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    • 专利摘要:
    The pyrimidinone compounds of formula (I) are inhibitors of the Lp-PLA 2 enzyme and are used for the treatment, in particular for the treatment of atherosclerosis. <Formula I>
    公开号:KR20020012200A
    申请号:KR1020017013976
    申请日:2000-04-25
    公开日:2002-02-15
    发明作者:애쉴리 에드워드 펜위크；데이어더 메리 버나데트 힉키；로버트 존 이페；콜린 앤드류 리이치；이반 레오 핀토；스티븐 앨런 스미스
    申请人:피터 기딩스；스미스클라인비이참피이엘시이；
    IPC主号:
    专利说明:

    Pyrimidinone Compounds
    [2] WO 95/00649 (SimthKline Beecham plc) includes lipoprotein related phospholipase A 2 (Lp-PLA 2 ), a phospholipase A2 enzyme, sequences thereof, isolation and purification thereof, isolated nucleic acids encoding such enzymes, and A recombinant host preparation transformed with DNA encoding the enzyme is described. Atherosclerosis, diabetes mellitus, rheumatoid arthritis, stroke, myocardial infarction, reperfusion injury, and acute and chronic inflammation have been proposed for therapeutic use of inhibitors of these enzymes. Later publications in the same group (Tew D et al, Arterioscler Thromb Vas Biol 1996: 16; 591-9) describe the enzyme as LDL-PLA 2 . Subsequent patent applications (WO 95/09921, Icos Corporation) and related documents in Nature (Tjoelker et al, vol 374,6 April 1995,549) show that PAFs are essentially identical in sequence to Lp-PLA 2. -AH enzyme is described, which has been suggested to be potent as a therapeutic protein for the control of pathological inflammation development.
    [3] Lp-PLA 2 is known to act to convert phosphatidylcholine to lysophosphatidylcholine during the conversion of low density lipoprotein (LDL) to the oxidized form. This enzyme is known to hydrolyze the sn-2 ester of oxidized phosphatidylcholine to produce lysophosphatidylcholine and oxidatively modified fatty acids. Both products by Lp-PLA 2 action are biologically active, and lysophosphatidylcholine, a component of oxidized LDL, is known as a potent chemoattractant for monocytes in the blood. Thus, lysophosphatidylcholine is thought to play an important role in the development of atherosclerosis by acting to accumulate cholesterol-containing cells in the arteries. Thus, inhibition of the Lp-PLA 2 enzyme is expected to stop the accumulation of damaged macrophages (by inhibiting the formation of lysophosphatidylcholine and oxidized free fatty acids), which is expected to be useful in the treatment of atherosclerosis.
    [4] In addition, increased content of lysophosphatidylcholine in oxidatively modified LDL is thought to be associated with endothelial dysfunction found in atherosclerosis patients. Thus, inhibition of Lp-PLA 2 would be beneficial for the treatment of this phenomenon. In addition, Lp-PLA 2 inhibitors will be useful for diabetes, hypertension, angina, and other disorders indicating endothelial dysfunction, including subsequent diseases of ischemia and reperfusion.
    [5] In addition, Lp-PLA 2 inhibitors would be universally applicable to any disease associated with activated monocytes, macrophages or lymphocytes that are cell types expressing Lp-PLA 2 . Examples of such diseases include psoriasis.
    [6] In addition, Lp-PLA 2 inhibitors may be universally applied to any disease in which Lp-PLA 2 activity produces two damaging products, lysophosphatidylcholine and oxidatively modified fatty acids, by lipid oxidation. Such symptoms include the aforementioned atherosclerosis, diabetes, rheumatoid arthritis, stroke, myocardial infarction, reperfusion injury, and acute and chronic inflammation. Such symptoms also include various neuropsychiatric diseases such as schizophrenia (see Psychopharmacology Bulletin, 31,159-165, 1995).
    [7] Patent applications WO 96/12963, WO 96/13484, W096 / 19451, WO 97/02242, W097 / 217675, W097 / 217676, WO 96/41098 and W097 / 41099 (SmithKline Beecham plc) Describes a series of various 4-thionyl / sulfinyl / sulfonyl azetidinone compounds that are inhibitors of the Lp-PLA 2 enzyme. These compounds are irreversible acylation inhibitors (Tew et al, Biochemistry, 37, 10087, 1998).
    [8] Patent applications WO 99/24420 and WO 00/10980 (SmithKline Beecham plc, published after the priority date of the present application) disclose a new class of reversible non-acylation inhibitors for Lp-PLA 2 enzymes, specifically a group of Pyrimidone compounds are described. Early 2- (alkylthio) pyrimidin-4-one leader compounds are described in Bioorganic and Medicinal Chemistry Letters, 2000, 10, 395-8.
    [1] The present invention relates to certain novel pyrimidinone compounds, methods for their preparation, intermediates useful for the preparation thereof, pharmaceutical compositions comprising them, and their use in therapy (specifically in the treatment of atherosclerosis).
    [9] Another group of pyrimidone compounds that are inhibitors of the Lp-PLA 2 enzyme have been identified in the present invention.
    [10] Accordingly, the present invention provides a compound of formula (I).
    [11]
    [12] Where
    [13] R 1 is C (1-18) alkyl, C (1-18) alkoxy, C (1-18) alkylthio, arylC (1-18) alkoxy, hydroxy, halogen, CN, COR 6 , carboxy, COOR 6 , CONR 9 R 10 , NR 6 COR 7 , SO 2 NR 9 R 10 , NR 6 SO 2 R 7 , NR 9 R 10 , mono to perfluoro-C (1-4) alkyl and mono to perfluoro -C (1-4) alkoxy and optionally substituted by the same or different substituents 1, 2, 3 or 4, or as single substituents, optionally with additional substituents as defined above, CH 2 COOH or a salt thereof, CH 2 COOR 8 , CH 2 CONR 9 R 10 , CH 2 CN, (CH 2 ) m NR 9 R 10 , (CH 2 ) mOH or (CH 2 ) mOR 6 , wherein m is from 1 to 3 An aryl or heteroaryl group which may be substituted by
    [14] R 2 is C (1-18) alkyl, C (1-18) alkoxy, C (1-18) alkylthio, arylC (1-18) alkoxy, hydroxy, halogen, CN, COR 6 , carboxy, COOR 6 , CONR 9 R 10 , NR 6 COR 7 , SO 2 NR 9 R 10 , NR 6 SO 2 R 7 , NR 9 R 10 , mono to perfluoro-C (1-4) alkyl, mono to perfluoro Is an aryl or heteroaryl group selected from -C (1-4) alkoxy and acylC (1-4) alkyl and optionally substituted by the same or different substituents 1, 2, 3 or 4;
    [15] R 3 is hydrogen or hydroxy, OR 6 , COR 6 , carboxy, COOR 6 , CONR 9 R 10 , NR 9 R 10 , mono- or di- (hydroxyC (1-6) alkyl) amino or N - hydroxyl and hydroxy C (1-6) alkyl, -NC (1-6) alkylamino, C (1-4) that can be unsubstituted or substituted by alkyl,
    [16] R 4 is C (1-18) alkyl, C (1-18) alkoxy, C (1-18) alkylthio, arylC (1-18) alkoxy, hydroxy, halogen, CN, COR 6 , carboxy, COOR 6 , CONR 9 R 10 , NR 6 COR 7 , SO 2 NR 9 R 10 , NR 6 SO 2 R 7 , NR 9 R 10 , mono to perfluoro-C (1-4) alkyl and mono to perfluoro -C (1-4) is an aryl or heteroaryl group selected from alkoxy and optionally substituted by the same or different substituents 1, 2, 3 or 4,
    [17] R 5 is C (1-18) alkyl, C (1-18) alkoxy, C (1-18) alkylthio, arylC (1-18) alkoxy, hydroxy, halogen, CN, COR 6 , carboxy, COOR 6 , CONR 9 R 10 , NR 6 COR 7 , SO 2 NR 9 R 10 , NR 6 SO 2 R 7 , NR 9 R 10 , mono to perfluoro-C (1-4) alkyl and mono to perfluoro -C (1-4) is an aryl ring selected from alkoxy and optionally further substituted by the same or different substituents 1, 2, 3 or 4,
    [18] R 6 and R 7 are independently hydrogen or C (1-20) alkyl, for example C (1-4) alkyl (methyl or ethyl),
    [19] R 8 is C (1-4) alkyl, or a pharmaceutically acceptable in vivo hydrolyzable ester group,
    [20] R 9 and R 10 are the same or different and are each selected from hydrogen, C (1-12) alkyl, CH 2 R 11 , CHR 12 CO 2 H or salts thereof, or R 9 and R 10 are bonded to them Together with nitrogen, it may optionally contain one or more heteroatoms selected from oxygen, nitrogen and sulfur, and include hydroxy, oxo, C (1-4) alkyl, C (1-4) alkylCO, aryl (eg 4- to 7-membered, preferably 5- to 7-membered rings (eg, phenyl) or optionally substituted by one or two substituents selected from aralkyl (e.g. benzyl) Morpholine or piperazine),
    [21] R 11 is COOH or a salt thereof, COOR 8 , CONR 6 R 7 , CN, CH 2 0H or CH 2 0R 6 ,
    [22] R 12 is an amino acid side chain such as CH 2 OH from serine,
    [23] n is an integer from 1 to 4, preferably 1 or 3,
    [24] X is O or S,
    [25] Z is CR 13 R 14 , wherein R 13 and R 14 are each hydrogen or C (1-4) alkyl, or R 13 and R 14 together form a C (3-6) cycloalkyl ring via a carbon atom; Can be formed.
    [26] Preferably Z is CH 2 .
    [27] Exemplary R 1 in the case of an aryl group include phenyl and naphthyl.
    [28] Examples of representative R 1 in the case of a heteroaryl group include monocyclic 5- or 6-membered heteroaryl groups containing 1 or 2 nitrogen heteroatoms.
    [29] Preferably R 1 is oxo, arylC (1-4) alkyl (eg benzyl), C (1-6) alkyl (eg methyl or ethyl), C (3-6) cycloalkyl, Hydroxy, C (1-4) alkoxy (e.g., methoxy), carboxyC (1-6) alkyl, C (1-6) alkylcarboxyC (1-6) alkyl, di-C (1- 6) pyrimidyl, which may be optionally substituted by one or two substituents preferably selected from alkylamino and morpholino, or optionally substituted by C (1-6) alkyl (eg, methyl or ethyl) It can be pyrazolyl.
    [30] Preferably pyrimid-5-ylmethyl wherein ZR 1 may be optionally substituted by 2-methoxy, 2-trifluoromethyl, 2- (4-morpholino) or 2-dimethylamino; 2-oxo-pyrimid-5-ylmethyl; Or 1-methyl-4-pyrazolylmethyl.
    [31] Preferably X is S.
    [32] Examples of representative R 2 in the case of an aryl group include phenyl and naphthyl. Examples of representative R 2 in the case of a heteroaryl group include pyridyl, pyrimidinyl, pyrazolyl, furanyl, thienyl, thiazolyl, quinolyl, benzothiazolyl, pyridazolyl and pyrazinyl. Preferably R 2 is phenyl which may be optionally substituted by halogen.
    [33] Representative examples of R 2 CH 2 X include 4-fluorobenzylthio.
    [34] Representative examples of R 3 include hydrogen; And amino, C (1-3) alkylamino, diC (1-3) alkylamino, hydroxy C (1-3) alkylamino, hydroxy, C (1-3) alkoxy, carboxy, C (1- 3) methyl, ethyl and propyl, which may be optionally substituted by alkylcarboxy and heterocyclyl (eg, piperidino, piperazino, pyrrolidono and morpholino), wherein alkyl moieties are present If so, methyl or ethyl is preferred.
    [35] Representative examples of R 4 include phenyl, which may be optionally substituted by halogen; Thiophene; Pyridine and pyrimidine.
    [36] Representative examples of R 5 include phenyl which may be optionally substituted by halogen, trifluoromethyl or trifluoromethoxy, preferably in the 4-position.
    [37] Preferably R 4 and R 5 together form a 4- (phenyl) phenyl substituent, wherein the far outer phenyl ring may be optionally substituted by halogen or trifluoromethyl, preferably in the 4-position .
    [38] For R 8 , pharmaceutically acceptable in vivo hydrolyzable ester groups include those which are readily degraded in the human body and become parent acids or salts thereof.
    [39] Representative examples of R 8 that are valuable as pharmaceutically acceptable in vivo hydrolyzable ester groups are
    [40] -CH (R a ) O.CO.R b ,
    [41] -CH (R a ) O.CO.OR c ,
    [42] -CH (R a ) CO.NR e R f ,
    [43] -R d NR e R f ,
    [44] -CH 2 0R g ,
    [45]
    [46] CH (R a ) O.CO.C 6 H 4 Y 1 COCH (R i ) NH 2 , and
    [47]
    [48] Is included; here
    [49] R a is hydrogen, (C 1-6 ) alkyl, especially methyl, (C 3-7 ) cycloalkyl or phenyl, each of which may be optionally substituted,
    [50] R b is (C 1-6 ) alkyl, (C 1-6 ) alkoxy (C 1-6 ) alkyl, phenyl, benzyl, (C 3-7 ) cycloalkyl, (C 1-6 ) alkyl (C 3- 7 ) cycloalkyl, 1-amino (C 1-6 ) alkyl or 1- (C 1-6 alkyl) amino (C 1-6 ) alkyl, each of which may be optionally substituted, or
    [51] R a and R b together form a 1,2-phenylene group which may be optionally substituted by 1 or 2 methoxy groups,
    [52] R c is (C 1-6 ) alkyl, (C 3-7 ) cycloalkyl or (C 1-6 ) alkyl (C 3-7 ) cycloalkyl,
    [53] R d is (C 1-6 ) alkylene which may be optionally substituted by methyl or ethyl groups,
    [54] R e and R f are the same or different and are each (C 1-6 ) alkyl, or aryl (C 1-6 ) alkyl, which may be optionally substituted by hydroxy,
    [55] R g is (C 1-6 ) alkyl,
    [56] R h is hydrogen, (C 1-6 ) alkyl or phenyl,
    [57] R i is hydrogen or phenyl which may be optionally substituted with up to 3 groups selected from halogen, (C 1-6 ) alkyl or (C 1-6 ) alkoxy,
    [58] Y 1 is oxygen or NH;
    [59] Examples of such groups are
    [60] (a) acetoxymethyl, isobutyryloxymethyl, pivaloyloxymethyl, benzoyloxymethyl, α-acetoxyethyl, α-pivaloyloxyethyl, 1- (cyclohexylcarbonyloxy) ethyl, (1 -Acyloxyalkyl groups such as -aminoethyl) carbonyloxymethyl, 2-methoxyprop-2-ylcarbonyloxymethyl, phenylcarbonyloxymethyl and 4-methoxyphenyl-carbonyloxymethyl,
    [61] (b) alkoxy such as ethoxycarbonyloxymethyl, t-butyloxycarbonyloxymethyl, cyclohexyloxycarbonyloxymethyl, 1-methylcyclohexyloxycarbonyloxymethyl and α-ethoxycarbonyloxyethyl Cycloalkoxycarbonyloxyalkyl group,
    [62] (c) dialkylaminoalkyl groups (particularly di-lower alkylamino alkyl groups) such as dimethylaminomethyl, dimethylaminoethyl, diethylaminomethyl or diethylaminoethyl,
    [63] (d) acetamido groups such as N, N-dimethylaminocarbonylmethyl, N, N- (2-hydroxyethyl) aminocarbonylmethyl,
    [64] (e) lactone groups such as phthalidyl and dimethoxyphthalidyl,
    [65] (f) (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl, and
    [66] (g) (2-methoxycarbonyl-E-but-2-en-yl) methyl.
    [67] Representative examples of the pharmaceutically acceptable in vivo hydrolysable ester group for R 8 include (2-methoxycarbonyl-E-but-2-en-yl) methyl, isobutyryloxymethyl, 2-methoxyprop P-2-ylcarbonyloxymethyl, phenylcarbonyloxymethyl, 4-methoxyphenyl-carbonyloxymethyl, t-butyloxycarbonyloxymethyl, cyclohexyloxy-carbonyloxymethyl, 1-methylcyclo Hexyloxycarbonyloxymethyl, N, N-dimethylaminocarbonylmethyl and (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl.
    [68] It will be appreciated that in some cases, the compounds of the present invention may include basic groups such as amino groups as substituents. Such basic groups can be used to form acid addition salts, specifically pharmaceutically acceptable salts. Pharmaceutically acceptable salts include Berge, Bighley, and Monkhouse, J. Pharm. Sci., 1977, 66, 1-19. Such salts can be produced from inorganic and organic acids. Typical examples include maleic acid, fumaric acid, benzoic acid, ascorbic acid, palmic acid, succinic acid, bismethylenesalicylic acid, methanesulfonic acid, p-toluenesulfonic acid, ethanedisulfonic acid, acetic acid, propionic acid, tartaric acid, salicylic acid, citric acid, gluconic acid, aspartic acid, Stearic acid, palmitic acid, itaconic acid, glycolic acid, p-aminobenzoic acid, glutamic acid, taurocholic acid, benzenesulfonic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, cyclohexylsulfamic acid, phosphoric acid and nitric acid.
    [69] It will be appreciated that in some cases, compounds of the present invention may include a carboxy group as a substituent. Such carboxy groups can be used to form salts, specifically pharmaceutically acceptable salts. Pharmaceutically acceptable salts include Berge, Bighley, and Monkhouse, J. Pharm. Sci., 1977, 66, 1-19. Preferred salts include alkali metal salts such as sodium salts and potassium salts.
    [70] As used herein, the terms "alkyl" and similar "alkoxy" include both straight and branched chain isomers. Representative examples include methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, t-butyl, n-pentyl and n-hexyl.
    [71] The term "aryl" as used herein, unless defined otherwise, refers to monocyclic or bicyclic aromatic ring systems containing up to 10 carbon atoms in the ring system. For example, phenyl or naphthyl.
    [72] The term "heteroaryl" as used herein refers to a monocyclic or bicyclic heteroaromatic ring system containing up to 4, preferably 1 or 2 heteroatoms each selected from oxygen, nitrogen and sulfur. Bicyclic heteroaromatic ring systems can include carbocyclic rings.
    [73] As used herein, the terms "halogen" and "halo" include fluorine, chlorine, bromine and iodine, and are denoted fluoro, chloro, bromo and iodo, respectively.
    [74] Particularly preferred compounds of formula I are
    [75] 1- (N-methyl-N- (4- (4-chlorophenyl) benzyl) aminocarbonylmethyl) -2- (4-fluorobenzyl) thio-5- (1-methylpyrazol-4-ylmethyl Pyrimidin-4-one,
    [76] 1- (N-methyl-N- (4- (4-trifluoromethylphenyl) benzyl) aminocarbonylmethyl) -2- (4-fluorobenzyl) thio-5- (1-methylpyrazole-4- Ylmethyl) pyrimidin-4-one,
    [77] 1- (N- (2-dimethylaminoethyl) -N- (4- (4-chlorophenyl) benzyl) aminocarbonylmethyl) -2- (4-fluoro-benzyl) thio-5- (1-methyl Pyrazol-4-ylmethyl) pyrimidin-4-one,
    [78] 1- (N-methyl-N- (4- (4-chlorophenyl) benzyl) aminocarbonylmethyl) -2- (4-fluorobenzyl) thio-5- (2- (4-morpholino) pyridine Mid-5-ylmethyl) pyrimidin-4-one,
    [79] 1- (N- (2- (dimethylamino) ethyl) -N- (4- (4-trifluoromethylphenyl) benzyl) aminocarbonylmethyl) -2- (4-fluorobenzyl) thio-5- ( 1-methyl-4-pyrazolylmethyl) pyrimidin-4-one,
    [80] 1- (N- (2- (diethylamino) ethyl) -N- (4- (4-chlorophenyl) benzyl) aminocarbonylmethyl) -2- (4-fluorobenzyl) thio-5- (1 -Methyl-4-pyrazolylmethyl) pyrimidin-4-one,
    [81] 1- (N- (2- (diethylamino) ethyl) -N- (2- (4-trifluoromethylphenyl) pyrid-5-ylmethyl) aminocarbonylmethyl) -2- (4-fluoro Benzyl) thio-5- (1-methyl-4-pyrazolylmethyl) pyrimidin-4-one,
    [82] 1- (N- (2- (1-piperidino) ethyl) -N- (4- (4-trifluoromethylphenyl) benzyl) aminocarbonylmethyl) -2- (4-fluorobenzyl) thio- 5- (1-methyl-4-pyrazolylmethyl) pyrimidin-4-one hydrogen stannate,
    [83] 1- (N- (carboxymethyl) -N- (4- (4-trifluoromethylphenyl) benzyl) aminocarbonylmethyl) -2- (4-fluorobenzyl) thio-5- (1-methyl-4 Pyrazolylmethyl) pyrimidin-4-one sodium salt, and
    [84] 1- (N- (2- (diethylamino) ethyl) -N- (4- (4-trifluoromethylphenyl) benzyl) aminocarbonylmethyl) -2- (4-fluorobenzyl) thio-5- (1-methyl-4-pyrazolylmethyl) pyrimidin-4-one, or
    [85] Pharmaceutically acceptable salts thereof, including hydrochloride, hydrogen stannate, citrate and tosylate.
    [86] Since the compounds of the invention, in particular the compounds of formula (I), are for use in pharmaceutical compositions, these compounds are in substantially pure form, for example at least 50% pure, more suitably at least 75%, most preferably Of course it should be provided in the form of at least 95% (% is weight / weight%). It may be prepared in a purer form that can be used in pharmaceutical compositions using formulations of the formula (I) compound of low purity. While the purity of the intermediate compounds of the present invention is relatively less important, it will be readily understood that substantially pure forms are preferred for the compounds of formula (I). It is preferred that the compounds of the invention are obtained in as crystalline form as possible.
    [87] When some compounds of the present invention are crystallized or recrystallized from organic solvents, a crystallization solvent may be present in the crystalline product. Such solvates are also included within the scope of the present invention. Similarly, some compounds of the present invention can be crystallized or recrystallized from solvents containing water. In such cases, hydrates may be produced. The scope of the present invention includes not only stoichiometric hydrates but also compounds containing various amounts of water which can be produced by processes such as lyophilization. In addition, different crystallization conditions can result in crystalline products of different polymorphs. The scope of the present invention includes all polymorphs of the compound of formula I.
    [88] The compounds of the present invention are inhibitors of lipoprotein related phospholipase A 2 (Lp-PLA 2 ) enzymes and are expected to be used in the treatment (specifically in the treatment of atherosclerosis). Thus, a further aspect of the invention provides a compound of formula (I) for use in therapy.
    [89] Compounds of formula (I) are inhibitors of lysophosphatidylcholine production by Lp-PLA 2 and are thus universally resistant to any disease associated with endothelial dysfunction, including atherosclerosis, diabetes, hypertension, angina, and subsequent diseases of ischemia and reperfusion. Applicable In addition, the compounds of formula (I) can be used not only for symptoms such as atherosclerosis and diabetes, but also for inflammatory symptoms of the brain such as rheumatoid arthritis, stroke, Alzheimer's disease, myocardial infarction, reperfusion injury, sepsis, and acute and chronic inflammation. Likewise applicable universally to any disease associated with lipid oxidation by enzyme activity. Such symptoms also include various neuropsychiatric diseases such as schizophrenia (see Psychopharmacology Bulletin, 31,159-165, 1995).
    [90] Further applicable diseases include any disease associated with activated monocytes, macrophages or lymphocytes that are cell types expressing Lp-PLA 2 . Examples of such diseases include psoriasis.
    [91] Accordingly, there is provided a method of treating the disorders which comprises treatment In a further aspect of the present invention to a patient in need of treatment of diseases which are associated with activation of the enzyme Lp-PLA 2 inhibitor in a therapeutically effective amount. The disease may include increased relevance of monocytes, macrophages or lymphocytes; Production of lysophosphatidylcholine and oxidized free fatty acids; Oxidation of lipids associated with Lp-PLA 2 activity; Or endothelial dysfunction.
    [92] In addition, the compounds of the present invention can be used in the treatment of the above-mentioned diseases in combination with the treatment of hyperlipidemia, the treatment of atherosclerosis, the treatment of diabetes, the treatment of angina, the anti-inflammatory agent, or the treatment of hypertension or agents that lower Lp (a). Examples include cholesterol synthesis inhibitors such as statins, antioxidants such as probucol, insulin sensitizers, calcium channel antagonists, and anti-inflammatory agents such as NSAIDs. Agents that lower Lp (a) include aminophosphonates described in WO 97/02037, WO 98/28310, WO 98/28311 and WO 98/28312 (Symphar SA and SmithKline Beecham).
    [93] Preferred combination therapy is the use of a compound of the invention and statins. Statins are a well known class of cholesterol lowering agents, including atorvastatin, simvarstatin, pravastatin, cerivastatin, fluvastatin, lovastatin and ZD 4522 (also called S-4522, Astra Zeneca). At the physician's discretion, the two agents may be administered at substantially the same time or at different times.
    [94] A further preferred combination therapy is the use of a compound of the invention and a diabetes therapeutic or insulin sensitizer, since the main cause of death of diabetes is coronary heart disease. Preferred compounds for use with the compounds of the invention in this class include PPARgamma activators such as G1262570 (Glaxo Wellcome), and glitazone classes of compounds such as rosiglitazone (Avandia, SmithKline Beecham), troglitazone and pioglitazone. Calling is included.
    [95] For therapeutic use, the compounds of the present invention are usually administered in the form of standard pharmaceutical compositions. Accordingly, in a further aspect of the invention there is provided a pharmaceutical composition comprising a compound of formula I and a pharmaceutically acceptable carrier.
    [96] Suitable pharmaceutical compositions include those suitable for oral or parenteral administration, or those suitable as suppositories. The compounds of formula (I) which show activity upon oral administration can be formulated as liquids, tablets, capsules and lozenges such as syrups, suspensions or emulsions. Liquid formulations are generally included in such suitable liquid carrier (s), for example ethanol, glycerin, non-aqueous solvents (polyethylene glycol), oils or water, together with suspending agents, preservatives, flavoring agents or coloring agents. It consists of a suspension or solution of an acceptable salt. Compositions in tablet form may be prepared using any suitable carrier (s) conventionally used in the preparation of solid dosage forms. Examples of such carriers include magnesium stearate, starch, lactose, sucrose and cellulose. Compositions in capsule form can be prepared using conventional encapsulation procedures. For example, pellets containing the active ingredient are prepared using standard carriers and then filled into hard gelatin capsules; Alternatively, the composition in capsule form may be prepared by preparing a dispersion or suspension using any suitable pharmaceutical carrier (s) such as aqueous rubber, cellulose, silicate or oil, and then filling the dispersion or suspension into soft gelatin capsules. Can be. Typical parenteral compositions consist of a dispersion or suspension of a compound of formula (I) contained in a sterile aqueous carrier or parenterally acceptable oil, such as polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil. . Alternatively, the solution may be lyophilized and then reconstituted with a suitable solvent just prior to administration. Typical suppository formulations include compounds of formula (I) which are active when administered in a suitable manner with polymeric glycols, gelatin, or binders and / or lubricants such as cocoa butter or other low melting vegetable or synthetic waxes or fats. .
    [97] Preferably, the composition is in unit dosage form such as a tablet or capsule. Each dosage unit for oral administration preferably contains 1 to 500 mg of the compound of formula I (preferably containing 0.1 to 25 mg for parenteral administration). For example, in the case of oral administration, the daily dose of an adult patient is 1 mg to 1000 mg, preferably 1 mg to 500 mg, or 0.1 for intravenous, subcutaneous or intramuscular injection of the compound of formula (I). mg to 100 mg, preferably 0.1 mg to 25 mg, which is administered 1 to 4 times a day. It will be suitable to administer the compounds of the invention for a period of continuous treatment, for example one week or longer.
    [98] The compound of formula I is
    [99] (a) reacting a compound of formula II with a compound of formula III under amide forming conditions,
    [100]
    [101] Wherein X, Y, Z, R 1 and R 2 are as defined above
    [102]
    [103] Wherein R 3 , R 4 , R 5 are as defined above
    [104] (b) reacting a compound of formula IV with a compound of formula V in an inert solvent such as dichloromethane in the presence of a base such as a secondary or tertiary amine, for example di-iso-propylethylamine,
    [105]
    [106] Wherein X, Z, R 1 and R 2 are as defined above
    [107]
    [108] Wherein n, R 3 , R 4 and R 5 are as defined above and L 1 is a halogen, for example a leaving group such as bromo or iodo
    [109] (c) reacting a compound of formula (VI) with a compound of formula (VII) in an inert solvent such as dichloromethane in the presence of a base such as a secondary or tertiary amine, for example di-iso-propylethylamine, when X is S Step, or
    [110]
    [111] Wherein n, Z, R 1 , R 3 , R 4 and R 5 are as defined above
    [112]
    [113] Wherein R 2 and L 1 are as defined above
    [114] (d) when X is O, it can be prepared by a variety of methods including the step of reacting a compound of formula VIII with a compound of formula IX in an inert solvent such as pyridine in the presence of a base such as 4-dimethylaminopyridine.
    [115]
    [116] Wherein n, Z, R 1 , R 3 , R 4 and R 5 are as defined above and L 2 is a leaving group such as halogen or alkylthio, for example methylthio
    [117]
    [118] Wherein R 2 is as defined above
    [119] Compounds of formulas (II), (IV), (VI) and (VIII) used in the above process may be prepared by the method described in Scheme (I)
    [120]
    [121] (Wherein L 3 is a C (1-6) alkyl group such as methyl;
    [122] R 15 is a C (1-6) alkyl group such as methyl, ethyl or t-butyl
    [123] L 1 , L 2 , R 1 , R 2 , R 3 , R 4 , R 5 , n, X and Z are as defined above)
    [124] With regard to Scheme I, the amide formation conditions of step (a) are well known in the art. Preferably, the acid of formula (II) is reacted at room temperature in the presence of an activator such as 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide and hydroxybenzotriazole in an inert solvent such as dichloromethane. React with amines.
    [125] The alkylation conditions of step (b) include reaction in an inert solvent such as dichloromethane in the presence of a base such as secondary or tertiary amine, for example di-iso-propylethylamine, through which intermediate esters are formed. To the acid of formula II by hydrolysis (e.g. using aqueous sodium hydroxide solution in a solvent such as dioxane) or alternatively removing the protecting group (e.g. using trifluoroacetic acid in a solvent such as dichloromethane). Switch.
    [126] The conditions of step (c) include thioether formation conditions. The reaction is carried out in the presence of a base such as sodium ethoxide or potassium carbonate, preferably in ethanol or dimethyl formamide, or in a solvent such as dichloromethane in the presence of a secondary or tertiary amine base such as di-isopropylethyl amine. It is advantageous to carry out.
    [127] In step (d), the compound of formula XVII is reacted with thiourea in the presence of sodium ethoxide (preferably produced in the reaction system from sodium and ethanol).
    [128] In step (e), the compound of formula XVIII is reacted with ethyl formate in the presence of a base such as sodium hydride or potassium isopropoxide.
    [129] In step (f), the compound of formula IV is reacted with compound of formula (V) in an inert solvent such as dichloromethane in the presence of a base such as a secondary or tertiary amine, for example di-isopropylethylamine.
    [130] In step (g), the compound of formula XIII is reacted with a compound of formula XIV in a solvent such as dimethylformamide to form intermediate thiourea, which is then treated with a base such as sodium methoxide.
    [131] In step (h), the compound of formula XVI is reacted with a metal thiocyanate, for example potassium thiocyanate, in a solvent such as acetonitrile.
    [132] In step (i), the compound of formula (XVII) is reacted with a methylating agent such as dimethyl sulphate in the presence of a base such as potassium carbonate, followed by hydrolysis of the intermediate ester by conventional methods (e.g. with sodium hydroxide Base hydrolysis) to form the corresponding carboxylic acid, which is then converted to acyl chloride by a method such as the treatment of oxalyl chloride.
    [133] In step (j), a catalyst such as 4-dimethylaminopyridine and a solvent such as pyridine are used.
    [134] In step (k), the compound of formula XIII is reacted with a compound of formula XV in a solvent such as dimethylformamide to form intermediate thiourea, which is then treated with a base such as sodium methoxide.
    [135] The invention will now be illustrated by the following examples.
    [136] The structure and purity of the intermediates and the examples are confirmed by 1 H-NMR and (in almost all cases) mass spectrometry, even if not specified below.
    [137] Intermediate A1-4- (4-chlorophenyl) benzaldehyde
    [138]
    [139] (a) 4-formylbenzeneboronic acid (2.50 g, 2 equiv), 4-chloroiodobenzene (1.98 g, 1 equiv), tetrakis (triphenylphosphine) palladium (0) (0.50 g, 0.05 equiv ), A mixture of aqueous sodium carbonate solution (18 ml, 2M solution, 2 equiv) and dimethoxyethane (50 ml) were stirred under reflux overnight under argon, then cooled and diluted with ethyl acetate. The mixture was filtered sufficiently to remove inorganic residue, and then the organic layer was washed successively with aqueous citric acid solution and brine, dried and evaporated. The crude product was purified by chromatography (silica, 5% ethyl acetate in hexanes); The product fractions were evaporated to give a white solid (1.32 g, 72%).
    [140] (b) 4-chlorobenzeneboronic acid (19.4 g, 1 equiv), 4-bromobenzaldehyde (22.9 g, 1 equiv), palladium acetate (II) acetate (1.4 g, 0.05 equiv), aqueous sodium carbonate solution (144 ml solution) 30.3 g, 2 equivalents) and dimethoxyethane (500 ml) were stirred under reflux for 2.5 h under argon, then evaporated to small volume and diluted with dichloromethane. Continued as in (a) above to give the same compound (25.2 g, 94%). 1 H-NMR (CDCl 3 ) δ 10.5 (1H, s), 7.96 (2H, d), 7.73 (2H, d), 7.57 (2H, d), 7.46 (2H, d); MS (AP +) found (M + 1) = 217, theoretical value of C 13 H 9 35 ClO 216.
    [141] Intermediate A2-N-methyl-4- (4-chlorophenyl) benzylamine
    [142]
    [143] A mixture of intermediate A1 (3.5 g, 1 equiv), methylamine (32.3 ml of 2M solution in THF, 4 equiv) and anhydrous magnesium sulfate (4.47 g, 2 equiv) was stirred at rt for 16 h and then filtered to give a solid Was washed thoroughly with ethyl acetate and the filtrates were combined and evaporated to give a white solid (3.7 g). This imine intermediate was suspended in ethanol (100 ml), cooled in ice and added sodium borohydride (0.61 g, 1 equiv) in portions. The ice bath was removed and the mixture was stirred at room temperature for 45 minutes and then at 50 ° C. for 1 hour. The solvent was removed in vacuo, water was added to the residue and the product was extracted with dichloromethane. The solvent was evaporated to dryness to afford a white solid (3.56 g). 1 H-NMR (CDCl 3 ) δ 7.51 (4H, d), 7.40 (4H, d), 3.79 (2H, s), 2.48 (3H, s); MS (APCI +) found (M + 1) = 232, theoretical value of C 14 H 14 35 ClN 231.
    [144] Intermediate A3-N- (2-diethylaminoethyl) -4- (4-chlorophenyl) benzylamine
    [145]
    [146] A mixture of intermediate A1 (55.0 g), N, N-diethylethylenediamine (35.6 ml), 4A molecular sieve (37 g) and dichloromethane (1100 ml) was reacted with frequent stirring under argon at room temperature for 16 hours. The solid was filtered off and washed with dichloromethane and the filtrates combined and evaporated to give a yellow foam (72.4 g). This intermediate imine was reduced with sodium borohydride (8.7 g) in ethanol (850 ml) as described in intermediate A2 to give the title compound as a yellow oil (72.7 g). 1 H-NMR (CDCl 3 ) δ 1.70 (2H, t), 2.22 (6H, s), 2.33 (2H, t), 2.69 (2H, br.m), 3.83 (2H, s), 7.37-7.43 (4H, m), 7.52-7.56 (4H, m).
    [147] Intermediate A4-4- (4-Chlorophenyl) benzyl Alcohol
    [148]
    [149] A mixture of A1 intermediate (1.73 g, 1 equiv), sodium borohydride (0.3 g, 1 equiv) and ethanol (20 ml) was stirred to give a clean solution; Some exothermic reaction was observed. The temperature was raised to 50 ° C. and stirring continued for 2 hours, after which the solvent was removed in vacuo and the residue was added water to extract the product with dichloromethane. The solvent was dried and evaporated to give a white solid (1.67 g). 1 H-NMR (CDCl 3 ) δ 1.73 (1H, t), 4.74 (2H, d), 7.2-7.6 (8H, m).
    [150] Intermediate A5-N- (4- (4-chlorophenyl) benzyl) phthalimide
    [151]
    [152] Intermediate A4 (1.62 g, 1 equiv), phthalimide (1.42 g, 1.3 equiv) and triphenylphosphine (2.53 g, 1.3 equiv) were dissolved in anhydrous THF (50 ml) and the solution cooled on ice and Diethyl azodicarboxylate (1.52 ml, 1.3 equiv) was slowly added with stirring. The yellow solution was stirred for 16 hours at room temperature, after which the solvent was evaporated. Chromatography (silica, 1: 1 dichloromethane / pet. Ether) was carried out and homogenized with ether to give the desired product (2.03 g, 79%). 1 H-NMR (CDCl 3 ) δ 4.89 (2H, s), 7.36-7.50 (8H, m), 7.69-7.74 (2H, m), 7.82-7.89 (2H, m).
    [153] Intermediate A6-4- (4-Chlorophenyl) benzylamine
    [154]
    [155] A mixture of intermediate A5 (1.98 g, 1 equiv) and hydrazine hydrate (0.55 ml, 2 equiv) in ethanol (40 ml) was heated to reflux for 2 hours, after which the solvent was evaporated. The residue was shaken with dichloromethane and 0.5 M aqueous sodium hydroxide solution, the aqueous layer was reextracted with dichloromethane and the organic layers combined and purified by chromatography (silica, 1-3% methanol ammonia in dichloromethane). The product fractions were evaporated to give a white solid (0.53 g, 43%). 1 H-NMR (CDCl 3 ) δ3.92 (2H, s), 7.28-7.41 (4H, m), 7.49-7.54 (4H, m).
    [156] Intermediate A7-N-methyl-N- (4- (4-chlorophenyl) benzyl) bromoacetamide
    [157]
    [158] Bromine acetyl bromide (0.123 ml, 1.1 equiv) was added to a well stirred mixture of intermediate A2 (0.3 g, 1 equiv), sodium hydroxide (0.06 g, 1.2 equiv), water and dichloromethane. Stirring was continued at room temperature for 3 hours, after which the phases were separated and the organic layer was evaporated to dryness. Chromatography (silica, 3: 1 hexanes / ethyl acetate) gave the desired product as an oil (0.37 g). 1 H-NMR (CDCl 3 ) δ 7.78-7.68 (8H, m), 4.77 (2H, s), 4.07 (2H, s), 3.24 (3H, s); MS (APCI +) found (M + 1) = 352, theoretical value of C 16 H 15 79 Br 35 ClNO 351.
    [159] Intermediate A8-5-hydroxymethyl-2- (4-fluorophenyl) pyridine
    [160]
    [161] A solution of intermediate A23 (4.63 g) in anhydrous dichloromethane (100 ml) was cooled to -78 ° C under argon, after which DIBAL-H (26.7 ml, 1.5 M solution in toluene) was added dropwise over 20 minutes. Stirring was continued at −78 ° C. for 40 minutes, then 2 M hydrochloric acid (52 ml) was added dropwise over 15 minutes. The solution was allowed to warm slowly to room temperature, then the organic layer was separated, washed with water, dried and evaporated. Chromatography (silica, 1: 1 ethyl acetate / hexanes) gave the product as a white solid (3.03 g, 75%). 1 H-NMR (CDCl 3 ) δ (1H, d), 7.98 (2H, m), 7.77 (1H, m), 7.68 (1H, d), 7.15 (2H, t), 4.77 (2H, d), 1.802 (1 H, t); MS (APCI +) found (M + 1) = 204, C 12 H 10 FNO theoretical 203.
    [162] Intermediate A9-5-formyl-2- (4-fluorophenyl) pyridine
    [163]
    [164] Activated magnesium dioxide (3.19 g) was added to a solution of intermediate A8 (0.75 g) in dichloromethane (50 ml) and stirred at room temperature for 16 hours. The solid was filtered off and the filtrate was evaporated to give a pale yellow solid (0.57 g). 1 H-NMR (CDCl 3 ) δ 10.15 (1H, s), 9.11 (1H, s), 8.22 (1H, dd), 8.10 (2H, m), 7.87 (1H, d), 7.20 (2H, t ); MS (APCI +) found (M + 1) = 202, theoretical value of C 12 H 8 FNO 201.
    [165] Intermediate A10-N-methyl-4- (4-chlorophenyl) -3-fluorobenzylamine
    [166]
    [167] Borane (1M solution in THF, 2 equiv) was stirred with ice cooling under argon, and an intermediate A39 (1 equiv) suspension in dry THF was added gradually over several minutes. After 5 minutes the ice bath was removed and the mixture was heated to reflux for 1 hour and then cooled to room temperature. 5 M hydrochloric acid was added dropwise and the THF was removed from the resulting suspension by distillation. The residue was diluted with water and made strong base with sodium hydroxide, then the product was extracted with ether. The organic solution was dried and evaporated and then chromatographed to give the title compound as an oil (88%). 1 H-NMR (CDCl 3 ) δ 2.48 (3H, s), 3.79 (2H, s), 7.12-7.18 (2H, m), 7.33-7.50 (5H, m); MS (APCI +) found (M + 1) = 250; C 14 H 13 ClFN Theoretical 249.
    [168] Intermediate A11-N- (ethoxycarbonylmethyl) -4- (4-chlorophenyl) benzylamine
    [169]
    [170] A mixture of intermediate A1 (0.5 g, 1 equiv), glycine ethyl ester hydrochloride (0.32 g, 1 equiv), diisopropylethylamine (0.4 ml, 1 equiv) and 1,2-dichloroethane (10 ml) at room temperature Stirred, sodium triacetoxyborohydride (0.73 g, 1.5 equiv) was added and stirring continued overnight. After dilution with dichloromethane, the solution was washed with water and dried over potassium carbonate. The solvent was evaporated to afford the title compound (0.57 g) as a waxy white solid. 1 H-NMR (CDCl 3 ) δ1.22-1.37 (3H, t), 3.44 (2H, s), 3.85 (2H, s), 4.15-4.32 (2H, q), 7.35-7.62 (8H, m) ; MS (APCI +) found (M + 1) = 304; C 17 H 18 ClNO 2 requires 303.
    [171] Intermediate A12-2-hydroxymethyl-5- (4-chlorophenyl) pyridine
    [172]
    [173] To a solution of intermediate A41 (0.77 g) in dichloromethane (10 ml) add m-chloroperbenzoic acid (0.93 g) in portions over 30 minutes, after which the mixture is stirred at room temperature for several hours, diluted with dichloromethane, Washed with aqueous sodium bicarbonate solution, dried and evaporated. Chromatography (silica, 5% methanol in dichloromethane) was performed to yield 2-methyl-5- (4-chlorophenyl) pyridine-N-oxide (0.79 g) as a white solid. The material was dissolved in dichloromethane (15 ml) and trifluoroacetic anhydride (1.9 ml) was added and the mixture was stirred at rt for 1 h and then refluxed for 1 h. The volatiles were removed in vacuo, then the residue was redissolved in dichloromethane (15 ml) and 2M aqueous sodium bicarbonate solution (14 ml) was added and stirred vigorously for 2 hours. The mixture was diluted with dichloromethane and water and the organic layer was washed with water, dried and evaporated. Chromatography (silica, 5% methanol in dichloromethane) gave the title compound (0.67 g) as off-white replacement. 1 H-NMR (CDCl 3 ) δ3.61 (1H, t), 4.82 (2H, d), 7.33 (1H, d), 7.45 (2H, m), 7.51 (2H, m), 7.85 (1H, dd ), 7.78 (1 H, d); MS (APCI +) found (M + 1) = 220/222; C 12 H 10 ClNO Theoretical 219/221.
    [174] Intermediate A13-Ethyl 2- (4-chlorophenyl) -4-oxopyrimidine-5-carboxylate
    [175]
    [176] Sodium ethoxide (11.12 ml, 2 equiv), a 21% weight / volume solution in ethanol, was diluted with diethyl ethoxymalonate (3.03 ml, 1 equiv) and 4-chlorobenzamidine hydrochloride (4.23 g) in ethanol (30 ml). , 1 equivalent), and the mixture was then heated to reflux for 4 hours. After cooling, the solvent was removed in vacuo and the residue was homogenized with ether. The solid was filtered off and then resuspended in water and acidified to pH 2. The product was filtered off, washed with water and dried; Yield 2.94 g. 1 H-NMR (d 6 -DMSO) δ 1.29 (3H, t), 4.26 (2H, q), 7.65 (2H, m), 8.18 (2H, m), 8.65 (1H, s); MS (APCI-) found (M-1) = 277/279; C 13 H 11 ClN 2 O 3 requires 278/280.
    [177] Intermediate A14-Ethyl 2- (4-chlorophenyl) -4-chloropyrimidine-5-carboxylate
    [178]
    [179] Oxalyl chloride (0.31 ml, 2 equiv) was added to intermediate A13 (0.49 g) in dichloromethane (20 ml) cooled with ice, and the mixture was then stirred with warming to room temperature for 3 hours. The volatile components were evaporated to afford the product as a white solid (2.94 g). 1 H-NMR (CDCl 3 ) δ 1.44 (3H, t), 4.48 (2H, q), 7.50 (2H, m), 8.45 (2H, m), 9.17 (1H, s); MS (APCI +) found (M + 1) = 297; C 13 H 10 Cl 2 N 2 O 2 Theoretical 296.
    [180] Intermediate A15-Ethyl 2- (4-chlorophenyl) pyrimidine-5-carboxylate
    [181]
    [182] A mixture of intermediate A14 (6.8 g, 1 equiv), zinc powder (1.79 g, 1.2 equiv), acetic acid (1.57 ml, 1.2 equiv) and THF (100 ml) was stirred for 18 h under argon at 60 ° C., and then added Acetic acid (1 ml) and zinc (1.0 g) were added in portions, and the reaction was allowed to proceed for an additional 24 hours. The solvent was removed in vacuo, the residue was taken up in a dichloromethane and methanol mixture and the undissolved zinc powder was filtered off. After evaporation of the solvent, the product was crystallized from ethanol; Yield 2.02 g. 1 H-NMR (CDCl 3 ) δ 1.44 (3H, t), 4.46 (2H, q), 7.48 (2H, m), 8.48 (2H, m), 9.30 (2H, s); MS (APCI +) found (M + 1) = 263; C 13 H 11 ClN 2 O 2 requires 262.
    [183] Intermediate A16-5-hydroxymethyl-2- (4-trifluoromethylphenyl) pyrimidine
    [184]
    [185] Intermediate A129 (0.96 g) was hydrogenated with 10% palladium on charcoal in a mixture of triethylamine (2 ml) and ethanol (20 ml) at 1 atmosphere for 90 minutes. The catalyst was filtered off, the solvent was evaporated and the residue was taken up in ethyl acetate and washed successively with aqueous ammonium chloride solution and aqueous sodium bicarbonate solution. Drying and evaporation gave the title compound (2.02 g). 1 H-NMR (CDCl 3 ) δ4.82 (2H, s), 7.75 (2H, m), 8.57 (2H, m), 8.85 (2H, s); MS (APCI +) found (M + 1) = 255; C 11 H 9 ClN 2 O Theoretical 254.
    [186] The following intermediates were prepared by the method of intermediate A1.
    [187]
    [188]
    [189]
    [190] The following intermediates were prepared by the method of intermediate A2 using the appropriate amines in place of methylamines as needed.
    [191]
    [192]
    [193] A67 : N-methyl-4-phenylbenzylamine can be manufactured from 4-biphenyl carboxaldehyde which is commercially available.
    [194] The following intermediates were prepared by the method of intermediate A3.
    [195]
    [196]
    [197]
    [198] The following intermediates were prepared by the method of intermediate A4.
    [199]
    [200] The following intermediates were prepared by the method of intermediate A5.
    [201]
    [202] The following intermediates were prepared by the method of intermediate A6.
    [203]
    [204] A124 : 4-phenylbenzylamine is commercially available.
    [205] The following intermediates were prepared by the method of intermediate A8.
    [206]
    [207] The following intermediates were prepared by the method of intermediate A9.
    [208]
    [209] The following intermediates were prepared by the method of intermediate A12.
    [210]
    [211] The following intermediates were prepared by the method of intermediate A13.
    [212]
    [213] The following intermediates were prepared by the method of intermediate A14.
    [214]
    [215] The following intermediates were prepared by the method of intermediate A7.
    [216]
    [217] The following intermediates were prepared by the method of intermediate A11.
    [218]
    [219] Intermediate B1-ethyl 2-trifluoromethyl-4-oxopyrimidine-5-carboxylate
    [220]
    [221] To a solution of trifluoroacetamidine (36.5 g) and diethyl ethoxymalonate (71 g) in ethanol (300 ml) was added a solution of sodium ethoxide (21 wt.%, 109.5 ml) in ethanol over 5 minutes. . The mixture was heated to reflux for 6 hours, then cooled, concentrated and water (200 ml) was added. The solid formed was obtained by filtration, washed with cooled water (50 ml) and diethyl ether (2 × 100 ml) and then suspended in water (400 ml). Dichloromethane (300 ml) was added and the mixture was acidified with dilute HCl (2.5 M, 125 ml). The organic extract was washed with water, dried (MgSO 4 ) and evaporated to afford the title compound as a tan solid (53 g, 68%). 1 H-NMR (CDCl 3 ) δ 12.00 (1H, br s), 9.18 (1H, s), 4.57 (2H, q), 1.49 (3H, t); 13 C-NMR (CDCl 3 ) δ 171.4, 167.3, 160.4, 160.2 (q, J = 38 Hz), 118.8 (q, J = 276 Hz), 109.2, 63.8, 14.0; MS (APCI +) found (M + 1) = 237, C 8 H 7 F 3 N 2 O 3 requires 236.
    [222] Intermediate B2-ethyl 2-trifluoromethyl-4-chloropyrimidine-5-carboxylate
    [223]
    [224] Oxalyl chloride (57.4 ml) is added to a solution of ethyl 4-hydroxy-2-trifluoromethylpyrimidine-5-carboxylate (51.8 g) in dichloromethane (600 ml) cooled in an ice bath, followed by dimethyl Formamide (0.2 ml) was added. The mixture was stirred at rt for 16 h and then evaporated. Toluene was added and evaporated. The residue was dissolved in dichloromethane, washed with water, dried (MgSO 4 ) and evaporated to give the title compound as an orange oil (55.7 g, 100%). 1 H-NMR (CDCl 3 ) δ 9.25 (1H, s), 4.51 (2H, q), 1.46 (3H, t); 13 C-NMR (CDCl 3 ) δ 162.0 (2C), 161.1, 158.1 (q, J = 39 Hz), 127.0, 118.9 (q, J = 276 Hz), 63.5, 14.4.
    [225] Intermediate B3-ethyl 2-trifluoromethylpyrimidine-5-carboxylate
    [226]
    [227] Ethyl 4-chloro-2-trifluoromethylpyrimidine-5-carboxylate (55.7 g), 10% palladium on carbon (0.3 g), ethanol (1000 ml) and N, N-diisopropylethylamine (90 ml) mixture was shaken for 2 hours while maintaining at 1 atmosphere under hydrogen pressure. The catalyst was then filtered off and the solvent was evaporated. The residue was dissolved in dichloromethane, washed with ammonium chloride solution, then with water, dried (MgSO 4 ) and evaporated to give the title compound as a dark solid (48 g, 100%). 1 H-NMR (CDCl 3 ) δ9.42 (2H, s), 4.51 (2H, q), 1.45 (3H, t); 13 C-NMR (CDCl 3 ) δ 162.7, 159.4 (2C), 159.3 (q, J = 37 Hz), 126.3, 119.6 (q, J = 275 Hz), 62.9, 14.4.
    [228] Intermediate B4-2-trifluoromethyl-5-formylpyrimidine
    [229]
    [230] A solution of diisobutylaluminum hydride (25% by weight, 31 ml) in ethyl 2-trifluoromethylpyrimidine-5-carboxylate (5.17 g) in toluene (120 ml) cooled with dry ice / acetone was 15 minutes Added over. The mixture was stirred at −78 ° C. for 45 minutes, after which time dilute HCl (2M, 120 ml) was added carefully. The mixture was allowed to warm to room temperature and then diethyl ether was added. The organic phase was separated, washed with water, then brine, dried (MgSO 4 ) and evaporated to afford the title compound as a colorless solid (3.46 g, 84%). 1 H-NMR (CDCl 3 ) δ 10.29 (1H, s), 9.37 (2H, s); 13 C-NMR (CDCl 3 ) δ 187.7, 159.6 (q, J = 38 Hz), 159.1 (2C) 129.6, 119.2 (q, J = 276 Hz).
    [231] Intermediate B5-1- (2-methoxyethyl) pyrazole
    [232]
    [233] 2-bromomethyl methyl ether (10.22 g) was added dropwise with stirring to a mixture of pyrazole (5.0 g), potassium hydroxide fine powder (8.25 g) and tetrabutylammonium bromide (1.19 g), occasionally cooling on ice The temperature was kept below 10 ° C. The mixture was left at room temperature for 48 hours, then purified by silica column and eluted with ether. The product fractions were evaporated to give a pale green oil (7.27 g). 1 H-NMR (CDCl 3 ) δ3.33 (3H, s), 3.75 (2H, t), 4.30 (2H, t), 6.25 (1H, s), 7.47 (1H, d), 7.52 (1H, d ); MS (APCI +) found (M + H) = 127; C 6 H 10 N 2 O Theoretical 126.
    [234] Intermediate B6-1- (2-methoxyethyl) pyrazole-4-carboxaldehyde
    [235]
    [236] A solution of 1- (2-methoxyethyl) pyrazole (7.27 g) in anhydrous DMF (11.4 ml) was heated to 90 ° C., and then phosphorus oxychloride (5.4 ml) was added dropwise over 1 hour but the temperature was 95 to 100 Kept between ° C. After an additional 2 hours of heating, the mixture was cooled and poured into ice. Sodium hydroxide was added to adjust pH to 4, after which the product was extracted with dichloromethane. The organic extract was dried and evaporated to give a brown oil (7.19 g). 1 H-NMR (CDCl 3 ) δ3.34 (3H, s), 3.75 (2H, m), 4.32 (2H, m), 7.98 (1H, s), 8.02 (1H, s), 9.85 (1H, s ).
    [237] Intermediate B10-3- (1-methylpyrazol-4-yl) acrylic acid
    [238]
    [239] A mixture of 1-methylpyrazole-4-carboxaldehyde (85.55 g), malonic acid (80.85 g), pyridine (69.2 ml) and piperidine (1.5 ml) was heated to 110 ° C. under argon for 4 hours. After cooling, water (100 ml) was added followed by an aqueous ammonia solution (75 ml) to give a clear solution which was acidified to pH 1 with hydrochloric acid. The solid formed was filtered off, washed with water and dried to give the title compound (93.5 g). 1 H-NMR (d 6 -DMSO) δ3.83 (3H, s), 6.18 (1H, d), 7.44 (1H, d), 7.83 (1H, s), 8.07 (1H, s). (APCI) found (M + H) = 153. C 7 H 8 N 2 O 2 Theoretical 152.
    [240] Intermediate B11-Methyl 3- (1-methylpyrazol-4-yl) acrylate
    [241]
    [242] 3- (1-methylpyrazol-4-yl) acrylic acid (86.8 g) is added to a solution of sulfuric acid (20 ml) in methanol (690 ml), the mixture is refluxed for 2.5 hours, cooled and then on ice Poured. The acid was neutralized with aqueous sodium hydroxide solution and the product was extracted with dichloromethane, dried and evaporated. Crystallization from ether / essential oil gave methyl 3- (1-methylpyrazol-4-yl) acrylate (89.0 g). 1 H-NMR (d 6 -DMSO) δ 3.77 (3H, s), 3.91 (3H, s), 6.16 (1H, d), 7.54 (1H, s), 7.56 (1H, d), 7.69 (1H , s). (APCI) found (M + H) = 167. C 8 H 10 N 2 O 2 Theoretical 166.
    [243] Intermediate B12-ethyl 3- (5-pyrimidinyl) acrylate
    [244]
    [245] A mixture of 5-bromopyrimidine (5.93 g), ethyl acrylate (5.08 g), palladium acetate (0.112 g), triphenyl phosphine (0.23 g) and triethylamine (4.5 g) in a pressure vessel at 150 ° C Stirred for 6 h. After cooling overnight, water (50 ml) was added to the dark residue and the product was extracted with toluene. Dried, adsorbed with charcoal and evaporated to give a pale oil which is petroleum. Homogenization with ether gave ethyl 3- (5-pyrimidyl) acrylate (4.78 g). 1 H-NMR (CDCl 3 ) δ 1.36 (3H, t), 4.27 (2H, q), 6.59 (1H, d), 7.62 (1H, d), 8.88 (2H, s), 9.20 (1H, s ).
    [246] Intermediate B13-Ethyl 3- (2-methoxypyrimidin-5-yl) acrylate
    [247]
    [248] 2-methoxy-5-bromopyrimidine (75.43 g, 0.399 mol), ethyl acrylate (47.5 ml, 0.439 mol), palladium acetate (II) (1.07 g, 0.0048 mol), tri-o-tolylphosphine (2.92 g, 0.0096 mol) and triethylamine (84 ml) were heated with stirring at 135 ° C. (oil bath temperature) under argon for 12 hours. After allowing to cool, the resulting solid mass was dissolved in water and ethyl acetate, filtered and the aqueous phase was separated and further extracted with ethyl acetate. The extracts were combined, washed with saturated aqueous ammonium chloride solution, dried (MgSO 4 ) and evaporated. The obtained solid was homogenized with ether / light oil (1: 3, 350 ml), filtered, washed and dried to give 52.41 g (63%). 1 H-NMR (CDCl 3 ) δ1.33 (3H, t), 4.06 (3H, s), 4.28 (2H, q), 6.45 (1H, d), 7.58 (1H, d), 8.67 (2H, s ); MS (APCI +) found (M + H) = 209; C 10 H 12 N 2 O 3 Theoretical 208.
    [249] The following intermediates were prepared by the method of intermediate B10 (Knoevenagel).
    [250]
    [251] The following intermediates were prepared by the method of ester B11 (esterification).
    [252]
    [253] The following intermediates were prepared by the method of Intermediate B13 (Acrylic Heck).
    [254]
    [255] Intermediate B20-Methyl 3- (1-methylpyrazol-4-yl) propionate
    [256]
    [257] Hydrogenation of methyl 3- (1-methylpyrazol-4-yl) acrylate (181 g) in methanol (2 liters) on 10% palladium (5.2 g) on charcoal until inhalation stops at 50 ° C./50 psi I was. The catalyst was filtered off, the methanol was removed in vacuo and finally removed by azeotrope with toluene. The title compound was obtained as an oil (179 g). 1 H-NMR (d 6 -DMSO) δ 2.56 (2H, t), 2.79 (2H, t), 3.67 (3H, s), 3.85 (3H, s), 7.17 (1H, s), 7.31 (3H , s). (APCI) M + H = 169. C 8 H 12 N 2 O 2 Theoretical 168.
    [258] Intermediate B21-ethyl 3- (2-methoxypyrimidin-5-yl) propanoate
    [259]
    [260] A suspension of ethyl 3- (2-methoxypyrimidin-5-yl) acrylate (52.4 g, 0.252 mol) in ethanol (400 ml) and triethylamine (50 ml) was added to 10% palladium on carbon (3 g). And hydrogenated at 50 psi for 1.75 h. The catalyst was filtered off through hyflo and the filtrate was evaporated. The residue was dissolved in dichloromethane, washed twice with saturated aqueous ammonium chloride solution, dried (MgSO 4 ) and evaporated to give 41.2 g (78%) of oil. 1 H-NMR (CDCl 3 ) δ1.23 (3H, t), 2.61 (2H, t), 2.87 (2H, t), 3.99 (3H, s), 4.13 (2H, q), 8.39 (2H, s ); MS (APCI +) found (M + H) = 211; C 10 H 14 N 2 O 3 Theoretical 210.
    [261] The following intermediates were prepared by the method of intermediate B20 (ethyl ester in ethanol solvent, methyl ester in methanol solvent).
    [262]
    [263] The following intermediates were prepared by the method of intermediate B21 (ethyl ester in ethanol solvent, methyl ester in methanol solvent).
    [264]
    [265] Intermediate B30-5-((1-methylpyrazol-4-yl) methyl) -2-thiouracil
    [266]
    [267] To a solution of potassium t-butoxide (284 g) in anhydrous THF (1800 ml) with stirring and ice cooling, methyl 3- (1-methylpyrazol-4-yl) propionate in anhydrous diethyl ether (2000 ml) ( 170 g) and a solution of methyl formate (131 ml) were added dropwise over 2 hours under argon. The mixture was then allowed to warm to room temperature and stirring continued for 16 hours. The solvent was evaporated in vacuo to give a pale solid. Methanol (2500 ml) and thiourea (154 g) were added and the mixture was heated to 50 ° C. with vigorous stirring for 16 h. The solvent was evaporated and the light brown solid residue was taken in water (750 ml). The ice cooled solution was adjusted to pH 3 with hydrochloric acid, stirred in an ice bath for 2 hours, after which the precipitate was filtered off and washed with water and ether to give the title compound (120 g). 1 H-NMR (d 6 -DMSO) δ 3.33 (3H, s), 3.75 (3H, s), 7.15 (1H, s), 7.23 (1H, s), 7.46 (1H, s), 12.2 (1H , 12.4 (1H, br). (APCI) M + H = 223. C 9 H 10 N 4 OS theoretical 222.
    [268] Intermediate B31-Ethyl 2-formyl-3- (5-pyrimidyl) propionate
    [269]
    [270] A mixture of ethyl 3- (5-pyrimidyl) propionate (2.28 g) and ethyl formate (1.41 ml) in anhydrous dimethoxyethane (5 ml) was subjected to DME over 30 minutes while maintaining the temperature below 0 ° C. under nitrogen. To dropwise addition of a sodium hydride (60%, 4.0 g) suspension (5 ml). Stirring was continued for an additional 24 hours, after which the mixture was poured into ice and washed with ether. The aqueous layer was adjusted to pH 7 and then evaporated to extract the residue with acetone. Filtration and evaporation gave the crude product which was taken up in ethyl acetate, adsorbed with charcoal, dried and evaporated to give ethyl 2-formyl-3- (5-pyrimidyl) propionate. Like other compounds of this type, it is difficult to characterize and used without further purification.
    [271] Intermediate B32-5- (pyrimid-5-ylmethyl) -2-thiouracil
    [272]
    [273] Sodium (0.25 g) was dissolved in ethanol (5 ml), thiourea (0.77 g) was added and the mixture was stirred under reflux for 1 hour. A solution of ethyl 2-formyl-3- (5-pyrimidyl) propionate (1.99 g) in ethanol (5 ml) was added slowly and refluxing continued for 18 hours. The solvent was evaporated and the residue was taken up in water and washed with dichloromethane. The aqueous layer was adjusted to pH 5 and the precipitate was filtered off, washed with water and dried to give 5- (pyrimid-5-ylmethyl) -2-thiouracil (0.71 g). 1 H-NMR (d 6 -DMSO) δ 3.58 (2H, s), 7.54 (1H, s), 8.70 (2H, s) and 9.02 (1H, s). Melting point 265-6 ° C.
    [274] The following intermediates were prepared by the method of Intermediate B30 (thiouracil).
    [275]
    [276] Intermediate B40-2- (methoxymethylene) -3- (2-methoxypyrimidin-5-yl) propionic acid, methyl / ethyl ester mixture
    [277]
    [278] Methyl formate (1.54 ml) in anhydrous 1,2-dimethoxyethane (6 ml) and in a stirring suspension of sodium hydride (0.83 g dispersed in 60% oil in oil) in anhydrous 1,2-dimethoxyethane (6 ml) and Ethyl 3- (2-methoxypyrimid-5-yl) propionate (3.5 g) solution was added dropwise at a rate such that the reaction temperature was maintained at 25-30 ° C. After 1 hour ether was added and the precipitated oil was allowed to settle completely. The solution was poured off and exchanged with fresh ether to slowly solidify the oil. The solid 2- (hydroxymethylene) derivative was filtered off, washed with ether and dried to give 3.8 g. 1.33 g was divided and suspended in dimethyl formamide (10 ml) with anhydrous potassium carbonate (1.15 g), and a solution of dimethyl sulfate (0.48 ml) in dimethylformamide (10 ml) was added dropwise with stirring over 30 minutes. After 16 hours, the solvent was evaporated and the residue was treated with water and extracted with ethyl acetate. The extract was washed with water, dried (MgSO 4 ) and evaporated to give the product as an oil, yield 0.91 g. 1 H-NMR (CDCl 3 ) δ1.23 (3H, t), 3.46 (2H, s), 3.69 (3H, s, methyl ester), 3.88 (3H, s), 3.97 (3H, s), 4.16 ( 2H, q), 7.39 (1H, s), 8.40 (2H, s). The ratio of methyl: ethyl ester is 3: 2. MS (APCI +) found (M + 1) = 253, 239 (ethyl and methyl ester); C 12 H 16 N 2 O 4 requires 252, C 11 H 14 N 2 O 4 requires 238.
    [279] Intermediate B41-2- (methoxymethylene) -3- (2-methoxypyrimidin-5-yl) propionic acid
    [280]
    [281] A suspension of the ester mixture (0.9 g) of intermediate B40 in 2 M aqueous sodium hydroxide solution (3.6 ml) was stirred at ambient temperature for 16 hours to give a clear solution. It was diluted with water, extracted with dichloromethane and evaporated to about half volume, then acidified with pH 3-4 (2 M hydrochloric acid) to crystallize the product. The white solid was filtered off, washed with ice cold water and dried, yield 0.46 g. 1 H-NMR (CDCl 3 ) δ3.43 (2H, s), 3.91 (3H, s), 3.99 (3H, s), 7.49 (1H, s), 8.42 (2H, s); MS (APCI +) found (M + 1) = 225, C 10 H 12 N 2 O 4 requires 224.
    [282] Intermediate B42-1- (3-ethoxycarbonylprop-1-yl) -5- (2-methoxypyrimid-5-ylmethyl) -2-thiouracil
    [283]
    [284] Oxalyl chloride (3.94 ml, 2 equiv) was added to a solution of intermediate B41 (5.0 g, 1 equiv) and DMF (1 drop) in anhydrous dichloromethane (50 ml) over 5 minutes, after which the mixture was added under 4 with argon. Stir for hours. The solvent was evaporated and the residue was put in dichloromethane and redevaporated twice to remove volatile impurities. The chloride acid was dissolved in acetonitrile (100 ml) and treated with anhydrous potassium thiocyanate powder (3.2 g, 1.5 equiv). The resulting suspension was stirred for 24 h under argon and then evaporated to dryness. The residue is suspended in anhydrous DMF (100 ml), cooled to 10 ° C., ethyl 4-aminobutyrate hydrochloride (4.60 g, 1.25 equiv) and triethylamine (7.34 ml, 2.4 equiv) are added and the mixture Was stirred at RT for 20 h. Sodium methoxide solution (prepared by dissolving sodium (1.26 g, 2.5 equiv) in methanol (25 ml)) was added to the DMF solution and the mixture was heated to 110 ° C. for 2 hours. The solvent was evaporated, water was added, acidified to pH 5 with acetic acid and then the product was extracted with ethyl acetate. Drying, evaporation and homogenization with ether gave a pale brown solid (4.55 g). Some ether / ester exchange takes place during the reaction so that the title compound is obtained as a mixture with about 30% of the corresponding compound of 2-ethoxypyrimidine. 1 H-NMR (DMSO-d 6 ) δ 1.17 (3H, t), 1.31 (t, ethoxy), 1.97 (2H, t), 2.36 (2H, t), 3.49 (s, ethoxy), 3.51 (s, methoxy), 3.88 (s, methoxy), 4.04 (2H, q), 4.16 (2H, t), 4.31 (q, ethoxy), 7.81 (1H, s), 8.48 (s, ethoxy ), 8.50 (s, methoxy), 12.50 (bs, NH) (light brown solid).
    [285] The following intermediates were prepared by the method of intermediate B40.
    [286]
    [287] The following intermediates were prepared by the method of intermediate B41.
    [288]
    [289] The following intermediates were prepared by the method of intermediate B42.
    [290]
    [291] Intermediate B50-2- (4-fluorobenzylthio) -5-((1-methylpyrazol-4-yl) methyl) pyrimidin-4-one
    [292]
    [293] 5-((1-methylpyrazol-4-yl) methyl) -2-thiouracil (118 g), 4-fluorobenzyl chloride (76.8 g), potassium carbonate (183.5 g) and anhydrous DMF (100 ml) The mixture of was stirred for 16 h at 80 ° C. under argon, then cooled and evaporated. The solid residue was suspended by vigorous stirring in water (1500 ml), then acidified to pH 2 with hydrochloric acid and stirred for an additional hour. The white solid was filtered off and washed with water and ether to give the title compound (168 g). 1 H-NMR (d 6 -DMSO) δ 3.47 (2H, s), 3.81 (3H, s), 4.41 (2H, s), 7.19 (2H, s), 7.29 (1H, s), 7.48 (3H , m), 7.84 (1 H, s), 12.74 (1 H, br.s); MS (APCI +) found (M + 1) = 331; C 16 H 15 FN 4 OS Theoretical 330.
    [294] Intermediate B51-1- (3-ethoxycarbonylprop-1-yl) -2- (4-fluorobenzyl) thio-5- (2-methoxy-pyrimid-5-ylmethyl) pyrimidine- 4-on
    [295]
    [296] Intermediate B24 (1.0 g, 1 equiv) in dichloromethane (60 ml) was treated with diisopropylethylamine (0.63 ml, 1.3 equiv) followed by brominated 4-fluorobenzyl (0.38 ml, 1.1 equiv) An orange solution was obtained which was stirred for 4 hours under argon, then washed with water, dried and evaporated. Chromatography (silica, 5% ethanol in ethyl acetate) first eluted the 2-epoxy pyrimidine impurity followed by the title compound (0.35 g). 1 H-NMR (CDCl 3 ) δ 1.25 (3H, t), 2.03 (2H, m), 2.33 (2H, t), 3.64 (2H, s), 3.83 (2H, m), 3.99 (3H, s ), 4.12 (2H, q), 4.47 (2H, s), 6.98 (3H, m), 7.37 (2H, m), 8.46 (2H, s); MS (APCI +) found M + 1 = 473; C 23 H 25 FN 4 O 4 S Theoretical 472 (light waxy solid).
    [297] The following intermediates were prepared by the method of intermediate B50.
    [298]
    [299]
    [300] The following intermediates were prepared by the method of intermediate B51.
    [301]
    [302] Intermediate B70-1- (t-butoxycarbonylmethyl) -2- (4-fluorobenzylthio) -5-((1-methylpyrazol-4-yl) methyl) pyrimidin-4-one
    [303]
    [304] 2- (4-fluorobenzylthio) -5-((1-methylpyrazol-4-yl) methyl) pyrimidin-4-one (175 g), t-butyl iodoacetate (128.3 g), di A mixture of isopropylethylamine (101.5 ml) and dichloromethane (200 ml) was stirred under argon at room temperature for 48 hours. The solution was washed with aqueous sodium bicarbonate solution and then with aqueous ammonium chloride solution, dried and evaporated to pale. A color viscous oil was obtained. Ethyl acetate (300 ml) was added and the precipitate was filtered off and the solution was chromatographed (silica, 2.5% -10% methanol + 0.5% aqueous ammonia solution in dichloromethane). The product fractions were evaporated to give an orange solid which was left to solidify (140 g). 1 H-NMR (d 6 -DMSO) δ 1.36 (9H, s), 3.37 (2H, s), 3.76 (3H, s), 4.42 (2H, s), 4.65 (2H, s), 7.13 (2H , m), 7.23 (1 H, m), 7.45 (4 H, m); MS (APCI +) found (M + 1) = 445; C 22 H 25 FN 4 O 3 S Theoretical 444.
    [305] Intermediate B71-1- (carboxymethyl) -2- (4-fluorobenzylthio) -5-((1-methylpyrazol-4-yl) methyl) pyrimidin-4-one
    [306]
    [307] 1- (t-butoxycarbonylmethyl) -2- (4-fluorobenzylthio) -5-((1-methylpyrazol-4-yl) methyl) pyrimidin-4-one (96.8 g) Dissolve in dichloromethane (195 ml), cool in ice / water, and slowly add trifluoroacetic acid (130 ml) with rapid stirring. After a further 36 hours of stirring, the solvent was evaporated and the glassy residue was homogenized with ether; Yield 78.6 g. 1 H-NMR (d 6 -DMSO) δ 3.36 (2H, s), 3.76 (3H, s), 4.41 (2H, s), 4.67 (2H, s), 7.14 (2H, m), 7.23 (1H , s), 7.43-7.49 (4H, m); MS (APCI +) found (M + 1) = 389; C 18 H 17 FN 4 O 3 S Theoretical 388.
    [308] Intermediate B72-1-ethoxycarbonylmethyl-2- (4-fluorobenzyl) thio-5- (pyrimid-5-ylmethyl) pyrimidin-4-one
    [309]
    [310] A mixture of intermediate B52 (10 g), ethyl bromoacetate (3.38 ml), diisopropylethylamine (5.84 ml) and dichloromethane (50 ml) was stirred overnight, after which the solution was in turn an aqueous solution of ammonium chloride and sodium bicarbonate Washed with aqueous solution. Chromatography (silica, 5-10% methanol in ethyl acetate) was performed and homogenized with ether to give the desired product (7.02 g). 1 H-NMR (CDCl 3 ) δ 1.26 (3H, t), 3.71 (2H, s), 4.26 (2H, q), 4.46 (2H, s), 4.48 (2H, s), 6.91 (1H, s ), 6.98 (2H, m), 7.35 (2H, m), 8.70 (2H, s), 9.09 (1H, s); MS (APCI + ) M + 1 = 415, C 20 H 19 FN 4 O 3 S Theoretical 414. Melting point 145.1 ° C
    [311] Intermediate B73-l-carboxymethyl-2- (4-fluorobenzyl) thio-5- (pyrimid-5-ylmethyl) pyrimidin-4-one
    [312]
    [313] 0.5 M aqueous sodium hydroxide solution (33.8 ml) was added slowly to a solution of intermediate B72 (7.01 g) in dioxane (150 ml). The mixture was stirred for 2.5 hours at room temperature, then the dioxane was evaporated, water was added, and the mixture was acidified with aqueous sodium bisulfate solution. The precipitate was filtered off, washed with water and dried to give the desired product (6.31 g). 1 H-NMR (d 6 -DMSO) δ 3.59 (2H, s), 4.41 (2H, s), 4.67 (2H, s), 7.11 (2H, m), 7.45 (2H, m), 7.72 (1H , s), 8.70 (2H, s), 9.03 (1H, s), 13.55 (1H, bs); MS (APCI-) M-1 = 385, C 18 H 15 FN 4 O 3 S Theoretical 386. Melting point 206-207 ° C.
    [314] Intermediate B74-1-ethoxycarbonylmethyl-2- (4-fluorobenzyl) thio-5- (2-oxopylimide-5-ylmethyl) pyrimidin-4-one
    [315]
    [316] Prepared by the method of Example 21 from intermediate B86, except that only 2 equivalents of B-bromocatecholborane were used. 1 H-NMR (d 6 -DMSO) δ 1.28 (3H, t), 4.26 (4H, q), 4.53 (2H, s), 4.90 (2H, s), 7.26 (2H, m), 7.57 (2H , m), 7.69 (1 H, s), 8.25 (2 H, br.s); MS (APCI +) found (M + 1) = 431; C 20 H 19 FN 4 O 4 S Theoretical 430.
    [317] Intermediate B75-1-ethoxycarbonylmethyl-2- (4-fluorobenzyl) thio-5- (1-ethyl-2-oxopyrimid-5-ylmethyl) pyrimidin-4-one
    [318]
    [319] To a solution of intermediate B74 (3.1 g) in anhydrous dimethylformamide (40 ml) was added ethyl iodide (1.4 g) and anhydrous potassium carbonate (2.5 g) under argon. The mixture was stirred at rt for 20 h and the solvent was removed in vacuo. The residue was separated between ethyl acetate and water. The organic layer was washed with brine and equally divided into three 10 g silica cartridges. Each column was eluted with EtOAc to 18% MeOH: EtOAc and the appropriate fractions were combined to give the title compound. 1 H-NMR (CDCl 3 ) δ1.27t, 1.39t), 3.46 (2H, s), 3.94 (2H, q), 4.25 (2H, q), 4.48 (2H, s), 4.57 (2H, s) , 6.9-7.15 (2H, m), 7.21 (1H, s), 7.3-7.4 (2H, m), 7.9 (1H, m), 8.4 (1H, m), MS (APCI +) found (M + 1 ) = 459; C 22 H 23 FN 4 O 4 S Theoretical 458.
    [320] The following intermediates were prepared by the method of intermediate B70.
    [321]
    [322] The following intermediates were prepared by the method of intermediate B72.
    [323]
    [324] The following intermediates were prepared by the method of intermediate B71.
    [325]
    [326] The following intermediates were prepared by the method of intermediate B73.
    [327]
    [328] Example 1-1- (N-methyl-N- (4- (4-chlorophenyl) benzyl) aminocarbonylmethyl) -2- (4-fluorobenzyl) thio-5- (1-methylpyrazole- 4-ylmethyl) pyrimidin-4-one
    [329]
    [330] Intermediate A2 (0.27 g, 1 equiv), intermediate B71 (0.45 g, 1 equiv), hydroxybenzotriazole (0.018 g, 0.1 equiv), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide ( 0.25 g, 1.1 equiv) and dichloromethane (15 ml) were stirred overnight at room temperature, then diluted with dichloromethane and washed with aqueous sodium bicarbonate solution. The organic layer was immediately placed on a 10 g silica cartridge and eluted with 0-10% methanol in ethyl acetate. The product fractions were evaporated to give an oil which was homogenized with ether to give a white solid (0.39 g). 1 H-NMR (d 6 -DMSO) δ 2.95 and 3.08 (3H, 2Xs), 3.61 (2H, m), 3.86 (3H, m), 4.46-4.61 (6H, m), 6.74 and 6.80 (1H, 2Xs), 6.91-6.99 (2H, m), 7.21-7.49 (12H, m); MS (APCI +) found (M + 1) = 602; C 32 H 29 ClFN 5 O 2 S Theoretical 601.
    [331] Example 2-1- (N-methyl-N- (4- (4-trifluoromethylphenyl) benzyl) aminocarbonylmethyl) -2- (4-fluorobenzyl) thio-5- (1-methylpyra Zol-4-ylmethyl) pyrimidin-4-one
    [332]
    [333] Prepared by the method of Example 1 from intermediates A45 and B71. 1 H-NMR (DMSO) δ 2.96 (3H, s), 3.39 (2H, m), 3.77 (3H, s), 4.43 (2H, s), 4.57 (2H, s), 4.97 (2H, s) , 7.12 (3H, m), 7.25 (1H, s), 7.34-7.48 (6H, m), 7.62-6.70 (2H, m), 8.84 (4H, m) .; MS (APCI +) found (M + 1) = 636; C 33 H 29 F 4 N 5 O 2 S Theoretical 635.
    [334] Example 3-1- (N- (2-dimethylaminoethyl) -N- (4- (4-chlorophenyl) benzyl) aminocarbonylmethyl) -2- (4-fluorobenzyl) thio-5- ( 1-methylpyrazol-4-ylmethyl) pyrimidin-4-one hydrochloride
    [335]
    [336] Prepared by the method of Example 1 from intermediates A61 and B71. 1 H-NMR (CDCl 3 ) δ 2.95 (3H, s), 2.96 (3H, s), 3.19 (2H, m), 3.58 (2H, s), 3.87 (3H, s), 3.91 (2H, m ), 4.42 (2H, s), 4.68 (2H, s), 4.99 (2H, s), 6.88-6.93 (2H, m), 7.25-7.29 (6H, m), 7.36-7.45 (6H, m), 7.62 (1 H, s); MS (APCI +) found (M + 1) = 659; C 35 H 36 ClFN 6 O 2 S Theoretical 658.
    [337] Example 4-1- (N-methyl-N- (4- (4-chlorophenyl) benzyl) aminocarbonylmethyl) -2- (4-fluorobenzyl) thio-5- (2- (4-mor Polyno) pyrimid-5-ylmethyl) pyrimidin-4-one
    [338]
    [339] A solution of intermediate A7 (0.23 g, 1 equiv), intermediate B55 (0.27 g, 1 equiv) and diisopropylethylamine (0.10 g, 1.2 equiv) in anhydrous dichloromethane (6 ml) was stirred at room temperature under argon for 20 hours It was then diluted further by further dichloromethane and washed sequentially with water and aqueous ammonium chloride solution. The organic phase was dried and evaporated followed by chromatography (silica, 0-5% methanol in ethyl acetate) to afford the desired product as a pale solid (0.19 g). 1 H-NMR (DMSO-d 6 ) δ: 2.95 (d, 3H), 3.42 (d, 2H), 3.64 (s, 8H), 4.40 (d, 2H), 4.60 (d, 2H), 4.95 (d , 2H), 7.1 (m, 2H), 7.30 (d, 2H), 7.35-7.6 (m, 6H), 7.65 (m, 3H), 8.30 (s, 2H). MS (APCI +) found (M + 1) = 685/687; C 36 H 34 ClFN 6 O 3 S Theoretical 685.
    [340] Example 5-1- (N- (2- (dimethylamino) ethyl) -N- (4- (4-trifluoromethylphenyl) benzyl) aminocarbonylmethyl) -2- (4-fluorobenzyl) thio -5- (1-methyl-4-pyrazolylmethyl) pyrimidin-4-one
    [341]
    [342] Prepared by the method of Example 1 from intermediates A72 and B71. 1 H-NMR (CDCl 3 ) δ 2.98 (3H, s), 2.99 (3H, s), 3.20 (2H, m), 3.60 (2H, s), 3.93 (5H, m), 4.42 (3H, s ), 4.69 (2H, s), 5.00 (2H, s), 6.89 (2H, m), 7.2-7.3 (4H, m), 7.47 (4H, m), 7.55 (2H, d), 7.70 (3H, m), 11.7 (1 H, broad singlet); MS (APCI +) found (M + 1) = 693; C 36 H 36 F 4 N 6 O 2 S Theoretical 692.
    [343] Example 6- 1- (N- (2- (diethylamino) ethyl) -N- (4- (4-chlorophenyl) benzyl) aminocarbonylmethyl) -2- (4-fluorobenzyl) thio- 5- (1-methyl-4-pyrazolylmethyl) pyrimidin-4-one
    [344]
    [345] Intermediate A3 (82.7 g, 1 equiv), B71 (101.3 g, 1 equiv), hydroxybenzotriazole (39.9 g, 1 equiv), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (100.0 g, 2 equiv) and dichloromethane (1200 ml) were stirred overnight at room temperature under argon, followed by the slow addition of aqueous sodium bicarbonate solution. The organic layer was separated, the aqueous layer extracted twice more with dichloromethane, the organic extracts combined and dried over potassium carbonate and evaporated to give a brown oil. Homogenized with ether to give a solid which was filtered off and purified by silica chromatography eluting with methanol / dichloromethane, then eluting with methanol ammonia / dichloromethane. The product fractions were evaporated to give a yellow foam (98 g). 1 H-NMR (CDCl 3 , rotamomer mixture) δ 0.9-1.0 (6H, m) δ 2.4-2.6 (6H, m), 3.23 / 3.52 (4H, 2x t), 3.58 / 3.61 (4H, 2x s), 3.85 (3H, s), 4.46 / 4.53 / 4.64 / 4.82 (6H, 4x s), 6.75 / 6.79 (1H, 2x s), 6.9 (2H, m), 7.2-7.5 (12H, m); MS (APCI +) found (M + 1) = 687/689; C 37 H 40 ClFN 6 O 2 S requires 686/688.
    [346] Example 7-1- (N- (2- (diethylamino) ethyl) -N- (4- (4-chlorophenyl) benzyl) aminocarbonylmethyl) -2- (4-fluorobenzyl) thio- 5- (1-methyl-4-pyrazolylmethyl) pyrimidin-4-one hydrochloride
    [347] The free base of Example 6 (8.7 g, 1 equiv) was dissolved in dichloromethane (50 ml) and 1M hydrogen chloride (1 equiv) in ether was added dropwise under argon. The mixture was evaporated to about half volume and sonicated to give a clear solution which was transferred to a syringe and added dropwise to ether (200 ml) with vigorous stirring. The resulting white solid was filtered off, washed with ether and dried in vacuo, yield 8.55 g. 1 H-NMR (DMSO, about 2: 1 rotamomer mixture) δ 1.14-1.24 (6H, m), 3.1 (6H, m), 3.6 (2H, m), 3.76 (3H, s), 4.38 / 4.45 (2H, 2x s), 4.61 / 4.70 (2H, 2x s), 4.98 / 5.11 (2H, 2x s), 6.75 / 6.79 (1H, 2x s), 7.1-7.7 (15H, m), 10.15 / 10.75 ( 1H, 2x br s); MS (APCI +) found (M + 1) = 687/689; C 37 H 40 ClFN 6 O 2 S requires 686/688.
    [348] Example 8- 1- (N- (2- (diethylamino) ethyl) -N- (4- (4-chlorophenyl) benzyl) aminocarbonylmethyl) -2- (4-fluorobenzyl) thio- 5- (1-methyl-4-pyrazolylmethyl) pyrimidin-4-one hydrogen stannate
    [349] A solution of L-Tartaric acid (0.75 g, 1 equiv) in 2-propanol (12 ml) was added to the solution of the free base (3.43 g, 1 equiv) of Example 6 in 2-propanol (25 ml) with stirring. The mixture was evaporated to approximately one third volume, diluted with ether, then the solids were filtered off, washed with ether and dried in vacuo, yield 3.87 g. 1 H-NMR (DMSO, approximately 60:40 rotary isomer mixture) δ 0.9-1.1 (6H, m), 2.5-2.8 (4H, m), 3.2-3.4 (6H, m), 3.76 (3H, s) , 4.20 (2H, s), 4.39 / 4.43 (2H, 2x s), 4.60 / 4.67 (2H, 2x s), 4.92 / 5.08 (2H, 2x s), 7.1-7.7 (15H, m); MS (APCI +) found (M + 1) = 687/689; C 37 H 40 ClFN 6 O 2 S requires 686/688.
    [350] Example 9-1- (N- (2- (diethylamino) ethyl) -N- (4- (4-chlorophenyl) benzyl) aminocarbonylmethyl) -2- (4-fluorobenzyl) thio- 5- (1-methyl-4-pyrazolylmethyl) pyrimidin-4-one maleate
    [351] A maleic acid (0.58 g, 1 equiv) solution in methanol (10 ml) was added to the free base solution of Example 6 in stirring methanol (10 ml). The mixture was evaporated to approximately half volume, diluted with ether and then the supernatant was poured off. The oil was homogenized with ether to give a solid which was filtered off, washed with ether and dried under vacuum; Yield 3.69 g. 1 H-NMR (DMSO, approximately 3: 1 rotary isomeric mixture) essentially similar to Example 7, further δ2.33 (3H, s); MS (APCI +) found (M + 1) = 687/689; C 37 H 40 ClFN 6 O 2 S requires 686/688.
    [352] Example 10-1- (N- (2- (diethylamino) ethyl) -N- (4- (4-chlorophenyl) benzyl) aminocarbonylmethyl) -2- (4-fluorobenzyl) thio- 5- (1-methyl-4-pyrazolylmethyl) pyrimidin-4-one mesylate
    [353] Prepared according to the method of Example 9 using methanesulfonic acid (0.32 ml, 1 equiv) instead of maleic acid; Yield 3.59 g. 1 H-NMR (DMSO, approximately 3: 1 rotary isomeric mixture) essentially similar to Example 7, further with δ6.03 (2H, s); MS (APCI +) found (M + 1) = 687/689; C 37 H 40 ClFN 6 O 2 S requires 686/688.
    [354] Example 11- 1- (N- (2- (diethylamino) ethyl) -N- (4- (4-chlorophenyl) benzyl) aminocarbonylmethyl) -2- (4-fluorobenzyl) thio- 5- (1-methyl-4-pyrazolylmethyl) pyrimidin-4-one taurocholate
    [355] Prepared according to the method of Example 9 using taurocholic acid (2.57 g, 1 equiv) instead of maleic acid; Yield 5.56 g. 1 H-NMR (DMSO, approximately 3: 1 rotary isomeric mixture) essentially similar to Example 7, further (especially) δ 0.58 (3H, s), 0.81 (3H, s), 0.91 (3H, d ); MS (APCI +) found (M + 1) = 687/689; C 37 H 40 ClFN 6 O 2 S requires 686/688.
    [356] Example 12-1- (N- (2- (diethylamino) ethyl) -N- (4- (4-trifluoromethylphenyl) benzyl) aminocarbonylmethyl) -2- (4-fluorobenzyl) Thio-5- (1-methyl-4-pyrazolylmethyl) pyrimidin-4-one
    [357]
    [358] Prepared by the method of Example 1 from intermediates A73 and B71. 1 H-NMR (CDCl 3 , rotational isomer) δ 0.9-1.0 (6H, m) δ 2.4-2.6 (6H, m), 3.24 / 3.4-3.6 (4H, 2x m), 3.85 (3H, s) 4.46 / 4.53 / 4.66 / 4.83 (6H, 4x s), 6.75 / 6.8 (1H, 2x s), 6.9-7.0 (2H, m), 7.3-7.7 (12H, m); MS (APCI +) found (M + 1) = 721; C 38 H 40 F 4 N 6 O 2 S Theory 720.
    [359] Example 13-1- (N- (2- (diethylamino) ethyl) -N- (4- (4-trifluoromethylphenyl) benzyl) aminocarbonylmethyl) -2- (4-fluorobenzyl) Thio-5- (1-methyl-4-pyrazolylmethyl) pyrimidin-4-one hydrochloride
    [360] The free base of Example 12 (0.75 g, 1 equiv) was dissolved in dichloromethane (5 ml) and 1 M hydrogen chloride (1 equiv) in ether was added dropwise under argon, then excess ether was added with vigorous stirring. . The white solid was filtered off, washed with ether and dried in vacuo; Yield 0.73 g. 1 H-NMR (DMSO, approximately 3: 1 rotamomer mixture) δ 1.1-1.2 (6H, m), 3.1 (6H, m), 3.37 (2H + H 2 O, m), 3.66 (2H, m) , 3.76 (3H, s), 4.37 / 4.45 (2H, 2x s), 4.63 / 4.72 (2H, 2x s), 4.97 / 5.12 (2H, 2x s), 7.1 (2H, m), 7.24 / 7.26 (1H , 2x s), 7.4-7.5 (6H, m), 6.62 / 6.71 (2H, 2x d), 7.84 (4H, m), 10.1 / 10.65 (1H, 2x br s); MS (APCI +) found (M + 1) = 721; C 38 H 40 F 4 N 6 O 2 S Theoretical 720.
    [361] Example 14- 1- (N- (2- (diethylamino) ethyl) -N- (4- (4-trifluoromethylphenyl) benzyl) aminocarbonylmethyl) -2- (4-fluorobenzyl) Thio-5- (1-methyl-4-pyrazolylmethyl) pyrimidin-4-one hydrogen stannate
    [362] Prepared by the method of Example 8 from the free base of Example 12. 1 H-NMR (DMSO, approximately 60:40 rotary isomer mixture) δ 0.9-1.0 (6H, m), 2.5-2.8 (4H, m), 3.2-3.5 (6H, m), 3.76 (3H, s) , 4.19 (2H, s), 4.38 / 4.43 (2H, 2x s), 4.62 / 4.69 (2H, 2x s), 4.92 / 5.10 (2H, 2x s), 7.0-7.5 (12H, m), 7.6 / 7.7 (1H, 2x d), 7.84 (2H, m); MS (APCI +) found (M + 1) = 721; C 38 H 40 F 4 N 6 O 2 S Theoretical 720.
    [363] Example 15-1- (N- (2- (diethylamino) ethyl) -N- (4- (4-trifluoromethylphenyl) benzyl) aminocarbonylmethyl) -2- (4-fluorobenzyl) Thio-5- (1-methyl-4-pyrazolylmethyl) pyrimidin-4-one citrate
    [364] The free base of Example 12 (0.69 g, 1 equiv) was added to acetone (10 ml) followed by citric acid (0.20 g, 1 equiv). The mixture was warmed to dissolve the solid and then allowed to cool so that the solid was filtered off and dried in vacuo; Yield 0.80 g, 90%, Melting point 130-133 ° C. 1 H-NMR (d 6 -DMSO, approximately 1: 1 rotary isomer mixture) essentially similar to Example 14, further δ2.61 (2H, d); MS (APCI +) found (M + 1) = 721; C 38 H 40 F 4 N 6 O 2 S Theoretical 720.
    [365] Example 16-1- (N- (2- (diethylamino) ethyl) -N- (4- (4-trifluoromethylphenyl) benzyl) aminocarbonylmethyl) -2- (4-fluorobenzyl) Thio-5- (1-methyl-4-pyrazolylmethyl) pyrimidin-4-one tosylate
    [366] The free base of Example 12 (1.0 g, 1 equiv) and tosic acid (0.26 g, 1 equiv) were dissolved in acetone (20 ml) at room temperature and then isopropyl acetate (60 ml) was added with stirring. After stirring for a further 2 hours, the mixture was allowed to stand overnight, after which the resulting solid was filtered off, washed with 3: 1 isopropyl acetate / acetone and dried under vacuum; Yield 0.87 g, Melting point 147 ° C. 1 H-NMR (d 6 -DMSO, approximately 3: 1 rotary isomeric mixture) essentially similar to Example 13, further (particularly) δ 2.28 (3H, s); MS (APCI +) found (M + 1) = 721; C 38 H 40 F 4 N 6 O 2 S Theoretical 720.
    [367] Example 17-1- (N- (2- (diethylamino) ethyl) -N- (2- (4-trifluoromethylphenyl) pyrid-5-ylmethyl) aminocarbonylmethyl) -2- ( 4-fluorobenzyl) thio-5- (1-methyl-4-pyrazolylmethyl) pyrimidin-4-one
    [368]
    [369] Mixture of intermediate A106 (0.523 g, 1 equiv), intermediate B71 (0.473 g, 1 equiv), HATU (0.55 g, 1.2 equiv), diisopropylethylamine (0.622 ml, 2.4 equiv) and dichloromethane (20 ml) Was stirred overnight at room temperature under argon, then washed with aqueous ammonium chloride solution and aqueous ammonium bicarbonate solution. The organic layer was dried and evaporated and the free base product was isolated by chromatography (silica, 3-8% methanol in dichloromethane) as pale foam (0.39 g). 1 H-NMR (CDCl 3 , major isomer) δ 0.94 (6H, t), 2.47 (4H, q), 2.58 (2H, m), 3.26 (2H, m), 3.61 (2H, s), 3.85 (3H, s), 4.52 (2H, s), 4.66 (2H, s), 4.82 (2H, s), 6.78 (1H, s), 6.98 (2H, m), 7.3-7.4 (4H, m), 7.6-7.8 (2H, m), 8.08 (2H, m), 8.57 (1H, m); MS (APCI +) found (M + 1) = 722; C 37 H 39 F 4 N 7 O 2 S Theoretical 721.
    [370] Example 18-1- (N- (2- (diethylamino) ethyl) -N- (2- (4-trifluoromethylphenyl) pyrid-5-ylmethyl) aminocarbonylmethyl) -2- ( 4-fluorobenzyl) thio-5- (1-methyl-4-pyrazolylmethyl) pyrimidin-4-one hydrochloride
    [371] The free base of Example 17 (0.373 g, 1 equiv) was dissolved in dichloromethane (10 ml) and hydrogen chloride (0.517 ml, 1.0 M solution, 1 equiv) in ether was added dropwise with stirring. The solvent was removed in vacuo and the residue was homogenized with ether to give a white solid (0.362 g). 1 H-NMR (DMSO, approximately 60:40 rotamomer mixture) δ1.1-1.3 (6H, m), 3.77 (3H, s), 4.38 / 4.43 (2H, s), 4.65 / 4.76 (2H, s) , 5.00 / 5.08 (2H, s), 7.10 (2H, m), 7.25 (1H, m), 7.3-7.5 (4H, m), 7.78 (1H, m), 7.87 (2H, d), 7.97 / 8.06 (1H, d), 8.28 (2H, d), 8.61 / 8.70 (1H, m); MS (APCI +) found (M + 1) = 722; C 37 H 39 F 4 N 7 O 2 S Theoretical 721.
    [372] Example 19- 1- (N- (2- (diethylamino) ethyl) -N- (2- (4-trifluoromethylphenyl) pyrid-5-ylmethyl) aminocarbonylmethyl) -2- ( 4-fluorobenzyl) thio-5- (1-methyl-4-pyrazolylmethyl) pyrimidin-4-one hydrogen stannate
    [373] Prepared by the method of Example 8 from the free base of Example 17. 1 H-NMR (DMSO, approximately 60:40 rotamomer mixture) δ0.88-1.05 (6H, m), 3.76 (3H, s), 4.39 / 4.42 (2H, s), 4.65 / 4.74 (2H, s) , 4.97 / 5.10 (2H, s), 7.11 (2H, m), 7.25 (1H, m), 7.3-7.5 (4H, m), 7.78 (1H, m), 7.87 (2H, m), 7.98 / 8.07 (1H, d), 8.28 (2H, d), 8.61 / 8.70 (1H, m); MS (APCI +) found (M + 1) = 722; C 37 H 39 F 4 N 7 O 2 S Theoretical 721.
    [374] Example 20-1- (N- (2- (1-piperidino) ethyl) -N- (4- (4-trifluoromethylphenyl) benzyl) aminocarbonylmethyl) -2- (4-fluoro Benzyl) thio-5- (1-methyl-4-pyrazolylmethyl) pyrimidin-4-one hydrogen stannate
    [375]
    [376] A free base was prepared from the intermediates A108 and B71 by the method of Example 1 and then converted to hydrogen stannate by the method of Example 8. 1 H-NMR (DMSO, approximately 60:40 rotary isomeric mixture) δ1.3-1.6 (6H, m) δ2.3-2.7 (6H, m), 3.3-3.6 (4H, m), 3.77 (3H, s ), 4.22 (2H, s), 4.37 / 4.44 (2H, 2x s), 4.62 / 4.69 (2H, 2x s), 4.88 / 5.08 (2H, 2x s), 7.1-7.5 (12H, m), 7.6 / 7.7 (1 H, 2x d), 7.83 (2H, m); MS (APCI +) found (M + 1) = 733; C 39 H 40 F 4 N 6 O 2 S Theoretical 732.
    [377] Example 21-1- (N- (carboxymethyl) -N- (4- (4-trifluoromethylphenyl) benzyl) aminocarbonylmethyl) -2- (4-fluorobenzyl) thio-5- (1 -Methyl-4-pyrazolylmethyl) pyrimidin-4-one sodium salt
    [378]
    [379] Example 102 (130 mg) was added to a solution of sodium bicarbonate (16 mg) in water (4 ml) and stirred at room temperature for 1 hour. A small amount of methanol was added and warmed and sonicated to give a clear solution. Filtration and freeze drying gave the desired sodium salt as a white solid. 1 H-NMR (DMSO) δ 3.49 (2H, s), 3.76 (3H, s), 4.42 (2H, s), 4.85 (2H, s), 7.14 (2H, m), 7.26 (1H, s) , 7.36 (3H, m), 7.49 (3H, m), 7.60 (2H, m), 7.84 (4H, m); MS (APCI-) found (M + 1) = 678; C 34 H 29 F 4 N 5 O 4 S Theoretical 679.
    [380] Example 22-1- (N- (2-aminoethyl) -N- (4- (4-chlorophenyl) benzyl) aminocarbonylmethyl) -2- (4-fluorobenzyl) thio-5- (1 -Methyl-4-pyrazolylmethyl) pyrimidin-4-one hydrochloride
    [381]
    [382] The product protected with Boc was prepared by the method of Example 1 from intermediates A84 and B71, and then the protecting group was removed by suspending in dioxane and treating excess hydrogen chloride (4M solution in dioxane). After stirring for 1 hour, stirring was continued until an excess of ether was added to obtain a fine white solid. It was filtered off, washed with ether and dried to afford the crude product which was purified by chromatography (silica, 10-20% methanol in dichloromethane). 1 H-NMR (DMSO, approximately 60:40 rotamomer mixture) δ 2.97 / 3.04 (2H, m) δ 3.37 (2H, m), 3.55 (2H, m), 3.77 (3H, s), 4.36 / 4.45 (2H, 2x s), 4.60, 4.67 (2H, 2x s), 4.93 / 5.09 (2H, 2x s), 7.0-7.7 (15H, m), 8.05 / 8.20 (2H, 2x br s); MS (APCI +) found (M + 1) = 733; C 39 H 40 F 4 N 6 O 2 S Theoretical 732.
    [383] Example 23-1- (N-methyl-N- (4- (4-chlorophenyl) benzyl) aminocarbonylmethyl) -2- (4-fluorobenzyl) thio-5- (2-oxopyrimid- 5-ylmethyl) pyrimidin-4-one
    [384]
    [385] A mixture of Example 121 (0.73 g, 1.2 mmol), B-bromocatecholborane (1.01 g, 5.1 mmol) and anhydrous dichloromethane (20 ml) was stirred overnight at room temperature under argon to give a clear orange solution. Water was added and stirring continued for 30 minutes, after which the organic layer was separated and immediately placed on a 10 g silica cartridge, which was eluted with 0-14% methanol in dichloromethane. The product fractions were evaporated to give a pale yellow solid (0.36 g). 1 H-NMR (DMSO) δ2.80-3.06 (3H, 2xs), 3.37 (2H, s), 4.33-4.49 (2H, 2xs), 4.50-4.72 (2H, 2xs), 4.87-5.06 (2H, m ), 7.04-7.75 (13H, m), 8.19 (2H, s); MS (APCI-) found (M-1) = 614; C 32 H 27 N 5 O 3 SFCl requires 615.
    [386] The following examples were prepared by the method of Example 1 (EDC coupling) or Example 15 (HATU coupling); If indicated, the salt is prepared in the next step by a suitable method in Examples 7-8.
    [387]
    [388]
    [389]
    [390]
    [391]
    [392]
    [393]
    [394]
    [395]
    [396]
    [397]
    [398]
    [399]
    [400] The following examples were prepared by the method of Example 4; Salts were prepared in the following steps by suitable methods in Examples 7-8.
    [401]
    [402] The following examples were prepared by the method of Example 22; Salts were prepared in the following steps by suitable methods in Examples 7-8.
    [403]
    [404] The following examples were prepared by the method of Example 21.
    [405]
    [406] Biological Data
    [407] 1. Screening for Lp-PLA 2 Inhibition.
    [408] At 37 ° C., by measuring the metabolic rate of artificial substrate (A) in 50 mM HEPES (N-2-hydroxyethylpiperazine-N′-2-ethanesulfonic acid) buffer (pH 7.4) containing 150 mM NaCl Enzyme activity was determined.
    [409]
    [410] Assays were performed in 96 well titration plates.
    [411] Recombinant Lp-PLA 2 was uniformly purified from baculovirus infected Sf9 cells using zinc chelating column, blue sepharose affinity chromatography and anion exchange column. After purification and ultrafiltration, the enzyme was stored at 4 ° C. at a concentration of 6 mg / ml. An assay plate of compound or assay plate of vehicle and buffer was set to a volume of 170 μl using an automated robot. The reaction was initiated by adding 20 μl of the 10 × concentration of substrate (A) to a final substrate concentration of 20 μM and 10 μl of diluted Lp-PLA 2 enzyme to a final concentration of 0.2 nM.
    [412] The reaction was carried out at 450 nm and 37 ° C. using a plate reader equipped with an automatic mixer. The reaction rate was measured as the rate of change of absorbance.
    [413] <Result>
    [414] The compounds described in the examples were tested as described above with IC 50 values between 0.001 and 0.00005 μΜ.
    权利要求:
    Claims (20)
    [1" claim-type="Currently amended] Compound of Formula (I).
    <Formula I>

    Where
    R 1 is C (1-18) alkyl, C (1-18) alkoxy, C (1-18) alkylthio, arylC (1-18) alkoxy, hydroxy, halogen, CN, COR 6 , carboxy, COOR 6 , CONR 9 R 10 , NR 6 COR 7 , SO 2 NR 9 R 10 , NR 6 SO 2 R 7 , NR 9 R 10 , mono to perfluoro-C (1-4) alkyl and mono to perfluoro -C (1-4) alkoxy and optionally substituted by the same or different substituents 1, 2, 3 or 4, or as a single substituent, optionally with additional substituents as defined above, CH 2 COOH or a salt thereof, CH 2 COOR 8 , CH 2 CONR 9 R 10 , CH 2 CN, (CH 2 ) mNR 9 R 10 , (CH 2 ) mOH or (CH 2 ) mOR 6 , wherein m is from 1 to 3 An aryl or heteroaryl group which may be substituted by
    R 2 is C (1-18) alkyl, C (1-18) alkoxy, C (1-18) alkylthio, arylC (1-18) alkoxy, hydroxy, halogen, CN, COR 6 , carboxy, COOR 6 , CONR 9 R 10 , NR 6 COR 7 , SO 2 NR 9 R 10 , NR 6 SO 2 R 7 , NR 9 R 10 , mono to perfluoro-C (1-4) alkyl, mono to perfluoro Is an aryl or heteroaryl group selected from -C (1-4) alkoxy and acylC (1-4) alkyl and optionally substituted by the same or different substituents 1, 2, 3 or 4;
    R 3 is hydrogen or hydroxy, OR 6 , COR 6 , carboxy, COOR 6 , CONR 9 R 10 , NR 9 R 10 , mono- or di- (hydroxyC (1-6) alkyl) amino or N - hydroxyl and hydroxy C (1-6) alkyl, -NC (1-6) alkylamino, C (1-4) that can be unsubstituted or substituted by alkyl,
    R 4 is C (1-18) alkyl, C (1-18) alkoxy, C (1-18) alkylthio, arylC (1-18) alkoxy, hydroxy, halogen, CN, COR 6 , carboxy, COOR 6 , CONR 9 R 10 , NR 6 COR 7 , SO 2 NR 9 R 10 , NR 6 SO 2 R 7 , NR 9 R 10 , mono to perfluoro-C (1-4) alkyl and mono to perfluoro -C (1-4) is an aryl or heteroaryl group selected from alkoxy and optionally substituted by the same or different substituents 1, 2, 3 or 4,
    R 5 is C (1-18) alkyl, C (1-18) alkoxy, C (1-18) alkylthio, arylC (1-18) alkoxy, hydroxy, halogen, CN, COR 6 , carboxy, COOR 6 , CONR 9 R 10 , NR 6 COR 7 , SO 2 NR 9 R 10 , NR 6 SO 2 R 7 , NR 9 R 10 , mono to perfluoro-C (1-4) alkyl and mono to perfluoro -C (1-4) is an aryl ring selected from alkoxy and optionally further substituted by the same or different substituents 1, 2, 3 or 4,
    R 6 and R 7 are independently hydrogen or C (1-20) alkyl, for example C (1-4) alkyl (eg methyl or ethyl),
    R 8 is C (1-4) alkyl, or a pharmaceutically acceptable in vivo hydrolyzable ester group,
    R 9 and R 10 are the same or different and are each selected from hydrogen, C (1-12) alkyl, CH 2 R 11 , CHR 12 CO 2 H or salts thereof, or R 9 and R 10 are bonded to them Together with nitrogen, it may optionally contain one or more heteroatoms selected from oxygen, nitrogen and sulfur, and include hydroxy, oxo, C (1-4) alkyl, C (1-4) alkylCO, aryl (eg 4- to 7-membered, preferably 5- to 7-membered rings (eg, phenyl) or optionally substituted by one or two substituents selected from aralkyl (e.g. benzyl) Morpholine or piperazine),
    R 11 is COOH or a salt thereof, COOR 8 , CONR 6 R 7 , CN, CH 2 0H or CH 2 0R 6 ,
    R 12 is an amino acid side chain such as CH 2 OH from serine,
    n is an integer from 1 to 4, preferably 1 or 3,
    X is O or S,
    Z is CR 13 R 14 , wherein R 13 and R 14 are each hydrogen or C (1-4) alkyl, or R 13 and R 14 together form a C (3-6) cycloalkyl ring via a carbon atom; Can be formed.
    [2" claim-type="Currently amended] The compound of formula I according to claim 1, wherein Z is CH 2 .
    [3" claim-type="Currently amended] 3. The hetero according to claim 1, wherein R 1 is an aryl group selected from phenyl and naphthyl or comprises a 5- or 6-membered monocyclic heteroaryl group containing 1 or 2 nitrogen heteroatoms. A compound of formula (I) which is an aryl group.
    [4" claim-type="Currently amended] 4. The compound of claim 1, wherein R 1 is oxo, arylC (1-4) alkyl, C (1-6) alkyl, C (3-6) cycloalkyl, hydroxy, C ( 1-4) 1 selected from alkoxy, carboxyC (1-6) alkyl, C (1-6) alkylcarboxyC (1-6) alkyl, di-C (1-6) alkylamino and morpholino A compound of formula (I ) which is pyrimidyl, which may be optionally substituted by two substituents, or pyrazolyl, which may be optionally substituted by C (1-6) alkyl.
    [5" claim-type="Currently amended] The compound of claim 4, wherein ZR 1 is pyrimid-5-ylmethyl, which may be optionally substituted by 2-methoxy, 2-trifluoromethyl, 2- (4-morpholino) or 2-dimethylamino; 2-oxo-pyrimid-5-ylmethyl; Or 1-methyl-4-pyrazolylmethyl.
    [6" claim-type="Currently amended] The compound of formula I according to any one of claims 1 to 5, wherein X is S.
    [7" claim-type="Currently amended] The compound according to any one of claims 1 to 6, wherein R 2 is an aryl group selected from phenyl and naphthyl, or pyridyl, pyrimidinyl, pyrazolyl, furanyl, thienyl, thiazolyl, quinolyl And a heteroaryl group selected from benzothiazolyl, pyridazolyl and pyrazinyl.
    [8" claim-type="Currently amended] The method of claim 7, wherein the phenyl of the formula Ⅰ that R 2 may be optionally substituted by halogen.
    [9" claim-type="Currently amended] 9. The compound of claim 1, wherein R 3 is hydrogen; And amino, C (1-3) alkylamino, diC (1-3) alkylamino, hydroxy C (1-3) alkylamino, hydroxy, C (1-3) alkoxy, carboxy, C (1- 3) A compound of formula I selected from methyl, ethyl and propyl, which may optionally be substituted by alkylcarboxy and heterocyclyl.
    [10" claim-type="Currently amended] The compound of formula (I) according to claim 1, wherein R 4 is selected from phenyl, thiophene, pyridine and pyrimidine, which may be optionally substituted by halogen.
    [11" claim-type="Currently amended] The compound of formula I according to any one of claims 1 to 10, wherein R 5 is phenyl optionally substituted by halogen, trifluorophenyl or trifluoromethoxy.
    [12" claim-type="Currently amended] 12. The formula of claim 10 or 11, wherein R 4 and R 5 together form a 4- (phenyl) phenyl substituent, wherein the outer phenyl ring may be optionally substituted by halogen or trifluoromethyl. Compound of I.
    [13" claim-type="Currently amended] A compound of formula (I) as claimed in claim 1 and named in any of Examples 1 to 157.
    [14" claim-type="Currently amended] The method of claim 13,
    1- (N-methyl-N- (4- (4-chlorophenyl) benzyl) aminocarbonylmethyl) -2- (4-fluorobenzyl) thio-5- (1-methylpyrazol-4-ylmethyl Pyrimidin-4-one,
    1- (N-methyl-N- (4- (4-trifluoromethylphenyl) benzyl) aminocarbonylmethyl) -2- (4-fluorobenzyl) thio-5- (1-methylpyrazole-4- Ylmethyl) pyrimidin-4-one,
    1- (N- (2-dimethylaminoethyl) -N- (4- (4-chlorophenyl) benzyl) aminocarbonylmethyl) -2- (4-fluoro-benzyl) thio-5- (1-methyl Pyrazol-4-ylmethyl) pyrimidin-4-one,
    1- (N-methyl-N- (4- (4-chlorophenyl) benzyl) aminocarbonylmethyl) -2- (4-fluorobenzyl) thio-5- (2- (4-morpholino) pyridine Mid-5-ylmethyl) pyrimidin-4-one,
    1- (N- (2- (dimethylamino) ethyl) -N- (4- (4-trifluoromethylphenyl) benzyl) aminocarbonylmethyl) -2- (4-fluorobenzyl) thio-5- ( 1-methyl-4-pyrazolylmethyl) pyrimidin-4-one,
    1- (N- (2- (diethylamino) ethyl) -N- (4- (4-chlorophenyl) benzyl) aminocarbonylmethyl) -2- (4-fluorobenzyl) thio-5- (1 -Methyl-4-pyrazolylmethyl) pyrimidin-4-one,
    1- (N- (2- (diethylamino) ethyl) -N- (2- (4-trifluoromethylphenyl) pyrid-5-ylmethyl) aminocarbonylmethyl) -2- (4-fluoro Benzyl) thio-5- (1-methyl-4-pyrazolylmethyl) pyrimidin-4-one,
    1- (N- (2- (1-piperidino) ethyl) -N- (4- (4-trifluoromethylphenyl) benzyl) aminocarbonylmethyl) -2- (4-fluorobenzyl) thio- 5- (1-methyl-4-pyrazolylmethyl) pyrimidin-4-one hydrogen stannate,
    1- (N- (carboxymethyl) -N- (4- (4-trifluoromethylphenyl) benzyl) aminocarbonylmethyl) -2- (4-fluorobenzyl) thio-5- (1-methyl-4 Pyrazolylmethyl) pyrimidin-4-one sodium salt, and
    1- (N- (2- (diethylamino) ethyl) -N- (4- (4-trifluoromethylphenyl) benzyl) aminocarbonylmethyl) -2- (4-fluorobenzyl) thio-5- (1-methyl-4-pyrazolylmethyl) pyrimidin-4-one, or a pharmaceutically acceptable salt thereof, including hydrochloride, hydrogen stannate, citrate and tosylate salt thereof.
    [15" claim-type="Currently amended] A pharmaceutical composition comprising a compound of formula (I) as claimed in claim 1 and a pharmaceutically acceptable carrier.
    [16" claim-type="Currently amended] The compound of formula I according to claim 1 for use in therapy.
    [17" claim-type="Currently amended] Use of a compound of formula (I) as claimed in claim 1 in the manufacture of a medicament for the treatment of atherosclerosis.
    [18" claim-type="Currently amended] A method of treating a disease comprising administering to a patient in need thereof a treatment for a disease associated with the activity of Lp-PLA 2 enzyme.
    [19" claim-type="Currently amended] A method of treating atherosclerosis comprising administering an effective amount of a compound of formula (I) and statin as claimed in claim 1 to a patient in need of treatment of atherosclerosis.
    [20" claim-type="Currently amended] (a) reacting a compound of formula II with a compound of formula III under amide forming conditions,
    <Formula II>

    Wherein X, Y, Z, R 1 and R 2 are as defined in claim 1
    <Formula III>

    Wherein R 3 , R 4 and R 5 are as defined in claim 1
    (b) reacting a compound of formula IV with a compound of formula V in an inert solvent in the presence of a base such as a secondary or tertiary amine,
    <Formula IV>

    Wherein X, Z, R 1 and R 2 are as defined in claim 1
    <Formula Ⅴ>

    Wherein R 3 , R 4 and R 5 are as defined in claim 1 and L 1 is a leaving group such as halogen.
    (c) when X is S, reacting a compound of formula VI with a compound of formula VII in an inert solvent in the presence of a base such as a secondary or tertiary amine, or
    <Formula VI>

    Wherein n, Z, R 1 , R 3 , R 4 and R 5 are as defined in claim 1
    <Formula Ⅶ>

    Wherein R 2 and L 1 are as defined in claim 1
    (d) reacting a compound of formula (VII) with a compound of formula (VII) in an inert solvent in the presence of a base when X is O
    <Formula Ⅷ>

    Wherein n, Z, R 1 , R 3 , R 4 and R 5 are as defined in claim 1 and L 2 is a leaving group.
    <Formula Ⅸ>

    Wherein R 2 is as defined in claim 1
    A method of preparing a compound of formula I as claimed in claim 1.
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    1999-05-01|Priority to GB9910048.9
    1999-05-01|Priority to GB9910048A
    2000-01-28|Priority to GB0002096.6
    2000-01-28|Priority to GB0002096A
    2000-04-25|Application filed by 피터 기딩스, 스미스클라인비이참피이엘시이
    2000-04-25|Priority to PCT/EP2000/003727
    2002-02-15|Publication of KR20020012200A
    优先权:
    申请号 | 申请日 | 专利标题
    GB9910048.9|1999-05-01|
    GB9910048A|GB9910048D0|1999-05-01|1999-05-01|Novel compounds|
    GB0002096.6|2000-01-28|
    GB0002096A|GB0002096D0|2000-01-28|2000-01-28|Novel compounds|
    PCT/EP2000/003727|WO2000066567A1|1999-05-01|2000-04-25|Pyrimidinone compounds|
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