonylamino-2-butanol (13.9 g, 61.8 mmol) in methylene chloride (40 mL). The mixture was stirred at -78 < 0 > C for 1 hour and thereto was added triethylamine (21 mL). Warmed to room temperature (rt) and washed successively with 1N hydrochloric acid and aqueous sodium bicarbonate solution. The methylene chloride solution was dried under Na 2 SO 4 and concentrated to give 1-benzyloxycarbonylamino-2-butanone (11.2 g, 82%) as a solid which was pure enough for use in the next reaction.
    1 H NMR (CDCl 3) δ 7.32 (m, 5H), 5.50 (s, 1H), 5.06 (s, 2H), 4.07 (s, 2H), 2.43 (q, J = 7.6Hz, 2H), 1.06 ( q, J = 7.6 Hz, 3H).
    C. Preparation of 1-amino-2-butanone
    A solution of 1-benzyloxycarbonylamino-2-butanone (9.30 mg, 42 mmol) in ethanol (50 mL) and 1 N hydrochloric acid (46 mL) was added to a solution of Pd / C (1.5 g, 10% Lt; / RTI > The mixture was filtered through a celite layer and the filtrate solution was concentrated. The residue was triturated with ethyl ether to give 1-amino-2-butanone (5.3 g, 102%) as a hydrochloride salt.
    1 H NMR (CD 3 OD) δ 3.97 (s, 2H), 2.60 (q, J = 7.6Hz, 2H), 1.08 (t, J = 7.6Hz, 3H).
    D. Preparation of 2-amino-5-thiocyanatothiazole
    2-Aminothiazole (41 g, 410 mM) and sodium thiocyanate (60 g, 740 mM, dried in a vacuum oven at 130 < 0 > C overnight) were dissolved in 450 mL anhydrous methanol and the solution was cooled in a cold water bath. Bromine (23 mL, 445 mM) was added dropwise thereto while stirring well. After the addition, the mixture was stirred at room temperature for 4 hours. To the mixture was added 500 mL of water and stirred for 5 minutes, then filtered through a celite layer and washed with water. The pH of the filtrate solution was about 1. Most of the methanol was removed under reduced pressure and the pH of the solution was adjusted to about 7 by adding aqueous sodium carbonate slowly with stirring. The precipitated solid was filtered off, washed with water and dried to give 37 g (57%) of a dark brownish desired product. The melting point was 140-143 占 폚.
    1 H NMR (CD 3 OD) δ 7.33 (s, 1H); MS (CI / NH 3) m / e 179 (M + Na) +, 158 (M + H) +.
    E. Preparation of 2-acetylamino-5-thiocyanatothiazole
    To a mixture of 2-amino-5-thiocyanatothiazole (15.7 g, 0.1 mol) and pyridine (12 g, 0.15 mol) in methylene chloride (100 mL) was added acetic anhydride (1.2 g, 0.12 mol) . The mixture was stirred at room temperature for 6 hours. The mixture was concentrated and dried, and methanol (50 mL) was added to the residue. The precipitate was recovered and washed with water. The solid was dried and recrystallized from methanol to give 2-acetylamino-5-thiocyanatothiazole (15.2 g, 76%) as a solid with a melting point of 212 캜.
    1 H NMR (CD 3 OD) 7.79 (s, 1H), 2.23 (s, 3H).
    F. Preparation of [[2- (acetylamino) -5-thiazolyl] -thio] acetic acid-1,1-dimethylethyl ester
    To a mixture of 2-acetamino-5-thiocyanatothiazole (5.97 g, 30 mmol) in methanol (360 mL) was added dithiothreitol (9.26 g, 60 mmol) under argon at room temperature. The mixture was stirred at room temperature for 2 hours and then concentrated to give a reduced solid product. This solid product was dissolved in DMF (30 mL) and tert-butyl bromoacetate (5.85 g, 30 mmol) and potassium carbonate (5.0 g, 36 mmol) were added to the resulting solution. The mixture was stirred at room temperature for 2 hours and water (200 mL) was added. The precipitate was collected, washed with water and dried. The solids were dissolved in methylene chloride (100 mL) and methanol (10 mL) and filtered through a pad of silica gel. The filtrate solution was concentrated to give the desired product (7.5 g, 87%) having a melting point of 162-163 DEG C as a solid.
    1 H NMR (CDCl 3 ) 12.2 (s, IH), 7.48 (s, IH), 3.37 (s, 2H), 2.32 (s, 3H), 1.45 (s, 9H); MS m / e 289 (M + H) < + & gt ; , 287 (MH) - .
    HPLC (Column: YMC S3 ODS 4.6x150mm; flow rate: 2.5mL / min; solvent system: 0-100% to 8 minutes B. Solvent A: 10% methanol -90% water -0.2% H 3 PO 4; Solvent B: 90% methanol-10% water-0.2% H 3 PO 4 ; UV: 220 nm): retention time 6.44 min.
    G. Preparation of [[2- (acetylamino) -5-thiazolyl] thio] acetic acid
    A solution of [[2- (acetylamino) -5-thiazolyl] thio] acetic acid 1,1-dimethylethyl ester (4.32 g, 15 mmol) and trifluoroacetic acid (20 mL) in methylene chloride (30 mL) ≪ / RTI > and concentrated in vacuo. Ethyl ether (50 mL) was added to the residue. The precipitated solid was collected, washed with ethyl ether and dried to give the desired product (3.38 g, 97%) as a solid with a melting point of 210 캜.
    1 H NMR (CD 3 OD) δ 7.48 (s, 1H), 3.47 (s, 2H), 2.20 (s, 3H) ppm; MS m / e 231 (MH) - ; HPLC: Column: Zorbax Rapid resolution C-18; Flow rate: 2.5 mL / min; Solvent system: 0-100% in 8 min B. Solvent A: 10% Methanol-90% 3 PO 4 ; solvent B: 90% methanol-10% water-0.2% H 3 PO 4 ; UV: 254 nm): retention time 4.32 min.
    Preparation of H. [[2- (acetylamino) -5-thiazolyl] thio] -N- (2-oxobutyl) acetamide
    (9.0 g, 38.8 mmol), HOBT (5.94 g, 38.3 mmol), and ethyldimethylaminopropylcarbodiimide hydrochloride salt (5.9 g, 38.3 mmol) in DMF (50 mL) 11.16 g, 58.2 mmol) was stirred at 0 < 0 > C for 0.5 h. To this mixture was added 1-amino-2-butanone hydrochloride (5.27 g, 42.7 mmol) followed by triethylamine (15 mL, 107.5 mmol). The mixture was stirred at 0 < 0 > C for 0.5 h and at room temperature for 1 h. Water (200 mL) was added and the product was extracted with methylene chloride (5 x 100 mL) containing 10% methanol. The methylene chloride extract was dried over Na 2 SO 4 and concentrated. The residue was triturated with water and the precipitated solid product was collected by filtration. This was dried to give the desired product (10.5 g, 90%) with a melting point of 195-196 [deg.] C.
    1 H NMR (CDCl 3) δ 7.53 (s, 1H), 4.14 (s, 2H), 3.46 (s, 2H), 2.50 (q, J = 7.6Hz, 2H), 2.25 (s, 3H), 1.12 ( t, J = 7.6 Hz, 3 H); MS m / e 302 (M + H) < + & gt ; .
    Solvent system: 0-100% in 8 minutes B. Solvent A: 10% methanol-90% water-0.2% H 3 PO 4 : solvent (solvent: B: 90% methanol-10% water-0.2% H 3 PO 4 ; UV: 254 nm): retention time 4.36 min.
    I. Preparation of N- [5 - [[(5-ethyl-2-oxazolyl) methyl] thio] -2-thiazolyl] acetamide
    To a solution of [[2- (acetylamino) -5-thiazolyl] thio] -N- (2- oxobutyl) acetamide (10.5 g, 34.8 mmol) in acetic anhydride (100 mL) ). The mixture was stirred at 55-60 < 0 > C for 2 hours, sodium acetate (15 g, 0.18 mmol) was added and the mixture was concentrated in vacuo. To the residue was added cold water (100 mL). The precipitated solid was recovered, washed with water and dried. This flash column chromatography (SiO 2; methylene chloride: MeOH / 100: 5) to N- [5 having a melting point of 147-148 ℃ was purified by - [[(5-ethyl-2-oxazolyl) methyl] thio ] -2-thiazolyl] acetamide (4.2 g, 43%) as a solid.
    1 H NMR (CDCl 3) δ 12.47 (s, 1H), 7.29 (s, 1H), 6.61 (s, 1H), 3.91 (s, 2H), 2.64 (q, J = 7.6Hz, 2H), 2.25 ( s, 3H), 1.21 (t, J = 7.6 Hz, 3 H) ppm; MS m / e 284 (M + H) < + & gt ; .
    Solvent system: 0-100% in 8 minutes B. Solvent A: 10% methanol-90% water-0.2% H 3 PO 4 : solvent (solvent: B: 90% methanol-10% water-0.2% H 3 PO 4 ; UV: 254 nm): retention time 6.50 min.
    Example 2
    N- [5 - [[(5-ethyl-2-oxazolyl) methyl] thio] -2-thiazolyl]
    A. Preparation of 2-amino-5 - [[(5-ethyl-2-oxazolyl) methyl] thio]
    A solution of N- [5 - [[(5-ethyl-2-oxazolyl) methyl] thio] -2-thiazolyl] acetamide (1.3 g, 4.6 mmol) in 1N hydrochloric acid (15 mL) And stirred for 3 hours. It was cooled to room temperature and the pH of the solution was adjusted to 7 by sodium carbonate. The product was extracted with methylene chloride (3 x 10 mL). The combined extracts were dried over Na 2 SO 4 and concentrated. The residue was triturated with ethyl ether and the precipitated solid was collected to give 2-amino-5 - [[(5-ethyl-2-oxazolyl) methyl] thio] -thiazole , 55%) as a solid.
    1 H NMR (CDCl 3) δ 6.93 (s, 1H), 6.61 (s, 1H), 5.41 (s, 2H), 3.82 (s, 3H), 2.62 (q, J = 7.6Hz, 2H), 1.18 ( t, J = 7.6 Hz, 3 H); MS m / e 242 (M + H) < + >;
    Solvent system: 0-100% in 8 minutes B. Solvent A: 10% methanol-90% water-0.2% H 3 PO 4 : solvent (solvent: B: 90% methanol-10% water-0.2% H 3 PO 4 ; UV: 254 nm): retention time 3.96 min.
    B. Preparation of N- [5 - [[(5-ethyl-2-oxazolyl) methyl] thio] -2-thiazolyl] benzamide
    Methyl] thio] -thiazole (48.2 mg, 0.2 mmol), benzoyl chloride (24.4 mg, 0.21 mmol) in methylene chloride (0.5 mL) And triethylamine (35 mg, 0.35 mmol) was stirred at room temperature for 10 minutes. The organic solution was washed with water and concentrated. The residue was purified by a flash column (SiO 2 ; hexane: ethyl acetate / 2: 1) to give N- [5 - [[(5-ethyl-2-oxazolyl) methyl] thio] -2-thiazolyl] benzamide (41 mg, 59%) as a solid.
    1 H NMR (CDCl 3 ) 12.65 (s, IH), 7.96 (m, 2H), 7.61 (m, IH), 7.49 3.93 (s, 2H), 2.61 (q, J = 7.6 Hz, 2H), 1.20 (t, J = 7.6 Hz, 3H); MS m / e 346 (M + H) < + >;
    Solvent system: 0-100% in 8 minutes B. Solvent A: 10% methanol-90% water-0.2% H 3 PO 4 : solvent (solvent: B: 90% methanol -10% water -0.2% H 3 PO 4; UV : 254nm): retention time 7.94 minutes.
    Example 3
    N- [5 - [[(5-ethyl-2-oxazolyl) methyl] thio] -2-thiazolyl] benzenesulfonamide
    (24.1 mg, 0.1 mmol), benzenesulfonyl chloride (19.4 mg, 0.11 mmol, 0.1 mmol) in methylene chloride (0.3 mL) ) And triethylamine (22 mg, 0.21 mmol) was stirred at room temperature for 10 hours. The resulting reaction mixture was purified by preparative HPLC (column: YMC Pack ODSA S3 20 x 100 mm; method: 0% B to 100% B gradient in 20 min and flow rate 20 mL / min; UV: 254 nm; solvent A: 10% [5 - [[(5-ethyl-2-oxazolyl) methyl] piperidine hydrochloride, Thio] -2-thiazolyl] benzenesulfonamide (2.5 mg) as a solid.
    1 H NMR (CDCl 3) δ 7.88 (d, J = 8.0Hz, 1H), (s, 2H), 7.49 (m, 3H), 6.89 (s, 1H), 6.64 (s, 1H), 4.01 (s , 2H), 2.68 (q, J = 7.4 Hz, 2H), 1.27 (t, J = 7.4 Hz, 3H); MS m / e 382 (M + H) < + & gt ; .
    Solvent system: 0-100% in 8 minutes B. Solvent A: 10% methanol-90% water-0.2% H 3 PO 4 : solvent (solvent: B: 90% methanol-10% water-0.2% H 3 PO 4 ; UV: 254 nm): retention time 6.84 min.
    Example 4
    N- [5 - [[(4,5-dimethyl-2-oxazolyl) methyl] thio] -2-thiazolyl] acetamide
    A. Preparation of 2- (bromomethyl) -4,5-dimethyloxazole
    A solution of 2,4,5-trimethyloxazole (0.50 mL, 4.3 mmol), N-bromosuccinimide (0.77 g, 4.3 mmol) and benzoyl peroxide (0.21 g, 0.86 mmol) in carbon tetrachloride (4 mL) The mixture was heated at 76 < 0 > C for 3 hours under a nitrogen atmosphere. After cooling to room temperature, the solid was removed by filtration. The filtrate solution was washed with saturated aqueous NaHCO 3 (20 mL) and concentrated. The residue was purified by flash column chromatography (SiO 2 ; hexane: ethyl acetate / 4: 1) to give 2- (bromomethyl) -4,5-dimethyloxazole (64 mg) as yellow oil.
    1 H NMR (CDCl 3 ) 4.4 (s, 2H), 2.25 (s, 3H), 2.05 (s, 3H).
    B. Preparation of N- [5 - [[(4,5-dimethyl-2-oxazolyl) methyl] thio] -2-thiazolyl] acetamide
    (0.050 g, 0.23 mmol) was dissolved in dry THF (10 mL) and thereto was added potassium tert-butoxide (1.0 M solution in THF, 0.25 mL, 0.25 mmol). The reaction mixture was stirred at room temperature for 15 minutes and 2- (bromomethyl) -4,5-dimethyloxazole (0.064 g, 0.34 mmol) was added to the mixture. The reaction mixture was stirred at room temperature for 3 hours and was added to saturated aqueous NaHCO 3 solution (20mL). The organic layer was separated and the aqueous layer was extracted with dichloromethane (3 x 20 mL). After concentrating the combined organic layers the residue was purified by flash column chromatography (SiO 2; methanol: dichloromethane / 1: 20) to N- [5 was a yellow oil was purified by - [[(4,5-dimethyl-2-oxazolyl ) Methyl] thio] -2-thiazolyl] acetamide (15 mg, 23%).
    1 H NMR (CDCl 3) δ 11.78 (s, 1H), 7.38 (s, 1H), 3.90 (s, 2H), 2.30 (s, 3H), 2.22 (s, 3H), 2.05 (s, 3H); MS m / e 284 (M + H) < + & gt ; .
    10% CH 3 OH-90% H 2 O-0.2% H 3 ( solvent: water) PO 4 ; solvent B: 90% CH 3 OH-10% H 2 O-0.2% H 3 PO 4 ; UV: 254 nm): retention time 5.87 min.
    Example 5
    N- [5 - [[(5-t-butyl-2-oxazolyl) methyl] thio] -2-thiazolyl] acetamide
    A. Preparation of diazomethane
    To a mixture of 15 mL of a 40% aqueous KOH solution and 50 mL of diethyl ether was added 5 g (68 mmol) of N-methyl-N'-nitro-N-nitrosoguanidine at 0 ° C with partial stirring. The resulting mixture was stirred at 0 < 0 > C for 0.5 h. The organic phase was separated into a supernatant with a drying flask, and the solid KOH pellet was dried to obtain 50 mL of diazomethane solution (ca 0.5 M, acetic acid titration).
    B. Preparation of 1-diazo-3,3-dimethyl-2-butanone
    To the diazomethane solution at 0 < 0 > C was added dropwise 1.23 mL (1.21 g, 10 mmol, Aldrich) trimethylacetyl chloride in 1 mL diethyl ether with stirring. The resulting mixture was maintained at 0 < 0 > C for 16 hours. The solution was sparged with argon to remove excess diazomethane and diethyl ether was removed under reduced pressure. As a result, 1.33 g (10 mmol, 100%) of crude 1-diazo-3,3-dimethyl-2-butanone was obtained as a yellow liquid.
    C. Preparation of 2-chloromethyl-5-t-butyloxazole
    To a solution of 2 mL (2.3 g, 16 mmol) boron trifluoride etherate in 20 mL chloroacetonitrile at 0 C was added a solution of 1.33 g (10 mmol) 1-diazo-3,3-dimethyl-2-butanone in 5 mL chloroacetonitrile Was added. The resulting solution was stirred at 0 < 0 > C for 0.5 h. The reaction mixture was added to a saturated aqueous sodium bicarbonate solution to neutralize the acid and the product was extracted three times using dichloromethane. The combined extracts were dried (sodium sulfate), concentrated and purified by flash column chromatography (Merck silica, 25 x 200 mm, dichloromethane) to give 1.1 g of 2- (chloromethyl) -5- Butyloxazole (6.4 mmol, 64% total from hydrochloric acid).
    1 H NMRδ (CDCl 3): 1.30 (s, 9H), 4.58 (s, 2H), 6.68 (s, 1H); MS 174 (M + H) < + >; TLC: Rf (silica gel, dichloromethane) = 0.33; HPLC: t R (YMC S- 3 ODS 4.6x50mm rapid resolution; 2.5mL / min, 8 min gradient 0-100% B in, Solvent A: 10% CH 3 OH- 90% H 2 O-0.2% H 3 PO 4; solvent B: 90% CH 3 OH- 10% H 2 O-0.2% H 3 PO 4; UV: 254nm) = 6.5 min.
    D. Preparation of N- [5 - [[(5-t-butyl-2-oxazolyl) methyl] thio] -2-thiazolyl] acetamide
    0.25 mL of potassium tert-butoxide solution (1 M solution, 0.25 mmol) was added to 50 mg (0.23 mmol, used in the chemical laboratory) of N- [5- (acetylthio) -2- thiazolyl] acetamide in 10 mL THF at room temperature Was added under argon. The resulting suspension was stirred at room temperature for 15 minutes and then a solution of 59 mg of 2- (chloromethyl) -5-t-butyloxazole (0.34 mmol) in 1 mL of THF was added. The resulting mixture was stirred at room temperature for 16 hours, concentrated under reduced pressure and then purified by flash column chromatography (silica gel, 25 x 200 mm, 1: 1 EtOAc / hexane followed by 100% EtOAc) to give 44 mg mmol, 61%) of N- [5 - [[5-t-butyl-2-oxazolyl) methyl] thio] -2-thiazolyl] acetamide.
    1 H NMRδ (CDCl 3) 1.27 (s, 9H), 2.27 (s, 3H), 3.95 (s, 2H), 6.59 (s, 1H), 7.31 (s, 1H), 11.03 ( broad s, 1H); MS 312 (M + H) < + >;
    TLC: Rf (silica gel, ethyl acetate) = 0.53, UV;
    HPLC: retention time (YMC S-3 ODS 4.6x50mm rapid resolution; 2.5mL / min, gradient 0-100% B over 8 min, Solvent A: 10% CH 3 OH- 90% H 2 O-0.2% H 3 PO 4 ; solvent B: 90% CH 3 OH-10% H 2 O-0.2% H 3 PO 4 ; UV: 254 nm) = 6.8 min.
    Example 6
    N- [5 - [[(5-t-butyl-2-oxazolyl) methyl] thio] -2-thiazolyl] trimethylacetamide
    A. Preparation of N - [(5-thiocyanato) -2-thiazolyl] trifluoroacetamide (18)
    (30 mmol), 2,6-lutidine (35 mmol), and dichloromethane (50 mL) in tetrahydrofuran (25 ml) (33 mmol) was slowly added under argon. After addition, the mixture was allowed to warm to room temperature and stirred overnight. The mixture was diluted with dichloromethane (100 mL) and the organic solution was washed with 5% aqueous citric acid and then brine. Dried under magnesium sulfate and passed through a pad of silica gel. The product containing the eluent was concentrated to give 5.3 g of a light brown solid.
    1 H NMR (CHCl 3) δ 12.4 (br, 1H), 7.83 (s, 1H).
    B. Preparation of 4-hydroxymethyl-3-methoxyphenyloxy-mercapto (Merrifield) resin (16)
    To a suspension of sodium hydride (11.7 g, 60% in mineral oil, 293 mmol) in dimethylformamide (30 mL) at 0 C was added a solution of 4-hydroxy-3-methoxybenzyldihydro , 292.5 mmol) was slowly added under argon. To the resulting mixture was added a catalytic amount of Merrifield resin (1% DVB, Advanced Chemtech, loading 1.24 mmol / g, 50 g, 62 mmol) and tetra-n-butylammonium iodide. And this was heated at 65 [deg.] C for one day. The resin was filtered and washed with water (2x), 50% dimethylformamide in water (3x), dimethylformamide (2x) and methanol (5x) and dried in vacuo. The dried resin (15 g) was treated with sodium borohydride (3.4 g, 90 mmol) and ethanol (50 mL) in tetrahydrofuran (50 mL) overnight. The resin was filtered and washed with 50% dimethylformamide (3x), dimethylformamide (2x), methanol (2x) and dichloromethane (5x) in water and dried in vacuo.
    C. Preparation of 4-chloromethyl-3-methoxyphenyloxy-methyleryfield resin (17)
    To a solution of triphenylphosphine (17 g, 65 mmol) in dichloromethane (200 mL) at 0 ° C was added a portion of triphosgene (9.2 g, 31 mmol) slowly over a period of 30 min. After the addition, the reaction mixture was stirred at 0 ° C for 10 minutes. The solvent was removed in vacuo and the residue redissolved in dichloromethane (200 mL). To this mixture was added 4-hydroxymethyl-3-methoxyphenyloxy methyleryfield resin (12 g). The resulting mixture was stirred for 4 hours. The resin was washed with dry dichloromethane (6x) and dried in vacuo.
    D. Preparation of 4- [N - [(5-thiocyanato) -2-thiazolyltrifluoroacetamido] methyl] -3-methoxyphenyloxy methyleryfield resin (19)
    To a solution of 15 g of 4-chloromethyl-3-methoxyphenyloxy methyleryfield resin and N - [(5-thiocyanato) -2-thiazolyl] trifluoroacetamide (14 g, 55.3 mmol) in dimethylformamide mmol) and diisopropylethylamine (7.8 mL, 45 mmol) and dichloromethane (100 mL) was stirred overnight. The resin was washed with dimethylformamide (2x), methanol (2x) and dichloromethane (4x) and dried in vacuo.
    E. Preparation of 4 - [[N - [(5-mercapto) -2-thiazolyl] trifluoroacetamido] methyl] -3-methoxyphenyloxy-
    Methyl] -3-methoxyphenyloxy methyleryfield resin (19, 18.5 g) in tetrahydrofuran (100 mL) was added dropwise to a solution of 4- [N - [(5-thiocyanato) -2-thiazolyltrifluoroacetamido] And dithiothreitol (12 g, 78 mmol), and methanol (100 mL) was stirred overnight. The resin was washed with dimethylformamide (2x), methanol (2x) and dichloromethane (4x), dried in vacuo and stored at -20 [deg.] C under argon.
    F. 4-N- [5 - [[[5-t-butyl-2-oxazolyl) methyl] thio] -2-thiazolyl] trifluoroacetamido] methyl- Production of field resin (21)
    The argon stream was added to a solution of 4 - [[N - [(5-mercapto) -2-thiazolyl] trifluoroacetamido] methyl] -3-methoxyphenyloxy methyleryfield resin 20 (DBU, 1.5 mmol), and the mixture was stirred for 5 min. The mixture was stirred at room temperature for 2 h. And heated at 80 占 폚 for 2 hours. The resin was washed with dimethylformamide (2x), methanol (2x) and dichloromethane (4x) and dried in vacuo.
    G. Preparation of 4-N- [5 - [[(5-t-butyl-2-oxazolyl) methyl] thio] -2-thiazolyl] methyl-3-methoxyphenyloxy-
    Methyl] thio] -2-thiazolyl] trifluoroacetamido] methyl-3- (4-fluorophenyl) thiazol- A mixture of methoxyphenyloxy methyleryfield resin (21, 500 mg), sodium borohydride (4 mmol), and ethanol (2 mL) was stirred overnight. The resin was washed with 50% dimethylformamide (2x), dimethylformamide (2x), methanol (2x) and dichloromethane (4x) in water and dried in vacuo.
    H. 4-N- [5 - [[[5-t-butyl-2-oxazolyl) methyl] thio] -2-thiazolyl] trimethylacetamido] methyl-3-methoxyphenyloxy- (23)
    [5 - [[(5-t-butyl-2-oxazolyl) methyl] thio] -2-thiazolyl] piperazine in a polypropylene tube composed of a polyethylene glass raw material and a Ruizcock stopper in dichloromethane (2 mL) A mixture of methyl-3-methoxyphenyloxy methyleryfield resin (22, 100 mg), diisopropylethylamine (1.2 mmol) and trimethylacetyl chloride (1 mmol) was stirred overnight. The resin was washed with dimethylformamide (2x), methanol (2x) and dichloromethane (4x) and used in the next step without drying.
    I. Preparation of N- [5 - [[(5-t-butyl-2-oxazolyl) methyl] thio] -2-thiazolyl] trimethylacetamide
    Methyl] thio] -2-thiazolyl] trimethylacetamido] methyl-3-methoxyphenyloxy methyieldield resin (23 (5-t-butyl- ) Were treated for 4 hours with 60% trifluoroacetic acid in dichloromethane (2 mL) in a polypropylene tube composed of a polyethylene glass raw material and a Ruiz cocktail. The solution was top separated from the tube and the resin was washed with dichloromethane. The mixed organic solution was concentrated in a Speed Vac. The residue was purified by preparative-HPLC to give 11.3 mg of the desired product.
    MS m / e 354 (M + H) < + & gt ; .
    Example 7
    N- [5 - [[(4-ethyl-2-oxazolyl) methyl] thio] -2-thiazolyl] acetamide
    A. Preparation of 2- (2-chloroacetamido) -1-butanol
    To a mixture of 2-amino-1-butanol (5.0 mL, 53 mmol) and triethylamine (15.0 mL, 111 mmol) in dichloromethane (20 mL) at -70 ° C was added dropwise chloroacetyl chloride (4.6 mL, 58 mmol). The reaction mixture was stirred at -70 < 0 > C for 15 minutes and then allowed to warm to room temperature. This was diluted with EtOAc (50 mL) and water (50 mL) was added and the reaction was quenched with water. The organic layer was separated and the aqueous layer was extracted with EtOAc (3 x 30 mL). The combined organic layers were concentrated to give 2- (2-chloroacetamido) -1-butanol (8.6 g, 98%) as a brown solid.
    1 H NMR (CDCl 3) δ 6.75 (bs, 1H), 4.10 (s, 2H), 4.08 (dd, 1H), 3.90 (m, 1H), 3.68 (m, 2H), 2.98 (bs, 1H), 1.60 (m, 2 H), 0.97 (t, 3 H).
    B. Preparation of 2- (2-chloroacetamido) -1-butyraldehyde
    DMSO (2.75 mL, 38.8 mmol) was added dropwise over 5 minutes to a solution of oxalyl chloride (14.5 mL, 29.0 mmol) in dichloromethane (30 mL) at -78 <0> C. After stirring at -78 占 폚 for 10 minutes, a solution of 2- (2-chloroacetamido) -1-butanol (4.0 g, 24 mmol) in 20 mL dichloromethane was added dropwise over 15 minutes. The reaction mixture was stirred at -78 &lt; 0 &gt; C for 40 min. Triethylamine (9.4 mL, 68 mmol) was added dropwise thereto over 5 minutes, and the reaction mixture was warmed to room temperature and stirred for 2 hours. The solid was removed by filtration and washed with EtOAc. The organic phase was washed with 1N HCl (2 x 100 mL) and saturated aqueous NaHCO 3 (1 x 10 mL) and concentrated to give 2- (2-chloroacetamido) -1-butyraldehyde (3.7 g, 95%) as a brown oil .
    1 H NMR (CDCl 3) δ 9.60 (s, 1H), 4.52 (q, 1H), 4.12 (s, 2H), 2.05 (m, 1H), 1.80 (m, 1H), 0.97 (t, 3H).
    C. Preparation of 2-chloromethyl-4-ethyloxazole
    To a solution of 2- (2-chloroacetamido) -1-butyraldehyde (3.7 g, 23 mmol) in toluene (10 mL) was added POCl 3 (6.3 mL, 68 mmol). The reaction mixture was heated at 90 &lt; 0 &gt; C for 1 hour under nitrogen. After cooling the reaction mixture to room temperature, it was poured into ice water (10 mL) and the pH of the solution was adjusted to 7 using 5N NaOH. The toluene layer was separated and the aqueous layer was washed with dichloromethane (3 x 20 mL). The combined organic solution was concentrated and distilled to give 2-chloromethyl-4-ethyloxazole (1.1 g, 31%) as a colorless liquid.
    1 H NMR (CDCl 3 ) 7.30 (s, IH), 4.22 (s, 2H), 2.50 (q, 2H), 1.22 (t, 3H).
    D. Preparation of N- [5 - [[(4-ethyl-2-oxazolyl) methyl] thio] -2-thiazolyl] acetamide
    To a solution of 2-acetylamino-5-thiazolylthiol (0.010 g, 0.050 mmol) in dry THF (5 mL) was added potassium tert-butoxide (1.0 M solution in THF, 0.060 mL, 0.060 mmol). The reaction mixture was stirred at room temperature for 15 minutes and 2-chloromethyl-4-ethyloxazole (0.015 g, 0.10 mmol) was added thereto. After 3 hours, it was added saturated aqueous NaHCO 3 solution (5mL) to the mixture. The organic layer was separated and the aqueous layer was washed with dichloromethane (3 x 10 mL) and the combined organic layer was concentrated. The residue was purified by flash chromatography (SiO 2; methanol: dichloromethane / 1: 20) as a white solid was purified by N- [5 - [[(4- ethyl-2-oxazolyl) methyl] thio] -2- Thiazolyl] acetamide (5 mg, 36%).
    1 H NMR (CDCl 3) δ 11.25 (s, 1H), 7.34 (s, 1H), 7.31 (s, 1H), 3.95 (s, 2H), 2.50 (q, 2H), 2.27 (s, 3H), 1.19 (t, 3 H); MS m / e 284 (M + H) &lt; + &gt;; 10% CH 3 OH-90% H 2 O-0.2% H 3 ( solvent: water) PO 4 ; solvent B: 90% CH 3 OH-10% H 2 O-0.2% H 3 PO 4 ; UV: 254 nm): retention time 6.14 min.
    Additional compounds were prepared and described in Table 1 below using modified methods known to those skilled in the art using the methods described herein.
    [Table 1]


















    Example 636
    Methyl] thio] -2-thiazolyl] -N'-cyano-N '' - (2,6-difluorophenyl) guanidine Manufacturing
    A solution of 100 mg of N- [5 - [[(5-t-butyl-2-oxazolyl) methyl] thio] -2-aminothiazole and 68 mg of 2,6-difluorophenyl isothiocyanate in 65 Lt; 0 &gt; C for 16 hours. The solution was distilled for drying and the residue was purified by flash chromatography to give 91 mg of thiourea intermediate.
    To a solution of 30 mg of N- [5 - [[(5-t-butyl-2-oxazolyl) methyl] thio] -2-thiazolyl] -N "- (2,6-difluorophenyl) To a solution of thiourea, 52 mg of ethyl-3 (3-dimethylamino) propyl carbodiimide hydrochloride and 48 μl of diisopropylethylamine was added 29 mg of cyanamide solution in 0.1 mL of tetrahydrofuran. After stirring for 1 hour, the solvent was removed and the crude material was purified by HPLC to give 8 mg of the compound of Example 636.
    MS: (M + H) &lt; + & gt ; 449 +
    1 H NMR (400MHz, CDCl 3 ): d 1.27 (9H, s), 4.19 (2H, s), 6.69 (1H, s), 7.03 (2H, m), 7.35 (1H, m), 8.74 (1H, s).
    Example 637
    Preparation of N- [5 - [[(5-isopropyl-2-oxazolyl) fluoro] methyl] thio] -2-thiazolyl acetamide
    To a stirred mixture of 2-acetamido-5-thiazolethiol acetate (141 mg) in 3 mL of dry THF was added 1N t-BuOK in THF (0.72 mL) under argon. The mixture was stirred at room temperature for 25 minutes and a solution of 5-isopropyl- (2- (chlorofluoromethyl) oxazole (116 mg) in 2 mL of dry THF was added. The reaction mixture was stirred at 60 &lt; Diluted with EtOAc and washed with saturated NH 4 Cl solution (2 x 25 mL), saturated NaHCO 3 solution (1 x 25 mL), and brine (1 x 25 mL) The organic layer was dried (MgSO 4 ), filtered and concentrated in vacuo 637 &lt; / RTI &gt;
    MS: (M + H) &lt; + & gt ; 316
    HPLC retention time 3.52 min. (Column: YMC ODS S05 4.6x50mm column, gradient 0-100% B over 4 min, solvent A: 10% CH 3 OH- 90% H 2 O-0.2% H 3 PO 4; Solvent B : 90% CH 3 OH-10 % H 2 O-0.2% H 3 PO 4; UV: 220nm).
    权利要求:
    Claims (45)
    [1" claim-type="Currently amended] Compounds of the formula

    And a pharmaceutically acceptable salt thereof:
    Wherein R 1 and R 2 are independently hydrogen, fluorine or alkyl;
    R &lt; 3 &gt; is aryl or heteroaryl
    R 4 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, cycloalkylalkyl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl; or
    CO-alkyl, heteroaryl, CO-heterocycloalkyl, CO-alkyl-heterocyclo Alkyl; or
    CONH-alkyl, CONH-cycloalkyl, CONH-aryl, CONH-alkyl-cycloalkyl, CONH-alkyl-aryl, CONH-heteroaryl, CONH-alkyl- heteroaryl, CONH-heterocycloalkyl, CONH-alkyl-heterocyclo Alkyl; or
    Alkyl-COO-alkyl, COO-cycloalkyl, COO-aryl, COO-alkyl-cycloalkyl, COO-alkyl-aryl, COO-heteroaryl, Alkyl; or
    SO 2 -alkyl, SO 2 -alkyl, SO 2 -cycloalkyl, SO 2 -aryl, SO 2 -alkyl-cycloalkyl, SO 2 -alkyl-aryl, SO 2 -heteroaryl, SO 2 -alkyl-heteroaryl, SO 2 -heterocyclo alkyl, SO 2 - alkyl-heterocycloalkyl; or
    C (NCN) NH-alkyl, C (NCN) NH-cycloalkyl, C (NCN) NH- C (NCN) NH-alkyl-heteroaryl, C (NCN) NH-heterocycloalkyl, C (NCN) NH-alkyl-heterocycloalkyl; or
    C (NNO 2) NH- alkyl, C (NNO 2) NH- cycloalkyl, C (NNO 2) NH- aryl, C (NNO 2) NH- alkyl-cycloalkyl, C (NNO 2) NH- alkyl-aryl C (NNO 2 ) NH -heteroaryl, C (NNO 2 ) NH-alkyl-heteroaryl, C (NNO 2 ) NH -heterocycloalkyl, C (NNO 2 ) NH-alkyl-heterocycloalkyl; or
    C (NH) NH-alkyl, C (NH) NH-alkyl, C (NH) NH-Cycloalkyl, Heteroaryl, C (NH) NH-alkyl-heteroaryl, C (NH) NH -heterocycloalkyl, C (NH) NH-alkyl-heterocycloalkyl; or
    C (NH) NHCO-alkyl, C (NH) NHCO-cycloalkyl, C (NH) NHCO- Heteroaryl, C (NH) NHCO-alkyl-heteroaryl, C (NH) NHCO-heterocycloalkyl, C (NH) NHCO-alkyl-heterocycloalkyl; or
    C (NOR 6) NH- alkyl, C (NOR 6) NH- cycloalkyl, C (NOR 6) NH- aryl, C (NOR 6) NH- alkyl-cycloalkyl, C (NOR 6) NH- alkyl-aryl C (NOR 6 ) NH -heteroaryl, C (NOR 6 ) NH -alkyl-heteroaryl, C (NOR 6 ) NH -heterocycloalkyl, C (NOR 6 ) NH -alkyl-heterocycloalkyl;
    R &lt; 5 &gt; is hydrogen or alkyl;
    R 6 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, cycloalkylalkyl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl;
    m is an integer from 0 to 2; And
    n is an integer from 1 to 3;
    [2" claim-type="Currently amended] The method according to claim 1,
    Wherein R 1 and R 2 are independently hydrogen, fluorine or alkyl;
    R 3 is
    (Wherein Y is oxygen, sulfur or NR &lt; 9 &gt;);
    R 4 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, cycloalkylalkyl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl; or
    CO-alkyl, heteroaryl, CO-heterocycloalkyl, CO-alkyl-heterocyclo Alkyl; or
    CONH-alkyl, CONH-cycloalkyl, CONH-aryl, CONH-alkyl-cycloalkyl, CONH-alkyl-aryl, CONH-heteroaryl, CONH-alkyl- heteroaryl, CONH-heterocycloalkyl, CONH-alkyl-heterocyclo Alkyl; or
    Alkyl-COO-alkyl, COO-cycloalkyl, COO-aryl, COO-alkyl-cycloalkyl, COO-alkyl-aryl, COO-heteroaryl, Alkyl; or
    SO 2 -alkyl, SO 2 -alkyl, SO 2 -cycloalkyl, SO 2 -aryl, SO 2 -alkyl-cycloalkyl, SO 2 -alkyl-aryl, SO 2 -heteroaryl, SO 2 -alkyl-heteroaryl, SO 2 -heterocyclo alkyl, SO 2 - alkyl-heterocycloalkyl; or
    C (NCN) NH-alkyl, C (NCN) NH-cycloalkyl, C (NCN) NH- C (NCN) NH-alkyl-heteroaryl, C (NCN) NH-heterocycloalkyl, C (NCN) NH-alkyl-heterocycloalkyl; or
    C (NNO 2) NH- alkyl, C (NNO 2) NH- cycloalkyl, C (NNO 2) NH- aryl, C (NNO 2) NH- alkyl-cycloalkyl, C (NNO 2) NH- alkyl-aryl C (NNO 2 ) NH -heteroaryl, C (NNO 2 ) NH-alkyl-heteroaryl, C (NNO 2 ) NH -heterocycloalkyl, C (NNO 2 ) NH-alkyl-heterocycloalkyl; or
    C (NH) NH-alkyl, C (NH) NH-alkyl, C (NH) NH-Cycloalkyl, Heteroaryl, C (NH) NH-alkyl-heteroaryl, C (NH) NH -heterocycloalkyl, C (NH) NH-alkyl-heterocycloalkyl; or
    C (NH) NHCO-alkyl, C (NH) NHCO-cycloalkyl, C (NH) NHCO- Heteroaryl, C (NH) NHCO-alkyl-heteroaryl, C (NH) NHCO-heterocycloalkyl, C (NH) NHCO-alkyl-heterocycloalkyl; or
    C (NOR 6) NH- alkyl, C (NOR 6) NH- cycloalkyl, C (NOR 6) NH- aryl, C (NOR 6) NH- alkyl-cycloalkyl, C (NOR 6) NH- alkyl-aryl C (NOR 6 ) NH -heteroaryl, C (NOR 6 ) NH -alkyl-heteroaryl, C (NOR 6 ) NH -heterocycloalkyl, C (NOR 6 ) NH -alkyl-heterocycloalkyl;
    R &lt; 5 &gt; is hydrogen or alkyl; And
    R 6 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, cycloalkylalkyl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl;
    R 7 and R 8 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, cycloalkylalkyl, arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, heterocycloalkyl, Cycloalkylalkyl;
    R 9 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, alkylcycloalkyl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl;
    m is an integer from 0 to 2; And
    and n is an integer from 1 to 3.
    [3" claim-type="Currently amended] The method according to claim 1,
    Wherein R 1 and R 2 are independently hydrogen, fluorine or alkyl;
    R 3 is
    (Wherein Y is oxygen);
    R 4 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, cycloalkylalkyl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl; or
    CO-alkyl, heteroaryl, CO-heterocycloalkyl, CO-alkyl-heterocyclo Alkyl; or
    CONH-alkyl, CONH-cycloalkyl, CONH-aryl, CONH-alkyl-cycloalkyl, CONH-alkyl-aryl, CONH-heteroaryl, CONH-alkyl- heteroaryl, CONH-heterocycloalkyl, CONH-alkyl-heterocyclo Alkyl; or
    Alkyl-COO-alkyl, COO-cycloalkyl, COO-aryl, COO-alkyl-cycloalkyl, COO-alkyl-aryl, COO-heteroaryl, Alkyl; or
    SO 2 -alkyl, SO 2 -alkyl, SO 2 -cycloalkyl, SO 2 -aryl, SO 2 -alkyl-cycloalkyl, SO 2 -alkyl-aryl, SO 2 -heteroaryl, SO 2 -alkyl-heteroaryl, SO 2 -heterocyclo alkyl, SO 2 - alkyl-heterocycloalkyl; or
    C (NCN) NH-alkyl, C (NCN) NH-cycloalkyl, C (NCN) NH- C (NCN) NH-alkyl-heteroaryl, C (NCN) NH-heterocycloalkyl, C (NCN) NH-alkyl-heterocycloalkyl; or
    C (NNO 2) NH- alkyl, C (NNO 2) NH- cycloalkyl, C (NNO 2) NH- aryl, C (NNO 2) NH- alkyl-cycloalkyl, C (NNO 2) NH- alkyl-aryl C (NNO 2 ) NH -heteroaryl, C (NNO 2 ) NH-alkyl-heteroaryl, C (NNO 2 ) NH -heterocycloalkyl, C (NNO 2 ) NH-alkyl-heterocycloalkyl; or
    C (NH) NH-alkyl, C (NH) NH-alkyl, C (NH) NH-Cycloalkyl, Heteroaryl, C (NH) NH-alkyl-heteroaryl, C (NH) NH -heterocycloalkyl, C (NH) NH-alkyl-heterocycloalkyl; or
    C (NH) NHCO-alkyl, C (NH) NHCO-cycloalkyl, C (NH) NHCO- Heteroaryl, C (NH) NHCO-alkyl-heteroaryl, C (NH) NHCO-heterocycloalkyl, C (NH) NHCO-alkyl-heterocycloalkyl; or
    C (NOR 6) NH- alkyl, C (NOR 6) NH- cycloalkyl, C (NOR 6) NH- aryl, C (NOR 6) NH- alkyl-cycloalkyl, C (NOR 6) NH- alkyl-aryl C (NOR 6 ) NH -heteroaryl, C (NOR 6 ) NH -alkyl-heteroaryl, C (NOR 6 ) NH -heterocycloalkyl, C (NOR 6 ) NH -alkyl-heterocycloalkyl;
    R 5 is hydrogen;
    R 6 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, cycloalkylalkyl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl;
    R 7 and R 8 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, cycloalkylalkyl, arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, heterocycloalkyl, Cycloalkylalkyl;
    m is an integer from 0 to 2; And
    and n is an integer from 1 to 3.
    [4" claim-type="Currently amended] The method according to claim 1,
    Wherein R 1 and R 2 are independently hydrogen, fluorine or alkyl;
    R 3 is
    (Wherein Y is sulfur);
    R 4 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, cycloalkylalkyl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl; or
    CO-alkyl, heteroaryl, CO-heterocycloalkyl, CO-alkyl-heterocyclo Alkyl; or
    CONH-alkyl, CONH-cycloalkyl, CONH-aryl, CONH-alkyl-cycloalkyl, CONH-alkyl-aryl, CONH-heteroaryl, CONH-alkyl- heteroaryl, CONH-heterocycloalkyl, CONH-alkyl-heterocyclo Alkyl; or
    Alkyl-COO-alkyl, COO-cycloalkyl, COO-aryl, COO-alkyl-cycloalkyl, COO-alkyl-aryl, COO-heteroaryl, Alkyl; or
    SO 2 -alkyl, SO 2 -alkyl, SO 2 -cycloalkyl, SO 2 -aryl, SO 2 -alkyl-cycloalkyl, SO 2 -alkyl-aryl, SO 2 -heteroaryl, SO 2 -alkyl-heteroaryl, SO 2 -heterocyclo alkyl, SO 2 - alkyl-heterocycloalkyl; or
    C (NCN) NH-alkyl, C (NCN) NH-cycloalkyl, C (NCN) NH- C (NCN) NH-alkyl-heteroaryl, C (NCN) NH-heterocycloalkyl, C (NCN) NH-alkyl-heterocycloalkyl; or
    C (NNO 2) NH- alkyl, C (NNO 2) NH- cycloalkyl, C (NNO 2) NH- aryl, C (NNO 2) NH- alkyl-cycloalkyl, C (NNO 2) NH- alkyl-aryl C (NNO 2 ) NH -heteroaryl, C (NNO 2 ) NH-alkyl-heteroaryl, C (NNO 2 ) NH -heterocycloalkyl, C (NNO 2 ) NH-alkyl-heterocycloalkyl; or
    C (NH) NH-alkyl, C (NH) NH-alkyl, C (NH) NH-Cycloalkyl, Heteroaryl, C (NH) NH-alkyl-heteroaryl, C (NH) NH -heterocycloalkyl, C (NH) NH-alkyl-heterocycloalkyl; or
    C (NH) NHCO-alkyl, C (NH) NHCO-cycloalkyl, C (NH) NHCO- Heteroaryl, C (NH) NHCO-alkyl-heteroaryl, C (NH) NHCO-heterocycloalkyl, C (NH) NHCO-alkyl-heterocycloalkyl; or
    C (NOR 6) NH- alkyl, C (NOR 6) NH- cycloalkyl, C (NOR 6) NH- aryl, C (NOR 6) NH- alkyl-cycloalkyl, C (NOR 6) NH- alkyl-aryl C (NOR 6 ) NH -heteroaryl, C (NOR 6 ) NH -alkyl-heteroaryl, C (NOR 6 ) NH -heterocycloalkyl, C (NOR 6 ) NH -alkyl-heterocycloalkyl;
    R 5 is hydrogen;
    R 6 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, cycloalkylalkyl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl;
    R 7 and R 8 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, cycloalkylalkyl, arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, heterocycloalkyl, Cycloalkylalkyl;
    m is an integer from 0 to 2; And
    and n is an integer from 1 to 3.
    [5" claim-type="Currently amended] The method according to claim 1,
    Wherein R 1 and R 2 are independently hydrogen, fluorine or alkyl;
    R 3 is
    (Wherein Y is NR &lt; 9 &gt;);
    R 4 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, cycloalkylalkyl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl; or
    CO-alkyl, heteroaryl, CO-heterocycloalkyl, CO-alkyl-heterocyclo Alkyl; or
    CONH-alkyl, CONH-cycloalkyl, CONH-aryl, CONH-alkyl-cycloalkyl, CONH-alkyl-aryl, CONH-heteroaryl, CONH-alkyl- heteroaryl, CONH-heterocycloalkyl, CONH-alkyl-heterocyclo Alkyl; or
    Alkyl-COO-alkyl, COO-cycloalkyl, COO-aryl, COO-alkyl-cycloalkyl, COO-alkyl-aryl, COO-heteroaryl, Alkyl; or
    SO 2 -alkyl, SO 2 -alkyl, SO 2 -cycloalkyl, SO 2 -aryl, SO 2 -alkyl-cycloalkyl, SO 2 -alkyl-aryl, SO 2 -heteroaryl, SO 2 -alkyl-heteroaryl, SO 2 -heterocyclo alkyl, SO 2 - alkyl-heterocycloalkyl; or
    C (NCN) NH-alkyl, C (NCN) NH-cycloalkyl, C (NCN) NH- C (NCN) NH-alkyl-heteroaryl, C (NCN) NH-heterocycloalkyl, C (NCN) NH-alkyl-heterocycloalkyl; or
    C (NNO 2) NH- alkyl, C (NNO 2) NH- cycloalkyl, C (NNO 2) NH- aryl, C (NNO 2) NH- alkyl-cycloalkyl, C (NNO 2) NH- alkyl-aryl C (NNO 2 ) NH -heteroaryl, C (NNO 2 ) NH-alkyl-heteroaryl, C (NNO 2 ) NH -heterocycloalkyl, C (NNO 2 ) NH-alkyl-heterocycloalkyl; or
    C (NH) NH-alkyl, C (NH) NH-alkyl, C (NH) NH-Cycloalkyl, Heteroaryl, C (NH) NH-alkyl-heteroaryl, C (NH) NH -heterocycloalkyl, C (NH) NH-alkyl-heterocycloalkyl; or
    C (NH) NHCO-alkyl, C (NH) NHCO-cycloalkyl, C (NH) NHCO- Heteroaryl, C (NH) NHCO-alkyl-heteroaryl, C (NH) NHCO-heterocycloalkyl, C (NH) NHCO-alkyl-heterocycloalkyl; or
    C (NOR 6) NH- alkyl, C (NOR 6) NH- cycloalkyl, C (NOR 6) NH- aryl, C (NOR 6) NH- alkyl-cycloalkyl, C (NOR 6) NH- alkyl-aryl C (NOR 6 ) NH -heteroaryl, C (NOR 6 ) NH -alkyl-heteroaryl, C (NOR 6 ) NH -heterocycloalkyl, C (NOR 6 ) NH -alkyl-heterocycloalkyl;
    R 5 is hydrogen;
    R 6 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, cycloalkylalkyl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl;
    R 7 and R 8 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, cycloalkylalkyl, arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, heterocycloalkyl, Cycloalkylalkyl;
    R 9 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, cycloalkylalkyl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl;
    m is an integer from 0 to 2; And
    and n is an integer from 1 to 3.
    [6" claim-type="Currently amended] The method according to claim 1,
    Wherein R 1 and R 2 are independently hydrogen, fluorine or alkyl;
    R 3 is
    (Wherein Y is oxygen);
    R 4 is CO-alkyl, CO-alkyl-aryl, CO-cycloalkyl, CONH-cycloalkyl or CONH-alkyl-heterocycloalkyl;
    R 5 is hydrogen; And
    R 7 and R 8 are independently selected from the group consisting of hydrogen;
    m is an integer 0; And
    and n is an integer of 1.
    [7" claim-type="Currently amended] The method according to claim 1,
    Wherein R 1 and R 2 are independently hydrogen, fluorine or alkyl;
    R 3 is
    (Wherein Y is oxygen);
    R 4 is CO-alkyl, CO-alkyl-aryl, CO-alkyl-heteroalkyl, CONH-cycloalkyl or CONH-alkyl-heterocycloalkyl;
    R 5 is hydrogen;
    R 7 and R 8 are independently selected from the group consisting of alkyl;
    m is an integer 0; And
    and n is an integer of 1.
    [8" claim-type="Currently amended] The method according to claim 1,
    Wherein R 1 and R 2 are independently hydrogen, fluorine or alkyl;
    R 3 is
    (Wherein Y is oxygen);
    R 4 is CO-alkyl, CO-alkyl-aryl, CO-alkyl-heteroalkyl, CONH-cycloalkyl or CONH-alkyl-heterocycloalkyl;
    R 5 is hydrogen;
    R 7 is hydrogen;
    R 8 is alkyl;
    m is an integer 0; And
    and n is an integer of 1.
    [9" claim-type="Currently amended] The method according to claim 1,
    Wherein R 1 and R 2 are independently hydrogen, fluorine or alkyl;
    R 3 is
    (Wherein Y is oxygen);
    R 4 is CO-alkyl, CO-alkyl-aryl, CO-alkyl-heteroalkyl, CONH-cycloalkyl or CONH-alkyl-heterocycloalkyl;
    R 5 is hydrogen;
    R 7 is alkyl;
    R 8 is hydrogen;
    m is an integer 0; And
    and n is an integer of 1.
    [10" claim-type="Currently amended] The method according to claim 1,
    Wherein R 1 and R 2 are independently hydrogen, fluorine or alkyl;
    R 3 is
    (Wherein Y is sulfur);
    R 4 is CO-alkyl, CO-alkyl-aryl, CO-alkyl-heteroalkyl, CONH-cycloalkyl or CONH-alkyl-heterocycloalkyl;
    R 5 is hydrogen;
    R 7 is hydrogen;
    R 8 is alkyl;
    m is an integer 0; And
    and n is an integer of 1.
    [11" claim-type="Currently amended] The method according to claim 1,
    Wherein R 1 and R 2 are independently hydrogen, fluorine or alkyl;
    R 3 is
    (Wherein Y is sulfur);
    R 4 is CO-alkyl, CO-alkyl-aryl, CO-alkyl-heteroalkyl, CONH-cycloalkyl or CONH-alkyl-heterocycloalkyl;
    R 5 is hydrogen;
    R 7 is alkyl;
    R 8 is hydrogen;
    m is an integer 0; And
    and n is an integer of 1.
    [12" claim-type="Currently amended] The method according to claim 1,
    Wherein R 1 and R 2 are independently hydrogen, fluorine or alkyl;
    R 3 is
    (Wherein Y is NR &lt; 9 &gt;);
    R 4 is CO-alkyl, CO-alkyl-aryl, CO-alkyl-heteroalkyl, CONH-cycloalkyl or CONH-alkyl-heterocycloalkyl;
    R 5 is hydrogen;
    R 7 is hydrogen;
    R 8 is alkyl;
    R 9 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, alkyl-cycloalkyl, alkyl-aryl, heteroaryl, alkyl-heteroaryl, heterocycloalkyl or alkyl-heterocycloalkyl;
    m is an integer 0; And
    and n is an integer of 1.
    [13" claim-type="Currently amended] The method according to claim 1,
    Wherein R 1 and R 2 are independently hydrogen, fluorine or alkyl;
    R 3 is
    (Wherein Y is NR &lt; 9 &gt;);
    R 4 is CO-alkyl, CO-alkyl-aryl, CO-alkyl-heteroalkyl, CONH-cycloalkyl or CONH-alkyl-heterocycloalkyl;
    R 5 is hydrogen;
    R 7 is alkyl;
    R 8 is hydrogen;
    R 9 is alkyl;
    m is an integer 0; And
    and n is an integer of 1.
    [14" claim-type="Currently amended] The method according to claim 1,
    Wherein R 1 and R 2 are independently hydrogen, fluorine or alkyl;
    R 3 is
    (Wherein Y is NR &lt; 9 &gt;);
    R 4 is CO-alkyl, CO-alkyl-aryl, CO-cycloalkyl, CONH-cycloalkyl or CONH-alkyl-heterocycloalkyl;
    R 5 is hydrogen;
    R 7 is alkyl;
    R 8 is hydrogen;
    R 9 is hydrogen
    m is an integer 0; And
    and n is an integer of 1.
    [15" claim-type="Currently amended] The compound according to claim 1, wherein said compound is
    N- [5 - [[(5-ethyl-2-oxazolyl) methyl] thio] -2-thiazolyl] acetamide;
    N- [5 - [[(5-ethyl-2-oxazolyl) methyl] thio] -2-thiazolyl] benzamide;
    N- [5 - [[(5-ethyl-2-oxazolyl) methyl] thio] -2-thiazolyl] benzenesulfonamide;
    N- [5 - [[(4,5-dimethyl-2-oxazolyl) methyl] thio] -2-thiazolyl] acetamide;
    N- [5 - [[(5-t-butyl-2-oxazolyl) methyl] thio] -2-thiazolyl] acetamide;
    N- [5 - [[(5-t-butyl-2-oxazolyl) methyl] thio] -2-thiazolyl] trimethylacetamide;
    N- [5 - [[(4-ethyl-2-oxazolyl) methyl] thio] -2-thiazolyl] acetamide; Or a pharmacologically acceptable salt thereof.
    [16" claim-type="Currently amended] 14. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
    [17" claim-type="Currently amended] A pharmaceutical composition comprising a compound of claim 1 in combination with a pharmaceutically acceptable carrier and an anti-cancer agent formulated in a fixed dose.
    [18" claim-type="Currently amended] 17. A pharmaceutical composition according to claim 16, comprising a compound of claim 1 in combination with a pharmaceutically acceptable carrier, wherein said pharmaceutical composition is administered sequentially with an anticancer therapy or an anticancer agent.
    [19" claim-type="Currently amended] 19. A pharmaceutical composition according to claim 18, wherein the composition comprising the compound of claim 1 and the pharmacologically acceptable carrier is administered prior to the chemotherapeutic or anti-cancer agent administration,
    [20" claim-type="Currently amended] The pharmaceutical composition according to claim 18, wherein the composition comprising the compound of claim 1 and the pharmacologically acceptable carrier is administered after the administration of the chemotherapeutic or anticancer agent.
    [21" claim-type="Currently amended] A method for inhibiting protein kinase comprising administering to a mammal an amount of a compound of claim 1 effective to inhibit protein kinase.
    [22" claim-type="Currently amended] 1. A method for inhibiting cyclokinin dependent kinase comprising administering to a mammal an amount of a compound of claim 1 effective to inhibit cyclin dependent kinase.
    [23" claim-type="Currently amended] A method of inhibiting cdc2 (cdk1) comprising administering to a mammal an amount of a compound of claim 1 effective to inhibit cdc2.
    [24" claim-type="Currently amended] A method of inhibiting cdk2 comprising administering to a mammal an amount of a compound of claim 1 effective to inhibit cdk2.
    [25" claim-type="Currently amended] A method of inhibiting cdk3 comprising administering to a mammal an amount of a compound of claim 1 effective to inhibit cdk3.
    [26" claim-type="Currently amended] A method of inhibiting cdk4 comprising administering to a mammal an amount of a compound of claim 1 effective to inhibit cdk4.
    [27" claim-type="Currently amended] A method of inhibiting cdk5 comprising administering to a mammal an amount of a compound of claim 1 effective to inhibit cdk5.
    [28" claim-type="Currently amended] A method of inhibiting cdk6 comprising administering to a mammal an amount of a compound of claim 1 effective to inhibit cdk6.
    [29" claim-type="Currently amended] A method of inhibiting cdk7 comprising administering to a mammal an amount of a compound of claim 1 effective to inhibit cdk7.
    [30" claim-type="Currently amended] A method of inhibiting cdk8 comprising administering to a mammal an amount of a compound of claim 1 effective to inhibit cdk8.
    [31" claim-type="Currently amended] A method of treating a proliferative disease comprising administering to a mammal a therapeutically effective amount of the composition of claim 16.
    [32" claim-type="Currently amended] A method of treating cancer comprising administering to a mammal a therapeutically effective amount of the composition of claim 16.
    [33" claim-type="Currently amended] A method of treating an inflammatory, inflammatory bowel disease or transplant rejection response comprising administering to a mammal a therapeutically effective amount of the composition of claim 16.
    [34" claim-type="Currently amended] A method of treating arthritis comprising administering to a mammal a therapeutically effective amount of the composition of claim 16.
    [35" claim-type="Currently amended] 16. A method for the treatment of an infection by HIV or the treatment and inhibition of AIDS comprising administering to a mammal a therapeutically effective amount of the composition of claim 16.
    [36" claim-type="Currently amended] A method of treating a viral infection comprising administering to a mammal a therapeutically effective amount of the composition of claim 16.
    [37" claim-type="Currently amended] A method of treating a fungal infection comprising administering to a mammal a therapeutically effective amount of the composition of claim 16.
    [38" claim-type="Currently amended] A method for inhibiting the development of cancer or tumor recurrence comprising administering to a mammal a therapeutically effective amount of the composition of claim 16.
    [39" claim-type="Currently amended] A method for treating a neurodegenerative disease comprising administering to a mammal a therapeutically effective amount of the composition of claim 16.
    [40" claim-type="Currently amended] 18. A method of treating a proliferative disease comprising administering to a mammal a therapeutically effective amount of the composition of claim 17.
    [41" claim-type="Currently amended] A method of treating cancer comprising administering to a mammal a therapeutically effective amount of the composition of claim 17.
    [42" claim-type="Currently amended] 17. A method of inhibiting the development of cancer or tumor recurrence comprising administering to a mammal a therapeutically effective amount of the composition of claim 17.
    [43" claim-type="Currently amended] 18. A method of treating a proliferative disease comprising administering to a mammal a therapeutically effective amount of the composition of claim 18.
    [44" claim-type="Currently amended] 18. A method of treating cancer comprising administering to a mammal a therapeutically effective amount of the composition of claim 18.
    [45" claim-type="Currently amended] 18. A method of inhibiting the development of cancer or tumor recurrence comprising administering to a mammal a therapeutically effective amount of the composition of claim 18.
    类似技术:
    公开号 | 公开日 | 专利标题
    US10292987B2|2019-05-21|Heterocyclic amides as kinase inhibitors
    US20190330202A1|2019-10-31|Novel compounds
    US20180134665A1|2018-05-17|Heterocyclic amides as kinase inhibitors
    US8889691B2|2014-11-18|Indole compounds as an inhibitor of cellular necrosis
    KR101464060B1|2014-11-20|Pyrazol-4-yl-heterocyclyl-carboxamide compounds and methods of use
    US10604533B2|2020-03-31|Heterocycle amines and uses thereof
    DE69837282T2|2007-11-08|USE OF PYRAZOLO Ä 3,4-bÜ PYRIDINE AS A CYCLIN-DEPENDENT KINASE HEMMER
    RU2330030C2|2008-07-27|Derivatives of heteroarylcarbamoylbenzene
    ES2271322T3|2007-04-16|Inhibitors of n-terminal kinases c-jun and other quinasa proteins.
    AU2008273017B2|2013-10-10|Heterocyclic compounds useful as Raf kinase inhibitors
    AU2001279089B2|2006-02-02|Indazole derivatives as jnk inhibitors
    ES2305081T3|2008-11-01|Substituted quinozoline derivatives and its use as inhibitors.
    JP4120586B2|2008-07-16|2-acylaminothiazole derivatives or salts thereof
    JP5128283B2|2013-01-23|Mitotic kinesin inhibitors and methods of use thereof
    AU2002331621B2|2008-06-05|2H-phthalazin-1-ones and methods for use thereof
    KR101553418B1|2015-09-15|Pyridazinone derivates
    KR100802368B1|2008-02-13|Imidazolo-5-yl-2-anilino-pyrimidines as agents for the inhibition of the cell proliferation
    ES2401138T3|2013-04-17|Thiazole-based enzyme inhibitors that use ATP
    AU778071B2|2004-11-11|Diaminothiazoles and their use for inhibiting protein kinases
    TWI395741B|2013-05-11|Pyridazinone derivatives
    TWI421078B|2014-01-01|Checkpoint kinase inhibitors and use thereof
    AU785013B2|2006-08-24|Indazole compounds, pharmaceutical compositions, and methods for mediating or inhibiting cell proliferation
    ES2315566T3|2009-04-01|Tiazolidin-4-onas to inhibit hyak3 proteins.
    Kim et al.2002|Discovery of aminothiazole inhibitors of cyclin-dependent kinase 2: synthesis, X-ray crystallographic analysis, and biological activities
    EP1430051B1|2006-12-27|N-|pyrimidin-2-yl)-n-phenylamines as antiproliferative compounds
    同族专利:
    公开号 | 公开日
    AT374771T|2007-10-15|
    CZ20001744A3|2001-05-16|
    KR100454426B1|2004-10-26|
    EP1042307A4|2003-01-29|
    IL135589D0|2001-05-20|
    TW593292B|2004-06-21|
    NO316773B1|2004-05-03|
    KR20030036862A|2003-05-09|
    US6040321A|2000-03-21|
    AU1295599A|1999-05-31|
    CO4990957A1|2000-12-26|
    PL204642B1|2010-01-29|
    NO20002153D0|2000-04-27|
    CZ297907B6|2007-04-25|
    JP4344084B2|2009-10-14|
    JP2001522842A|2001-11-20|
    CA2309551C|2006-03-28|
    ZA9810332B|2000-05-11|
    RU2211839C2|2003-09-10|
    AR017182A1|2001-08-22|
    CY1107509T1|2013-03-13|
    DK1042307T3|2008-01-28|
    HU0004559A2|2002-04-29|
    EP1042307B1|2007-10-03|
    CA2309551A1|1999-05-20|
    EP1042307A1|2000-10-11|
    DE69838515D1|2007-11-15|
    TR200001344T2|2000-09-21|
    AU730607B2|2001-03-08|
    CN1278806A|2001-01-03|
    NO20002153L|2000-05-11|
    IL135589A|2004-06-20|
    NZ503828A|2003-03-28|
    MY120779A|2005-11-30|
    UY25239A1|2000-12-29|
    DE69838515T2|2008-07-03|
    BR9814124A|2000-10-03|
    ES2296347T3|2008-04-16|
    WO1999024416A1|1999-05-20|
    EG24028A|2008-03-26|
    HU0004559A3|2002-05-28|
    ID23983A|2000-06-14|
    CN1160343C|2004-08-04|
    PT1042307E|2007-11-15|
    PE131699A1|2000-03-08|
    PL340540A1|2001-02-12|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    1997-11-12|Priority to US6519597P
    1997-11-12|Priority to US60/065,195
    1998-11-02|Application filed by 말라테스티닉 니콜라스 피., 브리스톨-마이어즈 스퀴브 컴페니
    2001-04-16|Publication of KR20010031896A
    2004-10-26|Application granted
    2004-10-26|Publication of KR100454426B1
    优先权:
    申请号 | 申请日 | 专利标题
    US6519597P| true| 1997-11-12|1997-11-12|
    US60/065,195|1997-11-12|
    [返回顶部]