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    • 专利摘要:
    The present invention relates to pyrimidine derivatives of formula (I), pharmaceutically acceptable salts thereof or in vivo hydrolysable esters thereof. It also relates to methods of preparation thereof, pharmaceutical compositions and their use as cyclin dependent serine / threonine kinases (CDK) and focal adhesion kinase (FAK) inhibitors. Formula I In the above formula, the substituent of formula (Ia) -NH- bond in Q 1 and Q 2, or any one, Q 1 and Q 2 are both to but substituted on a ring carbon by one substituent of formula (Ia), only Q 1 of Not neighboring, Q 1 , Q 2 , G, R 1 , X, Y 1 , Y 2 , Z, n and m are as defined herein. Formula Ia
    公开号:KR20020079978A
    申请号:KR1020027011440
    申请日:2001-02-26
    公开日:2002-10-21
    发明作者:피즈일리저버쓰재닛；브롤트글로리아앤；브래드버리로버트휴
    申请人:아스트라제네카 아베；
    IPC主号:
    专利说明:

    Pyrimidine compound {PYRIMIDINE COMPOUNDS}
    [2] A type of intracellular protein called cyclin plays an important role in the cell cycle. Synthesis and degradation of cyclins are strongly regulated such that their expression varies during the cell cycle. Cyclin binds to cyclin dependent serine / threonine kinase (CDK), the binding of which is essential for intracellular CDK (eg, CDK1, CDK2, CDK4 and / or CDK6) activity. Although there is some lack of understanding of the details of how each of these factors bind to modulate CDK activity, the balance between these two will determine whether a cell will progress during the cell cycle.
    [3] Recent intensive research into the study of tumor sources and tumor suppressor genes has revealed that regulation of entry into the cell cycle in tumors is an important regulatory point of mitosis. In addition, CDK has been shown to be downstream of many oncogenic signaling pathways. Subregulation of CDK activity by regulation of cyclins and / or deletion of endogenous inhibitors has been shown to be an important axis between tumor cell proliferation and mitogenic signaling pathways.
    [4] Thus, inhibitors of cell cycle kinases, in particular CDK2, CDK4 and / or CDK6, which act in each of the S stages, G1-S and G1-S stages, are of importance as selective inhibitors of cell proliferation such as the growth of mammalian cancer cells.
    [5] In addition, inhibition of focal adhesion kinase (FAK) involved in signal transduction pathways leads to apoptosis (cell necrosis) and / or inhibits cell migration, whereby FAK inhibitors have important significance as anticancer agents.
    [1] FIELD OF THE INVENTION The present invention relates to pyrimidine derivatives, pharmaceutically acceptable salts thereof or hydrolyzable esters in vivo, which have cell cycle inhibitory activity and are therefore anticancer (such as anti-cell proliferative, anti-cell migration and / or apoptosis). It is useful for activity and thus useful for methods of treating warm-blooded animals such as humans. In addition, the present invention provides methods for the preparation of pyrimidine derivatives, their use in the manufacture of pharmaceutical compositions and medicaments comprising the same, and anticancer (anti-cell proliferative / migrating and / or apoptosis) efficacy in warm-blooded animals, including humans. To use in
    [6] The present invention inhibits the effects of cell cycle kinases in which certain 2,4-pyrimidine compounds exhibit selectivity for CDK2, CDK4 and CDK6, and also inhibits FAK, and thus anticancer (anti-cell proliferation, anti-cell migration and And / or apoptosis). These characteristics include abnormal cell cycle and cell proliferation such as cancer (solid cancer and leukemia), fibrotic and differentiation diseases, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, hemangioma, acute and chronic nephropathy, atherosclerosis, atherosclerosis, arterial restenosis, It is expected to be important in the treatment of autoimmune diseases, acute and chronic infections, bone diseases, and disease states associated with ocular diseases following retinal vessel proliferation.
    [7] The present invention relates to a pyrimidine derivative of formula (I), a pharmaceutically acceptable salt thereof or an in vivo hydrolysable ester thereof.
    [8]
    [9] In the formula, Q 1 and Q 2 are independently aryl or is selected from a heteroaryl bonded carbon, Q 1 and Q 2 one or Q 1 and Q 2 are all to one on a ring carbon by a substituent of formula (Ia) Is substituted,
    [10]
    [11] Provided that when present in Q 1 , the substituent of Formula Ia is not neighboring a —NH— bond;
    [12] Wherein X is -CH 2- , -O-, -NH-, -NR a -or -S- wherein R a is 1 selected from halo, amino, cyano, C 1 -C 4 alkoxy or hydroxy C 1 -C 4 alkyl optionally substituted by 2 substituents;
    [13] Y 1 is as defined for H, C 1 -C 4 alkyl or Z;
    [14] Y 2 is H or C 1 -C 4 alkyl;
    [15] Z is R b O-, R c R d N-, R e S-, R f R g NNR h- , nitrogen-bonded heteroaryl or nitrogen-bonded heterocycle, wherein the heterocycle is C 1 -C 4 Optionally substituted on the ring carbon or ring nitrogen by alkyl or C 1 -C 4 alkanoyl, wherein R b , R c , R d , R e , R f , R g and R h are independently hydrogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 3 -C 8 cycloalkyl, wherein C 1 -C 4 alkyl and C 2 -C 4 alkenyl are optionally substituted by one or more phenyl ;
    [16] n is 1, 2 or 3;
    [17] m is 1, 2 or 3;
    [18] G is -O- or -S-;
    [19] R 1 is hydrogen, halo, hydroxy, nitro, amino, N- (C 1 -C 3 alkyl) amino, N, N-di- (C 1 -C 3 alkyl) amino, cyano, trifluoromethyl, Trichloromethyl, C 1 -C 3 alkyl [halo, cyano, amino, N- (C 1 -C 3 alkyl) amino, N, N-di- (C 1 -C 3 alkyl) amino, hydroxy and tri Optionally substituted with 1 or 2 substituents independently selected from fluoromethyl], C 3 -C 5 alkenyl [substituted with up to 3 halo substituents or with 1 trifluoromethyl substituent], C 3- C 5 alkynyl, C 1 -C 3 alkoxy, mercapto, C 1 -C 3 alkylsulfanyl, carboxy and C 1 -C 3 alkoxycarbonyl;
    [20] Q 1 is halo, mercapto, nitro, formyl, formamido, carboxy, cyano, amino, ureido, carbamoyl, sulfamoyl, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, wherein the C 1 -C 4 alkyl, C 2 -C 4 alkenyl and C 2 -C 4 alkynyl are optionally substituted with one or more groups selected from R i , C 1 -C 4 alkanoyl, C 1 -C 4 alkoxycarbonyl, heterocyclic group, C 1 -C 4 alkylS (O) a , wherein a is 0 to 2 [optionally substituted with hydroxy], N '-( C 1 -C 4 alkyl) ureido, N ', N'-di- (C 1 -C 4 alkyl) ureido, N- (C 1 -C 4 alkyl) -N- (C 1 -C 4 alkyl) Ureido, N ', N'-di- (C 1 -C 4 alkyl) -N- (C 1 -C 4 alkyl) ureido, NC 1 -C 4 alkylamino, N, N-di- (C 1 -C 4 alkyl) amino, N- (C 1 -C 4 alkyl) sulfamoyl, N, N-di- (C 1 -C 4 alkyl) sulfamoyl, NC 1 -C 4 alkylcarbamoyl, N, N 1 to 4 substitutions independently selected from -di- (Ci-C 4 alkyl) carbamoyl and C 1 -C 4 alkanoylamino Sieve optionally substituted on the ring carbon;
    [21] And independently or in addition to the above substituents, Q 1 may be optionally substituted with 1 or 2 substituents independently selected from aryl, C 3 -C 8 cycloalkyl and a heterocyclic group, wherein said aryl, C 3 -C An 8 cycloalkyl or heterocyclic group may be optionally substituted on the ring carbon with one or more groups selected from R j ; Wherein if said heterocyclic group comprises an —NH— moiety that nitrogen may be optionally substituted by a group selected from R k ;
    [22] Q 2 is halo, hydroxy, mercapto, nitro, formyl, formamido, carboxy, cyano, amino, ureido, carbamoyl, sulfamoyl, C 1 -C 4 alkyl, C 2 -C 4 al Kenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkoxy [wherein the C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl and C 1 -C 4 alkoxy Optionally substituted with one or more groups selected from R 1 ], C 1 -C 4 alkanoyl, C 1 -C 4 alkoxycarbonyl, a heterocyclic group, C 1 -C 4 alkylS (O) a , wherein a is 0 2)) [optionally substituted with hydroxy], N '-(C 1 -C 4 alkyl) ureido, N', N'-di- (C 1 -C 4 alkyl) ureido, N '-( C 1 -C 4 alkyl) -N- (C 1 -C 4 alkyl) ureido, N ', N'-di- (C 1 -C 4 alkyl) -N- (C 1 -C 4 alkyl) ureido , NC 1 -C 4 alkylamino, N, N-di- (C 1 -C 4 alkyl) amino, N- (C 1 -C 4 alkyl) sulfamoyl, N, N-di- (C 1 -C 4 Alkyl) sulfamoyl, NC 1 -C 4 alkylcarbamoyl, N, N-di- (C 1 -C 4 alkyl) carbamoyl, C 2 -C 4 alkenyloxy, C 2 -C Optionally substituted on the ring carbon with 4 alkynyloxy, C 1 -C 4 alkanoylamino and 1-4 substituents independently selected from the groups of formula (Ia) or formula (Ia ′) above;
    [23] In addition, independently of or in addition to the above substituents, Q 2 may be optionally substituted with 1 or 2 substituents independently selected from aryl, C 3 -C 8 cycloalkyl or a heterocyclic group, wherein said aryl, C 3 − C 8 cycloalkyl or heterocyclic group may be optionally substituted on the ring carbon with one or more groups selected from R m , wherein if the heterocyclic group comprises a —NH— moiety, nitrogen may be optionally substituted with a group selected from R n Can;
    [24] R i and R l are hydroxy, halo, amino, cyano, formyl, formamido, carboxy, nitro, mercapto, carbamoyl, sulfamoyl, NC 1 -C 4 alkylamino, N, N-di -(C 1 -C 4 alkyl) amino, C 1 -C 4 alkanoyl, C 1 -C 4 alkanoyloxy, C 1 -C 4 alkoxy, C 1 -C 4 alkoxycarbonyl, NC 1 -C 4 alkyl carbamoyl, N, N- di - (C 1 -C 4 alkyl) carbamoyl, C 1 -C 4 alkanoylamino, C 1 -C 4 alkyl, S (O) a (wherein, a is 0 to 2 ), C 1 -C 4 alkylsulfonylamino, N- (C 1 -C 4 alkyl) sulfamoyl, N- (C 1 -C 4 alkyl) 2 sulfamoyl, N- (C 1 -C 4 alkyl) Independently selected from carbamoyl, N- (C 1 -C 4 alkyl) 2 carbamoyl, phenyl, phenylthio, phenoxy, C 3 -C 8 cycloalkyl, and a heterocyclic group; Wherein said phenyl, phenylthio, phenoxy, C 3 -C 8 cycloalkyl or heterocyclic group may be optionally substituted on the ring carbon with one or more groups selected from R o ; When the heterocyclic group comprises an —NH— moiety, nitrogen may be optionally substituted by a group selected from R p ;
    [25] R j , R m and R o are hydroxy, halo, amino, cyano, formyl, formamido, carboxy, nitro, mercapto, carbamoyl, sulfamoyl, C 1 -C 4 alkyl [which is halo, Optionally substituted with one or more groups selected from cyano, amino, NC 1 -C 4 alkylamino, N, N-di- (C 1 -C 4 alkyl) amino or hydroxy], C 2 -C 4 alkenyl [ Optionally substituted with one or more groups selected from halo], C 2 -C 4 alkynyl, NC 1 -C 4 alkylamino, N, N-di- (C 1 -C 4 alkyl) amino, C 1 -C 4 alka Noyl, C 1 -C 4 alkanoyloxy, C 1 -C 4 alkoxy [optionally substituted with one or more groups selected from halo], C 1 -C 4 alkoxycarbonyl, NC 1 -C 4 alkylcarbamoyl, N , N- di - (C 1 -C 4 alkyl) carbamoyl, C 1 -C 4 alkanoylamino, C 1 -C 4 alkyl, S (0) a (wherein, a is 0 to 2 Im), C 1 -C 4 alkylsulfonylamino, N- (C 1 -C 4 alkyl) sulfamoyl, N- (C 1 -C 4 alkyl) 2 sulfamoyl, phenyl, C 3 -C 8 cycloal Independently selected from a kill and a heterocyclic group; And
    [26] R k , R n and R p are C 1 -C 4 alkyl, C 1 -C 4 alkanoyl, C 1 -C 4 alkylsulfonyl, C 1 -C 4 alkoxycarbonyl, carbamoyl, N- (C Independently selected from 1- C 4 alkyl) carbamoyl, N, N- (C 1 -C 4 alkyl) carbamoyl, benzyl, benzyloxycarbonyl, benzoyl and phenylsulfonyl.
    [27] "Aryl" means a fully or partially unsaturated monocyclic or bicyclic carbon ring containing 4 to 12 atoms. "Aryl" is preferably a monocyclic ring containing 5 or 6 atoms or a bicyclic ring containing 9 or 10 atoms. "Aryl" is more preferably phenyl, naphthyl, tetralinyl or indanyl. In particular, "aryl" is phenyl, naphthyl or indanyl. In particular "aryl" is phenyl.
    [28] A "carbon bonded heteroaryl" is a fully unsaturated 5 or 6 membered monocyclic ring or 9 or 10 membered bicyclic ring wherein at least one atom is selected from nitrogen, sulfur or oxygen. This ring is bonded to —NH— (for Q 1 ) or G (for Q 2 ) via a carbon atom. "Carbon-bonded heteroaryl" refers to furanyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, furazanyl, triazolyl, thidiazolyl, pyridyl , Pyrimidyl, pyrazinyl, pyridazinyl, triazinyl, indolyl, quinolyl or benzimidazolyl. More preferably, "carbon bonded heteroaryl" is pyridyl, thiazolyl or pyrazolyl. In particular "carbon bonded heteroaryl" is pyridyl.
    [29] A "heterocyclic group" is one or more atoms selected from nitrogen, sulfur or oxygen, and unless otherwise specified, can be carbon or nitrogen bonded, wherein -CH 2 -group can be optionally substituted with -C (O)-, Ring sulfur atoms are saturated, partially saturated or unsaturated monocyclic rings or dicyclic rings containing 4 to 12 atoms, optionally oxidized to form S-oxide (s). "Heterocyclic group" means pyrrolidinyl, morpholino, piperidyl, pyridyl, pyranyl, pyrrolyl, isothiazolyl, indolyl, quinolyl, thienyl, furyl, 1,3-benzodioxolyl, thia Diazolyl, piperazinyl, thiazolidinyl, pyrrolidinyl, thiomorpholino, pyrazolyl, pyrrolinyl, homopiperazinyl, tetrahydropyranyl, imidazolyl, pyrimidyl, pyrazinyl, pyridazinyl , Isoxazolyl, 4-pyridone, 1-isoquinolone, 2-pyrrolidone, 4-thiazolidone, imidazo [1,2-a] pyridine or 3-aza-8-oxabicyclo [3, 2,1] hexane is preferred. "Heterocyclic group" means pyrrolidinyl, morpholino, piperidyl, indolyl, thienyl, furyl, piperazinyl, thiomorpholino, pyrazolyl, imidazolyl, 2-pyrrolidone, imidazo [ 1,2-a] pyridine or 3-aza-8-oxabicyclo [3,2,1] hexane.
    [30] "Nitrogen-bonded heteroaryl" refers to an unsaturation, wherein at least one of 4 to 12 atoms is selected from nitrogen, and optionally one to three additional elements comprise 4 to 12 atoms selected from nitrogen, sulfur or oxygen. Having a monocyclic ring or a bicyclic ring, wherein the —CH 2 — group may be optionally replaced with —C (O) —, and the ring sulfur and / or nitrogen atoms are optionally oxidized to S-oxide (s) and / or Forms an N-oxide. A "nitrogen bonded heteroaryl" is a monocyclic ring containing 5 or 6 atoms or a bicyclic ring containing 9 or 10 atoms. Neutral compounds are formed by nitrogen bonding. Examples of "nitrogen linked heteroaryl" include imidazol-1-yl, pyrrolin-1-yl, imidazolin-1-yl, pyrazolin-1-yl, triazol-1-yl, indole-1- One, isoindol-2-yl, indolin-1-yl, benzimidazol-1-yl, pyrrole-1-yl or pyrazol-1-yl. "Nitrogen bonded heteroaryl" is preferably imidazol-1-yl.
    [31] A "nitrogen bonded heterocycle" is an unsaturated monocyclic ring containing at least one of 4 to 12 atoms selected from nitrogen, optionally one to three additional atoms comprising 4 to 12 atoms selected from nitrogen, sulfur or oxygen. Ring or a bicyclic ring, wherein the —CH 2 — group may optionally be replaced with —C (O) — and the ring sulfur is optionally oxidized to form S-oxide (s). A "nitrogen bonded heterocycle" is a monocyclic ring containing 5 or 6 atoms or a bicyclic ring containing 9 or 10 atoms. Suitable examples of “nitrogen linked heterocycles” include pyrrolidin-1-yl, piperidino, piperazin-1-yl, morpholino, thiomorpholino, homopiperidin-1-yl or homopipe Razin-1-yl. "Nitrogen linked heterocycle" is preferably pyrrolidin-1-yl, piperazin-1-yl or morpholino. More preferably, the "nitrogen linked heterocycle" is pyrrolidin-1-yl or piperazin-1-yl.
    [32] As used herein, the term "alkyl" has straight and branched chain alkyl groups, and each alkyl group, such as "propyl", is limited to straight chain profiles only. Similar naming applies to other generic names. "Halo" is fluoro, chloro, bromo and iodo.
    [33] Examples of C 2 -C 4 alkenyl are vinyl and allyl, examples of C 2 -C 6 alkenyl are C 3 -C 5 alkenyl, vinyl and allyl, and examples of C 3 -C 6 alkenyl are Allyl; examples of C 3 -C 6 alkynyl are C 3 -C 5 alkynyl and propyn-2-yl; examples of C 2 -C 4 alkynyl are ethynyl and propyn-2-yl And examples of C 2 -C 6 alkynyl include ethynyl and propyn-2-yl, examples of C 1 -C 4 alkanoyl include acetyl and propionyl, C 1 -C 4 alkoxycarbonyl Examples are C 1 -C 3 alkoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and t-butoxycarbonyl, and examples of C 1 -C 4 alkylene are methylene, ethylene and Propylene, and examples of C 1 -C 4 alkyl are C 1 -C 3 alkyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and t-butyl, C 1 -C 6 alkyl Examples of methyl, ethyl, propyl, isopropyl, butyl, Isobutyl, sec- butyl, t- butyl, and 3-methyl and the butyl, C 1 -C 4 alkoxy are examples of the C 1 -C 3 alkoxy, methoxy, ethoxy, propoxy, isopropoxy and butoxy are An example of C 2 -C 4 alkenyloxy is allyloxy, an example of C 2 -C 4 alkynyloxy is propynyloxy, and C 1 -C 4 alkylS (O) a (where a Are 0 to 2) Examples include C 1 -C 3 alkylsulfanyl, methylthio, ethylthio, propylthio, methylsulfinyl, ethylsulfinyl, propylsulfinyl, mesyl, ethylsulfonyl and propylsulfonyl Examples of NC 1 -C 4 alkylcarbamoyl are N-methylcarbamoyl, N-ethylcarbamoyl and N-propylcarbamoyl, and N, N-di- (C 1 -C 4 alkyl) Examples of carbamoyl are N, N-dimethylcarbamoyl, N-ethyl-N-methylcarbamoyl and N, N-diethylcarbamoyl, and examples of NC 1 -C 4 alkylamino are N- (C 1 -C 3 alkyl) amino, methylamino, ethylamino and propylamino And, N, N- di - (C 1 -C 4 alkyl) amino is for example N, N- di - (C 1 -C 3 alkyl) amino, dimethylamino, N- ethyl -N- methylamino, diethylamino Amino, N-methyl-N-propylamino and dipropylamino; examples of C 1 -C 4 alkanoylamino include acetamido, propionamido and butyramido, and C 3 -C 8 cycloalkyl Examples are cyclopropyl, cyclopentyl and cyclohexyl, examples of C 1 -C 4 alkanoyl are acetyl and propionyl, examples of C 1 -C 4 alkanoyloxy are acetyloxy and propionyloxy and Examples of, N '-(C 1 -C 4 alkyl) ureido include N'-methylureido and N'-ethylureido and N', N'-di- (C 1 -C 4 alkyl) urea Examples of these islands include N ', N'-dimethylureido, N', N'-diisopropylureido and N'-methyl-N'-propylureido and N '-(C 1 -C 4 alkyl Examples of) -N- (C 1 -C 4 alkyl) ureido are N'-methyl-N-ethylureido And N'-methyl-N-methylureido, an example of N ', N'-di- (C 1 -C 4 alkyl) -N- (C 1 -C 4 alkyl) ureido is N', N There are '-dimethyl-N-ethylureido and N'-methyl-N'-propyl-N-butylureido, and examples of N- (C 1 -C 4 alkyl) sulfamoyl are N-methylsulfamoyl and N isopropyl and the sulfamoyl, N, N- di-examples of (C 1 -C 4 alkyl) sulfamoyl is a N- methyl -N- ethyl-sulfamoyl, and N, N- dipropyl-sulfamoyl, and; Examples of C 1 -C 4 alkylsulfonylamino are mesylamino, ethylsulfonylamino and propylsulfonylamino.
    [34] Suitable examples of pharmaceutically acceptable salts of the pyrimidine derivatives of the invention include acid addition salts of the pyrimidine derivatives of the invention with sufficient basicity, for example inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid. And acid addition salts with citric acid or maleic acid. In addition, suitable examples of pharmaceutically acceptable salts of the pyrimidine derivatives of the present invention having sufficient acidity are those that provide alkali metal salts such as sodium or potassium salts, alkaline earth metal salts such as calcium or magnesium salts, ammonium salts or physiologically acceptable cations. Salts with bases, such as methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris- (2-hydroxyethyl) amine.
    [35] The compound of formula (I) can be administered in the form of prodrugs that degrade in the human or animal body to produce the compound of formula (I). Examples of such prodrugs are the in vivo hydrolyzable esters of the compounds of formula (I).
    [36] Examples of in vivo hydrolyzable esters of compounds of formula (I) containing carboxy or hydroxy groups are pharmaceutically acceptable esters that degrade in the human or animal body to produce the parent acid or alcohol. Examples of suitable pharmaceutically acceptable esters of carboxy include C 1 -C 6 alkoxymethyl esters such as methoxymethyl esters, C 1 -C 6 alkanoyloxymethyl esters such as pivaloyloxymethyl esters, phthalidyl esters, C 3 -C 8 cycloalkoxycarbonyloxyC 1 -C 6 alkyl esters such as 1-cyclohexylcarbonyloxyethyl; 1,3-dioxolene-2-onylmethyl esters such as 5-methyl-1,3-dioxolene-2-onylmethyl; And C 1 -C 6 alkoxycarbonyloxyethyl esters such as 1-methoxycarbonyloxyethyl and the like, which may be formed at any carboxy group in the compounds of the present invention.
    [37] Examples of in vivo hydrolyzable esters of formula I comprising hydroxy groups include inorganic esters such as phosphate esters and α-acyloxyalkyl ethers and related compounds, which are degraded by in vivo hydrolysis of the esters to produce the parent hydroxy group. do. Examples of α-acyloxyalkyl ethers are acetoxymethoxy and 2,2-dimethylpropionyloxy-methoxy. Examples of in vivo hydrolyzable esters that form groups for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (which forms alkyl carbonate esters), dialkylcarbamoyl and N- (dialkylaminoethyl) -N-alkylcarbamoyl (forms a carbamate), dialkylaminoacetyl, carboxyacetyl and the like. Examples of substituents on benzoyl include morpholino and piperazino bonded to the 3- or 4-position of the benzoyl ring by a methylene group from a ring nitrogen atom.
    [38] Some compounds of formula (I) may have chiral centers and / or geometric isomeric centers (E- and Z-isomers), which all the optical isomers, diastereomers of the invention have CDK and / or FAK inhibitory activity. It is understood to encompass geometric isomers.
    [39] The present invention relates to all tautomeric forms of the compounds of formula (I) having CDK and / or FAK inhibitory activity.
    [40] It is also understood that certain compounds of formula I may exist in solvated forms as well as unsolvated forms such as, for example, hydrated forms. It is also understood that the present invention also encompasses all solvated forms having CDK and / or FAK inhibitory activity.
    [41] Particularly preferred compounds of the invention include pyrimidine derivatives of formula (I), pharmaceutically acceptable salts thereof or in vivo hydrolyzable esters thereof, wherein R 1 , Q 1 , Q 2 and G have the meanings as described above Or the following meanings. This meaning may be used in any suitable sense with the definitions, claims or embodiments defined above or below.
    [42] Q 1 and Q 2 are preferably selected independently from phenyl, pyridyl, thiazolyl and pyrazolyl.
    [43] More preferably Q 1 and Q 2 are independently selected from phenyl and thiazolyl.
    [44] In one embodiment of the invention, more preferably Q 1 and Q 2 are independently selected from phenyl and thiazolyl.
    [45] It is preferable that Q <1> is phenyl.
    [46] Q 2 is preferably phenyl, pyridyl, thiazolyl or pyrazolyl.
    [47] More preferably Q 2 is phenyl or thiazolyl.
    [48] In another embodiment of the invention, it is more preferred that Q 2 is phenyl or pyridyl.
    [49] Q 1 is phenyl and Q 2 is preferably selected from phenyl, pyridyl, thiazolyl and pyrazolyl.
    [50] Q 1 is phenyl and Q 2 is more preferably selected from phenyl and thiazolyl.
    [51] In another embodiment of the invention, it is preferred that Q 1 is phenyl and Q 2 is selected from phenyl and pyridyl.
    [52] In substituents of formula (Ia), X is -O-, Y 1 is OH, Y 2 is H, Z is R c R d N- or a nitrogen-bonded heterocycle, wherein the heterocycle is C 1 -C on ring nitrogen 4 optionally substituted with alkanoyl, R c and R d are independently selected from hydrogen, C 1 -C 4 alkyl and C 3 -C 8 cycloalkyl, n is 1 and m is 1.
    [53] In the substituent of formula la, X is -O-, Y 1 is OH, Y 2 is H, Z is amino, methylamino, ethylamino, isopropylamino, isobutylamino, t-butylamino, dimethylamino, cyclopentyl It is more preferred that amino, pyrrolidin-1-yl or 4-acetylpiperazin-1-yl, n is 1 and m is 1.
    [54] In particular, substituents of formula (Ia) include 3-amino-2-hydroxypropoxy, 3-methylamino-2-hydroxypropoxy, 3-dimethylamino-2-hydroxypropoxy, 3-ethylamino-2-hydroxy Propoxy, 3-isopropylamino-2-hydroxypropoxy, 3-isobutylamino-2-hydroxypropoxy, 3-t-butylamino-2-hydroxypropoxy, 3- (4-acetylpipepe Razin-1-yl) -2-hydroxypropoxy, 3-cyclopentylamino-2-hydroxypropoxy or 3-pyrrolidin-1-yl-2-hydroxypropoxy.
    [55] In particular, substituents of formula la may be 3-dimethylamino-2-hydroxypropoxy, 3-isopropylamino-2-hydroxypropoxy, 3-t-butylamino-2-hydroxypropoxy or 3-cyclopentyl Amino-2-hydroxypropoxy.
    [56] Substituents of formula (Ia) are preferably present on ring Q 1 .
    [57] When Q 1 is phenyl, the substituent of formula (Ia) is preferably present in the para- or meta- position relative to -NH-.
    [58] If Q 1 is phenyl, the substituent of formula (Ia) is more preferably present in the para-position relative to —NH—.
    [59] In one embodiment of the invention, G is preferably -O-.
    [60] In another embodiment of the invention, G is preferably -S-.
    [61] R 1 is preferably fluoro, chloro or bromo.
    [62] More preferably, R 1 is bromo.
    [63] Q 1 is preferably unsubstituted except by a substituent of the formula (Ia).
    [64] Q 2 is preferably substituted by one methoxy group or unsubstituted.
    [65] Q 2 is preferably phenyl, 4-methoxyphenyl or thiazol-2-yl.
    [66] Therefore, in a preferred embodiment of the invention, Q 1 and Q 2 are independently selected from phenyl and thiazolyl, Q 2 is substituted or unsubstituted by one methoxy group and Q 1 is a ring as shown Substituted on the carbon by a substituent of Formula Ia, wherein X is -O-, Y 1 is OH, Y 2 is H, Z is R c R d N- or a nitrogen-bonded heterocycle [where the heterocycle is Optionally substituted by C 1 -C 4 alkanoyl on ring nitrogen, R c and R d are independently selected from hydrogen, C 1 -C 4 alkyl and C 3 -C 8 cycloalkyl, n is 1 , m is 1,
    [67] G is -O- or -S-,
    [68] R 1 relates to a pyrimidine derivative of formula (I) which is fluoro, chloro or bromo, or a pharmaceutically acceptable salt thereof or an in vivo hydrolysable ester thereof.
    [69] Therefore, in a more preferred embodiment of the invention,
    [70] Q 1 is phenyl and Q 2 is selected from phenyl and thiazolyl; Q 2 is substituted or unsubstituted by one methoxy group, Q 1 is 3-amino-2-hydroxypropoxy, 3-methylamino-2-hydroxypropoxy, 3-dimethylamino- on a ring carbon 2-hydroxypropoxy, 3-ethylamino-2-hydroxypropoxy, 3-isopropylamino-2-hydroxypropoxy, 3-isobutylamino-2-hydroxypropoxy, 3-t-butyl Amino-2-hydroxypropoxy, 3- (4-acetylpiperazin-1-yl) -2-hydroxypropoxy, 3-cyclopentylamino-2-hydroxypropoxy or 3-pyrrolidine-1 -Substituted by yl-2-hydroxypropoxy;
    [71] G is -O- or -S-,
    [72] R 1 relates to pyrimidine derivatives of formula (I), pharmaceutically acceptable salts thereof or hydrolyzable esters thereof in bromo.
    [73] In one embodiment of the invention, the compounds of the invention relate to the compounds of Examples 1, 6, 14, 15, 16 or 17 or pharmaceutically acceptable salts or in vivo hydrolysable esters thereof.
    [74] In a further embodiment of the invention, examples of preferred compounds of the invention relate to any compound of the Examples or a pharmaceutically acceptable salt thereof or to an in vivo hydrolysable ester thereof.
    [75] Preferred embodiments of the present invention are directed to compounds or pharmaceutically acceptable salts thereof.
    [76] The pyrimidine derivatives of formula (I), pharmaceutically acceptable salts thereof or in vivo hydrolyzable esters thereof may be prepared by any preparation known to be applicable for the preparation of chemically related compounds. When using these preparations to prepare the compounds of formula (I), their pharmaceutically acceptable salts or their in vivo hydrolyzable esters, they provide additional features of the present invention, which, unless stated otherwise, R 1 , Q 1 , Q 2 and G may be of any of the meanings set forth above for the pyrimidine derivative of formula I, and when no other substituent is located on ring Q 1 or Q 2 , the ring is any of the foregoing It is illustrated that it may have a substituent of (optionally protected if necessary). If the substituent is positioned on ring Q 1, this includes the possibility that may be present on ring Q 1, instead of the substituents present on the ring Q 1 (unless otherwise noted) or in addition to it. Essential starting materials can be obtained by standard procedures in organic chemistry, such as Advanced Organic Chemistry , Wiley-Interscience, Jerry March-also useful for general guidance on reaction conditions and reagents. The preparation of such starting materials is described in the non-limiting preparations and examples appended hereto. In addition, essential starting materials can be obtained by procedures similar to those exemplified within the ordinary skill of the organic chemist.
    [77] Therefore, as a further feature of the invention,
    [78] a) for compounds of formula I, pyrimidines of formula II are reacted with compounds of formula III,
    [79] b) reacting pyrimidine of formula IV with a compound of formula V,
    [80] c) For compounds of Formula (I) wherein n is 1, 2 or 3, m is 1, Y 2 is H and Y 1 is OH, NH 2 or SH, the 3-membered heteroalkyl ring of Formula VI is React with the nucleophile of VII,
    [81] d) for compounds of formula (I), wherein X is oxygen, reacting an alcohol of formula (VIII) with an alcohol of formula (IX),
    [82] e) X is -CH 2- , -O-, -NH- or -S-, Y 1 is OH, Y 2 is H and m is 2 or 3, Reacting a compound of with a nucleophile of formula VII,
    [83] f) X is -CH 2- , -O-, -NH- or -S-, Y 1 and Y 2 are H, n is 1, 2 or 3, m is 1, 2 or 3 For compounds of, the compounds of formula XI are reacted with the nucleophiles of formula VII,
    [84] g) for compounds of formula I wherein X is -O-, -NH- or -S-, Y 1 and Y 2 are H, n is 1, 2 or 3 and m is 1, 2 or 3, Reacting a compound of formula XII with a compound of formula XIII
    [85] h) for compounds of formula I wherein Z is HS-, converts the thioacetate group in the compound,
    [86] Then, if necessary,
    [87] i) converting the compound of formula I to another compound of formula I,
    [88] ii) remove any protecting group,
    [89] iii) a method comprising forming a pharmaceutically acceptable salt thereof or a hydrolyzable ester thereof in vivo.
    [90]
    [91]
    [92]
    [93]
    [94]
    [95] Z-D
    [96]
    [97]
    [98]
    [99]
    [100]
    [101]
    [102] In the above formula, L is a substitutable group as described above,
    [103] A is O, S or NH,
    [104] D is H or a suitable counterion,
    [105] LgO is a leaving group as described above.
    [106] L is a substitutable group, and suitable examples of L include halo, sulfonyloxy or sulfur groups such as chloro, bromo, methanesulfonyloxy, toluene-4-sulfonyloxy, mesyl, methylthio and methylsulfinyl and the like. There is this.
    [107] Specific reaction conditions for the reaction are as follows.
    [108] Recipe a)
    [109] The pyrimidine of formula II and the compound of formula III may optionally be reacted together in the presence of a suitable base such as an inorganic base such as potassium carbonate. The reaction can be carried out with a suitable inert solvent or diluent such as dichloromethane (DCM), acetonitrile, butanol, tetramethylene sulfone, tetrahydrofuran, 1,2-dimethoxyethane, N, N-dimethylformamide, N, N- In dimethylacetamide or N-methylpyrrolidin-2-one, for example, it is preferably carried out at a temperature of 0 ° C to 150 ° C, simply at or near room temperature.
    [110] The pyrimidine of formula (II) can be produced by the following scheme.
    [111]
    [112] In the above scheme, R a is an optionally substituted alkyl or aryl group and L is a substitutable group as described above. R a is preferably methyl, ethyl or p-tolyl.
    [113] Compounds of formula III are either commercially available or are produced by methods known in the art.
    [114] Manufacturing process b)
    [115] Pyrimidine of formula IV and aniline of formula V
    [116] i) in the presence of a suitable solvent such as a ketone such as acetone or an alcohol such as ethanol or butanol or an aromatic hydrocarbon such as toluene or N-methylpyrrolidine, optionally an appropriate acid such as as defined above In the presence of an acid (or suitable Lewis acid), from 0 ° C. to reflux temperature, preferably at reflux temperature, or
    [117] ii) all can be reacted under Buchwald conditions as described above.
    [118] Pyrimidine of formula IV is produced by the following scheme.
    [119]
    [120] In the above scheme, L is a substitutable group as described above.
    [121] Anilines of formula V are either commercially available or are produced by methods known in the art.
    [122] Compounds of formula (VA) are commercially available or can be reacted, for example, compounds of formula (VA), wherein L is -OH (eg uracil) with POCl 3 to produce compounds of formula (VA), wherein L is -Cl.
    [123] Manufacturing process c)
    [124] The ternary heteroalkyl ring of formula VI and the nucleophile of formula VII are optionally at a temperature of 20 ° C.-100 ° C., preferably 20 ° C.-50 ° C., optionally with a suitable solvent such as N, N-dimethylformamide, dimethyl sulfoxide or The reaction is carried out in the presence of tetrahydrofuran.
    [125] Compounds of Formula VI may be produced by Scheme 1 below.
    [126] For compounds of Formula VI, where A is O and X is not carbon:
    [127]
    [128] In addition, the conversion of the compound of formula VIB to the compound of formula VI is carried out by reacting with Br- (CH 2 ) n -CHO or the corresponding ester in DMF and in the presence of a base, followed by (Me 2 SOCH in an inert solvent such as THF). It can be obtained by reacting with sulfur illide such as 2 ). (See Scheme V).
    [129] For compounds of Formula VI wherein A is NH and X is not carbon:
    [130]
    [131] For PhINTs, reference is made to Tet. Let. , 1997, 38 (39), 6897-6900. In addition, compounds of formula VIC may be oxidized to epoxides using conditions similar to Scheme IV below.
    [132] For compounds of Formula VI wherein A is S and X is not carbon:
    [133]
    [134] See, eg, Synlett , 1994, 267-268.
    [135] For compounds of formula VI, wherein X is carbon:
    [136]
    [137] In the above scheme, R 3 together with the —COO- group to which it is attached form an ester moiety such as methyl ester or ethyl ester.
    [138] X is CH 2 , O, NH or S; Y 1 is OH; Y 2 is H; For compounds of Formula VI, where n is 1, 2 or 3 and m is 1
    [139]
    [140] Compounds of formula VIJ are reacted with compounds of formula IV (see Scheme I) to afford compounds of formula VI.
    [141] Corresponding esters of formula VIH may also be used. References Russ. Chem. Rev. 47, 975-990, 1978.
    [142] Compounds of formula (VIH), (VII), (VIA) and (VID-1) are commercially available or are produced by methods known in the art.
    [143] Manufacturing process d)
    [144] Alcohols of formula (VIII) (eg phenols) and alcohols of formula (IX) can both be reacted under standard Mitsunobu conditions. For example, in the presence of diethyl azodicarboxylate and triphenyl phosphine, in a suitable solvent such as dichloromethane, toluene or tetrahydrofuran, a temperature of 0 ° C. to 80 ° C., preferably 20 ° C. to 60 ° C. Perform on Alternatively, the alcohol (phenol) of formula (VIII) can be alkylated using a suitable compound of formula (IX) in which the terminal hydroxy group has been replaced with a suitable leaving group.
    [145] Alcohols of formula (VIII) were prepared by the process of (I) above for the synthesis of intermediates of formula (VIB), wherein X is oxygen.
    [146] Alcohols of formula (IX) are either commercially available or are produced by methods known in the art.
    [147] In a method analogous to preparation d), a compound wherein X is -S- can be produced by reacting a compound of formula VIII wherein the hydroxy group is -SH with a compound of formula IX wherein the hydroxy group is a leaving group such as mesylate or tosylate.
    [148] Recipe e)
    [149] X is -CH 2- , -O-, -NH- or -S-; Y 1 is OH, Y 2 is H, m is 2 or 3 and the nucleophile of the compound of formula VII and the nucleophile of formula VII is at a temperature of 20 ° C.-100 ° C., preferably 20 ° C.-50 ° C. For example in the presence of N, N-dimethylformamide, dimethyl sulfoxide or tetrahydrofuran, optionally in the presence of a suitable base such as potassium carbonate.
    [150] The compound of formula X is prepared by the following scheme (m being 2 or 3):
    [151]
    [152] The order of steps 1) and 2) in the final step may be reversed. Suitable base for step 2) is triethylamine.
    [153] Compounds of formula (XA) and (VII) are commercially available or are produced by methods known in the art. For example, compounds of formula (XA) wherein X is -NH-, -O- or -S- can be produced by reacting a compound of formula (VIA) with the appropriate haloaldehyde or corresponding ester under conditions of standard for such a reaction.
    [154] Manufacturing method f)
    [155] Compounds of formula (XI) and nucleophiles of formula (VII) were reacted together as described in preparation e) above.
    [156] The compound of formula (XI) was produced in a similar manner to step 2) in the final step of the preparation for preparing the compound of formula (X). Essential primary alcohol starting materials are commercially available or are produced by methods known in the art.
    [157] Manufacturing method g)
    [158] Compounds of formula (XII) and (XIII) are reacted in the presence of a base such as potassium carbonate in an inert solvent such as DMF.
    [159] The compound of formula XII has the same formula as the compound of formula VIB described herein, which was prepared as described for the compound (see Scheme I). Compounds of formula (XIII) are either commercially available or are produced by methods known in the art.
    [160] Manufacturing method h)
    [161] For compounds of formula (I), wherein Z is SH, the conversion reaction of thioacetate in the compound is performed as described herein to convert the compound of formula (IJ) to the compound of formula (IK).
    [162] Suitable starting materials comprising thioacetate groups can be prepared using thiol acetic acid as described herein to convert compounds of formula (IG) to compounds of formula (IJ) such as mesylate or tosylate (standard from the corresponding hydroxy compound). Produced using the method).
    [163] An example of a reaction for converting a compound of formula (I) to another compound of formula (I) is as follows.
    [164] i) a reaction for converting one side chain of formula (Ia) to another side chain of formula (Ia):
    [165] I) Y 2 is H and Y 1 is a non-hydroxy compound of formula (I reaction is shown using ammonia)
    [166]
    [167] II) For compounds of Formula I wherein Y 2 is H and Y 1 is S:
    [168]
    [169] III) For compounds of Formula I wherein Y 2 is H and Y 1 is H:
    [170]
    [171] It can also be seen that this reaction is suitable for converting one side chain of formula (Ia) to another side chain of formula (Ia).
    [172] ii) for example, using standard techniques, such as conversion of R 1 to convert the hydroxy to a C 1 -C 4 alkoxy the reaction of converting R 1 into another R 1.
    [173] Those skilled in the art will appreciate that the manipulation of the side chains of formula (Ia) described in formulas c) to i) can be used to produce intermediates of formula (II), formula (IA), formula (IIB) or formula (V).
    [174]
    [175] Preferred preparation of the present invention is preparation b).
    [176] Certain of the various ring substituents in the compounds of the present invention may be produced by standard aromatic substitution reactions, or by conventional functional group modifications either before or after the aforementioned methods, which are also embodiments of the methods of the present invention. It is obvious that it is included in. Such reactions and modifications include, for example, aromatic substitution reactions, reduction reactions of substituents, alkylation reactions of substituents and introduction of substituents by oxidation reactions of substituents. Reagents and reaction conditions for this procedure are well known in the chemical art. Specific examples of aromatic substitution reactions include the introduction of nitro groups using concentrated nitric acid, for example the introduction of acyl groups under Friedel Crafts conditions using acyl halides and Lewis acids (eg aluminum trichloride), for example alkyl halogens. Use of cargoes and Lewis acids (eg aluminum trichloride) includes the introduction of alkyl groups under Friedel Crafts conditions, the introduction of halo groups, and the like. Specific examples of the modification include, for example, reduction of the nitro group to an amino group by treatment with iron in the presence of hydrochloric acid under heating or by catalytic hydrogenation using a nickel catalyst; There is an oxidation reaction of alkylthio to alkylsulfinyl or alkylsulfonyl.
    [177] In some of the reactions mentioned herein, it is well known that it is desirable or desirable to protect any sensitive group in the compound. If protection is needed or desired, suitable methods for protection are known to those skilled in the art. Conventional protecting groups are used by standard practices. TW Green, Protective Groups in Organic Synthesis , John Wiley and Sons, 1991. If the reactants include groups such as amino, carboxy or hydroxy it will be desirable to protect the group in some of the reactions mentioned herein.
    [178] Examples of suitable protecting groups for amino or alkylamino include acyl groups such as alkanoyl groups such as acetyl, alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl or t-butoxycarbonyl groups, arylmethoxycarbonyl groups such as , Benzyloxycarbonyl, or aroyl groups such as benzoyl and the like. The deprotection conditions for the protecting group necessarily depend on the choice of protecting group. Thus, for example, acyl groups such as alkanoyl or alkoxycarbonyl groups or aroyl groups can be removed by hydrolysis with suitable bases, for example alkali metal hydroxides such as lithium hydroxide or sodium hydroxide. Alternatively, acyl groups such as t-butoxycarbonyl groups can be removed by treatment with a suitable acid such as hydrochloric acid, sulfuric acid, phosphoric acid or trifluoroacetic acid, and arylmethoxycarbonyl groups such as benzyloxycarbonyl groups are for example carbon It can be removed by hydrogenation on a catalyst such as phase palladium or by treatment with Lewis acid such as boron tris (trifluoroacetate). Another suitable protecting group for primary amino groups is phthaloyl groups which can be removed by treatment with alkylamines, for example dimethylaminopropylamine or with hydrazine.
    [179] Examples of suitable protecting groups for hydroxy groups are acyl groups such as alkanoyl groups such as acetyl, aroyl groups such as benzoyl or arylmethyl groups such as benzyl groups. The deprotection conditions for the protecting group may necessarily be modified depending on the choice of protecting group. Thus, for example, acyl groups such as alkanoyl or aroyl groups can be removed, for example, by hydrolysis with suitable bases such as alkali metal hydroxides such as lithium hydroxide or sodium hydroxide. Alternatively, arylmethyl groups such as benzyl groups can be removed by hydrogenation on a catalyst such as, for example, palladium on carbon.
    [180] Examples of suitable protecting groups for carboxyl groups are for example esterification groups which can be removed by hydrolysis with bases such as sodium hydroxide, for example methyl groups or ethyl groups, or acids such as organic acids, ie trifluoroacetic acid. T-butyl groups that can be removed by treatment or benzyl groups that can be removed by hydrogenation on a catalyst such as, for example, palladium on carbon.
    [181] The protecting group can be removed at any convenient step in the synthesis using conventional techniques well known in the art.
    [182] Many of the intermediates defined herein are, for example, novel compounds of the formulas (II) and (IV), which form a further feature of the present invention.
    [183] analysis
    [184] As mentioned above, pyrimidine derivatives as defined herein have anti-cell proliferative activity, such as anticancer activity, which is known to result from the CDK and / or FAK inhibitory activity of the compounds. This property can be evaluated, for example, using the following procedure.
    [185] CDK4 Inhibition Assay
    [186] The following abbreviations were used.
    [187] HEPES is N- (2-hydroxyethyl) piperazine-N '-(2-ethanesulfonic acid), DTT is dithiothritol and PMSF is fluorinated phenylmethylsulfonyl.
    [188] In vitro kinase assay in 96-well format using scintillation proximity analysis (SPA, available from Emersham) to determine the incorporation of [γ-33-P] -adenosine triphosphate into the test substrate (GST-retinoblastoma). The compound was tested. To each well was added the compound to be tested (diluted in DMSO and water to correct the concentration), and the control wells were either p16 as inhibitor control or DMSO as positive control.
    [189] Approximately 0.5 [mu] l of CDK4 / cyclin D1 partially purified enzyme diluted in 25 [mu] l of culture buffer (amount according to enzyme activity) was added to each well, followed by a GST-Rb / ATP / ATP33 mixture (0.5 [mu] g of GST-Rb and ATP). 20 μl of 0.2 μM and 0.14 μCi [γ-33-P] -adenosine triphosphate) were added and the resulting mixture was gently stirred and then incubated at room temperature for 60 minutes.
    [190] Each well was then added to [0.8 mg / well of protein A-PVT SPA beads (Amersham)], 20 pM / well of anti-glutathione transferase, rabbit IgG (obtained from molecular probe), 61 mM EDTA and , 150 μl of stop solution containing 50 mM HEPES pH 7.5 containing 0.05% sodium azide was added.
    [191] The plate was sealed using a Topseal-S plate sealer and left for 2 hours before it was spun for 5 minutes at 2500 rpm, 1124 xg. Plates were read for 30 seconds per well in Topcount.
    [192] The incubation buffer and substrate mixture used to dilute the enzyme were 50 mM HEPES pH 7.5, 10 mM MnCl 2 , 1 mM DTT, 100 μM sodium vanadate, 100 μM NaF, 10 mM sodium glycerophosphate, BSA (1 mg / Ml final).
    [193] As a control, another known inhibitor of CDK4 may be used in place of p16.
    [194] Testing substrate
    [195] In this assay, some of the retinoblastomas [ Science 1987 Mar 13; 235 (4794): 1394-1399; Lee WH, Bookstein R., Hong F., Young LJ, Shew JY, Lee EY] and used GST tag of retinoblastoma amino acids 379-928 (obtained from retinoblastoma plasmid ATCC pLRbRNL). PGEX 2T fusion vectors used to amplify amino acids 792-928 after fusion to PCR [Smith DB and Johnson, KS, Gene , 67, 31 (1988); This includes the tac promoter for inducible expression, the internal lac I q gene for use in any E. coli host and the coding region for thrombin cleavage, which is available from Pharmacia Biotech. This sequence is cloned back into pGEX 2T.
    [196] The retinoblastoma 792-928 sequences thus obtained were expressed in E. coli (BL21 (DE3) pLysS cells) using standard inducible expression techniques and purified as follows.
    [197] E. coli paste was prepared in 10 mL / g NETN buffer (50 mM Tris pH 7.5, 120 mM NaCl, 1 mM EDTA, 0.5% v / v NP-40, 1 mM PMSF, 1 μg / ml leupeptidine, 1 μg / Ml aprotinin and 1 μg / ml pepstatin) and sonicated for 2 × 45 seconds per 100 ml of homogenate. After centrifugation, the supernatant was loaded into a 10 ml glutathione Sepharose column (Pharmacia Biotech; Hertz, UK) and washed with NETN buffer. After washing with kinase buffer (50 mM HEPES pH 7.5, 10 mM MgCl 2 , 1 mM DTT, 1 mM PMSF, 1 μg / ml leupeptidine, 1 μg / ml aprotinin and 1 μg / ml pepstatin), the protein was washed. Elution with 50 mM reduced glutathione in kinase buffer. Fractions containing GST-Rb (792-927) were pooled and dialyzed against kinase buffer overnight. The final product was analyzed by Dodeca Sulfate (SDS) PAGE (polyacrylamide gel) using 8-16% Tris-glycine gel (Novex, San Diego, USA).
    [198] CDK4 and Cyclin D1
    [199] CDK4 and cyclin D1 were cloned from RNA from MCF-7 cell line (ATCC Accession No .: HTB22, breast adenocarcinoma line) as follows. RNA was generated from MCF-7 cells and then reverse transcribed using oligo dT primers. Each gene using PCR [CDK4 amino acids 1-303; Ref. Cell l992 Oct 16; 71 (2): 323-334; Matsushime H., Ewen ME, Stron DK, Kato JY, Hanks SK, Roussel MF, Sherr CJ and Cyclin Dl amino acids 1-296; Ref. Cold Spring Harb. Symp. Quant. Biol. , 1991; 56: 93-97; Arnold A., Motokura T., Bloom T. , Kronenburg, Ruderman J., Juppner H., Kim HG] were amplified.
    [200] After sequencing, the PCR products were cloned into insect expression vector pVL1393 (Invitrogen 1995 Catalog No .: V1392-20) using standard techniques. PCR products were then double transfected into insect SF21 cell line (Spoofterra purgiferda, commercially available derived from ovarian tissue of the Fall Army Worm) (using standard virus Baculogold co-infection technique).
    [201] The following example details the production of cyclin D1 / CDK4 in SF21 cells (TC100 + 10% FBS (TCS) + 0.2% Pluronic) double infected with MOI3 for each virus of Cyclin D1 and CDK4. do.
    [202] Preparation of Cyclin D1 / CDK4
    [203] SF21 cells propagated at 2.33 × 10 6 cells / ml were used to inoculate 10 × 500 ml roller bottles at 0.2 × 10 E6 cells / ml in a roller bottle incubator. The roller bottles were incubated at 28 ° C. in roller rigs.
    [204] After 3 days (72 hours), the cells were counted and the mean in the two bottles was found to be 1.86 × 10 E6 cells / mL (99% survival). The cultures were then infected using two viruses in MOI 3 for each virus.
    [205] 10 × 500 ml were infected with JS303 cyclin D1 virus (titer-9 × 10E7 pfu / ml) and JS304 CDK4 virus (titer −1 × 10E8 pfu / ml).
    [206] Cyclin D1 = 31 ml of virus for each 500 ml bottle
    [207] CDK4 = 28 ml virus for each 500 ml bottle
    [208] All were mixed before the virus was added to the culture and the culture was sent to a 28 ° C. roller rig.
    [209] After 3 days (72 hours) of infection, 5 liters of culture were recovered. Total cell count at recovery was 1.58 × 10 E6 cells / mL (99% survival). The cells were spun at 250 rpm aliquots at 4 ° C. Heraeus Omnifuge 2.0 RS at 2,500 rpm for 30 minutes. Discarded the fresh liquid. 20 pellets of ˜4 × 10 E8 cells / pellets were flash cooled in LN 2 and stored in the CCRF cold room at −80 ° C. SF21 cells were then lysed in lysis buffer (50 mM HEPES pH 7.5, 10 mM magnesium chloride, 1 mM DTT, 10 mM glycerophosphate, 0.1 mM PMSF, 0.1 mM sodium fluoride, 0.1 mM sodium orthovanadate, 5 μg / ml apro Tinine, 5 μg / ml leupetin and 20% w / v sucrose), resuspended in storage, and ice-cooled deionized water was added. After centrifugation, the supernatant was placed in a Poros HQ / M l / 4/100 anion exchange column (PE Biosystems, Hertford, UK). CDK4 and cyclin D1 were simultaneously eluted with 375 mM NaCl in lysis buffer and their presence was Western blot using appropriate anti-CDK4 and anti-cyclin D1 antibodies (obtained from Santa Cruz Biotechnology, CA, USA). Checked.
    [210] p16 control group ( Nature366.:704-707; 1993; Serrano M, Hannon GJ, Beach D)
    [211] p16 (natural inhibitor of CDK4 / cyclin D1) was amplified from HeLa cDNA (Hela cells obtained from ATCC CCL2, human epithelial cell carcinoma from cervical canal; Cancer Res . 12: 264, 1952) and had a 5 ′ His tag It was cloned into pTB 375 NBSE and transformed into BL21 (DE3) pLysS cells (obtained from Promega, Ref. Studier FW and Moffat BA, J. Mol. Biol. , 189, 113, 1986) using standard techniques. After 1 L of culture was grown to the appropriate OD, it was induced to express p16 overnight using IPTG. Cells were lysed by sonication in 50 mM sodium phosphate, 0.5 M sodium chloride, PMSF, 0.5 μg / ml leupetin and 0.5 μg / ml aprotinin. The mixture was spun down and the supernatant was added to nickel chelate beads and mixed for 1 hour 30 minutes. The beads were washed with sodium phosphate, NaCl pH 6.0, and the p16 product was eluted with sodium phosphate containing 200 mM imidazole, NaCl pH 7.4.
    [212] pTB NBSE was constructed from pTB 375 NBPE as described below.
    [213] pTB 375
    [214] The background vector used for the generation of pTB 375 is pZEN0042 (see British Patent No. 2,253,852), comprises a tetA / tetR inducible tetracycline resistance sequence from plasmid RP4, and the background vector derived from pAT153 is cer stable sequence from plasmid pKS492. It includes. pTB 375 is produced by the addition of a expression cassette consisting of a T7 gene 10 promoter, a multiple cloning site and a T7 gene 10 terminal sequence. In addition, termination sequences designed to reduce transcription from the background vector are included upstream of the expression cassette.
    [215] pTB 375 NBPE
    [216] Unique EcoRI restriction sites present in pTB 375 were removed. Introduction of a number of novel cloning sites, including recognition sequences for the restriction enzymes NdeI, BamHI, PstI and EcoRI, between the NdeI and BamHI sites in pTB 375 destroys the unique BamHI sites present in pTB 375.
    [217] pTB 375 NBSE
    [218] A number of novel cloning sites including recognition sequences for restriction enzymes NdeI, BamHI, SmaI and EcoRI were introduced between the NdeI and EcoRI sites in pTB 375 NBPE. In addition, oligonucleotides comprising such restriction sites include 6 histidine codons located between NdeI and BamHI in the same reading frame as the start codon (ATG) present in the NdeI site.
    [219] Similar to the above, an assay was constructed to assess the inhibition of CDK2 and CDK6. CDK2 (EMBL Accession No. X62071) was used in combination with Cyclin A or Cyclin E (EMBL Accession No. M73812), and further for this assay. Details are included in PCT International Publication No. WO 99/21845, Related Biochemical and Biological Evaluations section, which is incorporated herein by reference.
    [220] When CDK2 is used with cyclin E, partial simultaneous purification can be performed as follows.
    [221] Sf21 cells were lysed in lysis buffer (50 mM Tris pH 8.2, 10 mM MgCl 2 , 1 mM DTT, 10 mM glycophosphate, 0.1 mM sodium orthovanadate, 0.1 mM NaF, 1 mM PMSF, 1 μg / ml leupetin and 1 [Mu] g / ml aprotinin) and it was homogenized in 10 ml Dounce homogenizer for 2 minutes. After centrifugation, the supernatant was placed in a Poros HQ / M 1.4 / 100 anion exchange column (PE Biosystems, Permanent Hertford). CDK2 and cyclin E were co-eluted at the start of a 0-1 M NaCl gradient at 20 column volumes (done in lysis buffer without protease inhibitors). Simultaneous elution was checked by Western blot using both anti-CDK2 and anti-cyclin E antibodies (Santa Cruz Biotechnology, CA, USA).
    [222] FAK3 Kinase Inhibition Assay
    [223] This assay measures the ability of test compounds to inhibit tyrosine kinase activity of human focal adhesion kinase (FAK).
    [224] DNA encoding FAK was obtained by whole gene synthesis (Edwards M, International Biotechnology Lab 5 (3), 19-25, l987) or by cloning. This was then expressed in an appropriate expression system to obtain a polypeptide having tyrosine kinase activity. For example, FAK obtained by the expression of recombinant proteins in insect cells has been shown to exhibit intrinsic tyrosine kinase activity.
    [225] FAK (full length human cDNA, Andre et al., Biochemical and Biophysical Research Communications , 1993, 190 (1): 140-147; EMBL / GenBank Accession Number L05186)] is a protein that is produced by translation of N immediately before the initiating methionine. It is modified to have 6-histidine at the end. Active FAK proteins have already been expressed in baculovirus systems using similar N-terminal 6-histidine tags. Protein Expression And Purification , 1996, 7: 12-18. Human FAK cDNA was cloned into the baculovirus transfection vector, pFastbac 1 (Life Technologies), and the recombinant construct co-infected with insect cells (eg, Spodoptera purgiferda 21 (Sf21)) with viral DNA. To generate recombinant baculovirus. [Methods for Assembly of Recombinant DNA Molecules and Details on the Preparation and Use of Such Recombinant Vacuviruses are described, for example, in Sambrook et al., 1989, Molecular cloning-A Laboratory Manual, 2 Plates, Cold Spring Harbor Laboratory Press and O'Reilly et al., 1992, Baculovirus Expression Vectors-A Laboratory Manual, WH Freeman and Co, New York. Details on the use of the pFastbac ('Bac to Bac') system are provided in Anderson et al., 1995, FOCUS (Life Techno1ogies Bulletin Magazine), 17, p53].
    [226] For the expression of biologically active human FAK protein, Sf21 cells are infected 48 hours after infection with MOI3 with plaque-pure FAK presynthetic virus. The collected cells were washed with ice cold phosphate buffered saline (PBS) (10 mM sodium phosphate pH 7.4, 138 mM sodium chloride, 2.7 mM potassium chloride) and then ice cooled lysis buffer (50 mM HEPES pH 7.5, 1 mM Diti Otreitol, 100 μM sodium fluoride, 100 μM sodium orthovanadate, 10 mM glycerophosphate, 100 μM fluorinated phenylmethylsulfonyl (PMSF), 5 μg / ml aprotinine, 5 μg / ml leupetin, 10% Tween; PMSF was added immediately before use from freshly generated 100 mM solution in methanol) and resuspended using 250 μl lysis buffer per 10 million cells. The suspension was incubated for 15 minutes on ice and centrifuged at 4 ° C. at 13,000 rpm for 10 minutes. The supernatant (enzyme stock) was removed and the aliquots were flash frozen in liquid nitrogen and then stored at -70 ° C. For conventional batches, the stock enzyme is diluted 250: 1 with enzyme dilution (100 mM HEPES pH 7.4, 0.2 mM dithiothreitol, 200 μM sodium orthovanadate, 0.10% Triton X-100) and 50 ml Freshly diluted enzyme of was used in each assay well. (See FAK3 Protocol, below).
    [227] FAK3: In Vitro Enzyme Analysis Protocol
    [228] A stock of substrate solution is generated from a random copolymer containing tyrosine, for example Poly (GIu, Ala, Tyr) 6: 3: 1 (Sigma P3899), which is stored at −20 ° C. as a 1 mg / ml stock in PBS. And diluted 500: 1 for plate coating.
    [229] The day before assay, 100 μl of diluted substrate solution was dispensed into the wells of all assay plates (Maxisorp 96 well immunoplate, Life Technologies, Cat. No. 439454A), sealed with a plate sealer and left at 4 ° C. overnight. .
    [230] On the day of analysis, the substrate solution was discarded and the assay plate wells were washed once with 200 μl PBST (PBS with 0.05% v / v Tween 20) and once with 200 μl 50 mM Hepes pH7.4.
    [231] Test compounds were made into 10 mM or 30 mM stocks in DMSO and subsequently diluted with free distilled water to a concentration 10 times greater than the final assay concentration. 10 μl of diluted compound was transferred to wells in a washed assay plate. The control well of “no compound” contains 10 μl of free distilled water instead of the compound.
    [232] 40 μl of 25 mM manganese chloride containing 6.25 μM adenosine-5′-triphosphate (ATP) was added to all test wells. To initiate the reaction, 50 μl of freshly diluted enzyme was added to each well and the plate was incubated at 23 ° C. for 90 minutes. The reaction was then stopped by adding 100 μl of PBS containing 20 mM EDTA. The liquid was discarded and the wells washed twice with PBST.
    [233] 100 μl of mouse HRP-bound anti-phosphotyrosine antibody (Santa Cruz, Product SC 7020-HRP) diluted in PBST containing 0.5% w / v bovine serum albumin (BSA) at a ratio of 1500: 1 each After addition to the wells, the plate was incubated for 1 hour at room temperature, then the liquid was discarded and it was washed twice with 200 μl of PBST. 50 mg ABTS in one of 50 ml of freshly produced 50 mM phosphate-citrate buffer pH 5.0 + 0.03% sodium perborate (made of one sodium perborate and one phosphate citrate buffer (PCBS) capsule (Sigma P4922) per 100 ml distilled water) 100 μl of freshly generated 2,2′-azino-bis (3-ethylbenzthiazoline-6-sulfonic acid) (ABTS) solution was added to each well using a tablet (Boehringer 1204 521). Plates at room temperature Plates were incubated for 20 to 60 minutes at room temperature until the absorbance value of "no compound" control wells was near 1.0 as measured at 405 nm using a read spectrometer.
    [234] Dose software was used to generate dose response curves from absorbance readings. Compounds were graded for potency using inhibitory concentration 50 (IC 50 ) as defined by the origin software assay.
    [235] Although the pharmacological activity of the compound of formula (I) varies depending on the structure, in general, the activity by the compound of formula (I) in the above assays can be expressed in IC 50 concentrations or in doses of 250 μM to 1 nM.
    [236] When tested in the above in vitro assay, the CDK4 inhibitory activity of Example 13 was determined to be IC 50 = 0.896 μM. When tested in the in vitro assay, the FAK inhibitory activity of Example 14 was determined to be IC 50 = 0.366 μM.
    [237] In vivo activity of the compounds of the present invention can be assessed by standard techniques, for example by measuring inhibition of cell proliferation and assessing cytotoxicity. For example, details may be obtained from the following literature.
    [238] a) Attenution of the Expression of the Focal Adhesion Kinase induces Apoptosis in Tumor Cells. Xu Lh et al. Cell Growth & Differentiation (1996) 7, p413-418;
    [239] b) The COOH-Terminal Domain of the Focal Adhesion Kinase Induces Loss of Adhesion and Cell Death in Human Tumor Cells. Xu Lh et al. Cell Growth & Differentiation (1998) 9, p999-1005;
    [240] c) Inhibition of pp125-FAK in Cultured Fibroblasts Results in Apoptosis. Hungerford JE et al., The Journal of Cell Biology (1996) 135, p1383-1390;
    [241] d) Inhibition of Focal Adhesion Kinase (FAK) Signaling in Focal Adhesions Decreases Cell Motility and Proliferation. Gilmore AP and Romer LH Molecular Biology of the Cell (1996) 7, p1209-1224].
    [242] Inhibition of cell proliferation can be measured by staining cells with Sulforhodamine B (SRB), a fluorescent dye that stains proteins, thereby obtaining an estimated amount of protein (ie, cells) in the wells. Boyd, MR (1989) Status of the NCI preclinical antitumour drug discovery screen. Prin. Prac Oncol 10: 1-12]. Thus, the details for measuring inhibition of cell proliferation are as follows.
    [243] Cells were plated in a suitable medium at a volume of 100 μl in 96 well plates, and the medium was Dulbecco's Modified Eagle Medium for MCF-7, SK-UT-1B and SK-UT-1. After allowing the cells to attach overnight, the inhibitor compound was added at various concentrations at a maximum concentration of 1% DMSO (v / v). Control plates were analyzed to obtain values for the cells prior to administration. Cells were incubated at 37 ° C. for 3 days (5% CO 2 ).
    [244] At the end of 3 days, TCA was added to the plate at a final concentration of 16% (v / v). The plate was incubated at 4 ° C. for 1 hour, the supernatant was removed and the plate washed with tap water. After drying, 100 μl of SRB dye (0.4% SRB in 1% acetic acid) was added at 37 ° C. for 30 minutes. Excess SRB was removed and the plate washed in 1% acetic acid. SRB bound to protein was solubilized at 10 mM Tris pH 7.5 and stirred for 30 minutes at room temperature. OD was read at 540 nm and the concentration of inhibitor causing 50% inhibition of proliferation was determined by a half-log plot of inhibitor concentration against absorbance. At the start of the experiment, the concentration of the compound whose absorbance decreased below the value obtained when the cells were plated was regarded as the toxicity value.
    [245] Typical IC 50 values for compounds of the invention were 1 mM to 1 nM when the compounds of the invention were tested by SRB assay.
    [246] According to a further embodiment of the invention there is provided a pharmaceutical composition comprising a pyrimidine derivative of formula (I), a pharmaceutically acceptable salt thereof or an in vivo hydrolysable ester thereof as described above, together with a pharmaceutically acceptable diluent or carrier. A composition is provided.
    [247] Such compositions are, for example, formulations for oral administration as tablets or capsules, formulations for parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion) as sterile solutions, suspensions or emulsions, formulations for topical administration as ointments or creams, Or rectal dosage forms such as suppositories.
    [248] Generally the composition can be prepared by conventional methods using conventional excipients.
    [249] Pyrimidine is generally administered to warm-blooded animals in unit dosages ranging from 5 to 5,000 mg / m 2 of warm-blooded animal, ie about 0.1 to 100 mg / kg, which provides a therapeutically effective amount. Unit dosages such as tablets or capsules contain, for example, 1-250 mg of the active ingredient. Preference is given to using a daily dosage of 1-50 mg / kg. However, the daily dosage may vary depending on the host being treated, the route of administration and the severity of the disease to be treated. Thus, the optimal dosage can be determined by the attending physician treating any particular patient.
    [250] According to a further embodiment of the invention, a pyrimidine derivative of formula (I), a pharmaceutically acceptable salt thereof or an in vivo hydrolysable ester thereof as described above for use in the prophylactic or therapeutic treatment of a warm blooded animal such as human to provide.
    [251] Applicants are effective cell cycle inhibitors (anti-cell proliferators) wherein the pyrimidine derivatives, pharmaceutically acceptable salts thereof, or in vivo hydrolyzable esters thereof as defined herein are effective, and their properties (but not limited to theory) It was found to be due to its CDK inhibition. In addition, these compounds are effective inhibitors of FAK. Accordingly, the compounds of the present invention are expected to be effective in treating diseases or medical conditions mediated alone or in part by CDK and / or FAK enzymes, ie such compounds are useful in warm-blooded animals in need of such treatment. It can be used to produce CDK and / or FAK inhibitory efficacy. Thus, the compounds of the present invention provide a method for treating the proliferation and / or migration of malignant cells characterized by the inhibition of CDK and / or FAK enzymes, ie such compounds are inhibited by the inhibition of CDK and / or FAK. It can be used to produce anti-proliferative / migrating efficacy either alone or in part. Such compounds may also be useful as FAK inhibitors by inducing cell-killing (apoptosis). Since CDK and / or FAK are involved in cancer of the common human, such as leukemia, breast cancer, lung cancer, colon cancer, rectal cancer, gastric cancer, prostate cancer, bladder cancer, pancreatic cancer and ovarian cancer, the pyrimidine derivatives of the present invention have a wide range of anticancer properties. It is expected to have. Thus, the pyrimidine derivatives of the present invention are expected to have anticancer activity against these cancers. In addition, the pyrimidine derivatives of the present invention have activity against various leukemias, lymphoid malignant tumors and solid cancers such as carcinomas and sarcomas in tissues such as liver, kidney, prostate and pancreas. In particular, the compounds of the present invention are expected to advantageously delay the proliferation of primary and recurrent solid cancers such as, for example, colon, breast, prostate, lung and skin. In particular, such compounds of the present invention, pharmaceutically acceptable salts thereof, or in vivo hydrolyzable esters thereof, are highly resistant to primary and recurrent solid cancers associated with CDK and / or FAK, in particular CDK and / or FAK for their proliferation and metastasis. It is expected to inhibit proliferation in tumors in dependent cancers such as colon, breast, prostate, lung, genital and skin.
    [252] The pyrimidine derivatives of the present invention can be used for leukemia, fibroproliferative and differentiating diseases, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, hemangioma, acute and chronic nephropathy, atherosclerosis, atherosclerosis, arterial restenosis, autoimmune diseases, acute and chronic infections, It is expected to have activity against other cell proliferative / migrating diseases in bone diseases and in a wide variety of other disease states, including those associated with ocular diseases following retinal canal proliferation.
    [253] According to this embodiment of the invention, there is provided a pyrimidine derivative of formula (I), a pharmaceutically acceptable salt thereof or an in vivo hydrolysable ester thereof as described above for use as a medicament; As described above in the manufacture of a medicament for use in the production of anticancer, cell cycle inhibitory (anti-cell proliferative) effects and / or FAK inhibitory (inducing anti-cell migration and / or apoptosis) effects in warm blooded animals, including humans. Pyrimidine derivatives of formula (I), pharmaceutically acceptable salts thereof or in vivo hydrolysable esters thereof are provided as such. In particular, cell cycle inhibitory effects are produced in the S or G1-S phase by inhibition of CDK2, CDK4 and / or CDK6, in particular CDK4 and CDK6.
    [254] According to a further embodiment of the invention, anti-cancer, cell cycle inhibition (anti-cells) in warm-blooded animals, including those in need of treatment, comprising administering to the warm-blooded animals an effective amount of pyrimidine derivative as defined in the paragraphs above Proliferative) and / or FAK inhibitory (anti-cell migration and / or apoptosis inducing) effects are provided. In particular, such inhibitory efficacy is produced in the S or G1-S phase by inhibition of CDK2, CDK4 and / or CDK6, in particular CDK4 and CDK6.
    [255] As mentioned above, the size of dosage required for the treatment or prophylactic treatment of a particular cell proliferative disease will vary depending on the host being treated, the route of administration, and the severity of the disease to be treated. The unit dose is 1 to 100 mg / kg, preferably 1 to 50 mg / kg.
    [256] The aforementioned CDK and / or FAK inhibitory activity may be applied as a monotherapy or may comprise one or more other substances and / or treatments, in addition to the compounds of the present invention. Such concurrent treatment may be achieved by simultaneous, sequential or separate administration of the individual components of the treatment. In the medical oncology art, it is commonly practiced to combine various forms of treatment to treat each patient suffering from cancer. In medical oncology, in addition to the cell cycle suppression therapy described above, other component (s) of such a combination therapy may be surgery, radiation therapy or chemotherapy. Such chemotherapy may be three major categories of therapeutic agents.
    [257] (i) other cell cycle inhibitors acted by the same or different mechanisms as described above;
    [258] (ii) cytostatic agents such as antiestrogens (such as tamoxifen, toremifene, raloxifene, droroxifene, iodoxifene), progestogens (such as megestrol acetate), aromatase inhibitors (such as anastro) Sol, retrazole, borazol, exemestane), antiprogestogen, antiandrogen (e.g. flutamide, nirutamide, bicartamide, cyproterone acetate), LHRH agonists and antagonists ( For example, goserelin acetate, leuprolide, inhibitors of testosterone 5α-dehydroreductase (eg finasteride), anti-leaching agents (eg metalloproteinase inhibitors such as marimastat and urokinase plasminogen activity Inhibitors of body receptor function) and inhibitors of growth factor function (eg, growth factors include, for example, platelet derived growth factors, hepatocyte growth factors, and such inhibitors may be growth factors). Body, including growth factor receptor antibodies, tyrosine kinase inhibitors and serine / threonine kinase inhibitors);
    [259] (iii) anti-proliferative / anti-tumor drugs and combinations thereof, such as anti-metabolites (eg, antifolates such as methotrexate, fluoropyrimidine, such as 5-fluorouracil, furin and Adenosine analogs, cytosine arabinoside); Anti-tumor antibiotics (eg, anthracyclines such as doxorubicin, daunomycin, epirubicin and idarubicin, mitomycin-C, dactinomycin, mitramycin; platinum derivatives (eg cisplatin, carboplatin); alkylating agents ( For example nitrogen mustard, melphalan, chlorambucil, busulfan, cyclophosphamide, ifosfamide, nitrosourea, thiotepa); antimitotic agents (eg vinca alkaloids such as vincristine and taxoids, Taxol, taxotere); topoisomerase inhibitors (e.g. epipodophyllotoxins such as etoposide and teniposide, amsacrine, topotecan). According to the invention, as described above for the parallel treatment of cancer Pharmaceutical agents comprising such additional anti-tumor substances and pyrimidine derivatives of formula I, pharmaceutically acceptable salts thereof or in vivo hydrolysable esters thereof, as described above This product may be usefully administered, for example, when using a combination therapy as described above.
    [260] In addition to their use in medicine, the compounds of formula (I) and their pharmaceutically acceptable salts have shown the efficacy of inhibitors of cell cycle activity in laboratory animals such as cats, dogs, rabbits, monkeys, rats, and mice as part of the study of novel therapeutic agents. It is useful as a pharmacological tool in the development and standardization of in vivo and in vitro test systems for analysis.
    [261] In the above other pharmaceutical compositions, preparations and methods, uses and features of the manufacture of a medicament, alternative embodiments and preferred examples of the compounds of the present invention may also be applied.
    [262] The present invention is now intended to be illustrated by the following non-limiting examples, where techniques similar to those described in the standard techniques and examples known to those skilled in the art are used where necessary, and unless otherwise indicated, Conduct.
    [263] (i) Evaporation is carried out by rotary evaporation under vacuum and the work-up procedure is carried out after the removal of residual solids such as desiccants by filtration.
    [264] (ii) The operation is carried out at room temperature, in particular 18 ° C. to 25 ° C. and in the air unless otherwise noted, or otherwise by a person skilled in the art under the atmosphere of an inert gas such as argon.
    [265] (iii) Column chromatography (by flash process) and medium pressure liquid chromatography (MPLC) were obtained from Merck Kieselgel silica (Art. 9385) or Merck Lichroprep RP-18 (Art. 9303) obtained from E. Merck, Darmstadt, Germany. ) Performed on reversed phase silica; Bond elution chromatography is performed using a Varian Mega Bond Elut cartridge (10 g, order code 1225-6034) obtained from Varian Sample Preparation Products, California, USA.
    [266] (iv) Yields are shown for example only, and do not mean the maximum obtainable degree.
    [267] (v) The structure of the final product of formula (I) is generally identified by nuclear (generally proton) magnetic resonance (NMR) and mass spectral techniques; Proton magnetic resonance chemical shift values are measured in δ units (ppm downfield from tetramethysilane) in deuterium DMSO-d 6 (unless otherwise noted), Varian Gemini 2000 spectrometer operating at field strength of 300 MHz, 250 MHz Measured using a Bruker AM250 spectrometer operating at field strength of; Peak multiplicity is expressed as s singlet, d doublet, dd doublet, t triplet, tt triplet, q quartet, tq triplet, m multiplet, br wide, MS) was performed by electrospray on the VG platform.
    [268] (vi) Analytical high performance liquid chromatography (HPLC) was performed for 10 minutes on a Hypersil 10 cm base inactivated reversed phase column at a flow rate of 2 ml / min using a 5-95% acetonitrile / water gradient, with a wavelength of 254 nm. And the data are reported in retention time (RT) in minutes.
    [269] (vii) In general, the properties of the intermediates were not fully specified and purity was assessed by thin layer chromatography (TLC), HPLC, infrared (IR), MS or NMR analysis.
    [270] (viii) When drying the solution, magnesium sulfate is used as a desiccant.
    [271] (ix) Hereinafter, the following abbreviations can be used.
    [272] DCM: dichloromethane
    [273] DMF: N, N-dimethylformamide
    [274] DMSO: Dimethyl sulfoxide
    [275] NMP: N-methylpyrrolidin-2-one
    [276] THF: tetrahydrofuran
    [277] Example 1
    [278] 5-bromo-2- {4- [2-hydroxy-3- (N, N-dimethylamino) propoxy] anilino} -4- (4-methoxyphenoxy) pyrimidine
    [279] 5-bromo-2-chloro-4- (4-methoxyphenoxy) pyrimidine (method 1, 200 mg, 0.63 mmol) and 4- [2-hydroxy-3- (N in NMP (4 mL) A solution of, N-dimethylamino) propoxy] aniline hydrochloride (method 8, 156 mg, 0.56 mmol) was heated at 100 ° C. for 6 hours. Silica (1 g) was added and the volatiles were removed by evaporation. The residue was purified by column chromatography eluting with a 0-10% 2.0 M methanolic ammonia solution in DCM to afford the product as a colorless solid. (173 mg, 56%). MS (MH + ): 489, 491; HPLC (RT): 4.68.
    [280] Examples 2-4
    [281] The compounds below are 4- [2-hydroxy-3- (N, N-dimethylamino) propoxy] aniline hydrochloride (method 8) and appropriate 4,5-disubstituted 2-chloropyrimidines (method 2-4) Was produced in a similar manner to that described in Example 1.
    [282]
    [283] Example 5
    [284] 5-bromo-2- {4- [3- (isobutylamino) -2-hydroxypropoxy] anilino} -4- (4-methoxyphenoxy) pyrimidine
    [285] Ethereal hydrogen chloride (2.0 M; 0.57 mL, 1.14 mmol) was added with 5-bromo-2-chloro-4- (4-methoxyphenoxy) pyrimidine in NMP (4 mL) (Method 1, 200 mg, 0.63 mmol). ) And 4- [3- (isobutylamino) -2-hydroxypropoxy] aniline (method 10, 136 mg, 0.57 mmol). The solution was heated at 100 ° C. for 6 hours and silica (1 g) was added. The volatiles were removed by evaporation and the residue was purified by column chromatography eluting with a 0-100% 2.0 M methanolic ammonia solution in DCM to afford the product as a colorless solid. (76 mg, 26%). MS (MH + ): 517, 519; HPLC (RT): 6.48.
    [286] Examples 6-10
    [287] The following compound was prepared in a similar manner to that described in Example 5 using 5-bromo-2-chloro-4- (4-methoxyphenoxy) pyrimidine (method 4) and the appropriate substituted aniline (methods 11-15). It was prepared by.
    [288]
    [289] Examples 11-13
    [290] The following compounds are described as 2-chloro-5-fluoro-4- (4-methoxyphenoxy) pyrimidine (method 4) and suitable substituted anilines (methods 11, 16 or described in Pharmazie , 1980, 35, 278). Obtained as is by a method similar to that described in Example 5.
    [291]
    [292] Example 14
    [293] 5-bromo-2- {4- [2-hydroxy-3- (N, N-dimethylamino) propoxy] anilino} -4- (phenylthio) pyrimidine
    [294] A method similar to that described in Example 1 is used, but 5-bromo-2-chloro-4- (phenylthio) pyrimidine (method 6) and 4- [2-hydroxy-3- (N, The product was obtained using N-dimethylamino) propoxy] aniline hydrochloride (method 8).
    [295] NMR: 2.2 (s, 6H), 2.3 (m, 2H), 3.7 (m, 1H), 3.9 (m, 2H), 4.7 (d, 1H), 6.5 (d, 2H), 7.0 (d, 2H) , 7.6 (5H), 8.3 (s, 1 H), 9.5 (s, 1 H);
    [296] MS (MH + ): 475, 477.
    [297] Examples 15-17
    [298] The following compounds are examples using suitable 4-substituted 5-bromo-2-chloropyrimidines (method 6-7) and appropriately substituted anilines (obtained as described in the literature Pharmazie , 1980, 35, 278). Produced by a method similar to that described in 5.
    [299]
    [300] Preparation of Starting Material
    [301] The starting materials of this example are either commercially available or are readily prepared by standard methods from known materials. For example, the following reactions illustrate the starting materials used in the reactions above, but are not intended to limit the invention.
    [302] Method 1
    [303] 5-bromo-2-chloro-4- (4-methoxyphenoxy) pyrimidine
    [304] A mixture of 5-bromo-2,4-dichloropyrimidine (5.0 g, 22.0 mmol), 4-methoxyphenol (2.72 g, 22.0 mmol) and potassium carbonate (6.07 g, 44.0 mmol) in DMF (20 mL) Was stirred for 24 hours. The mixture was added to water (100 mL) and the separated solid collected by filtration, washed with water (50 mL) and dried under high pressure to give the product. (6.6 g, 96%).
    [305] NMR: 3.8 (s, 3H), 7.0 (d, 2H), 7.2 (d, 2H), 8.8 (s, 1H).
    [306] Method 2-4
    [307] The following intermediates were produced in a similar manner to that described in Method 1 using the appropriate phenol and the appropriate 2,4-dichloro-5-halopyrimidine (commercially obtained or obtained as described in Method 5).
    [308]
    [309] Method 5
    [310] 2,4,5-trichloropyrimidine
    [311] 5-chlorouracil (10.0 g, 68.5 mmol) was dissolved in phosphorus oxychloride (60 mL) and phosphorus pentachloride (16.0 g, 77.0 mmol) was added. The mixture was heated to reflux for 16 h, left to cool and then poured slowly into water (200 mL) with vigorous stirring. The mixture was stirred for 1.5 h, then ethyl acetate (250 mL) was added. The organic layer was separated and the aqueous layer was extracted with an additional fraction of ethyl acetate (250 mL). The extracts were combined and washed with saturated sodium bicarbonate (200 mL) and saturated sodium chloride solution (200 mL) and then dried. The volatiles were removed by evaporation and the residue was purified by column chromatography eluting with DCM to give the product as a yellow liquid. (6.37 g, 51%).
    [312] NMR (CDCl 3 ): 8.62 (s, 1 H); MS (MH + ): 182, 184, 186.
    [313] Method 6
    [314] 5-bromo-2-chloro-4- (phenylthio) pyrimidine
    [315] A method similar to that described in Method 1 was used but the product was obtained using 5-bromo-2,4-dichloropyrimidine and thiophenol as starting materials.
    [316] NMR: 7.6 (m, 5 H), 8.8 (s, 1 H).
    [317] Method 7
    [318] 5-bromo-2-chloro-4- (thiazolyl-2-ylthio) pyrimidine
    [319] 5-bromo-2,4-dichloropyrimidine (228 mg, 1.0 mmol), 2-mercaptothiazole (117 mg, 1.0 mmol) and N, N-diisopropylethylamine in n-butanol (10 mL) (0.174 mL, 1.0 mmol) was heated at lOOOC for 2 hours. The volatiles were removed by evaporation and the residue was crystallized from methanol to give a colorless needle-like product. (130 mg, 42%).
    [320] NMR (CDCl 3 ): 7.65 (d, 1 H), 7.99 (d, 1 H), 8.44 (s, 1 H); MS (MH <+> ): 307.8, 309.8.
    [321] Method 8
    [322] 4- [2-hydroxy-3- (N, N-dimethylamino) propoxy] aniline hydrochloride
    [323] A solution of 4- [2-hydroxy-3- (N, N-dimethylamino) propoxy] nitrobenzene (method 9, 3.75 g) in ethanol (40 mL) overnight over 10% palladium on carbon (0.4 g) Contact hydrogenation. The catalyst was removed by filtration through diatomaceous earth and the filtrate was concentrated. The residue was dissolved in diethyl ether containing a small amount of isopropanol and ethereal hydrogen chloride (1 M, 16 mL). Diethyl ether was removed by evaporation and the solid residue suspended in isopropanol. The mixture was heated in the steam bath for several minutes and then cooled. Insoluble solids were collected by filtration, washed with isopropanol and ether and dried to afford the product. (3.04 g, 72.4%).
    [324] NMR: 2.80 (s, 6H), 3.15 (m, 2H), 3.88 (m, 2H), 4.25 (m, 1H), 5.93 (br s, 1H), 6.88 (m, 4H); MS (MH + ): 211;
    [325] Elemental Analysis for C 11 H 18 N 2 O 2 · 1.6 HCl
    [326] Theoretical: C; 49.2, H; 7.4, N; 10.4, Cl; 21.7%;
    [327] Found: C; 49.2, H; 7.2, N; 10.1; Cl; 19.1%.
    [328] Method 9
    [329] 4- [2-hydroxy-3- (N, N-dimethylamino) propoxy] nitrobenzene
    [330] 4- (2,3-epoxypropoxy) nitrobenzene (obtained as described in Synthetic Communications , 1994, 24, 833; 4.3 g) was dissolved in methanol (30 mL) and DMF (10 mL). A solution of dimethylamine in methanol (2 M, 17 mL) was added and the mixture was stirred overnight. The volatiles were removed by evaporation and the residue was partitioned between saturated sodium bicarbonate (100 mL) and ethyl acetate (100 mL). The organic layer was separated and washed with saturated sodium chloride (2 x 100 mL) and it was dried. It was concentrated to give an oily product which crystallized slowly under high vacuum. (4.79 g, 89.9%).
    [331] NMR (CDCl 3 ): 2.33 (s, 6H), 2.98 (m, 1H), 2.54 (m, 1H), 4.00 (m, 3H), 7.00 (d, 2H), 8.20 (d, 2H); MS (MH + ): 241.
    [332] Method 10
    [333] 4- [3- (isobutylamino) -2-hydroxypropoxy] aniline
    [334] Isobutylamine (5.1 mL, 51.2 mmol) was obtained as described in 4- (2,3-epoxypropoxy) nitrobenzene in THF (1 mL), Synthetic Communications , 1994, 24, 833; 1.0 g , 5.12 mmol). The solution was heated at reflux for 3 hours and then the volatiles were removed by evaporation. The residue was dissolved in methanol (5 mL) and 100% palladium on carbon (0.50 g) and ammonium formate (3.23 g, 51.2 mmol) were added. The mixture was heated at reflux for 3 h and then filtered over diatomaceous earth. The filtrate was concentrated under reduced pressure to give the product as a dark brown oil (1.22 g, 100%), which was used without further purification.
    [335] MS (MH + ): 238.9.
    [336] Method 11-16
    [337] The following intermediates are prepared in a similar manner to that described in Method 10 using 4- (2,3-epoxypropoxy) nitrobenzene (prepared as described in Synthetic Communications , 1994, 24, 833) and appropriate amines. To produce.
    [338]
    [339] WayR 1 R 2 MS (MH + ) 11CyclopentylH250.9 12Pyrrolidino236.9 13 1 MeH196.9 14 1 HH182.9 15 1 EtH210.9 164-acetylpiperazin-1-yl296.91 prepared from the corresponding N-benzyl substituted precursors. For complete debenzylation, the reaction requires the addition of 10% palladium on carbon (0.50 g) and ammonium formate (3.23 g)
    [340] Example 18
    [341] The following illustrates a representative pharmaceutical dosage form containing a compound of formula (I), a pharmaceutically acceptable salt thereof, or an in vivo hydrolyzable ester thereof (hereinafter referred to as compound X) for therapeutic or prophylactic use in humans. .
    [342] (a) Tablet IMg / tablet Compound X100 Lactose Ph. Eur182.75 Croscarmellose sodium12.0 Corn starch paste (5% w / v paste)2.25 Magnesium stearate3.0
    [343] (b) tablets IIMg / tablet Compound X50 Lactose Ph.Eur.223.75 Croscarmellose sodium6.0 Corn starch15.0 Polyvinylpyrrolidone (5% w / v paste)2.25 Magnesium stearate3.0
    [344] (c) tablets IIIMg / tablet Compound X1.0 Lactose Ph.Eur93.25 Croscarmellose sodium4.0 Corn starch paste (5% w / v paste)0.75 Magnesium stearate1.0
    [345] (d) capsulesMg / capsules Compound X10 Lactose Ph.Eur488.5 Magnesium stearate1.5
    [346] (e) Injection I(50 mg / ml) Compound X5.0% w / v 1 M sodium hydroxide solution15% v / v 0.1 M hydrochloric acid(pH adjusted to 7.6) Polyethylene Glycol 4004.5% w / v Water for injectionUp to 100%
    [347] (f) water for injection II10 mg / ml Compound X1.0% w / v Sodium Phosphate BP3.6% w / v 0.1 M Sodium Hydroxide Solution15.0% v / v Water for injectionUp to 10O%
    [348] (g) Injection III(1 mg / ml, buffered at pH 6) Compound X0.1% w / v Sodium Phosphate BP2.26% w / v Citric acid0.38% w / v Polyethylene Glycol 4003.5% w / v Water for injectionUp to 100%
    [349] week
    [350] Such formulations can be obtained by conventional procedures well known in the pharmaceutical art. Tablets (a)-(c) may be enteric coated by conventional means, for example to provide a coating of cellulose acetate phthalate.
    权利要求:
    Claims (16)
    [1" claim-type="Currently amended] A pyrimidine derivative of formula (I), a pharmaceutically acceptable salt thereof, or an in vivo hydrolyzable ester thereof.
    Formula I

    In the formula, Q 1 and Q 2 are independently aryl or is selected from a heteroaryl bonded carbon, Q 1 and Q 2 one or Q 1 and Q 2 are all to one on a ring carbon by a substituent of formula (Ia) Is substituted,
    Formula Ia

    Provided that when present in Q 1 , the substituent of Formula Ia is not neighboring a —NH— bond;
    Wherein X is -CH 2- , -O-, -NH-, -NR a -or -S- wherein R a is 1 selected from halo, amino, cyano, C 1 -C 4 alkoxy or hydroxy C 1 -C 4 alkyl optionally substituted by 2 substituents;
    Y 1 is as defined for H, C 1 -C 4 alkyl or Z;
    Y 2 is H or C 1 -C 4 alkyl;
    Z is R b O-, R c R d N-, R e S-, R f R g NNR h- , nitrogen-bonded heteroaryl or nitrogen-bonded heterocycle, wherein the heterocycle is C 1 -C 4 Optionally substituted on the ring carbon or ring nitrogen by alkyl or C 1 -C 4 alkanoyl, wherein R b , R c , R d , R e , R f , R g and R h are independently hydrogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 3 -C 8 cycloalkyl, wherein C 1 -C 4 alkyl and C 2 -C 4 alkenyl are optionally substituted by one or more phenyl ;
    n is 1, 2 or 3;
    m is 1, 2 or 3;
    G is -O- or -S-;
    R 1 is hydrogen, halo, hydroxy, nitro, amino, N- (C 1 -C 3 alkyl) amino, N, N-di- (C 1 -C 3 alkyl) amino, cyano, trifluoromethyl, Trichloromethyl, C 1 -C 3 alkyl [halo, cyano, amino, N- (C 1 -C 3 alkyl) amino, N, N-di- (C 1 -C 3 alkyl) amino, hydroxy and tri Optionally substituted with 1 or 2 substituents independently selected from fluoromethyl], C 3 -C 5 alkenyl [optionally substituted with up to 3 halo substituents or 1 trifluoromethyl substituent], C 3- C 5 alkynyl, C 1 -C 3 alkoxy, mercapto, C 1 -C 3 alkylsulfanyl, carboxy and C 1 -C 3 alkoxycarbonyl;
    Q 1 is halo, mercapto, nitro, formyl, formamido, carboxy, cyano, amino, ureido, carbamoyl, sulfamoyl, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, wherein the C 1 -C 4 alkyl, C 2 -C 4 alkenyl and C 2 -C 4 alkynyl are optionally substituted with one or more groups selected from R i , C 1 -C 4 alkanoyl, C 1 -C 4 alkoxycarbonyl, heterocyclic group, C 1 -C 4 alkylS (O) a , wherein a is 0 to 2 [optionally substituted with hydroxy], N '-( C 1 -C 4 alkyl) ureido, N ', N'-di- (C 1 -C 4 alkyl) ureido, N- (C 1 -C 4 alkyl) -N- (C 1 -C 4 alkyl) Ureido, N ', N'-di- (C 1 -C 4 alkyl) -N- (C 1 -C 4 alkyl) ureido, NC 1 -C 4 alkylamino, N, N-di- (C 1 -C 4 alkyl) amino, N- (C 1 -C 4 alkyl) sulfamoyl, N, N-di- (C 1 -C 4 alkyl) sulfamoyl, NC 1 -C 4 alkylcarbamoyl, N, N 1 to 4 substitutions independently selected from -di- (Ci-C 4 alkyl) carbamoyl and C 1 -C 4 alkanoylamino Sieve optionally substituted on the ring carbon;
    Further, independently or in addition to the above substituents, Q 1 may be optionally substituted with 1 or 2 substituents independently selected from aryl, C 3 -C 8 cycloalkyl and a heterocyclic group, wherein the aryl, C 3 − A C 8 cycloalkyl or heterocyclic group may be optionally substituted on the ring carbon with one or more groups selected from R j ; Wherein if said heterocyclic group comprises an —NH— moiety that nitrogen may be optionally substituted by a group selected from R k ;
    Q 2 is halo, hydroxy, mercapto, nitro, formyl, formamido, carboxy, cyano, amino, ureido, carbamoyl, sulfamoyl, C 1 -C 4 alkyl, C 2 -C 4 al Kenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkoxy [wherein the C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl and C 1 -C 4 alkoxy Optionally substituted with one or more groups selected from R 1 ], C 1 -C 4 alkanoyl, C 1 -C 4 alkoxycarbonyl, a heterocyclic group, C 1 -C 4 alkylS (O) a , wherein a is 0 2)) [optionally substituted with hydroxy], N '-(C 1 -C 4 alkyl) ureido, N', N'-di- (C 1 -C 4 alkyl) ureido, N '-( C 1 -C 4 alkyl) -N- (C 1 -C 4 alkyl) ureido, N ', N'-di- (C 1 -C 4 alkyl) -N- (C 1 -C 4 alkyl) ureido , NC 1 -C 4 alkylamino, N, N-di- (C 1 -C 4 alkyl) amino, N- (C 1 -C 4 alkyl) sulfamoyl, N, N-di- (C 1 -C 4 Alkyl) sulfamoyl, NC 1 -C 4 alkylcarbamoyl, N, N-di- (C 1 -C 4 alkyl) carbamoyl, C 2 -C 4 alkenyloxy, C 2 -C Optionally substituted on the ring carbon with 4 alkynyloxy, C 1 -C 4 alkanoylamino and 1-4 substituents independently selected from the groups of formula (Ia) or formula (Ia ′) above;
    In addition, independently of or in addition to the above substituents, Q 2 may be optionally substituted with 1 or 2 substituents independently selected from aryl, C 3 -C 8 cycloalkyl or a heterocyclic group, wherein said aryl, C 3 − C 8 cycloalkyl or heterocyclic group may be optionally substituted on the ring carbon with one or more groups selected from R m , wherein if the heterocyclic group comprises a —NH— moiety, nitrogen may be optionally substituted with a group selected from R n Can;
    R i and R l are hydroxy, halo, amino, cyano, formyl, formamido, carboxy, nitro, mercapto, carbamoyl, sulfamoyl, NC 1 -C 4 alkylamino, N, N-di -(C 1 -C 4 alkyl) amino, C 1 -C 4 alkanoyl, C 1 -C 4 alkanoyloxy, C 1 -C 4 alkoxy, C 1 -C 4 alkoxycarbonyl, NC 1 -C 4 alkyl carbamoyl, N, N- di - (C 1 -C 4 alkyl) carbamoyl, C 1 -C 4 alkanoylamino, C 1 -C 4 alkyl, S (O) a (wherein, a is 0 to 2 ), C 1 -C 4 alkylsulfonylamino, N- (C 1 -C 4 alkyl) sulfamoyl, N- (C 1 -C 4 alkyl) 2 sulfamoyl, N- (C 1 -C 4 alkyl) Independently selected from carbamoyl, N- (C 1 -C 4 alkyl) 2 carbamoyl, phenyl, phenylthio, phenoxy, C 3 -C 8 cycloalkyl, and a heterocyclic group; Wherein said phenyl, phenylthio, phenoxy, C 3 -C 8 cycloalkyl or heterocyclic group may be optionally substituted on the ring carbon with one or more groups selected from R o ; When the heterocyclic group comprises an —NH— moiety, nitrogen may be optionally substituted by a group selected from R p ;
    R j , R m and R o are hydroxy, halo, amino, cyano, formyl, formamido, carboxy, nitro, mercapto, carbamoyl, sulfamoyl, C 1 -C 4 alkyl [which is halo, Optionally substituted with one or more groups selected from cyano, amino, NC 1 -C 4 alkylamino, N, N-di- (C 1 -C 4 alkyl) amino or hydroxy], C 2 -C 4 alkenyl [ Optionally substituted with one or more groups selected from halo], C 2 -C 4 alkynyl, NC 1 -C 4 alkylamino, N, N-di- (C 1 -C 4 alkyl) amino, C 1 -C 4 alka Noyl, C 1 -C 4 alkanoyloxy, C 1 -C 4 alkoxy [optionally substituted with one or more groups selected from halo], C 1 -C 4 alkoxycarbonyl, NC 1 -C 4 alkylcarbamoyl, N , N- di - (C 1 -C 4 alkyl) carbamoyl, C 1 -C 4 alkanoylamino, C 1 -C 4 alkyl, S (0) a (wherein, a is 0 to 2 Im), C 1 -C 4 alkylsulfonylamino, N- (C 1 -C 4 alkyl) sulfamoyl, N- (C 1 -C 4 alkyl) 2 sulfamoyl, phenyl, C 3 -C 8 cycloal Independently selected from a kill and a heterocyclic group; And
    R k , R n and R p are C 1 -C 4 alkyl, C 1 -C 4 alkanoyl, C 1 -C 4 alkylsulfonyl, C 1 -C 4 alkoxycarbonyl, carbamoyl, N- (C Independently selected from 1- C 4 alkyl) carbamoyl, N, N- (C 1 -C 4 alkyl) carbamoyl, benzyl, benzyloxycarbonyl, benzoyl and phenylsulfonyl.
    [2" claim-type="Currently amended] The pyrimidine derivative of formula I, a pharmaceutically acceptable salt thereof, or an in vivo hydrolyzable ester thereof according to claim 1, wherein Q 1 is phenyl.
    [3" claim-type="Currently amended] The pyrimidine derivative of formula (I), a pharmaceutically acceptable salt thereof, or an in vivo hydrolyzable ester thereof, according to claim 1 or 2, wherein Q 2 is phenyl or thiazolyl.
    [4" claim-type="Currently amended] The substituent of any one of claims 1-3, wherein the substituent of formula la is 3-amino-2-hydroxypropoxy, 3-methylamino-2-hydroxypropoxy, 3-dimethylamino-2- Hydroxypropoxy, 3-ethylamino-2-hydroxypropoxy, 3-isopropylamino-2-hydroxypropoxy, 3-isobutylamino-2-hydroxypropoxy, 3-t-butylamino- 2-hydroxypropoxy, 3- (4-acetylpiperazin-1-yl) -2-hydroxypropoxy, 3-cyclopentylamino-2-hydroxypropoxy or 3-pyrrolidin-1-yl Pyrimidine derivatives of formula (I), pharmaceutically acceptable salts thereof, or in vivo hydrolyzable esters thereof, wherein the compound is 2-hydroxypropoxy or thiazolyl.
    [5" claim-type="Currently amended] 5. The pyrimidine derivative of formula (I), a pharmaceutically acceptable salt thereof or in vivo hydrolyzable thereof according to claim 1, wherein the substituent of formula (Ia) is on ring Q 1 or thiazolyl. ester.
    [6" claim-type="Currently amended] The pyrimidine derivative of formula (I), a pharmaceutically acceptable salt thereof or an in vivo hydrolyzable ester thereof according to any one of claims 1 to 5, wherein G is -O-.
    [7" claim-type="Currently amended] The pyrimidine derivative of formula (I), a pharmaceutically acceptable salt thereof or an in vivo hydrolyzable ester thereof according to any one of claims 1 to 5, wherein G is -S-.
    [8" claim-type="Currently amended] 8. The pyrimidine derivative of formula I, a pharmaceutically acceptable salt thereof or an in vivo hydrolyzable ester thereof according to claim 1, wherein R 1 is fluoro, chloro or bromo. 9.
    [9" claim-type="Currently amended] The pyrimidine derivative of formula (I), a pharmaceutically acceptable salt thereof or in vivo hydrolysis thereof according to any one of claims 1 to 8, wherein Q 2 is unsubstituted or substituted by one methoxy group. Available esters.
    [10" claim-type="Currently amended] The method according to any one of claims 1 to 9,
    5-bromo-2- {4- [2-hydroxy-3- (N, N-dimethylamino) propoxy] anilino} -4- (4-methoxyphenoxy) pyrimidine;
    5-bromo-2- {4- [2-hydroxy-3- (cyclopentylamino) propoxy] anilino} -4- (4-methoxyphenoxy) pyrimidine;
    5-bromo-2- {4- [2-hydroxy-3- (N, N-dimethylamino) propoxy] anilino} -4- (phenylthio) pyrimidine;
    5-bromo-2- {4- [2-hydroxy-3- (isopropylamino) propoxy] anilino} -4- (phenylthio) pyrimidine;
    5-bromo-2- {4- [2-hydroxy-3- (t-butylamino) propoxy] anilino} -4- (phenylthio) pyrimidine; or
    5-Bromo-2- {4- [2-hydroxy-3- (isopropylamino) propoxy] anilino} -4- (thiazol-2-ylthio) pyrimidine Pyrimidine derivatives, pharmaceutically acceptable salts thereof or in vivo hydrolysable esters thereof.
    [11" claim-type="Currently amended] a) for compounds of formula I, pyrimidines of formula II are reacted with compounds of formula III,
    b) reacting pyrimidine of formula IV with a compound of formula V,
    c) For compounds of Formula (I) wherein n is 1, 2 or 3, m is 1, Y 2 is H and Y 1 is OH, NH 2 or SH, the 3-membered heteroalkyl ring of Formula VI is React with the nucleophile of VII,
    d) for compounds of formula I, wherein X is oxygen, reacting an alcohol of formula VIII with an alcohol of formula IX
    e) X is -CH 2- , -O-, -NH- or -S-, Y 1 is OH, Y 2 is H and m is 2 or 3, Reacting a compound of with a nucleophile of formula VII,
    f) X is -CH 2- , -O-, -NH- or -S-, Y 1 and Y 2 are H, n is 1, 2 or 3, m is 1, 2 or 3 For compounds of, the compounds of formula XI are reacted with the nucleophiles of formula VII,
    g) for compounds of formula I wherein X is -O-, -NH- or -S-, Y 1 and Y 2 are H, n is 1, 2 or 3 and m is 1, 2 or 3, Reacting a compound of formula XII with a compound of formula XIII
    h) for compounds of formula I wherein Z is HS-, converts the thioacetate group in the compound,
    Then, if necessary,
    i) converting the compound of formula I to another compound of formula I,
    ii) remove any protecting group,
    iii) A process for preparing pyrimidine derivatives according to any one of claims 1 to 10 selected from forming pharmaceutically acceptable salts thereof or hydrolyzable esters thereof in vivo.
    Formula II

    Formula III

    Formula IV

    Formula V

    Formula VI

    Formula VII
    Z-D
    Formula VIII

    Formula IX

    Formula X

    Formula XI

    Formula XII

    Formula XIII

    In the above formula, L is a substitutable group as described above,
    A is O, S or NH,
    D is H or a suitable counterion,
    LgO is a leaving group as described above.
    [12" claim-type="Currently amended] A pharmaceutical comprising a pyrimidine derivative of formula (I) according to any one of claims 1 to 10, a pharmaceutically acceptable salt thereof or an in vivo hydrolysable ester thereof, together with a pharmaceutically acceptable diluent or carrier. Composition.
    [13" claim-type="Currently amended] A pyrimidine derivative of formula I according to any one of claims 1 to 10, a pharmaceutically acceptable salt thereof or in vivo hydrolyzable thereof for use in a method for the prophylactic or therapeutic treatment of warm blooded animals, including humans. ester.
    [14" claim-type="Currently amended] A pyrimidine derivative of formula (I), a pharmaceutically acceptable salt thereof, or an in vivo hydrolysable ester thereof of any one of claims 1 to 10 for use as a medicament.
    [15" claim-type="Currently amended] First in the manufacture of a medicament for use in producing anticancer, cell cycle inhibitory (anti-cell proliferation) effects and / or FAK inhibitory (inducing anti-cell migration and / or apoptosis) effects in warm blooded animals, including humans Use of a pyrimidine derivative of formula (I), a pharmaceutically acceptable salt thereof, or an in vivo hydrolysable ester thereof according to any one of claims 10 to 11.
    [16" claim-type="Currently amended] Anticancer, cell cycle inhibition, comprising administering to a mammal, including humans, an effective amount of the pyrimidine derivative according to any one of claims 1 to 10, a pharmaceutically acceptable salt thereof or an in vivo hydrolysable ester thereof A method for producing such an effect in an animal in need of an (anti-cell proliferation) effect and / or an FAK inhibition (inducing anti-cell migration and / or apoptosis) effect.
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    同族专利:
    公开号 | 公开日
    AU3576801A|2001-09-12|
    AU2001235768B2|2005-01-06|
    GB0004886D0|2000-04-19|
    MXPA02008371A|2002-12-13|
    BR0108878A|2003-04-29|
    NO20024127D0|2002-08-29|
    US6710052B2|2004-03-23|
    JP2003525276A|2003-08-26|
    EP1286972A1|2003-03-05|
    CN1406229A|2003-03-26|
    IL150934A|2008-11-26|
    NO325177B1|2008-02-11|
    ZA200206812B|2003-11-26|
    US20030114473A1|2003-06-19|
    NZ520594A|2004-06-25|
    IL150934D0|2003-02-12|
    KR100762190B1|2007-10-04|
    CN1325479C|2007-07-11|
    NO20024127L|2002-08-29|
    WO2001064653A1|2001-09-07|
    CA2399704A1|2001-09-07|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    2000-03-01|Priority to GB0004886.8
    2000-03-01|Priority to GBGB0004886.8A
    2001-02-26|Application filed by 아스트라제네카 아베
    2002-10-21|Publication of KR20020079978A
    2007-10-04|Application granted
    2007-10-04|Publication of KR100762190B1
    优先权:
    申请号 | 申请日 | 专利标题
    GB0004886.8|2000-03-01|
    GBGB0004886.8A|GB0004886D0|2000-03-01|2000-03-01|Chemical compounds|
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