Bicyclic Pyrimidine Derivatives And Their Use As Anti-Coagulants

专利摘要:
The present invention relates to bicyclic pyrimidine derivatives of formulas (I) and (II) below which are useful as anticoagulants. <Formula I> <Formula II> Wherein A is -O-, -N (R 5 )-or -S (O) n- , where n is 0, 1 or 2; Z 1 and Z 2 are independently —O—, —N (R 5 ) — or —OCH 2 —. The invention also relates to pharmaceutical compositions comprising the compounds of the invention, and to methods of using the compounds of the invention to treat disease states characterized by thrombosis activity.
公开号:KR20000068173A
申请号:KR1019997001281
申请日:1997-08-14
公开日:2000-11-25
发明作者:마이클 엠. 모리세이；브래드 버크만；라주 모한
申请人:에바-마리아 시마-메이어, 얼설라 멜져, 마거, 하르트만；쉐링 악티엔게젤샤프트；
IPC主号:

专利说明:

Bicyclic pyrimidine derivatives and their use as anticoagulants {Bicyclic Pyrimidine Derivatives And Their Use As Anti-Coagulants}
Factor Xa is a member of the trypsin-like serine protease family of enzymes. One-to-one binding of factors Xa and Va with calcium ions and phospholipids forms a prothrombinase complex to convert prothrombin to thrombin. Thrombin also converts fibrinogen to fibrin and polymerizes to form insoluble fibrin.
The prothrombinase complex in the coagulation cascade is the point of convergence of the intrinsic (surface activated) and non-essential (vascular damage-tissue factor) pathways (see Biochemistry (1991), Vol. 30, p. 10363; and Cell (1988), Vol. 53, pp. 505-518). The coagulation cascade model has been further refined by discovering the mode of action of tissue factor pathway inhibitors (TFPI) (Seminars in Hematology (1992), Vol. 29, pp. 159-161). TFPI is a cyclic multi-domain serine protease inhibitor with three Kunitz-like serpin domains that compete with factor Va for free factor Xa. Once formed, the bicomponent complexes of Factor Xa and TFPI become potential inhibitors of Factor VIIa and tissue factor complexes.
Factor Xa may be activated in the coagulation cascade by two separate complexes, the tissue factor-VIIa complex on the “Xa rupture” pathway and the Factor IXa-VIIIA complex (TENase) of the “sustained Xa” pathway. After vascular injury, the "Xa rupture" pathway is activated through tissue factor (TF). Coagulation cascades are upregulated through enhanced factor Xa production via the “sustained Xa” pathway. The coagulation cascade is down regulated by the formation of the factor Xa-TFPI complex, which not only eliminates factor Xa but also further inhibits factor formation via the "Xa rupture" pathway. Thus, coagulation cascades are naturally regulated by factor Xa.
To prevent coagulation, a first advantage of the method of inhibiting factor Xa on thrombin is the role of the factor Xa on a number of thrombin functions. Thrombin not only catalyzes the conversion of fibrinogen to fibrin, the conversion of factor VIII to factor VIIIA, the conversion of factor V to factor Va and the conversion of factor XI to factor XIa, but also activates platelets and is a monocyte chemotactic factor, Mitogen for lymphocytes and smooth muscle cells. When thrombin binds to thrombomodulin, it activates the in vivo anticoagulant inactivators of proteins C, factors Va and VIIIa. In circulation, thrombin is rapidly inactivated by antithrombin III (ATIII) and heparin cofactor II (HCII) in reactions catalyzed by heparin or other proteoglycan bound glycosaminoglycans, while thrombin in tissues is protease nexin Inactivated by Thrombin is via a unique "binding ligand" thrombin receptor that requires the same anionic binding site and active site that utilizes multiple cell activation functions in fibronogen binding and cleavage (Cell (1991), Vol. 64, p. 1057 ), And thrombomodulin binding and protein C activation. Thus, various groups of molecular targets in vivo compete for binding to thrombin, and the physiological consequences of successive proteolysis will vary considerably depending on the cell type and the receptor, modulator, substrate or inhibitor that binds the thrombin.
Published data using protein antistacins and tick anticoagulant peptides (TAPs) indicate that Factor Xa inhibitors are effective anticoagulants (Thrombosis and Haemostasis (1992), Vol. 67, pp. 371-376; and Science (1990), Vol. 248, pp. 593-596).
The active site of factor Xa may be blocked by either a mechanism based inhibitor and a dense binding inhibitor (a tight binding inhibitor is different from a mechanism based inhibitor because there is no covalent bond between the enzyme and the inhibitor). Two types of mechanism based inhibitors are known, reversible and irreversible, which are characterized by easy hydrolysis of enzyme-inhibitor bonds (Thrombosis Res (1992), Vol. 67, pp. 221-231; and Trends Pharmacol Sci. (1987), Vol. 8, pp. 303-307). A series of guanidino compounds are examples of dense bound inhibitors (Thrombosis Res. (1980), Vol. 19, pp. 339-349). Arylsulfonyl-arginine-piperidinecarboxylic acid derivatives are also known as thrombin (Biochem. (1984), Vol. 23, pp. 85-90), as well as 3-amidinophenylaryl derivatives (Thrombosis Res. (1983). ), Vol. 29, pp. 635-642) and bis (amidino) benzyl cycloketones (Thrombosis Res. (1980), Vol. 17, pp. 545-548) It has been shown to be a tightly bound inhibitor. However, these compounds appear to have poor selectivity for factor Xa.
<Related literature>
EP-A-0 540 051 (Nagahara et al.) Describes aromatic amidine derivatives which have been mentioned which can exhibit potent anticoagulant effects through reversible inhibition of factor Xa.
The synthesis of α, α'-bis (amidinobenzylidene) cycloalkanones and α, α'-bis (amidinobenzyl) cycloalkanones is described in Pharmazie (1977), Vol. 32, no. 3, pp. 141-145. These compounds are described as being serine protease inhibitors.
<Summary of invention>
The present invention relates to a compound or a pharmaceutically acceptable salt thereof useful as a drug component for the treatment of a disease state characterized by thrombosis activity by inhibiting human factor Xa.
Thus, in one aspect, the present invention provides a compound as a single stereoisomer or mixture thereof, or a pharmaceutically acceptable salt thereof, selected from the group consisting of the following formulas (I) and (II).
Where
A is -O-, -N (R ⁵ )-or -S (O) _n- , where n is 0, 1 or 2;
Z ¹ and Z ² are independently —O—, —N (R ⁵ ) — or —OCH ₂ —;
R ¹ and R ⁴ are each independently hydrogen, halo, alkyl, -OR ⁸ , -C (O) OR ⁸ , -C (O) N (R ⁸ ) R ⁹ , -N (R ⁸ ) R ⁹ ,- N (R ⁸ ) C (O) R ⁹ or —N (H) S (O) ₂ R ¹¹ ;
R ² is -C (NH) NH ₂ , -C (NH) N (H) OR ⁸ , -C (NH) N (H) C (O) OR ¹¹ , -C (NH) N (H) C ( O) R ⁸ , -C (NH) N (H) S (O) ₂ R ¹¹ or -C (NH) N (H) C (O) N (H) R ⁸ ;
R ³ is halo, alkyl, haloalkyl, haloalkoxy, cyano, ureido, guanidino, -OR ⁸ , -C (NH) NH ₂ , -C (NH) N (H) OR ⁸ , -C ( O) N (R ⁸ ) R ⁹ , -R ¹⁰ -C (O) N (R ⁸ ) R ⁹ , -CH (OH) C (O) N (R ⁸ ) R ⁹ , -N (R ⁸ ) R ⁹ , -R ¹⁰ -N (R ⁸ ) R ⁹ , -C (O) OR ⁸ , -R ¹⁰ -C (O) OR ⁸ , -N (R ⁸ ) C (O) R ⁸ , (1,2 ) -Tetrahydropyrimidinyl (optionally substituted by alkyl), (1,2) -imidazolyl (optionally substituted by alkyl) or (1,2) -imidazolinyl (optionally substituted by alkyl) );
R ⁵ is hydrogen, alkyl, aryl (halo, alkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl or dialkyl, respectively) Optionally substituted by aminocarbonyl) or aralkyl (halo, alkyl, aryl, hydroxy, alkoxy, aralkyl, amino, dialkylamino, monoalkylamino, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylamino Carbonyl or optionally substituted by dialkylaminocarbonyl);
R ⁶ is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, cycloalkyl, cycloalkylalkyl, -C (O) OR ⁸ , -R ¹⁰ -C (O) OR ⁸ , -R ^10- C (O) N (R ⁸ ) R ⁹ , -C (O) -R ¹⁰ -N (R ⁸ ) R ⁹ , -R ¹⁰ -C (O) R ⁸ , -R ¹⁰ -C (O) N ( R ⁸ ) N (R ⁸ ) R ⁹ , -R ¹⁰ -C (R ⁸ ) (OR ⁹ ) -R ¹⁰ -N (R ⁸ ) (R ⁹ ), -C (R ⁸ ) (OR ⁸ ) C ( O) OR ⁹ , -R ¹⁰ -C (R ⁸ ) (C (O) OR ⁹ ) ₂ , -C (R ⁸ ) (N (R ⁸ ) R ⁹ ) C (O) OR ⁸ , -R ^10- C (R ⁸ ) (N (R ⁸ ) R ⁹ ) C (O) OR ⁸ , -C (R ⁸ ) (OR ⁸ ) R ⁹ , -R ¹⁰ -N (R ⁸ ) R ⁹ , -R ^10- N (R ⁸ ) C (O) OR ¹¹ , -R ¹⁰ -N (R ⁸ ) C (0) R ⁹ , -R ¹⁰ -N (R ⁸ ) C (NR ⁸ ) R ¹¹ , -R ¹⁰ -N (R ⁸ ) S (O) ₂ R ¹¹ , -R ¹⁰ -N (R ⁸ ) C (O) N (R ⁸ ) R ⁹ , -R ¹⁰ -N (R ⁸ ) C (NR ⁸ ) N (R ⁸ ) R ⁹ , -R ¹⁰ -N (R ⁸ ) C (NR ⁸ ) N (R ⁸ ) N (R ⁸ ) R ⁹ , -R ¹⁰ -N (R ⁸ ) -R ¹⁰ -C (R ⁸ ) (N (R ⁸ ) R ⁹ ) C (O) OR ⁸ , -R ¹⁰ -N (R ⁸ ) S (O) R ⁹ , -R ¹⁰ OR ⁸ , -R ¹⁰ -ON (R ⁸ ) C (NR ⁸ ) N (R ⁸ ) R ⁹ , -R ¹⁰ -OS (O) ₂ OR ⁸ , -R ¹⁰ -P (O) (OR ⁸ ) R ⁹ , -R ¹⁰ -OP (O) (OR ⁸ ) ₂ , -R ¹⁰ -P (O) (OR ⁸ ) ₂ , -R ¹⁰ -SR ⁸ , -R ¹⁰ -SR ¹⁰ -C (O) OR ⁸ , -R ¹⁰ -SR ¹⁰ -N (R ⁸ ) R ⁹ , -R ¹⁰ -SR ¹⁰ -C (R ⁸ ) (N (R ⁸ ) R ⁹ ) C (O) OR ⁸ , -R ¹⁰ -SR ¹⁰ -N (R ⁸ ) C (O) OR ⁸ , -R ¹⁰ -SR ¹⁰ -N (R ⁸ ) C (O) R ⁸ , -R ¹⁰ -SSR ¹⁰ -C (R ⁸ ) (N (R ⁸ ) R ⁹ ) C (O) OR ⁸ , -R ¹⁰ -SC (O) N (R ⁸ ) R ⁹ , -R ¹⁰ -SC (S) N (R ⁸ ) R ⁹ , -R ^10- S (O) R ⁸ , -R ¹⁰ -S (O) ₂ R ¹¹ , -R ¹⁰ -S (O) OR ⁸ , -R ¹⁰ -S (O) ₂ OR ⁸ , -R ¹⁰ -S (O) ₂ N (R ⁸ ) R ⁹ or —R ¹⁰ —S (O) (NR ⁸ ) R ⁹ ; or
R ⁶ is aryl (alkyl, halo, haloalkyl, haloalkoxy, -OR ⁸ , -SR ⁸ , -N (R ⁸ ) R ⁹ , -C (O) OR ⁸ , -C (O) N (R ⁸ ) R ⁹ , -S (O) ₂ OR ⁸ and -OP (O) (OR ⁸ ) ₂ optionally substituted with one or more substituents selected from the group consisting of; or
R ⁶ is aralkyl (alkyl, halo, haloalkyl, haloalkoxy, -OR ⁸ , -SR ⁸ , -N (R ⁸ ) R ⁹ , -C (O) OR ⁸ , -C (O) N (R ⁸ ) R ⁹ , -S (O) ₂ OR ⁸ and -OP (O) (OR ⁸ ) ₂ optionally substituted with one or more substituents selected from the group consisting of; or
R ⁶ is heterocyclyl (alkyl, halo, haloalkyl, haloalkoxy, aralkyl, -OR ⁸ , -C (O) OR ⁸ , -N (R ⁸ ) R ⁹ , -C (O) N (R ⁸ ) R ⁹ , -S (O) ₂ OR ⁸ and -OP (O) (OR ⁸ ) ₂ optionally substituted with one or more substituents selected from the group consisting of; or
R ⁶ is heterocyclylalkyl (the heterocyclyl radical is alkyl, halo, haloalkyl, haloalkoxy, aralkyl, -OR ⁸ , -SR ⁸ , -C (O) OR ⁸ , -N (R ⁸ ) R ⁹ , -C (O) N (R ⁸ ) R ⁹ , -S (O) ₂ OR ⁸ and -OP (O) (OR ⁸ ) ₂ optionally substituted with one or more substituents selected from the group consisting of; or
R ⁶ is adamantyl (alkyl, halo, haloalkyl, haloalkoxy, -OR ⁸ , -SR ⁸ , -C (O) OR ⁸ , -N (R ⁸ ) R ⁹ , -C (O) N (R ⁸ ) R ⁹ , -S (O) ₂ OR ⁸ and -OP (O) (OR ⁸ ) ₂ optionally substituted; or
R ⁶ is adamantylalkyl (the adamantyl radicals are alkyl, halo, haloalkyl, haloalkoxy, -OR ⁸ , -SR ⁸ , -C (O) OR ⁸ , -N (R ⁸ ) R ⁹ ,- C (O) N (R ⁸ ) R ⁹ , optionally substituted by —S (O) ₂ OR ⁸ and —OP (O) (OR ⁸ ) ₂ ;
R ⁷ is hydrogen, alkyl, cycloalkyl, aralkyl or aryl;
R ⁸ and R ⁹ are each independently hydrogen, alkyl, aryl (halo, alkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylamino Optionally substituted by carbonyl or dialkylaminocarbonyl) or aralkyl (halo, alkyl, aryl, hydroxy, alkoxy, aralkyl, amino, dialkylamino, monoalkylamino, carboxy, alkoxycarbonyl, aminocarbon Optionally substituted by carbonyl, monoalkylaminocarbonyl or dialkylaminocarbonyl);
R ¹⁰ is a straight or branched alkylene chain;
R ¹¹ is alkyl, aryl (halo, alkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl or dialkylaminocarbonyl Optionally substituted by) or aralkyl (halo, alkyl, aryl, hydroxy, alkoxy, aralkyl, amino, dialkylamino, monoalkylamino, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl or Optionally substituted with dialkylaminocarbonyl).
In another aspect, the present invention provides a treatment for a human with a disease characterized by thrombotic activity, comprising a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient as described above. Provides useful compositions.
In another aspect, the present invention provides a method for treating a diseased human characterized by thrombotic activity comprising administering to a human being in need thereof a therapeutically effective amount of a compound of the invention as described above. .
In another aspect, the invention provides a method of treating a human with a disease alleviated by inhibition of Factor Xa, comprising administering to a human being in need thereof a therapeutically effective amount of a compound of the invention as described above. to provide.
In another aspect, the invention provides a method of inhibiting human factor Xa in vitro or in vivo by administering a compound of the invention.
The present invention relates to bicyclic pyrimidine derivatives and their pharmaceutically acceptable salts which are useful as anticoagulants by inhibiting the enzyme factor Xa. The invention also relates to pharmaceutical compositions comprising said derivatives or pharmaceutically acceptable salts thereof, and methods of use thereof.
<Justice>
As used in the specification and the appended claims, unless otherwise indicated, the meanings of the following terms are as follows:
"Alkyl" means straight or branched monovalent or divalent radicals containing no unsaturated groups and consisting solely of carbon and hydrogen having 1 to 6 carbon atoms, for example methyl, ethyl, n-propyl, 1-methylethyl (iso-propyl ), n-butyl, n-pentyl, 1,1-dimethylethyl (tertiary butyl) and the like.
"Alkenyl" means a straight or branched chain monovalent or divalent radical containing only one or more double bonds and consisting only of carbon and hydrogen having 1 to 6 carbon atoms, for example ethenyl, prop-1-enyl, but-1 -Enyl, pent-1-enyl, penta-1,4-dienyl and the like.
"Alkynyl" means a straight or branched chain monovalent or divalent radical containing only one or more triple bonds and consisting only of carbon and hydrogen having 1 to 6 carbon atoms, for example ethynyl, prop-1-ynyl, but-1 -Inyl, pent-1-ynyl, pent-3-ynyl and the like.
“Alkoxy” means a radical of the formula —OR _a, wherein R _a is as defined above, for example methoxy, ethoxy, n-propoxy, 1-methylethoxy (iso-propoxy), n-butoxy, n-pentoxy, 1,1-dimethylethoxy (tertiary butoxy) and the like.
"Alkoxycarbonyl" means a radical of the formula -C (O) OR _a where R _a is as defined above, such as methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, Iso-propoxycarbonyl, tert-butoxycarbonyl and the like.
"Alkylene" means a straight or branched chain divalent radical containing no unsaturated group and consisting only of carbon and hydrogen having 1 to 6 carbon atoms, for example methylene, ethylene, propylene, n-butylene and the like.
"Amidino" means the radical -C (NH) -NH ₂ .
"Aminocarbonyl" means the radical -C (O) NH ₂ .
"Aryl" means a phenyl or naphthyl radical.
"Aralkyl" means a radical, such as benzyl, of the formula -R _a R _b , wherein R _a is as defined above and R _b is aryl as defined above.
"Aralkoxy" means a radical of the formula -OR _c, wherein R _c is aralkyl as defined above, for example benzyloxy and the like.
By "cycloalkyl" is meant a stable, 3- to 7-membered monocyclic cyclic radical, saturated, consisting only of carbon and hydrogen atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
"Cycloalkylalkyl" means an alkyl radical as defined above, such as (cyclobutyl) methyl, 2- (cyclopentyl) ethyl, 3- (cyclohexyl), substituted by a cycloalkyl radical as defined above Profile, etc.
"Dialkylamino" means a radical of the formula -NR _a R _a , wherein R _a is each independently an alkyl radical as defined above, for example dimethylamino, methylethylamino, diethylamino, dipropyl Amino, ethylpropylamino and the like.
"Dialkylaminocarbonyl" means a radical of the formula -C (O) NR _a R _a , wherein R _a is each independently an alkyl radical as defined above, for example dimethylaminocarbonyl, methylethyl Aminocarbonyl, diethylaminocarbonyl, dipropylaminocarbonyl, ethylpropylaminocarbonyl and the like.
"Halo" means bromo, iodo, chloro or fluoro.
"Haloalkyl" means an alkyl radical as defined above, ie substituted by one or more halo radicals as defined above, for example trifluoromethyl, difluoromethyl, trichloromethyl, 2-trifluoro Ethyl, 3-bromo-2-fluoropropyl, 1-bromomethyl-2-bromoethyl, and the like.
"Haloalkenyl" means an alkenyl radical as defined above, ie substituted by one or more halo radicals as defined above, for example 2-difluoroethenyl, 3-bromo-2-fluoro Rope-1-enyl, etc. are meant.
“Haloalkoxy” means a radical of the formula —OR _f, wherein R _f is haloalkyl as defined above, for example trifluoromethoxy, difluoromethoxy, trichloromethoxy, 2-trifluoro Ethoxy, 1-fluoromethyl-2-fluoroethoxy, 3-bromo-2-fluoropropoxy, 1-bromomethyl-2-bromoethoxy, and the like.
"Heterocyclyl" is saturated or unsaturated, is composed of carbon atoms, has 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein nitrogen, carbon or sulfur atoms can be optionally oxidized, It means a stable 3- to 10-membered monocyclic or bicyclic radical which may optionally be quaternized. Heterocyclyl radicals can be attached to the main structure at any heteroatom or carbon atom to form a stable structure. Examples of such heterocyclic radicals include piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazinyl, azepinyl, pyrrolyl , 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxa Zolidinyl, triazolyl, indanyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, isoindoleyl, indole Linyl, isoindolinyl, octahydroindolyl, octahydroisoindolyl, quinolyl, isoquinolyl, decahydroisoquinolyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzoxazolyl , Furyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothienyl, thiamor Rinil, thiazol-morpholinyl sulfoxide, sulfone and thiazol-morpholinyl include, but oxadiazolyl, they only are not limited. Preferred heterocyclyl radicals in the present invention are indolyl, imidazolyl, thiazolyl, isoxazolyl, triazolyl, pyridinyl, thienyl, benzothienyl, furyl and 3,4-dihydro-2,3-di Oxo-1 (2H) -pyrimidinyl.
“Heterocyclylalkyl” means a radical of the formula —R _a R _g , wherein R _a is an alkyl radical as defined above and R _g is a heterocyclyl radical as defined above, for example indole Linylmethyl or imidazolylmethyl and the like.
"(1,2) -imidazolyl" means an imidazolyl radical attached at the 1- or 2-position.
"(1,2) -imidazolinyl" means a 4,5-dihydroimidazolyl radical attached at the 1- or 2-position.
"Monoalkylamino" means _a radical of the formula -NHR _a , wherein R _a is an alkyl radical as defined above, for example methylamino, ethylamino, propylamino and the like.
“Monoalkylaminocarbonyl” means _a radical of the formula —C (O) NHR _a , wherein R _a is an alkyl radical as defined above, for example methylaminocarbonyl, ethylaminocarbonyl, propylamino Carbonyl and the like.
"(1,2) -tetrahydropyrimidinyl" means tetrahydropyrimidinyl attached at the 1- or 2-position.
"Adamantylalkyl" means a radical of the formula -R _a R _h , wherein R _a is an alkyl radical as defined above and R _h is an adamantyl radical, for example adamantylmethyl, 2 -Adamantyl ethyl, etc. are meant.
"Any" or "optionally" means that the case of a continuously described environment may or may not occur, so that the above description includes the above case or when the environment occurs and when it does not occur. For example, "optionally substituted aryl" means that the aryl radical may or may not be substituted, and that the description includes both substituted and unsubstituted aryl radicals.
"Pharmaceutically acceptable salts" include both acid and base addition salts.
"Pharmaceutically acceptable acid addition salts" retain the biological effectiveness and properties of the free base and are not biologically or otherwise undesirable, and include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, acetic acid, tri Organic such as fluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc. It means salts formed with acid.
"Pharmaceutically acceptable base addition salt" means a salt that retains the biological effectiveness and properties of the free acid and which is not biologically or otherwise undesirable. These salts are prepared by adding an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like. Preferred inorganic salts are the ammonium, sodium, potassium, calcium and magnesium salts. Salts derived from organic bases include primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and isopropylamine, trimethylamine, diethylamine, triethylamine, Tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, trimethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine Salts of basic ion exchange resins such as, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethamine, dicyclohexylamine, choline and caffeine.
By "therapeutically effective amount" is meant an amount of a compound of the invention sufficient to treat a disease state characterized by thrombogenic activity when administered to a human in need as defined below. The amount of a compound of the present invention that constitutes a "therapeutically effective amount" will vary depending on the compound, the disease state and its severity, and the age of the human to be treated, but can be routinely determined by him regarding the knowledge of the person skilled in the art and the disclosure herein. have.
As used herein, “treating” or “treatment” includes the treatment of a disease state characterized by thrombosis activity in humans,
(i) preventing such a condition from occurring in a human, especially when such a human is susceptible to a disease state but is not yet diagnosed with a disease,
(ii) inhibit a disease state, ie stop its development, or
(iii) alleviate the disease state, i.e. cause regression of the disease state;
It is included.
The yield of each of the reactions described herein is expressed as theoretical yield (%).
The compounds of the present invention or their pharmaceutically acceptable salts may have asymmetric carbon atoms of their structure. Thus, the compounds of the present invention and their pharmaceutically acceptable salts may exist as single stereoisomers, racemates, and mixtures of enantiomers and diastereomers. Such single stereoisomers, racemates and mixtures thereof are all intended to be included within the scope of this invention.
Note that when R ¹ is the same substituent as R ⁴ , R ² is the same substituent as R ^3, and Z ¹ and Z ² are the same, the compound of formula I is identical to the compound of formula II.
For compounds of the invention, R ¹ is at the 2-position of the phenyl group; R ² is at the 3-, 4- or 5-position of the phenyl group; R ³ is at the 3-, 4- or 5-position of the phenyl group; It is preferable that R ⁴ is present at the 2-position of the phenyl group.
The nomenclature used herein indicates that the compound of the present invention is 6 (5H) -phthalinone, 5H-pyrimido [4,5-b] [1,4] oxazine-6 (7H) -one or 5H-pyrimido [ A derivative of 4,5-b] [1,4] thiazin-6 (7H) -one, which is a modified form of the IUPAC system named according to "A". For example, A is -N (H)-; Z ¹ and Z ² are both —O—; R ¹ is hydrogen; R ² is —C (NH) NH ₂ ; R ³ is —C (O) N (CH ₃ ) ₂ ; R ⁴ is hydrogen; R ⁵ is hydrogen; R ⁶ is benzyl; Compounds of formula I wherein R ⁷ is hydrogen, for example

Is 2- (2-hydroxy-5-amidinophenoxy) -4- (3-dimethylaminocarbonylphenoxy) -7-benzyl-1,7-dihydro-6 (5H)-puteri It is named as dinon.
<Availability and Administration>
A. Usability
Since the compounds of the present invention are inhibitors of factor Xa, they are useful in disease states characterized by thrombosis activity based on their role in the coagulation cascade of factor Xa (see background art above). The first precursor to the compound is prevention during long-term risks involving myocardial infarction. A further precursor is the prevention of deep vein thrombosis (DVT) with orthopedic surgery or the prevention of selected patients with transient ischemia development. The compounds of the present invention may also be useful for prognostics that typically use coumadine, such as for DVT, or for other types of surgical interventions such as circuit composition and percutaneous coronary angioplasty. The compounds may also be used for thrombotic complications associated with acute promyelocytic leukemia, diabetes, complex myeloma, catabolic intravascular coagulation associated with septic shock, blunting purpura associated with infection, adult respiratory distress syndrome, unstable angina, and aortic valves or blood vessels. Useful for the treatment of complications and associated thrombosis complications. The compounds of the invention are also useful for the prevention of thrombosis diseases, especially in patients at high risk of developing such diseases.
The compounds of the present invention are also useful as in vitro diagnostic reagents for selectively inhibiting factor Xa without inhibiting other components of the coagulation cascade.
B. test
The first bioassay used to demonstrate the inhibitory effect on the factor Xa of the compounds of the present invention is a simple pigment productivity assay comprising only the serine protease, the compound of the present invention to be tested, the substrate and the buffer (see, eg, literature references). Thrombosis Res. (1979), Vol. 16, pp. 245-254). For example, four tissue human serine proteases can be used in the first bioassay, free factor Xa, prothrombinase, thrombin (IIa) and tissue plasminogen activator (tPA). Assays for TPA have been used successfully before exhibiting undesirable side effects in the inhibition of the fibrinolytic process (see, for example, J. Med. Chem. (1993), Vol. 36, pp. 314). -319]. Another bioassay useful in demonstrating the utility of the compounds of the invention in the inhibition of factor Xa shows the compound potential for free factor Xa in citrated plasma. For example, the anticoagulant efficacy of a compound of the present invention will be tested using either prothrombin time (PT) or activated partial thromboplastin time (aPTT), while the selectivity of the compound is determined by the thrombin clotting time ( TCT) is analyzed and checked. The correlation of K _i in the first enzyme assay with K _i for free factor Xa in citrated plasma will be screened for compounds that interact with or are inactivated by other plasma components. The interrelationship of K _i with PT extension is an essential in vitro demonstration of changing the potential in the free factor Xa inhibition assay to the potential in a clinical coagulation assay. PT can also be extended in citrated plasma to determine action time in continuous pharmacokinetic studies.
For further information in assays to indicate the activity of the compounds of the present invention, see R. Lottenberg et al., Methods in Enzymology (1981), Vol. 80, pp. 341-361 and H. Ohno et al., Thrombosis Research (1980), Vol. 19, pp. 579-588.
C. General Administration
Administration of the compounds of the present invention or their pharmaceutically acceptable salts, either in pure form or in the form of a suitable pharmaceutical composition, can be carried out using any of the dosage forms or ingredients permitted to provide similar utility. Thus, for example, oral, nasal, parenteral, topical, transdermal or rectal, and for example tablets, suppositories, pills, soft elastic capsules, hard gelatin capsules, powders, solutions, suspensions or aerosols. Solid, semi-solid, lyophilized powder or liquid formulations, such as agents, may be administered, preferably in unit dosage forms suitable for simple administration of the correct dosage. The composition will comprise a conventional pharmaceutical carrier or excipient and a compound of the invention as an active ingredient, and may also include other pharmaceutical ingredients, pharmaceutical ingredients, carriers, adjuvants and the like.
Typically, depending on the intended mode of administration, the pharmaceutically acceptable composition will contain from about 1 to about 99 weight percent of the compound (s) or pharmaceutically acceptable salts thereof of the present invention and from 99 to 1 Will contain by weight of suitable pharmaceutical excipients. Preferably, the composition will contain about 5 to 75% by weight of the compound (s) or pharmaceutically acceptable salts thereof of the present invention, with the remainder being suitable pharmaceutical excipients.
The preferred route of administration is oral using a convenient daily dosage regimen that can be adjusted according to the severity of the disease state to be treated. For such oral administration, pharmaceutically acceptable compositions containing a compound (s) of the present invention or a pharmaceutically acceptable salt thereof may be, for example, pharmaceutical grade mannitol, lactose, starch, pregelatinized It is formed by incorporating any of the commonly used excipients such as starch, magnesium stearate, sodium saccharin, talc, cellulose ether derivatives, glucose, gelatin, sucrose, citrate, propyl gallate and the like.
Preferably, since such compositions will take capsule, caplet or tablet formulations, they may also contain diluents such as lactose, sucrose, dicalcium phosphate and the like; Disintegrants such as croscarmellose sodium or derivatives thereof; Lubricants such as magnesium stearate and the like; And binders such as starch, gum arabic, polyvinylpyrrolidone, gelatin, cellulose ether derivatives and the like.
The compounds of the present invention or their pharmaceutically acceptable salts can also be used, for example, in carriers which dissolve slowly in the body, for example polyoxyethylene glycol and polyethylene glycol (PEG), for example PEG 1000 (96%) and About 0.5 to about 50% of the active ingredient deposited in PEG 4000 (4%) can be formulated as a suppository.
Pharmaceutically administrable liquid compositions include, for example, the compound (s) (about 0.5 to about 20%) or pharmaceutically acceptable salts thereof, and any pharmaceutical adjuvant, for example water, It can be prepared by forming a solution or suspension by dissolving, dispersing, or the like in a carrier such as saline, aqueous dextrose solution, glycerol, ethanol and the like.
In some cases, pharmaceutical compositions of the present invention may also contain small amounts of wetting agents, such as citric acid, sorbitan monolaurate, triethanolamine oleate, butylated hydroxytoluene, etc., emulsifiers, pH buffers, antioxidants, and the like. It may contain auxiliary substances.
The actual method of preparation of such formulations is known or will be apparent to those skilled in the art; See, eg, Remington's Pharmaceutical Sciences, 18th Ed., (Mack Publishing Company, Easton, Pennsylvania, 1990). In any case, the composition to be administered will contain a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof for the treatment of a disease state alleviated by inhibiting factor Xa in accordance with the teachings of the present invention.
The compounds of the present invention or their pharmaceutically acceptable salts include the activity of the specific compound employed, the metabolic stability and length of action of the compound, age, weight, general health, sex, diet, mode of administration, time of administration, excretion rate, drug combination, It will vary depending on various factors, including the severity of the particular disease state, and the host who performed the treatment. Typically, a therapeutically effective daily dosage will be from about 0.14 to about 14.3 mg / kg body weight per day of a compound of the invention or a pharmaceutically acceptable salt thereof; Preferably, about 0.7 to about 10 mg / kg body weight per day; Most preferably, about 1.4 to about 7.2 mg / kg body weight per day. For example, when administered to 70 kg of adult, the dosage is about 10 mg to about 1.0 g / day of the compound of the present invention or a pharmaceutically acceptable salt thereof, preferably about 50 to about 700 mg / day, most Preferably about 100 to about 500 mg / day.
<Desirable aspect>
Among the compounds of the present invention as described above in the Summary of the Invention, preferred groups A are -O- or -N (R ⁵ )-; Z ¹ and Z ² are both —O—; R ¹ and R ⁴ are each independently hydrogen, halo or -OR ⁸ ; R ² is —C (NH) NH ₂ , —C (NH) N (H) S (O) ₂ R ¹¹ or —C (NH) N (H) C (O) N (H) R ⁸ ; R ³ is ureido, guanidino, -OR ⁸ , -C (O) N (R ⁸ ) R ⁹ , -N (R ⁸ ) R ⁹ , -C (O) OR ⁸ , -N (R ⁸ ) C (O) R ⁸ , (1,2) -tetrahydropyrimidinyl (optionally substituted by alkyl), (1,2) -imidazolyl (optionally substituted by alkyl) or (1,2) Imidazolinyl (optionally substituted by alkyl); Each R ⁵ is hydrogen, alkyl, aryl (optionally substituted by halo) or aralkyl (optionally substituted by halo); R ⁶ is hydrogen, alkyl, -R ¹⁰ -C (O) OR ⁸ , -R ¹⁰ -C (O) N (R ⁸ ) R ⁹ , -R ¹⁰ -C (R ⁸ ) (C (O) OR ⁹ ) ₂ , -R ¹⁰ -N (R ⁸ ) R ⁹ , -R ¹⁰ -N (R ⁸ ) C (NR ⁸ ) R ¹¹ , -R ¹⁰ -N (R ⁸ ) C (O) N (R ⁸ ) R ⁹ , -R ¹⁰ -N (R ⁸ ) C (NR ⁸ ) N (R ⁸ ) R ⁹ , -R ¹⁰ OR ⁸ , -R ¹⁰ -OP (O) (OR ⁸ ) ₂ , -R ¹⁰ -SR ⁸ or -R ¹⁰ -S (O) ₂ R ¹¹ ; Or R ⁶ is aryl (optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, haloalkoxy and -OR ⁸ ); Or R ⁶ is aralkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, haloalkoxy and -OR ⁸ ); Or R ⁶ is heterocyclyl, optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, haloalkoxy and -OR ⁸ ; Or R ⁶ is heterocyclylalkyl, wherein the heterocyclyl radical is optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, haloalkoxy or -OR ⁸ ; R ⁷ is hydrogen, alkyl, cycloalkyl, aralkyl or aryl; R ⁸ and R ⁹ are each independently hydrogen, alkyl, aryl (optionally substituted by halo, alkyl, hydroxy or alkoxy) or aralkyl (optionally substituted by halo, alkyl, hydroxy or alkoxy); R ¹⁰ is a straight or branched alkylene chain; R ¹¹ is alkyl, aryl (optionally substituted by halo, alkyl, hydroxy or alkoxy) or aralkyl (optionally substituted by halo, alkyl, hydroxy or alkoxy).
Among these groups of compounds, preferred subgroups of compounds are those wherein A is -N (R ⁵ )-; Z ¹ and Z ² are both —O—; R ¹ and R ⁴ are each independently hydrogen or —OR ⁸ ; R ² is —C (NH) NH ₂ ; R ³ is -C (O) N (R ⁸ ) R ⁹ , (1,2) -tetrahydropyrimidinyl (optionally substituted by alkyl), (1,2) -imidazolyl (optionally by alkyl Substituted) or (1,2) -imidazolinyl (optionally substituted by alkyl); R ⁵ is hydrogen, alkyl, aryl (optionally substituted by halo) or aralkyl (optionally substituted by halo), respectively; R ⁶ is hydrogen, alkyl, -R ¹⁰ -C (O) OR ⁸ , -R ¹⁰ -C (O) N (R ⁸ ) R ⁹ , -R ¹⁰ -C (R ⁸ ) (C (O) OR ⁹ ) ₂ , -R ¹⁰ -N (R ⁸ ) R ⁹ , -R ¹⁰ -N (R ⁸ ) C (NR ⁸ ) R ¹¹ , -R ¹⁰ -N (R ⁸ ) C (O) N (R ⁸ ) R ⁹ , -R ¹⁰ -N (R ⁸ ) C (NR ⁸ ) N (R ⁸ ) R ⁹ , -R ¹⁰ OR ⁸ , -R ¹⁰ -OP (O) (OR ⁸ ) ₂ , -R ¹⁰ -SR ⁸ or -R ¹⁰ -S (O) ₂ R ¹¹ ; Or R ⁶ is aralkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, haloalkoxy and -OR ⁸ ); Or R ⁶ is imidazolylalkyl or indolylalkyl; R ⁷ is hydrogen or alkyl; R ⁸ and R ⁹ are each independently hydrogen, alkyl, aryl or aralkyl; R ¹⁰ is a straight or branched alkylene chain; R ¹¹ is a subgroup that is alkyl or aryl.
Among the subgroups of compounds, the preferred kind of compounds is that R ¹ is -OR ⁸ ; R ² is —C (NH) NH ₂ ; R ³ is -C (O) N (R ⁸ ) R ⁹ , (1,2) -imidazolyl (optionally substituted by methyl) or (1,2) -imidazolinyl (optionally substituted by methyl ); Each R ⁵ is hydrogen, alkyl, aryl or aralkyl; R ⁶ is hydrogen, alkyl, -R ¹⁰ -C (O) OR ⁸ , -R ¹⁰ -C (O) N (R ⁸ ) R ⁹ , -R ¹⁰ -C (R ⁸ ) (C (O) OR ⁹ ) ₂ , -R ¹⁰ -N (R ⁸ ) R ⁹ , -R ¹⁰ -N (R ⁸ ) C (NR ⁸ ) R ¹¹ , -R ¹⁰ -N (R ⁸ ) C (O) N (R ⁸ ) R ⁹ , -R ¹⁰ -N (R ⁸ ) C (NR ⁸ ) N (R ⁸ ) R ⁹ , -R ¹⁰ OR ⁸ , -R ¹⁰ -OP (O) (OR ⁸ ) ₂ , -R ¹⁰ -SR ⁸ or -R ¹⁰ -S (O) ₂ R ¹¹ ; Or R ⁶ is aralkyl (optionally substituted by one or more substituents selected from the group consisting of methyl and hydroxy); Or R ⁶ is imidazolylalkyl or indolylalkyl; R ⁷ is hydrogen or alkyl; R ⁸ and R ⁹ are each independently hydrogen, alkyl, aryl or aralkyl; R ¹⁰ is a straight or branched alkylene chain; R ¹¹ is alkyl or aryl.
Among the above kinds of compounds, preferred subclasses of compounds are those wherein A is -N (H)-; Z ¹ and Z ² are both —O—; R ¹ is hydroxy; R ² is —C (NH) NH ₂ ; R ³ is —C (O) N (CH ₃ ) ₂ ; R ⁴ , R ⁵ , R ⁶ and R ⁷ are subclasses which are hydrogen.
Preferred compounds of this subclass of compounds are those selected from formula I, i.e. 2- (2-hydroxy-5-amidinophenoxy) -4- (3- (dimethylaminocarbonyl) phenoxy) -1,7- Dihydro-6 (5H) -pteridinone.
Another preferred compound of this class of compounds is a compound selected from Formula II, namely 2- (3-dimethylaminocarbonylphenoxy) -4- (2-hydroxy-5-cyanophenoxy) -1,7- Dihydro-6 (5H) -pteridinone.
Another preferred subgroup of compounds is that A is -O-; Z ¹ and Z ² are both —O—; R ¹ and R ⁴ are each independently hydrogen or —OR ⁸ ; R ² is —C (NH) NH ₂ ; R ³ is -C (O) N (R ⁸ ) R ⁹ , (1,2) -tetrahydropyrimidinyl (optionally substituted by alkyl), (1,2) -imidazolyl (optionally by alkyl Substituted) or (1,2) -imidazolinyl (optionally substituted by alkyl); R ⁵ is hydrogen, alkyl, aryl (optionally substituted by halo) or aralkyl (optionally substituted by halo); R ⁶ is hydrogen, alkyl, -R ¹⁰ -C (O) OR ⁸ , -R ¹⁰ -C (O) N (R ⁸ ) R ⁹ , -R ¹⁰ -C (R ⁸ ) (C (O) OR ⁹ ) ₂ , -R ¹⁰ -N (R ⁸ ) R ⁹ , -R ¹⁰ -N (R ⁸ ) C (NR ⁸ ) R ¹¹ , -R ¹⁰ -N (R ⁸ ) C (O) N (R ⁸ ) R ⁹ , -R ¹⁰ -N (R ⁸ ) C (NR ⁸ ) N (R ⁸ ) R ⁹ , -R ¹⁰ OR ⁸ , -R ¹⁰ -OP (O) (OR ⁸ ) ₂ , -R ¹⁰ -SR ⁸ or -R ¹⁰ -S (O ₂ ) R ¹¹ ; Or R ⁶ is aralkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, haloalkoxy and -OR ⁸ ); Or R ⁶ is imidazolylalkyl or indolylalkyl; R ⁷ is hydrogen or alkyl; R ⁸ and R ⁹ are each independently hydrogen, alkyl, aryl or aralkyl; R ¹⁰ is a straight or branched alkylene chain; R ¹¹ is a subgroup that is alkyl or aryl.
Among the subgroups of compounds, the preferred kind of compounds is that R ¹ is -OR ⁸ ; R ² is —C (NH) NH ₂ ; R ³ is -C (O) N (R ⁸ ) R ⁹ , (1,2) -imidazolyl (optionally substituted by methyl) or (1,2) -imidazolinyl (optionally substituted by methyl ); R ⁵ is hydrogen, alkyl, aryl or aralkyl; R ⁶ is hydrogen, alkyl, -R ¹⁰ -C (O) OR ⁸ , -R ¹⁰ -C (O) N (R ⁸ ) R ⁹ , -R ¹⁰ -C (R ⁸ ) (C (O) OR ⁹ ) ₂ , -R ¹⁰ -N (R ⁸ ) R ⁹ , -R ¹⁰ -N (R ⁸ ) C (NR ⁸ ) R ¹¹ , -R ¹⁰ -N (R ⁸ -C (O) N (R ⁸ ) R ⁹ , -R ¹⁰ -N (R ⁸ ) C (NR ⁸ ) N (R ⁸ ) R ⁹ , -R ¹⁰ OR ⁸ , -R ¹⁰ -OP (O) (OR ⁸ ) ₂ , -R ¹⁰ -SR ⁸ or -R ¹⁰ -S (O) ₂ R ¹¹ ; or R ⁶ is aralkyl (optionally substituted by one or more substituents selected from the group consisting of methyl and hydroxy); or R ⁶ is imidazolylalkyl Or indolylalkyl; R ⁷ is hydrogen or alkyl; R ⁸ and R ⁹ are each independently hydrogen, alkyl, aryl or aralkyl; R ¹⁰ is a straight or branched alkylene chain; R ¹¹ is alkyl or It is a kind that is aryl.
Among the above kinds of compounds, preferred subclasses of the compounds are those wherein A is -O-; Z ¹ and Z ² are both —O—; R ¹ is hydroxy; R ² is —C (NH) NH ₂ ; R ³ is —C (O) N (CH ₃ ) ₂ ; R ⁴ , R ⁵ , R ⁶ and R ⁷ are subclasses which are hydrogen.
Preferred compounds of this subclass of compounds are those selected from formula I, namely 2- (2-hydroxy-5-amidinophenoxy) -4- (3- (dimethylaminocarbonyl) phenoxy) -5H-pyrimido [4,5-b] [1,4] oxazine-6 (7H) -one.
<Preparation of the compound of the present invention>
It is understood that combinations of substituents and / or variables (eg, R ⁶ and R ⁷ ) of the compounds described in the following description may be acceptable only if such combinations result in stable compounds.
A. Preparation of Compound of Formula (Ia)
Compounds of formula (Ia) are compounds of formula (I) wherein A is -N (H)-, Z ¹ and Z ² are both -O-, and R ² is -C (NH) NH ₂ . These compounds can be prepared as described in Scheme 1 below, wherein R ¹ and R ⁴ are each independently hydrogen, halo, alkyl, -OR ⁸ , -C (O) OR ⁸ , -C (O) N (R ⁸ ) R ⁹ , -N (R ⁸ ) R ⁹ , -N (R ⁸ ) C (O) R ⁹ or -N (H) S (O) ₂ R ¹¹ ; R ³ is halo, alkyl, haloalkyl, haloalkoxy, cyano, ureido, guanidino, -OR ⁸ , -C (NH) NH ₂ , -C (NH) N (H) OR ⁸ , -C ( O) N (R ⁸ ) R ⁹ , -R ¹⁰ -C (O) N (R ⁸ ) R ⁹ , -CH (OH) C (O) N (R ⁸ ) R ⁹ , -N (R ⁸ ) R ⁹ , -R ¹⁰ -N (R ⁸ ) R ⁹ , -C (O) OR ⁸ , -R ¹⁰ -C (O) OR ⁸ , -N (R ⁸ ) C (O) R ⁸ , (1,2 ) -Tetrahydropyrimidinyl (optionally substituted by alkyl), (1,2) -imidazolyl (optionally substituted by alkyl) or (1,2) -imidazolinyl (optionally substituted by alkyl) ); R ⁵ is hydrogen, alkyl, aryl (halo, alkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl or dialkylamino Optionally substituted by carbonyl) or aralkyl (halo, alkyl, aryl, hydroxy, alkoxy, aralkyl, amino, dialkylamino, monoalkylamino, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbons) Optionally substituted with carbonyl or dialkylaminocarbonyl); R ⁶ is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, cycloalkyl, cycloalkylalkyl, -C (O) OR ⁸ , -R ¹⁰ -C (O) OR ⁸ , -R ^10- C (O) N (R ⁸ ) R ⁹ , -C (O) -R ¹⁰ -N (R ⁸ ) R ⁹ , -R ¹⁰ -C (O) R ⁸ , -R ¹⁰ -C (O) N ( R ⁸ ) N (R ⁸ ) R ⁹ , -R ¹⁰ -C (R ⁸ ) (OR ⁹ ) -R ¹⁰ -N (R ⁸ ) (R ⁹ ), -C (R ⁸ ) (OR ⁸ ) C ( O) OR ⁹ , -R ¹⁰ -C (R ⁸ ) (C (O) OR ⁹ ) ₂ , -C (R ⁸ ) (N (R ⁸ ) R ⁹ ) C (O) OR ⁸ , -R ^10- C (R ⁸ ) (N (R ⁸ ) R ⁹ C (O) OR ⁸ , -C (R ⁸ ) (OR ⁸ ) R ⁹ , -R ¹⁰ -N (R ⁸ ) R ⁹ , -R ¹⁰ -N (R ⁸ ) C (O) OR ¹¹ , -R ¹⁰ -N (R ⁸ ) C (O) R ⁹ , -R ¹⁰ -N (R ⁸ ) C (NR ⁸ ) R ¹¹ , -R ¹⁰ -N ( R ⁸ ) S (O) ₂ R ¹¹ , -R ¹⁰ -N (R ⁸ ) C (O) N (R ⁸ ) R ⁹ , -R ¹⁰ -N (R ⁸ ) C (NR ⁸ ) N (R ⁸ R ⁹ , -R ¹⁰ -N (R ⁸ ) C (NR ⁸ ) N (R ⁸ ) N (R ⁸ ) R ⁹ , R ¹⁰ -N (R ⁸ ) -R ¹⁰ -C (R ⁸ ) (N (R ⁸ ) R ⁹ ) C (O) OR ⁸ , -R ¹⁰ -N (R ⁸ ) S (O) R ⁹ , -R ¹⁰ OR ⁸ , -R ¹⁰ -ON (R ⁸ ) C (NR ⁸ ) N (R ⁸ ) R ⁹ , -R ¹⁰ -OS (O) ₂ OR ⁸ , -R ¹⁰ -P (O) (OR ⁸ ) R ⁹ , -R ¹⁰ -OP (O) (OR ⁸ ) ₂ ,- R ¹⁰ -P (O) (OR ⁸ ) ₂ , -R ¹⁰ -SR ⁸ , -R ¹⁰ -SR ¹⁰ -C (O) OR ⁸ , -R ¹⁰ -SR ¹⁰ -N (R ⁸ ) R ⁹ ,- R ¹⁰ -SR ¹⁰ -C (R ⁸ ) (N (R ⁸ ) R ⁹ ) C (O) OR ⁸ , -R ^{1 0} -SR ¹⁰ -N (R ⁸ ) C (O) OR ⁸ , -R ¹⁰ -SR ¹⁰ -N (R ⁸ ) C (O) R ⁸ , -R ¹⁰ -SSR ¹⁰ -C (R ⁸ ) (N (R ⁸ ) R ⁹ ) C (O) OR ⁸ , -R ¹⁰ -SC (O) N (R ⁸ ) R ⁹ , -R ¹⁰ -SC (S) N (R ⁸ ) R ⁹ , -R ^10- S (O) R ⁸ , -R ¹⁰ -S (O) ₂ R ¹¹ , -R ¹⁰ -S (O) OR ⁸ , -R ¹⁰ -S (O) ₂ OR ⁸ , -R ¹⁰ -S (O) ₂ N (R ⁸ ) R ⁹ , -R ¹⁰ -S (O) (NR ⁸ ) R ⁹ ; Or R ⁶ is aryl (alkyl, halo, haloalkyl, haloalkoxy, -OR ⁸ , -SR ⁸ , -N (R ⁸ ) R ⁹ , -C (O) OR ⁸ , -C (O) N (R ⁸ ) R ⁹ , -S (O) ₂ OR ⁸ and -OP (O) (OR ⁸ ) ₂ optionally substituted with one or more substituents selected from the group consisting of; Or R ⁶ is aralkyl (alkyl, halo, haloalkyl, haloalkoxy, -OR ⁸ , -SR ⁸ , -N (R ⁸ ) R ⁹ , -C (O) OR ⁸ , -C (O) N (R ⁸ ) R ⁹ , -S (O) ₂ OR ⁸ and -OP (O) (OR ⁸ ) ₂ optionally substituted with one or more substituents selected from the group consisting of; Or R ⁶ is heterocyclyl (alkyl, halo, haloalkyl, haloalkoxy, aralkyl, -OR ⁸ , -C (O) OR ⁸ , -N (R ⁸ ) R ⁹ , -C (O) N (R ⁸ ) R ⁹ , -S (O) ₂ OR ⁸ and -OP (O) (OR ⁸ ) ₂ optionally substituted with one or more substituents selected from the group consisting of; Or R ⁶ is heterocyclylalkyl, wherein the heterocyclyl radical is alkyl, halo, haloalkyl, haloalkoxy, aralkyl, -OR ⁸ , -SR ⁸ , -C (O) OR ⁸ , -N (R ⁸ ) R ⁹ , -C (O) N (R ⁸ ) R ⁹ optionally substituted with one or more substituents selected from the group consisting of; Or R ⁶ is adamantyl (alkyl, halo, haloalkyl, haloalkoxy, -OR ⁸ , -SR ⁸ , -C (O) OR ⁸ , -N (R ⁸ ) R ⁹ , -C (O) N ( R ⁸ ) R ⁹ , -S (O) ₂ OR ⁸ and -OP (O) (OR ⁸ ) ₂ optionally substituted); Or R ⁶ is adamantylalkyl, wherein the adamantyl radical is alkyl, halo, haloalkyl, haloalkoxy, -OR ⁸ , -SR ⁸ , -C (O) OR ⁸ , -N (R ⁸ ) R ⁹ , —C (O) N (R ⁸ ) R ⁹ , optionally substituted by —S (O) ₂ OR ⁸ and —OP (O) (OR ⁸ ) ₂ ; R ⁷ is hydrogen, alkyl, cycloalkyl or aryl; R ⁸ and R ⁹ are each independently hydrogen, alkyl, aryl (halo, alkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylamino Optionally substituted by carbonyl or dialkylaminocarbonyl) or aralkyl (halo, alkyl, aryl, hydroxy, alkoxy, aralkyl, amino, dialkylamino, monoalkylamino, carboxy, alkoxycarbonyl, aminocarbon Optionally substituted by carbonyl, monoalkylaminocarbonyl or dialkylaminocarbonyl); R ¹⁰ is a straight or branched alkylene chain; R ¹¹ is alkyl, aryl (halo, alkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl or dialkylaminocarbonyl Optionally substituted by) or aralkyl (halo, alkyl, aryl, hydroxy, alkoxy, aralkyl, amino, dialkylamino, monoalkylamino, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl or Optionally substituted with dialkylaminocarbonyl); R ¹² is hydrogen, alkyl, aryl or aralkyl; X is halo.

Compounds of formulas A, B, D and G are described, for example, in Aldrich Chemical Co. Or Sigma Chemical Co. Or commercially available from ICN Biomedicals, or prepared according to methods known to those skilled in the art.
Typically, the compound of formula (Ia) is first equilibrated with a compound of formula (A) in the presence of a base, preferably cesium carbonate, at about −10 to about 10 ° C., preferably at about 0 ° C., in an aprotic solvent such as acetonitrile Prepared by treating with a compound of formula (B). The resulting reaction mixture was stirred at ambient temperature for about 12 to about 16 hours, preferably about 16 hours. The compound of formula C is then isolated from the reaction mixture by standard isolation techniques such as solvent removal and chromatography in vacuo.
The compound of formula C in an aprotic solvent, preferably acetonitrile, was treated with an equivalent amount of the compound of formula D in the presence of a base, preferably cesium carbonate, at about −10 to about 10 ° C., preferably at about 0 ° C. . The resulting mixture was warmed to ambient temperature and stirred for about 1 to about 4 hours, preferably about 2 hours. The compound of formula E is then isolated from the reaction mixture by standard isolation techniques such as evaporation of the solvent.
The compound of formula E in a protic solvent, preferably a lower alkanol, such as methanol, is then subjected to a powerful oxidizing agent such as potassium metabisulfite (KHSO ₅ ) in water at about −10 to about 10 ° C., preferably at about 0 ° C. Treated. The resulting reaction mixture was stirred at ambient temperature for about 12 to about 16 hours, preferably about 15 hours. The reaction mixture was then concentrated and extracted with an aprotic organic solvent such as methylene chloride. Compounds of Formula F were isolated from the organic layer by standard isolation techniques such as evaporation of the solvent.
The compound of formula F in an aprotic solvent, preferably acetonitrile, was treated with an equivalent amount of a compound of formula G in the presence of a base, preferably cesium carbonate, at about −10 to about 10 ° C., preferably at about 0 ° C. . The resulting reaction mixture was stirred for 15 minutes to about 1 hour, preferably about 15 minutes. Compounds of formula H were isolated from the reaction mixture by standard isolation techniques such as evaporation and chromatography of the solvent.
The compound of formula H in a mixture of a water miscible ethereal solvent such as tetrahydrofuran, and an aqueous weak inorganic acid such as 10% hydrochloric acid was treated with a reducing agent such as granular zinc or palladium on hydrogen / carbon. The reaction mixture was heated at about 50 ° C. to about 100 ° C., preferably about 70 ° C. for about 10 minutes to about 1 hour, preferably about 30 minutes. The volatiles were evaporated and the resulting acidic solution was neutralized with a weak base such as sodium bicarbonate. The compound of formula J is then isolated from the reaction mixture by standard isolation techniques such as extraction with organic solvents and evaporation of the solvent.
The compound of formula J is then dissolved in lower alkanols, preferably ethanol at about −10 to about 10 ° C., preferably at about 0 ° C., and then the resulting solution is saturated with inorganic acid gas, preferably hydrochloric acid. . The reaction mixture was sealed and warmed to ambient temperature over about 12 to about 16 hours, preferably about 16 hours. The reaction mixture was concentrated and a polar solvent such as ether was added to the concentrated mixture. The resulting precipitate is then dissolved in lower alkanols, preferably ethanol, and the resulting solution is cooled to about −10 to about 10 ° C., preferably about 0 ° C., and then about 5 to about 20 minutes, preferably Was treated with anhydrous ammonia (gas) for about 10 minutes. The reaction mixture was sealed and heated to near ambient temperature to about 100 ° C., preferably about 60 ° C. for about 1 to about 2 hours, preferably about 2 hours. The reaction mixture was cooled down and the solvent was evaporated. Compounds of formula (Ia) were isolated from the reaction mixture by standard isolation techniques such as filtration, evaporation of the solvent and purification by preparative HPLC.
Thus formed compounds of formula (Ia) are described in Marfat, A. et al., Synthesis (1987), Vol. 5, p. 515, further treated with a compound of formula XR ⁵ , wherein X is bromo or chloro and R ⁵ is alkyl or optionally substituted aralkyl as described above in the Summary of the Invention. Thus, the compound of formula la can be prepared wherein the nitrogen atom at the 5-position is substituted by alkyl or optionally substituted aralkyl.
Alternatively, the compound of formula (Ia) is further treated with an ortho-nitro-halo aromatic, preferably an ortho-nitro-fluoro aromatic, such as ortho-nitrofluorobenzene, in the presence of a strong base such as sodium hydride, thereby providing a 5-position A compound of formula (Ia) may be prepared in which the nitrogen of is substituted by nitro-aryl groups such as 2-nitrophenyl. Subsequently, reductive deamination of the nitro-aryl group is carried out by first determining the compound in Bellamy, FD et al., Tetrahedron Letters (1984), Vol. 26, p. 839, can be carried out by reducing the nitro group to the corresponding amino group by treatment with SnCl ₂ . The resulting amino compound can then be deaminated by treatment with a standard deaminizing agent such as tertiary butylnitrite in an aprotic solvent such as DMF at about 35 to about 90 ° C., preferably about 65 ° C. (see Doyle, MP et al., J. Org.Chem. (1974), Vol. 42, p. 3494).
Alternatively, instead of treating the resulting solution with anhydrous ammonia, the resulting solution is treated with a compound of the formula NH ₂ OR ^{8 to give} a compound of formula I wherein R ² is -C (NH) N (H) OR ⁸ . Can be obtained.
Compounds of formula (Ia) wherein R ³ is -C (NH) NH ₂ or -C (NH) N (H) OR ⁸ are prepared from the corresponding cyano compounds in a manner similar to that described above for compounds of formula J .
In addition, R ¹ , R ³ , R ⁴ , R ⁵ or R ⁶ is a -C (O) N (R ⁸ ) R ⁹ group or a -C (O) OR ⁸ group, wherein R ⁸ and R ⁹ are respectively Compounds of formula (Ia) independently containing alkyl, optionally substituted aryl or optionally substituted aralkyl are hydrolyzed under acidic conditions such that R ¹ , R ³ , R ⁴ , R ⁵ or R ⁶ contain a carboxyl group The compounds of the present invention can be prepared.
Furthermore, a compound of formula (Ia) in which R ¹ , R ³ , R ⁴ , R ⁵ or R ⁶ contains an amino group is treated with a suitable alkylating agent so that R ¹ , R ³ , R ⁴ , R ⁵ or R ⁶ is -N ( R ⁸ ) R ⁹ or —N (R ⁸ ) C (O) R ⁹ , wherein R ⁸ and R ⁹ are each independently hydrogen, alkyl, optionally substituted aryl or optionally substituted aralkyl Corresponding compounds of formula la can be obtained.
In addition, R ¹ , R ³ , R ⁴ , R ⁵ or R ⁶ contain a -C (O) OR ⁸ group, wherein R ⁸ is hydrogen, alkyl, optionally substituted aryl or optionally substituted aralkyl Wherein the compound of formula (Ia) is amidated under standard amidation conditions such that R ¹ , R ³ , R ⁴ , R ⁵ or R ⁶ is a -C (O) N (R ⁸ ) R ⁹ group, wherein R ⁸ and R ⁹ may independently be hydrogen, alkyl, optionally substituted aryl or optionally substituted aralkyl) to produce the corresponding compounds of formula (Ia).
The compound of formula (Ia) is further treated with a suitable acid halide, preferably an acid chloride, or a suitable acid anhydride or equivalent, such that R ² is -C (NH) N (H) C (O) R ⁸ , wherein R ⁸ can be hydrogen, alkyl, optionally substituted aryl or optionally substituted aralkyl. Alternatively, compounds of formula (Ia) may be further treated with carbamoyl chloride or equivalents thereof such that R ² is —C (NH) N (H) C (O) OR ¹¹ , wherein R ¹¹ is in the summary of the invention. As described above, compounds of the invention can be obtained.
Alternatively, the compound of formula (Ia) is further added as a compound of formula R ¹¹ -S (O) ₂ -imidazole, wherein R ¹¹ is as described in the Summary of the Invention, in a polar solvent such as methylene chloride at ambient temperature. Treatment can yield compounds of the invention wherein R ² is —C (NH) N (H) S (O) ₂ R ¹¹ .
Alternatively, the compound of formula (Ia) is further treated with an appropriately NR ⁸ -substituted phenylcarbamate at ambient temperature for about 6 to 24 hours, preferably about 12 hours, in a polar solvent, preferably methylene chloride, where R Compounds of the invention can be obtained wherein the ^divalent -C (NH) N (H) C (O) N (H) R ⁸ is obtained.
B. Preparation of Compound of Formula (IIa)
Compounds of Formula (IIa) wherein A is -N (H)-; Z ¹ and Z ² are both —O—; Is a compound of Formula II wherein R ² is -C (NH) NH ₂ . These compounds may be prepared as described in Scheme 2, wherein R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ or R ¹² are as defined above for Scheme 1 and X is halo:

Compounds of formulas (A), (B), (D) and (G) are, for example, Aldrich Chemical Co. Or Sigma Chemical Co. Or commercially available from ICN Biomedicals, or can be prepared by methods known to those skilled in the art.
Typically, compounds of formula (IIa) are prepared from compounds of formulas (F) and (G) by first treating compounds of formula (A) with compounds of formula (G), in a manner similar to that described above for the preparation of compounds of formula (H). The resulting compound of formula K was isolated from the reaction mixture and treated with the compound of formula D in a manner similar to that described above for the compound of formula C. The resulting compound of formula L was isolated from the reaction mixture and then oxidized in a similar manner as described above for the compound of formula E. The resulting compound of formula M was isolated from the reaction mixture and then treated with the compound of formula B in a manner similar to that described above for the compound of formula A. The resulting compound of formula (N) was isolated from the reaction mixture and then closed in a similar manner as described above for the compound of formula (H). The resulting compound of formula O was then treated in a similar manner as described above for the compound of formula J. The resulting compound of formula (IIa) was isolated from the reaction mixture by standard techniques.
In addition, all of the various substituent conversion methods described above for compounds of Formula (Ia) are applied to compounds of Formula (IIa) to obtain additional compounds of the invention that are not specifically described in the above scheme.
C. Preparation of Compound of Formula (Ib)
Compounds of formula (Ib) wherein A is -O-; Z ¹ and Z ² are both —O—; Is a compound of Formula II wherein R ² is -C (NH) NH ₂ . These compounds have R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ¹² as described above for Scheme 1; X can be prepared as described in Scheme 3 below with halo:

Compounds of formula C are prepared as described above in Scheme 1. Compounds of Formula P and Formula G are described, for example, in Aldrich Chemical Co. Or commercially available from Sigma Chemical Co., or may be prepared by methods known to those skilled in the art.
Usually, the compound of formula (Ib) is first prepared by treating the compound with a strong base, preferably sodium hydride, in a polar aprotic solvent, preferably tetrahydrofuran, at about 0 ° C. to about ambient temperature, preferably about 0 ° C. Prepared by forming alkoxide ions of the compound of formula P. The resulting solution containing the alkoxide was added dropwise to the compound of formula C at 0 to about 10 ° C, preferably at about 0 ° C, and the reaction mixture was added at about 0 to about 10 ° C, preferably about 0 ° C to about 30 minutes to Stir for about 2 hours, preferably about 1 hour. The reaction mixture was then warmed to ambient temperature and stirred for about 1 to about 3 hours, preferably about 2 hours. The compound of formula Q was then isolated from the reaction mixture by conventional isolation techniques such as evaporation of volatiles.
The compound of formula Q was then oxidized to the compound of formula R in a manner similar to that described above for the compound of formula E in the preparation of the compound of formula F. The compound of formula R thus formed is then treated with a compound of formula G to produce a compound of formula S in a manner similar to that described above for the compound of formula F in the preparation of compounds of formula H. The compound of formula S thus formed is then closed to prepare a compound of formula T in a manner similar to that described above for compounds of formula H in the preparation of compounds of formula J. The compound of formula T thus formed is then treated in a similar manner as described above for the compound of formula J in the preparation of the compound of formula Ia to produce the compound of formula Ib.
In addition, all of the various substituent conversion methods described above for the compounds of formula (Ia) are applied to the compounds of formula (Ib) thus formed to obtain additional compounds of the invention not specifically described in the above scheme.
D. Preparation of Compound of Formula (IIb)
Compound of formula (IIb) wherein A is -O-; Z ¹ and Z ² are both —O—; Is a compound of Formula II wherein R ² is -C (NH) NH ₂ . These compounds have R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ¹² as described above for Scheme 1; X may be prepared as described in Scheme 3:

Compounds of formula K are prepared as described above in Scheme 2. Compounds of Formula P and Formula B are described, for example, in Aldrich Chemical Co. Or commercially available from Sigma Chemical Co., or may be prepared by methods known to those skilled in the art.
Typically, the compound of formula (IIb) first forms an alkoxide ion of a compound of formula (P) as described above for the compound of formula (C) in the scheme, and then treats the compound of formula (U) by treating the compound of formula (K) with the alkoxide formed It manufactures by making. The compound of formula U is then oxidized to the compound of formula V in a manner similar to that described above for the compound of formula L in the preparation of the compound of formula M. The compound of formula (V) thus formed was then treated with a compound of formula (B) in a manner similar to that described above for the compound of formula (M) in the preparation of the compound of formula (N). The compound of formula (W) thus formed is then ring closed in a manner similar to that described above for the compound of formula (N) in the preparation of the compound of formula (O). The compound of formula (X) thus formed was then treated in a similar manner as described above for the compound of formula (O) in the preparation of the compound of formula (IIa) to prepare a compound of formula (IIb).
In addition, all of the various substituent conversion methods described above for the compounds of formula (Ia) are applied to the compounds of formula (IIb) thus formed to obtain additional compounds of the invention not specifically described in the above scheme.
In addition, all compounds of the present invention in free base form or free acid form may be treated with suitable inorganic or organic acids, or may be converted to pharmaceutically acceptable salts of these compounds with suitable inorganic or organic bases. have. Salts of the compounds of the present invention may also be converted into the free base form or the free acid form or another salt by methods known to those skilled in the art.
The following specific preparations and examples are provided as a guide to aid the practice of the invention and are not intended to limit the scope of the invention.
<Manufacturing method 1>
<Compound of Formula C, Formula N, and Formula W>
A. Cesium carbonate (8.82 g, 27.1 mmol) at 0 ° C. to 2-methylthio-4,6-dichloro-5-nitropyrimidine, ie compound of formula A (5.0 g, 20.8 mmol) in 200 mL acetonitrile ) Was added followed by the addition of 3- (dimethylaminocarbonyl) phenol (3.44 g, 20.8 mmol), i.e. a compound of formula B, and the reaction mixture was stirred for 16 h. The volatiles were evaporated and the residue was chromatographed on silica gel (CH ₂ Cl ₂ / ethyl acetate, 7:12) to 6.3 g (83% yield) of 2-methylthio-4-chloro-5-nitro-6- (3- (dimethylaminocarbonyl) phenoxy) pyrimidine, ie a compound of formula C, was obtained.
B. In a similar manner, the following compounds of formula C are prepared:
2-methylthio-4-chloro-5-nitro-6- (3- (diethylaminocarbonyl) phenoxy) pyrimidine;
2-methylthio-4-chloro-5-nitro-6- (5-methyl-3- (dimethylaminocarbonyl) phenoxy) pyrimidine;
2-methylthio-4-chloro-5-nitro-6- (5-trifluoromethyl-3- (dimethylaminocarbonyl) phenoxy) pyrimidine;
2-methylthio-4-chloro-5-nitro-6- (5-methoxy-3- (dimethylaminocarbonyl) phenoxy) pyrimidine;
2-methylthio-4-chloro-5-nitro-6- (5-carboxy-3- (dimethylaminocarbonyl) phenoxy) pyrimidine;
2-methylthio-4-chloro-5-nitro-6- (5-ethoxycarbonyl-3-methylphenoxy) pyrimidine;
2-methylthio-4-chloro-5-nitro-6- (5-dimethylamino-3- (imidazolin-2-yl) phenoxy) pyrimidine;
2-methylthio-4-chloro-5-nitro-6- (5-dimethylaminoethyl-3- (dimethylaminocarbonyl) phenoxy) pyrimidine;
2-methylthio-4-chloro-5-nitro-6- (5-dimethylaminoethyl-3- (dimethylaminocarbonyl) phenoxy) pyrimidine; And
2-methylthio-4-chloro-5-nitro-6- (5- (2-ethoxycarbonylethyl) -3- (tetrahydropyrimidin-2-yl) phenoxy) pyrimidine.
C. In a similar manner, 2-methylsulfonyl-4- (ethoxycarbonylmethyl) amino-5-nitro-6- (2-benzyloxy-5-cyanophenoxy) pyrimidine, i.e. The compound of formula M prepared as described above was treated with 3- (dimethylaminocarbonyl) phenol, i.e. compound of formula B, to treat 2- (3-dimethylaminocarbonylphenoxy) -4- (ethoxycarbonylmethyl ) Amino-5-nitro-6- (2-benzyloxy-5-cyanophenoxy) pyrimidine, ie a compound of formula (N).
D. In a similar manner, the following compounds of formula N are prepared:
2- (3-methylphenoxy) -4- (ethoxycarbonylmethyl) amino-5-nitro-6- (2-methoxy-5-cyanophenoxy) pyrimidine;
2- (3-chloro-5-methoxyphenoxy) -4- (ethoxycarbonylmethyl) amino-5-nitro-6- (2-ethoxy-5-cyanophenoxy) pyrimidine;
2- (3-trifluoromethylphenoxy) -4- (ethoxycarbonylmethyl) amino-5-nitro-6- (3-methoxy-5-cyanophenoxy) pyrimidine;
2- (3,5-dinitrophenoxy) -4- (ethoxycarbonylmethyl) amino-5-nitro-6- (3-ethoxy-5-cyanophenoxy) pyrimidine;
2- (3-guanidino-5-methylphenoxy) -4- (ethoxycarbonylmethyl) amino-5-nitro-6- (2-phenoxy-5-cyanophenoxy) pyrimidine;
2- (3-ureidophenoxy) -4- (ethoxycarbonylmethyl) amino-5-nitro-6- (3-phenoxy-5-cyanophenoxy) pyrimidine;
2- (3- (2-chloroethyl) -5-methylphenoxy) -4- (ethoxycarbonylmethyl) amino-5-nitro-6- (2-chloro-5-cyanophenoxy) pyrimidine ;
2- (3-dimethylaminocarbonylphenoxy) -4- (ethoxycarbonylmethyl) amino-5-nitro-6- (3-bromo-5-cyanophenoxy) pyrimidine;
2- (4-ethoxycarbonylphenoxy) -4- (ethoxycarbonylmethyl) amino-5-nitro-6- (2-methoxy-5-cyanophenoxy) pyrimidine;
2- (3- (1-methylimidazol-2-yl) phenoxy) -4- (ethoxycarbonylmethyl) amino-5-nitro-6- (2-methyl-5-cyanophenoxy) Pyrimidine;
2- (3-dimethylaminophenoxy) -4- (ethoxycarbonylmethyl) amino-5-nitro-6- (3-methyl-4-cyanophenoxy) pyrimidine;
2- (3- (1-methylimidazolin-2-yl) phenoxy) -4- (ethoxycarbonylmethyl) amino-5-nitro-6- (2-nitro-5-cyanophenoxy) Pyrimidine;
2- (3-tert-butoxycarbonylphenoxy) -4- (ethoxycarbonylmethyl) amino-5-nitro-6- (3-nitro-4-cyanophenoxy) pyrimidine;
2- (3- (1-methylimidazolin-2-yl) phenoxy) -4- (ethoxycarbonylmethyl) amino-5-nitro-6- (2-carboxy-5-cyanophenoxy) Pyrimidine;
2- (3- (1-methylimidazolin-2-yl) phenoxy) -4- (ethoxycarbonylmethyl) amino-5-nitro-6- (3-carboxy-4-cyanophenoxy) Pyrimidine;
2- (3- (1-methylimidazolin-2-yl) phenoxy) -4- (ethoxycarbonylmethyl) amino-5-nitro-6- (2-tert-butoxycarbonyl-5- Cyanophenoxy) pyrimidine;
2- (3- (1-methylimidazolin-2-yl) phenoxy) -4- (ethoxycarbonylmethyl) amino-5-nitro-6- (3-tert-butoxycarbonyl-4- Cyanophenoxy) pyrimidine;
2- (3- (1-methylimidazolin-2-yl) phenoxy) -4- (ethoxycarbonylmethyl) amino-5-nitro-6- (2-aminocarboxy-5-cyanophenoxy ) Pyrimidine;
2- (3- (1-methylimidazolin-2-yl) phenoxy) -4- (ethoxycarbonylmethyl) amino-5-nitro-6- (3-aminocarbonyl-4-cyanophenoxy C) pyrimidine;
2- (3- (1-methylimidazolin-2-yl) phenoxy) -4- (ethoxycarbonylmethyl) amino-5-nitro-6- (2-dimethylamino-5-cyanophenoxy ) Pyrimidine;
2- (3- (1-methylimidazolin-2-yl) phenoxy) -4- (ethoxycarbonylmethyl) amino-5-nitro-6- (3-dimethylamino-4-cyanophenoxy ) Pyrimidine;
2- (3- (1-methylimidazolin-2-yl) phenoxy) -4- (ethoxycarbonylmethyl) amino-5-nitro-6- (2-dimethylamino-5-cyanophenoxy ) Pyrimidine;
2- (3- (1-methylimidazolin-2-yl) phenoxy) -4- (ethoxycarbonylmethyl) amino-5-nitro-6- (3-dimethylamino-4-cyanophenoxy ) Pyrimidine;
2- (3- (1-methylimidazolin-2-yl) phenoxy) -4-amino-5-nitro-6- (2-methoxy-5-cyanophenoxy) pyrimidine;
2- (3- (1-methylimidazolin-2-yl) phenoxy) -4-amino-5-nitro-6- (2-ethoxy-5-cyanophenoxy) pyrimidine;
2- (3- (1-methylimidazolin-2-yl) phenoxy) -4-amino-5-nitro-6- (3-methoxy-5-cyanophenoxy) pyrimidine;
2- (3- (1-methylimidazolin-2-yl) phenoxy) -4-amino-5-nitro-6- (3-methoxy-5-cyanophenoxy) pyrimidine;
2- (3- (1-methylimidazolin-2-yl) phenoxy) -4-amino-5-nitro-6- (2-phenoxy-5-cyanophenoxy) pyrimidine;
2- (3-dimethylaminocarbonylphenoxy) -4-amino-5-nitro-6- (3-phenoxy-5-cyanophenoxy) pyrimidine;
2- (3-dimethylaminocarbonylphenoxy) -4-amino-5-nitro-6- (2-chloro-5-cyanophenoxy) pyrimidine;
2- (3-dimethylaminocarbonylphenoxy) -4-amino-5-nitro-6- (3-bromo-5-cyanophenoxy) pyrimidine;
2- (3-dimethylaminocarbonylphenoxy) -4-amino-5-nitro-6- (2-methyl-5-cyanophenoxy) pyrimidine;
2- (3-dimethylaminocarbonylphenoxy) -4-amino-5-nitro-6- (2-methyl-5-cyanophenoxy) pyrimidine;
2- (3-dimethylaminocarbonylphenoxy) -4-amino-5-nitro-6- (3-methyl-4-cyanophenoxy) pyrimidine;
2- (3-dimethylaminocarbonylphenoxy) -4-amino-5-nitro-6- (2-nitro-5-cyanophenoxy) pyrimidine;
2- (3-dimethylaminocarbonylphenoxy) -4-amino-5-nitro-6- (3-nitro-4-cyanophenoxy) pyrimidine;
2- (3-guanidinophenoxy) -4-amino-5-nitro-6- (2-carboxy-5-cyanophenoxy) pyrimidine;
2- (3-guanidinophenoxy) -4-amino-5-nitro-6- (3-carboxy-4-cyanophenoxy) pyrimidine;
2- (3-guanidinophenoxy) -4-amino-5-nitro-6- (tert-butoxycarbonyl-5-cyanophenoxy) pyrimidine;
2- (3-guanidinophenoxy) -4-amino-5-nitro-6- (tert-butoxycarbonyl-4-cyanophenoxy) pyrimidine;
2- (3-guanidinophenoxy) -4-amino-5-nitro-6- (2-aminocarbonyl-5-cyanophenoxy) pyrimidine;
2- (3-guanidinophenoxy) -4-amino-5-nitro-6- (3-aminocarbonyl-4-cyanophenoxy) pyrimidine;
2- (3-guanidinophenoxy) -4-amino-5-nitro-6- (2-dimethylamino-5-cyanophenoxy) pyrimidine;
2- (3-guanidinophenoxy) -4-amino-5-nitro-6- (3-dimethylamino-4-cyanophenoxy) pyrimidine;
2- (3-guanidinophenoxy) -4-amino-5-nitro-6- (2-dimethylamino-5-cyanophenoxy) pyrimidine;
2- (3-guanidinophenoxy) -4-amino-5-nitro-6- (3-dimethylamino-4-cyanophenoxy) pyrimidine;
2- (3-dimethylaminocarbonylphenoxy) -4- (1-carboxyethyl) amino-5-nitro-6- (3-bromo-5-cyanophenoxy) pyrimidine;
2- (3-dimethylaminocarbonylphenoxy) -4- (1-carboxy-2-methylpropyl) amino-5-nitro-6- (2-methyl-5-cyanophenoxy) pyrimidine;
2- (3-dimethylaminocarbonylphenoxy) -4- (1-carboxy-3-methylbutyl) amino-5-nitro-6- (2-methyl-5-cyanophenoxy) pyrimidine;
2- (3-dimethylaminocarbonylphenoxy) -4- (1-carboxy-2-methylbutyl) amino-5-nitro-6- (3-methyl-4-cyanophenoxy) pyrimidine;
2- (3-dimethylaminocarbonylphenoxy) -4- (1-carboxy-2-phenylethyl) amino-5-nitro-6- (2-nitro-5-cyanophenoxy) pyrimidine;
2- (3-dimethylaminocarbonylphenoxy) -4- (1-carboxy-2- (4-mercaptophenyl) amino-5-nitro-6- (3-nitro-4-cyanophenoxy) pyrid Midine;
2- (3-guanidinophenoxy) -4- (1-carboxy-3- (methylthio) propyl) amino-5-nitro-6- (2-carboxy-5-cyanophenoxy) pyrimidine;
2- (3-guanidinophenoxy) -4- (1-carboxy-2- (imidazol-4-yl) ethyl) amino-5-nitro-6- (3-carboxy-4-cyanophenoxy ) Pyrimidine;
2- (3-guanidinophenoxy) -4- (1-carboxy-2-hydroxyethyl) amino-5-nitro-6- (2-tert-butoxycarbonyl-5-cyanophenoxy) Pyrimidine;
2- (3-guanidinophenoxy) -4- (1-carboxy-2-hydroxypropyl) amino-5-nitro-6- (tert-butoxycarbonyl-4-cyanophenoxy) Pyrimidine;
2- (3-guanidinophenoxy) -4- (1-carboxy-2- (aminocarbonyl) ethyl) amino-5-nitro-6- (2-aminocarbonyl-5-cyanophenoxy) Pyrimidine;
2- (3-guanidinophenoxy) -4- (1-carboxy-3- (aminocarbonyl) ethyl) amino-5-nitro-6- (3-aminocarbonyl-4-cyanophenoxy) Pyrimidine;
2- (3-guanidinophenoxy) -4- (1,2-dicarboxyethyl) amino-5-nitro-6- (2-dimethylamino-5-cyanophenoxy) pyrimidine;
2- (3-guanidinophenoxy) -4- (1,3-dicarboxypropyl) amino-5-nitro-6- (3-dimethylamino-4-cyanophenoxy) pyrimidine;
2- (3-guanidinophenoxy) -4- (1-carboxy-5-aminopentyl) amino-5-nitro-6- (2-dimethylamino-5-cyanophenoxy) pyrimidine; And
2- (3-guanidinophenoxy) -4- (1-carboxy-40guanidinobutyl) amino-5-nitro-6- (3-dimethylamino-4-cyanophenoxy) pyrimidine.
E. In a similar manner, 2-methylsulfonyl-4- (ethoxycarbonyl) methoxy-5-nitro-6- (2-benzyloxy-5-cyanophenoxy) pyrimidine, ie a compound of formula V Is treated with 3- (dimethylaminocarbonyl) phenol, i.e. a compound of formula B, to give 2- (3-dimethylaminocarbonylphenoxy) -4- (ethoxycarbonyl) methoxy-5-nitro-6- ( 2-benzyloxy-5-cyanophenoxy) pyrimidine, ie a compound of formula W, is obtained.
F. In a similar manner, compounds of formula W are prepared:
2- (3-methylphenoxy) -4- (ethoxycarbonyl) methoxy-5-nitro-6- (2-methoxy-5-cyanophenoxy) pyrimidine;
2- (3-chloro-5-methoxyphenoxy) -4- (ethoxycarbonyl) methoxy-5-nitro-6- (2-ethoxy-5-cyanophenoxy) pyrimidine;
2- (4-trifluoromethylphenoxy) -4- (ethoxycarbonyl) methoxy-5-nitro-6- (3-ethoxy-5-cyanophenoxy) pyrimidine;
2- (3,5-dinitrophenoxy) -4- (ethoxycarbonyl) methoxy-5-nitro-6- (3-ethoxy-5-cyanophenoxy) pyrimidine;
2- (3-guanidino-5-methylphenoxy) -4- (ethoxycarbonyl) methoxy-5-nitro-6- (2-phenoxy-5-cyanophenoxy) pyrimidine;
2- (3-ureidophenoxy) -4- (ethoxycarbonyl) methoxy-5-nitro-6- (3-phenoxy-5-cyanophenoxy) pyrimidine;
2- (3- (2-chloroethyl) -5-methylphenoxy) -4- (ethoxycarbonyl) methoxy-5-nitro-6- (2-chlorophenoxy-5-cyanophenoxy) Pyrimidine;
2- (3-dimethylaminocarbonylphenoxy) -4- (ethoxycarbonyl) methoxy-5-nitro-6- (3-phenoxy-5-cyanophenoxy) pyrimidine;
2- (4-ethoxycarbonylphenoxy) -4- (ethoxycarbonyl) methoxy-5-nitro-6- (2-methyl-5-cyanophenoxy) pyrimidine;
2- (3- (1-methylimidazol-2-yl) phenoxy) -4- (ethoxycarbonyl) methoxy-5-nitro-6- (2-methyl-5-cyanophenoxy) Pyrimidine;
2- (3-dimethylaminophenoxy) -4- (ethoxycarbonyl) methoxy-5-nitro-6- (3-methyl-4-cyanophenoxy) pyrimidine;
2- (3- (1-methylimidazolin-2-yl) phenoxy-4- (ethoxycarbonyl) methoxy-5-nitro-6- (2-nitro-5-cyanophenoxy) pyrid Midine;
2- (3-tert-butoxycarbonylphenoxy-4- (ethoxycarbonyl) methoxy-5-nitro-6- (3-nitro-4-cyanophenoxy) pyrimidine;
2- (3- (1-methylimidazolin-2-yl) phenoxy-4- (ethoxycarbonyl) methoxy-5-nitro-6- (2-carboxy-5-cyanophenoxy) pyrid Midine;
2- (3- (1-methylimidazolin-2-yl) phenoxy-4- (ethoxycarbonyl) methoxy-5-nitro-6- (3-carboxy-4-cyanophenoxy) pyrid Midine;
2- (3- (1-methylimidazolin-2-yl) phenoxy-4- (ethoxycarbonyl) methoxy-5-nitro-6- (2-tert-butoxycarbonyl-5-sia Nophenoxy) pyrimidine;
2- (3- (1-methylimidazolin-2-yl) phenoxy-4- (ethoxycarbonyl) methoxy-5-nitro-6- (3-tert-butoxycarbonyl-4-sia Nophenoxy) pyrimidine;
2- (3- (1-methylimidazolin-2-yl) phenoxy-4- (ethoxycarbonyl) methoxy-5-nitro-6- (2-aminocarbonyl-5-cyanophenoxy ) Pyrimidine;
2- (3- (1-methylimidazolin-2-yl) phenoxy-4- (ethoxycarbonyl) methoxy-5-nitro-6- (3-aminocarbonyl-4-cyanophenoxy ) Pyrimidine;
2- (3- (1-methylimidazolin-2-yl) phenoxy-4- (ethoxycarbonyl) methoxy-5-nitro-6- (2-dimethylamino-5-cyanophenoxy) Pyrimidine;
2- (3- (1-methylimidazolin-2-yl) phenoxy-4- (ethoxycarbonyl) methoxy-5-nitro-6- (3-dimethylamino-4-cyanophenoxy) Pyrimidine;
2- (3- (1-methylimidazolin-2-yl) phenoxy-4- (ethoxycarbonyl) methoxy-5-nitro-6- (2-dimethylamino-5-cyanophenoxy) Pyrimidine;
2- (3- (1-methylimidazolin-2-yl) phenoxy-4- (ethoxycarbonyl) methoxy-5-nitro-6- (3-dimethylamino-4-cyanophenoxy) Pyrimidine;
2- (3-dimethylaminocarbonylphenoxy) -4- (1-carboxyethoxy) -5-nitro-6- (3-bromo-5-cyanophenoxy) pyrimidine;
2- (3-dimethylaminocarbonylphenoxy) -4- (1-carboxy-2-methylpropoxy) -5-nitro-6- (2-methyl-5-cyanophenoxy) pyrimidine;
2- (3-dimethylaminocarbonylphenoxy) -4- (1-carboxy-3-methylbutoxy) -5-nitro-6- (2-methyl-5-cyanophenoxy) pyrimidine;
2- (3-dimethylaminocarbonylphenoxy) -4- (1-carboxy-2-methylbutoxy) -5-nitro-6- (3-methyl-4-cyanophenoxy) pyrimidine;
2- (3-dimethylaminocarbonylphenoxy) -4- (1-carboxy-2-phenylethoxy) -5-nitro-6- (2-nitro-5-cyanophenoxy) pyrimidine;
2- (3-dimethylaminocarbonylphenoxy) -4- (1-carboxy-2- (4-mercaptophenyl) ethoxy) -5-nitro-6- (3-nitro-4-cyanophenoxy ) Pyrimidine;
2- (3-guanidinophenoxy) -4- (1-carboxy-3- (methylthio) propoxy) -5-nitro-6- (2-carboxy-5-cyanophenoxy) pyrimidine;
2- (3-guanidinophenoxy) -4- (1-carboxy-2- (imidazol-4-yl) ethoxy) -5-nitro-6- (3-carboxy-4-cyanophenoxy ) Pyrimidine;
2- (3-guanidinophenoxy) -4- (1-carboxy-2-hydroxyethoxy) -5-nitro-6- (2-tert-butoxycarbonyl-5-cyanophenoxy) Pyrimidine;
2- (3-guanidinophenoxy) -4- (1-carboxy-2-hydroxyethoxy) -5-nitro-6- (3-tert-butoxycarbonyl-4-cyanophenoxy) Pyrimidine;
2- (3-guanidinophenoxy) -4- (1-carboxy-2- (aminocarbonyl) ethoxy) -5-nitro-6- (2-aminocarbonyl-5-cyanophenoxy) Pyrimidine;
2- (3-guanidinophenoxy) -4- (1-carboxy-3- (aminocarbonyl) ethoxy) -5-nitro-6- (3-aminocarbonyl-4-cyanophenoxy) Pyrimidine;
2- (3-guanidinophenoxy) -4- (1,2-dicarboxyethoxy) -5-nitro-6- (2-dimethylamino-5-cyanophenoxy) pyrimidine;
2- (3-guanidinophenoxy) -4- (1,3-dicarboxyethoxy) -5-nitro-6- (3-dimethylamino-4-cyanophenoxy) pyrimidine;
2- (3-guanidinophenoxy) -4- (1-carboxy-5-aminophenoxy) -5-nitro-6- (2-dimethylamino-5-cyanophenoxy) pyrimidine; And
2- (3-guanidinophenoxy) -4- (1-carboxy-4-guanidinobutoxy) -5-nitro-6- (3-dimethylamino-4-cyanophenoxy) pyrimidine.
<Manufacturing Method 2>
<Compound of Formula E and Formula L>
A. 2-Methylthio-4-chloro-5-nitro-6- (3- (dimethylaminocarbonyl) phenoxy) pyrimidine in 80 ml of acetonitrile, i.e. compound of formula C (3.0 g, 8.14 mmol) To 0 was added glycine ethyl ester hydrochloride, i.e. compound of formula D (1.14 g, 8.14 mmol), followed by cesium carbonate (6.1 g, 18.7 mmol). The reaction mixture was allowed to warm up to ambient temperature and then stirred for 2 hours. The volatiles were evaporated to give 3.6 g of 2-methylthio-4- (ethoxycarbonylmethyl) amino-5-nitro-6- (3- (dimethylaminocarbonyl) phenoxypyrimidine, i.e. a compound of formula E Obtained.
B. In a similar manner, compounds of formula E are prepared:
2-methylthio-4- (ethoxycarbonylmethyl) amino-5-nitro-6- (3- (diethylaminocarbonyl) phenoxy) pyrimidine;
2-methylthio-4- (ethoxycarbonylmethyl) amino-5-nitro-6- (5-methyl-3- (dimethylaminocarbonyl) phenoxy) pyrimidine;
2-methylthio-4- (ethoxycarbonylmethyl) amino-5-nitro-6- (5-trifluoromethyl-3- (dimethylaminocarbonyl) phenoxy) pyrimidine;
2-methylthio-4- (ethoxycarbonylmethyl) amino-5-nitro-6- (5-methoxy-3- (dimethylaminocarbonyl) phenoxy) pyrimidine;
2-methylthio-4- (ethoxycarbonylmethyl) amino-5-nitro-6- (5-carboxy-3- (dimethylaminocarbonyl) phenoxy) pyrimidine;
2-methylthio-4- (ethoxycarbonylmethyl) amino-5-nitro-6- (5-ethoxycarbonyl-3-methylphenoxy) pyrimidine;
2-methylthio-4- (ethoxycarbonylmethyl) amino-5-nitro-6- (5-dimethylamino-3- (imidazolin-2-yl) phenoxy) pyrimidine;
2-methylthio-4- (ethoxycarbonylmethyl) amino-5-nitro-6- (5-dimethylaminocarbonyl) methyl-3- (imidazolin-2-yl) phenoxy) pyrimidine;
2-methylthio-4- (ethoxycarbonylmethyl) amino-5-nitro-6- (5-dimethylaminoethyl-3- (dimethylaminocarbonyl) phenoxy) pyrimidine;
2-methylthio-4- (ethoxycarbonylmethyl) amino-5-nitro-6- (5- (2-ethoxycarbonylethyl) -3- (tetrahydropyrimidin-2-yl) phenoxy) Pyrimidine;
2-methylthio-4- (1-carboxyethyl) amino-5-nitro-6- (3- (diethylaminocarbonyl) phenoxy) pyrimidine;
2-methylthio-4- (1-carboxy-2-methylpropyl) amino-5-nitro-6- (5-methyl-3- (diethylaminocarbonyl) phenoxy) pyrimidine;
2-methylthio-4- (1-carboxy-3-methylbutyl) amino-5-nitro-6- (5-trifluoromethyl-3- (dimethylaminocarbonyl) phenoxy) pyrimidine;
2-methylthio-4- (1-carboxy-2-methylbutyl) amino-5-nitro-6- (5-methoxy-3- (dimethylaminocarbonyl) phenoxy) pyrimidine;
2-methylthio-4- (1-carboxy-2-phenylethyl) amino-5-nitro-6- (5-carboxy-3- (dimethylaminocarbonyl) phenoxy) pyrimidine;
2-methylthio-4- (1-carboxy-2- (4-mercaptophenyl) ethyl) amino-5-nitro-6- (5-ethoxycarbonyl-3-methylphenoxy) pyrimidine;
2-methylthio-4- (1-carboxy-3- (methylthio) propyl) amino-5-nitro-6- (5-dimethylamino-3- (imidazolin-2-yl) phenoxy) pyrimidine ;
2-methylthio-4- (1-carboxy-2-mercaptoethyl) amino-5-nitro-6- (5-dimethylaminocarbonyl) methyl-3- (imidazol-2-yl) phenoxy) pyri) Midine;
2-methylthio-4- (1-carboxy-2- (indolin-3-yl) ethyl) amino-5-nitro-6- (5-dimethylaminocarbonylethyl-3- (dimethylaminocarbonyl) phenoxy C) pyrimidine;
2-methylthio-4- (1-carboxy-2- (imidazol-4-yl) ethyl) amino-5-nitro-6- (5- (2-ethoxycarbonylethyl) -3- (tetrahydro Pyrimidin-2-yl) phenoxy) pyrimidine;
2-methylthio-4- (1-carboxy-2-hydroxyethyl) amino-5-nitro-6- (5-carboxy-3- (dimethylaminocarbonyl) phenoxy) pyrimidine;
2-methylthio-4- (1-carboxy-2-hydroxyethyl) amino-5-nitro-6- (5-ethoxycarbonyl-3-methylphenoxy) pyrimidine;
2-methylthio-4- (1-carboxy-2- (aminocarbonyl) ethyl) amino-5-nitro-6- (5-dimethylamino-3- (imidazolin-2-yl) phenoxy) pyri) Midine;
2-methylthio-4- (1-carboxy-3- (aminocarbonyl) propyl) amino-5-nitro-6- (5-dimethylaminocarbonyl) -methyl-3- (imidazolin-2-yl ) Phenoxy) pyrimidine;
2-methylthio-4- (1,2-dicarboxyethyl) amino-5-nitro-6- (5-dimethylaminoethyl-3- (dimethylaminocarbonyl) phenoxy) pyrimidine;
2-methylthio-4- (1,3-dicarboxypropyl) amino-5-nitro-6- (5- (2-ethoxycarbonylethyl) -3- (tetrahydropyrimidin-2-yl) phenoxy C) pyrimidine;
2-methylthio-4- (1-carboxy-5-aminopentyl) amino-5-nitro-6- (5- (dimethylaminocarbonyl) methyl-3- (imidazol-2-yl) phenoxy) pyri) Midine; And
2-methylthio-4- (1-carboxy-4-guanidinobutyl) amino-5-nitro-6- (5- (dimethylaminoethyl-3- (dimethylaminocarbonyl) phenoxy) pyrimidine.
C. In a similar manner, 2-methylthio-4-chloro-5-nitro-6- (2-benzyloxy-5-cyanophenoxy) pyrimidine, ie the compound of formula K, is glycine ethyl ester hydrochloride, i.e. Treatment with the compound of D to yield 2-methylthio-4- (ethoxycarbonylmethyl) amino-5-nitro-6- (2-benzyloxy-5-cyanophenoxy) pyrimidine, ie the compound of formula L To obtain.
D. In a similar manner, compounds of formula L are prepared:
2-methylthio-4- (ethoxycarbonylmethyl) amino-5-nitro-6- (2-methoxy-5-cyanophenoxy) pyrimidine;
2-methylthio-4- (ethoxycarbonylmethyl) amino-5-nitro-6- (2-ethoxy-5-cyanophenoxy) pyrimidine;
2-methylthio-4- (ethoxycarbonylmethyl) amino-5-nitro-6- (3-methoxy-5-cyanophenoxy) pyrimidine;
2-methylthio-4- (ethoxycarbonylmethyl) amino-5-nitro-6- (3-ethoxy-5-cyanophenoxy) pyrimidine;
2-methylthio-4- (ethoxycarbonylmethyl) amino-5-nitro-6- (2-phenoxy-5-cyanophenoxy) pyrimidine;
2-methylthio-4- (ethoxycarbonylmethyl) amino-5-nitro-6- (3-phenoxy-5-cyanophenoxy) pyrimidine;
2-methylthio-4- (ethoxycarbonylmethyl) amino-5-nitro-6- (2-chloro-5-cyanophenoxy) pyrimidine;
2-methylthio-4- (ethoxycarbonylmethyl) amino-5-nitro-6- (3-bromo-5-cyanophenoxy) pyrimidine;
2-methylthio-4- (ethoxycarbonylmethyl) amino-5-nitro-6- (2-methyl-5-cyanophenoxy) pyrimidine;
2-methylthio-4- (ethoxycarbonylmethyl) amino-5-nitro-6- (2-methyl-5-cyanophenoxy) pyrimidine;
2-methylthio-4- (ethoxycarbonylmethyl) amino-5-nitro-6- (3-methyl-4-cyanophenoxy) pyrimidine;
2-methylthio-4- (ethoxycarbonylmethyl) amino-5-nitro-6- (2-nitro-5-cyanophenoxy) pyrimidine;
2-methylthio-4- (ethoxycarbonylmethyl) amino-5-nitro-6- (3-nitro-5-cyanophenoxy) pyrimidine;
2-methylthio-4- (ethoxycarbonylmethyl) amino-5-nitro-6- (2-carboxy-5-cyanophenoxy) pyrimidine;
2-methylthio-4- (ethoxycarbonylmethyl) amino-5-nitro-6- (3-carboxy-4-cyanophenoxy) pyrimidine;
2-methylthio-4- (ethoxycarbonylmethyl) amino-5-nitro-6- (tert-butoxycarbonyl-5-cyanophenoxy) pyrimidine;
2-methylthio-4- (ethoxycarbonylmethyl) amino-5-nitro-6- (tert-butoxycarbonyl-4-cyanophenoxy) pyrimidine;
2-methylthio-4- (ethoxycarbonylmethyl) amino-5-nitro-6- (2-aminocarbonyl-5-cyanophenoxy) pyrimidine;
2-methylthio-4- (ethoxycarbonylmethyl) amino-5-nitro-6- (3-aminocarbonyl-4-cyanophenoxy) pyrimidine;
2-methylthio-4- (ethoxycarbonylmethyl) amino-5-nitro-6- (2-dimethylamino-5-cyanophenoxy) pyrimidine;
2-methylthio-4- (ethoxycarbonylmethyl) amino-5-nitro-6- (3-dimethylamino-4-cyanophenoxy) pyrimidine;
2-methylthio-4- (ethoxycarbonylmethyl) amino-5-nitro-6- (2-dimethylamino-5-cyanophenoxy) pyrimidine;
2-methylthio-4- (ethoxycarbonylmethyl) amino-5-nitro-6- (3-dimethylamino-4-cyanophenoxy) pyrimidine;
2-methylthio-4-amino-5-nitro-6- (2-methoxy-5-cyanophenoxy) pyrimidine;
2-methylthio-4-amino-5-nitro-6- (2-ethoxy-5-cyanophenoxy) pyrimidine;
2-methylthio-4-amino-5-nitro-6- (3-methoxy-5-cyanophenoxy) pyrimidine;
2-methylthio-4-amino-5-nitro-6- (3-ethoxy-5-cyanophenoxy) pyrimidine;
2-methylthio-4-amino-5-nitro-6- (2-phenoxy-5-cyanophenoxy) pyrimidine;
2-methylthio-4-amino-5-nitro-6- (3-phenoxy-5-cyanophenoxy) pyrimidine;
2-methylthio-4-amino-5-nitro-6- (2-chloro-5-cyanophenoxy) pyrimidine;
2-methylthio-4-amino-5-nitro-6- (3-bromo-5-cyanophenoxy) pyrimidine;
2-methylthio-4-amino-5-nitro-6- (2-methyl-5-cyanophenoxy) pyrimidine;
2-methylthio-4-amino-5-nitro-6- (2-methyl-5-cyanophenoxy) pyrimidine;
2-methylthio-4-amino-5-nitro-6- (3-methyl-4-cyanophenoxy) pyrimidine;
2-methylthio-4-amino-5-nitro-6- (2-nitro-5-cyanophenoxy) pyrimidine;
2-methylthio-4-amino-5-nitro-6- (3-nitro-4-cyanophenoxy) pyrimidine;
2-methylthio-4-amino-5-nitro-6- (2-carboxy-5-cyanophenoxy) pyrimidine;
2-methylthio-4-amino-5-nitro-6- (3-carboxy-4-cyanophenoxy) pyrimidine;
2-methylthio-4-amino-5-nitro-6- (2-tert-butoxycarbonyl-5-cyanophenoxy) pyrimidine;
2-methylthio-4-amino-5-nitro-6- (tert-butoxycarbonyl-4-cyanophenoxy) pyrimidine;
2-methylthio-4-amino-5-nitro-6- (2-aminocarbonyl-5-cyanophenoxy) pyrimidine;
2-methylthio-4-amino-5-nitro-6- (3-aminocarbonyl-4-cyanophenoxy) pyrimidine;
2-methylthio-4-amino-5-nitro-6- (2-dimethylamino-5-cyanophenoxy) pyrimidine;
2-methylthio-4-amino-5-nitro-6- (3-dimethylamino-4-cyanophenoxy) pyrimidine;
2-methylthio-4-amino-5-nitro-6- (2-dimethylamino-5-cyanophenoxy) pyrimidine;
2-methylthio-4-amino-5-nitro-6- (3-dimethylamino-4-cyanophenoxy) pyrimidine;
2-methylthio-4- (1-carboxyethyl) amino-5-nitro-6- (3-bromo-5-cyanophenoxy) pyrimidine;
2-methylthio-4- (1-carboxy-2-methylpropyl) amino-5-nitro-6- (2-methyl-5-cyanophenoxy) pyrimidine;
2-methylthio-4- (1-carboxy-3-methylbutyl) amino-5-nitro-6- (2-methyl-5-cyanophenoxy) pyrimidine;
2-methylthio-4- (1-carboxy-2-methylbutyl) amino-5-nitro-6- (3-methyl-4-cyanophenoxy) pyrimidine;
2-methylthio-4- (1-carboxy-2-phenylethyl) amino-5-nitro-6- (2-nitro-5-cyanophenoxy) pyrimidine;
2-methylthio-4- (1-carboxy-2- (4-mercaptophenyl) ethyl) amino-5-nitro-6- (3-nitro-4-cyanophenoxy) pyrimidine;
2-methylthio-4- (1-carboxy-3- (methylthio) propyl) amino-5-nitro-6- (2-carboxy-5-cyanophenoxy) pyrimidine;
2-methylthio-4- (1-carboxy-2- (imidazol-4-yl) ethyl) amino-5-nitro-6- (3-carboxy-4-cyanophenoxy) pyrimidine;
2-methylthio-4- (1-carboxy-2-hydroxyethyl) amino-5-nitro-6- (tert-butoxycarbonyl-5-cyanophenoxy) pyrimidine;
2-methylthio-4- (1-carboxy-2-hydroxypropyl) amino-5-nitro-6- (tert-butoxycarbonyl-5-cyanophenoxy) pyrimidine;
2-methylthio-4- (1-carboxy-2- (aminocarbonyl) ethyl) amino-5-nitro-6- (2-aminocarbonyl-5-cyanophenoxy) pyrimidine;
2-methylthio-4- (1-carboxy-3- (aminocarbonyl) propyl) amino-5-nitro-6- (3-aminocarbonyl-4-cyanophenoxy) pyrimidine;
2-methylthio-4- (1,2-dicarboxyethyl) amino-5-nitro-6- (2-dimethylamino-5-cyanophenoxy) pyrimidine;
2-methylthio-4- (1,3-dicarboxypropyl) amino-5-nitro-6- (3-dimethylamino-4-cyanophenoxy) pyrimidine;
2-methylthio-4- (1-carboxy-5-aminopentyl) amino-5-nitro-6- (2-dimethylamino-5-cyanophenoxy) pyrimidine; And
2-methylthio-4- (1-carboxy-4-guanidinobutyl) amino-5-nitro-6- (3-dimethylamino-4-cyanophenoxy) pyrimidine.
<Manufacturing Method 3>
<Compound of Formula Q and Formula U>
A. Ethyl glycolate (1.15 mL, 12.09 mmol) was added over 10 minutes at 0 ° C. to sodium hydride (0.63 g, 15.72 mmol) in 30 mL tetrahydrofuran. The resulting alkoxide was then added to 2-methylthio-4-chloro-5-nitro-6- (3-dimethylaminocarbonylphenoxy) pyrimidine, i.e. compound of formula C (4.46 g, 12.09 mmol) at 0 ° C. Add dropwise over 5 minutes. After 1 h, the reaction mixture was warmed to ambient temperature and stirred for 2 h more. The volatiles were evaporated to give 2.55 g (48% yield) of 2-methylthio-4- (ethoxycarbonyl) methoxy-5-nitro-6- (3-dimethylaminocarbonylphenoxy) pyrimidine, i.e. The compound of Q was obtained as a yellow oil.
B. In a similar manner to prepare a compound of formula Q:
2-methylthio-4- (ethoxycarbonyl) methoxy-5-nitro-6- (3- (diethylaminocarbonyl) phenoxy) pyrimidine;
2-methylthio-4- (ethoxycarbonyl) methoxy-5-nitro-6- (5-methyl-3- (dimethylaminocarbonyl) phenoxy) pyrimidine;
2-methylthio-4- (ethoxycarbonyl) methoxy-5-nitro-6- (5-trifluoromethyl-3- (dimethylaminocarbonyl) phenoxy) pyrimidine;
2-methylthio-4- (ethoxycarbonyl) methoxy-5-nitro-6- (5-methoxy-3- (dimethylaminocarbonyl) phenoxy) pyrimidine;
2-methylthio-4- (ethoxycarbonyl) methoxy-5-nitro-6- (5-carboxy-3- (dimethylaminocarbonyl) phenoxy) pyrimidine;
2-methylthio-4- (ethoxycarbonyl) methoxy-5-nitro-6- (5-ethoxycarbonyl-3-methylphenoxy) pyrimidine;
2-methylthio-4- (ethoxycarbonyl) methoxy-5-nitro-6- (5-dimethylamino-3- (imidazolin-2-yl) phenoxy) pyrimidine;
2-methylthio-4- (ethoxycarbonyl) methoxy-5-nitro-6- (5- (dimethylaminocarbonyl) methyl-3- (imidazol-2-yl) phenoxy) pyrimidine;
2-methylthio-4- (ethoxycarbonyl) methoxy-5-nitro-6- (5- (dimethylaminoethyl-3- (dimethylaminocarbonyl) phenoxy) pyrimidine;
2-methylthio-4- (ethoxycarbonyl) methoxy-5-nitro-6- (5- (2-ethoxycarbonylethyl) -3- (tetrahydropyrimidin-2-yl) phenoxy) Pyrimidine;
2-methylthio-4- (1-carboxyethoxy) -5-nitro-6- (3- (diethylaminocarbonyl) phenoxy) pyrimidine;
2-methylthio-4- (1-carboxy-2-methylpropoxy) -5-nitro-6- (5-methyl-3- (dimethylaminocarbonyl) phenoxy) pyrimidine;
2-methylthio-4- (1-carboxy-3-methylpropoxy) -5-nitro-6- (5-trifluoromethyl-3- (dimethylaminocarbonyl) phenoxy) pyrimidine;
2-methylthio-4- (1-carboxy-2-methylbutoxy) -5-nitro-6- (5-methoxy-3- (dimethylaminocarbonyl) phenoxy) pyrimidine;
2-methylthio-4- (1-carboxy-2-phenylethoxy) -5-nitro-6- (5-carboxy-3- (dimethylaminocarbonyl) phenoxy) pyrimidine;
2-methylthio-4- (1-carboxy-2- (4-mercaptophenyl) ethoxy) -5-nitro-6- (5-ethoxycarbonyl-3-methylphenoxy) pyrimidine;
2-methylthio-4- (1-carboxy-3- (methylthio) propoxy) -5-nitro-6- (5-dimethylamino-3- (imidazolin-2-yl) phenoxy) pyrimidine ;
2-methylthio-4- (1-carboxy-2-mercaptoethoxy) -5-nitro-6- (5- (dimethylaminocarbonyl) methyl-3- (imidazol-2-yl) phenoxy) Pyrimidine;
2-methylthio-4- (1-carboxy-2- (indolin-3-yl) ethoxy) -5-nitro-6- (5- (dimethylaminoethyl-3- (dimethylaminocarbonyl) phenoxy ) Pyrimidine;
2-methylthio-4- (1-carboxy-2- (imidazol-4-yl) ethoxy) -5-nitro-6- (5- (2-ethoxycarbonylethyl) -3- (tetrahydro Pyrimidin-2-yl) phenoxy) pyrimidine;
2-methylthio-4- (1-carboxy-2-hydroxyethoxy) -5-nitro-6- (5-carboxy-3- (dimethylaminocarbonyl) phenoxy) pyrimidine;
2-methylthio-4- (1-carboxy-2-hydroxypropoxy) -5-nitro-6- (5-ethoxycarbonyl-3-methylphenoxy) pyrimidine;
2-methylthio-4- (1-carboxy-2- (aminocarbonyl) ethoxy) -5-nitro-6- (5-dimethylamino-3- (imidazolin-2-yl) phenoxy) pyri) Midine;
2-methylthio-4- (1-carboxy-3- (aminocarbonyl) propoxy) -5-nitro-6- (5-dimethylaminocarbonyl) methyl-3- (imidazolin-2-yl) Phenoxy) pyrimidine;
2-methylthio-4- (1,2-dicarboxyethoxy) -5-nitro-6- (5- (dimethylaminoethyl) -3- (dimethylaminocarbonyl) phenoxy) pyrimidine;
2-methylthio-4- (1,3-dicarboxypropoxy) -5-nitro-6- (5- (2-ethoxycarbonylethyl) -3- (tetrahydropyrimidin-2-yl) phenoxy C) pyrimidine;
2-methylthio-4- (1-carboxy-5-aminopentoxy) -5-nitro-6- (5- (dimethylaminocarbonyl) methyl-3- (imidazolin-2-yl) phenoxy) pyri) Midine; And
2-methylthio-4- (1-carboxy-4-guanidinobutoxy) -5-nitro-6- (5-dimethylaminoethyl-3- (dimethylaminocarbonyl) phenoxy) pyrimidine.
C. In a similar manner, 2-methylthio-4-chloro-5-nitro-6- (2-benzyloxy-5-cyanophenoxy) pyrimidine, i.e., a compound of formula K Treatment with a compound of affords 2-methylthio-4- (ethoxycarbonyl) methoxy-5-nitro-6- (2-benzyloxy-5-cyanophenoxy) pyrimidine, ie the compound of formula U do.
D. In a similar manner, compounds of formula U are prepared:
2-methylthio-4- (ethoxycarbonyl) methoxy-5-nitro-6- (2-methoxy-5-cyanophenoxy) pyrimidine;
2-methylthio-4- (ethoxycarbonyl) methoxy-5-nitro-6- (2-ethoxy-5-cyanophenoxy) pyrimidine;
2-methylthio-4- (ethoxycarbonyl) methoxy-5-nitro-6- (3-methoxy-5-cyanophenoxy) pyrimidine;
2-methylthio-4- (ethoxycarbonyl) methoxy-5-nitro-6- (3-ethoxy-5-cyanophenoxy) pyrimidine;
2-methylthio-4- (ethoxycarbonyl) methoxy-5-nitro-6- (2-phenoxy-5-cyanophenoxy) pyrimidine;
2-methylthio-4- (ethoxycarbonyl) methoxy-5-nitro-6- (3-phenoxy-5-cyanophenoxy) pyrimidine;
2-methylthio-4- (ethoxycarbonyl) methoxy-5-nitro-6- (2-chloro-5-cyanophenoxy) pyrimidine;
2-methylthio-4- (ethoxycarbonyl) methoxy-5-nitro-6- (3-bromo-5-cyanophenoxy) pyrimidine;
2-methylthio-4- (ethoxycarbonyl) methoxy-5-nitro-6- (2-methyl-5-cyanophenoxy) pyrimidine;
2-methylthio-4- (ethoxycarbonyl) methoxy-5-nitro-6- (2-methyl-5-cyanophenoxy) pyrimidine;
2-methylthio-4- (ethoxycarbonyl) methoxy-5-nitro-6- (3-methyl-4-cyanophenoxy) pyrimidine;
2-methylthio-4- (ethoxycarbonyl) methoxy-5-nitro-6- (2-nitro-5-cyanophenoxy) pyrimidine;
2-methylthio-4- (ethoxycarbonyl) methoxy-5-nitro-6- (3-nitro-4-cyanophenoxy) pyrimidine;
2-methylthio-4- (ethoxycarbonyl) methoxy-5-nitro-6- (2-carboxy-5-cyanophenoxy) pyrimidine;
2-methylthio-4- (ethoxycarbonyl) methoxy-5-nitro-6- (3-carboxy-4-cyanophenoxy) pyrimidine;
2-methylthio-4- (ethoxycarbonyl) methoxy-5-nitro-6- (tert-butoxycarbonyl-5-cyanophenoxy) pyrimidine;
2-methylthio-4- (ethoxycarbonyl) methoxy-5-nitro-6- (tert-butoxycarbonyl-4-cyanophenoxy) pyrimidine;
2-methylthio-4- (ethoxycarbonyl) methoxy-5-nitro-6- (2-aminocarbonyl-5-cyanophenoxy) pyrimidine;
2-methylthio-4- (ethoxycarbonyl) methoxy-5-nitro-6- (3-aminocarbonyl-4-cyanophenoxy) pyrimidine;
2-methylthio-4- (ethoxycarbonyl) methoxy-5-nitro-6- (2-dimethylamino-5-cyanophenoxy) pyrimidine;
2-methylthio-4- (ethoxycarbonyl) methoxy-5-nitro-6- (3-dimethylamino-4-cyanophenoxy) pyrimidine;
2-methylthio-4- (ethoxycarbonyl) methoxy-5-nitro-6- (2-dimethylamino-5-cyanophenoxy) pyrimidine;
2-methylthio-4- (ethoxycarbonyl) methoxy-5-nitro-6- (3-dimethylamino-4-cyanophenoxy) pyrimidine;
2-methylthio-4- (1-carboxyethoxy) -5-nitro-6- (3-bromo-5-cyanophenoxy) pyrimidine;
2-methylthio-4- (1-carboxy-2-methylpropoxy) -5-nitro-6- (2-methyl-5-cyanophenoxy) pyrimidine;
2-methylthio-4- (1-carboxy-3-methylbutoxy) -5-nitro-6- (2-methyl-5-cyanophenoxy) pyrimidine;
2-methylthio-4- (1-carboxy-2-methylbutoxy) -5-nitro-6- (3-methyl-4-cyanophenoxy) pyrimidine;
2-methylthio-4- (1-carboxy-2-phenylethoxy) -5-nitro-6- (2-nitro-5-cyanophenoxy) pyrimidine;
2-methylthio-4- (1-carboxy-2- (4-mercaptophenyl) ethoxy) -5-nitro-6- (3-nitro-4-cyanophenoxy) pyrimidine;
2-methylthio-4- (1-carboxy-3- (methylthio) propoxy) -5-nitro-6- (2-carboxy-5-cyanophenoxy) pyrimidine;
2-methylthio-4- (1-carboxy-2- (imidazol-4-yl) ethoxy) -5-nitro-6- (3-carboxy-4-cyanophenoxy) pyrimidine;
2-methylthio-4- (1-carboxy-2-hydroxyethoxy) -5-nitro-6- (tert-butoxycarbonyl-5-cyanophenoxy) pyrimidine;
2-methylthio-4- (1-carboxy-2-hydroxypropoxy) -5-nitro-6- (tert-butoxycarbonyl-4-cyanophenoxy) pyrimidine;
2-methylthio-4- (1-carboxy-2- (aminocarbonyl) ethoxy) -5-nitro-6- (2-aminocarbonyl-5-cyanophenoxy) pyrimidine;
2-methylthio-4- (1-carboxy-3- (aminocarbonyl) propoxy) -5-nitro-6- (3-aminocarbonyl-4-cyanophenoxy) pyrimidine;
2-methylthio-4- (1,2-dicarboxyethoxy) -5-nitro-6- (2-dimethylamino-5-cyanophenoxy) pyrimidine;
2-methylthio-4- (1,3-dicarboxypropoxy) -5-nitro-6- (3-dimethylamino-4-cyanophenoxy) pyrimidine;
2-methylthio-4- (1-carboxy-5-aminopentoxy) -5-nitro-6- (2-dimethylamino-5-cyanophenoxy) pyrimidine; And
2-methylthio-4- (1-carboxy-4-guanidinobutoxy) -5-nitro-6- (3-dimethylamino-4-cyanophenoxy) pyrimidine.
<Manufacturing Method 4>
<Compound of Formula F, Formula M, Formula R, and Formula V>
A. 2-methylthio-4- (ethoxycarbonylmethyl) amino-5-nitro-6- (3- (dimethylaminocarbonyl) phenoxypyrimidine in 40 ml of methanol, ie compound of formula E (3.54 g, 8.14 mmol), was added 40 ml of potassium metabisulfite (7.5 g, 24.4 mmol) in water at 0 ° C. The resulting suspension was allowed to warm to ambient temperature and stirred for 15 h. Concentrated to and extracted with methylene chloride (200 mL) The organic layer was dried (Na ₂ SO ₄ ) and evaporated to 3.5 g of 2-methylsulfonyl-4- (ethoxycarbonylmethyl) amino-5-nitro- 6- (3-dimethylaminocarbonyl) phenoxypyrimidine, ie the compound of formula F, was obtained as a white solid.
B. In a similar manner, compounds of formula F are prepared:
2-methylsulfonyl-4- (ethoxycarbonylmethyl) amino-5-nitro-6- (3-diethylaminocarbonyl) phenoxy) pyrimidine;
2-methylsulfonyl-4- (ethoxycarbonylmethyl) amino-5-nitro-6- (5-methyl-3- (dimethylaminocarbonyl) phenoxy) pyrimidine;
2-methylsulfonyl-4- (ethoxycarbonylmethyl) amino-5-nitro-6- (5-trifluoromethyl-3- (dimethylaminocarbonyl) phenoxy) pyrimidine;
2-methylsulfonyl-4- (ethoxycarbonylmethyl) amino-5-nitro-6- (5-methoxy-3- (dimethylaminocarbonyl) phenoxy) pyrimidine;
2-methylsulfonyl-4- (ethoxycarbonylmethyl) amino-5-nitro-6- (5-carboxy-3- (dimethylaminocarbonyl) phenoxy) pyrimidine;
2-methylsulfonyl-4- (ethoxycarbonylmethyl) amino-5-nitro-6- (5-ethoxycarbonyl-3-methylphenoxy) pyrimidine;
2-methylsulfonyl-4- (ethoxycarbonylmethyl) amino-5-nitro-6- (5-dimethylamino-3- (imidazolin-2-yl) phenoxy) pyrimidine;
2-methylsulfonyl-4- (ethoxycarbonylmethyl) amino-5-nitro-6- (5- (dimethylaminocarbonyl) methyl-3- (imidazol-2-yl) phenoxy) pyrimidine;
2-methylsulfonyl-4- (ethoxycarbonylmethyl) amino-5-nitro-6- (5- (dimethylaminoethyl-3- (dimethylaminocarbonyl) phenoxy) pyrimidine;
2-methylsulfonyl-4- (ethoxycarbonylmethyl) amino-5-nitro-6- (5- (2-ethoxycarbonylethyl) -3- (tetrahydropyrimidin-2-yl) phenoxy ) Pyrimidine;
2-methylsulfonyl-4- (1-carboxyethyl) amino-5-nitro-6- (3- (diethylaminocarbonyl) phenoxy) pyrimidine;
2-methylsulfonyl-4- (1-carboxy-2-methylpropyl) amino-5-nitro-6- (5-methyl-3- (dimethylaminocarbonyl) phenoxy) pyrimidine;
2-methylsulfonyl-4- (1-carboxy-3-methylbutyl) amino-5-nitro-6- (5-trifluoromethyl-3- (dimethylaminocarbonyl) phenoxy) pyrimidine;
2-methylsulfonyl-4- (1-carboxy-2-methylbutyl) amino-5-nitro-6- (5-methoxy-3- (dimethylaminocarbonyl) phenoxy) pyrimidine;
2-methylsulfonyl-4- (1-carboxy-2-phenylethyl) amino-5-nitro-6- (5-carboxy-3- (dimethylaminocarbonyl) phenoxy) pyrimidine;
2-methylsulfonyl-4- (1-carboxy-2- (4- sulfonylphenyl) ethyl) amino-5-nitro-6- (5-ethoxycarbonyl-3-methylphenoxy) pyrimidine;
2-methylsulfonyl-4- (1-carboxy-3- (methylsulfonyl) propyl) amino-5-nitro-6- (5-dimethylamino-3- (imidazolin-2-yl) phenoxy) Pyrimidine;
2-methylsulfonyl-4- (1-carboxy-2-sulfonylethyl) amino-5-nitro-6- (5-dimethylaminocarbonyl) methyl-3- (imidazol-2-yl) phenoxy) Pyrimidine;
2-methylsulfonyl-4- (1-carboxy-2- (indolin-3-yl) ethyl) amino-5-nitro-6- (5- (dimethylaminoethyl-3- (dimethylaminocarbonyl) phenoxy C) pyrimidine;
2-methylsulfonyl-4- (1-carboxy-2- (imidazol-4-yl) ethyl) amino-5-nitro-6- (5- (2-ethoxycarbonylethyl) -3- (tetra Hydropyrimidin-2-yl) phenoxy) pyrimidine;
2-methylsulfonyl-4- (1-carboxy-2-hydroxyethyl) amino-5-nitro-6- (5-carboxy-3- (dimethylaminocarbonyl) phenoxy) pyrimidine;
2-methylsulfonyl-4- (1-carboxy-2-hydroxypropyl) amino-5-nitro-6- (5-ethoxycarbonyl-3-methylphenoxy) pyrimidine;
2-methylsulfonyl-4- (1-carboxy-2- (aminocarbonyl) ethyl) amino-5-nitro-6- (5-dimethylamino-3- (imidazolin-2-yl) phenoxy) Pyrimidine;
2-methylsulfonyl-4- (1-carboxy-3- (aminocarbonyl) propyl) amino-5-nitro-6- (5-dimethylaminocarbonyl) methyl-3- (imidazol-2-yl) Phenoxy) pyrimidine;
2-methylsulfonyl-4- (1,2-dicarboxyethyl) amino-5-nitro-6- (5-dimethylaminoethyl-3- (dimethylaminocarbonyl) phenoxy) pyrimidine;
2-methylsulfonyl-4- (1,3-dicarboxypropyl) amino-5-nitro-6- (5- (2-ethoxycarbonylethyl) -3- (tetrahydropyrimidin-2-yl) Phenoxy) pyrimidine;
2-methylsulfonyl-4- (1-carboxy-5-aminopentyl) amino-5-nitro-6- (5- (dimethylaminocarbonyl) methyl-3- (imidazol-2-yl) phenoxy) Pyrimidine; And
2-methylsulfonyl-4- (1-carboxy-4-guanidinobutyl) amino-5-nitro-6- (5- (dimethylaminoethyl-3- (dimethylaminocarbonyl) phenoxy) pyrimidine.
C. In a similar manner, 2-methylthio-4- (ethoxycarbonylmethyl) amino-5-nitro-6- (2-benzyloxy-5-cyanophenoxy) pyrimidine, ie, a compound of formula Oxidation yields 2-methylsulfonyl-4- (ethoxycarbonylmethyl) amino-5-nitro-6- (2-benzyloxy-5-cyanophenoxy) pyrimidine, ie a compound of formula M.
D. In a similar manner, compounds of formula M are prepared:
2-methylsulfonyl-4- (ethoxycarbonylmethyl) amino-5-nitro-6- (2-methoxy-5-cyanophenoxy) pyrimidine;
2-methylsulfonyl-4- (ethoxycarbonylmethyl) amino-5-nitro-6- (2-ethoxy-5-cyanophenoxy) pyrimidine;
2-methylsulfonyl-4- (ethoxycarbonylmethyl) amino-5-nitro-6- (3-methoxy-5-cyanophenoxy) pyrimidine;
2-methylsulfonyl-4- (ethoxycarbonylmethyl) amino-5-nitro-6- (3-ethoxy-5-cyanophenoxy) pyrimidine;
2-methylsulfonyl-4- (ethoxycarbonylmethyl) amino-5-nitro-6- (2-phenoxy-5-cyanophenoxy) pyrimidine;
2-methylsulfonyl-4- (ethoxycarbonylmethyl) amino-5-nitro-6- (3-phenoxy-5-cyanophenoxy) pyrimidine;
2-methylsulfonyl-4- (ethoxycarbonylmethyl) amino-5-nitro-6- (2-chloro-5-cyanophenoxy) pyrimidine;
2-methylsulfonyl-4- (ethoxycarbonylmethyl) amino-5-nitro-6- (3-bromo-5-cyanophenoxy) pyrimidine;
2-methylsulfonyl-4- (ethoxycarbonylmethyl) amino-5-nitro-6- (2-methyl-5-cyanophenoxy) pyrimidine;
2-methylsulfonyl-4- (ethoxycarbonylmethyl) amino-5-nitro-6- (2-methyl-5-cyanophenoxy) pyrimidine;
2-methylsulfonyl-4- (ethoxycarbonylmethyl) amino-5-nitro-6- (3-methyl-4-cyanophenoxy) pyrimidine;
2-methylsulfonyl-4- (ethoxycarbonylmethyl) amino-5-nitro-6- (2-nitro-5-cyanophenoxy) pyrimidine;
2-methylsulfonyl-4- (ethoxycarbonylmethyl) amino-5-nitro-6- (3-nitro-4-cyanophenoxy) pyrimidine;
2-methylsulfonyl-4- (ethoxycarbonylmethyl) amino-5-nitro-6- (2-carboxy-5-cyanophenoxy) pyrimidine;
2-methylsulfonyl-4- (ethoxycarbonylmethyl) amino-5-nitro-6- (3-carboxy-4-cyanophenoxy) pyrimidine;
2-methylsulfonyl-4- (ethoxycarbonylmethyl) amino-5-nitro-6- (tert-butoxycarbonyl-5-cyanophenoxy) pyrimidine;
2-methylsulfonyl-4- (ethoxycarbonylmethyl) amino-5-nitro-6- (3-tert-butoxycarbonyl-4-cyanophenoxy) pyrimidine;
2-methylsulfonyl-4- (ethoxycarbonylmethyl) amino-5-nitro-6- (2-aminocarbonyl-5-cyanophenoxy) pyrimidine;
2-methylsulfonyl-4- (ethoxycarbonylmethyl) amino-5-nitro-6- (3-aminocarbonyl-4-cyanophenoxy) pyrimidine;
2-methylsulfonyl-4- (ethoxycarbonylmethyl) amino-5-nitro-6- (2-dimethylamino-5-cyanophenoxy) pyrimidine;
2-methylsulfonyl-4- (ethoxycarbonylmethyl) amino-5-nitro-6- (3-dimethylamino-4-cyanophenoxy) pyrimidine;
2-methylsulfonyl-4- (ethoxycarbonylmethyl) amino-5-nitro-6- (2-dimethylamino-5-cyanophenoxy) pyrimidine;
2-methylsulfonyl-4- (ethoxycarbonylmethyl) amino-5-nitro-6- (3-dimethylamino-4-cyanophenoxy) pyrimidine;
2-methylsulfonyl-4-amino-5-nitro-6- (2-methoxy-5-cyanophenoxy) pyrimidine;
2-methylsulfonyl-4-amino-5-nitro-6- (2-ethoxy-5-cyanophenoxy) pyrimidine;
2-methylsulfonyl-4-amino-5-nitro-6- (3-methoxy-5-cyanophenoxy) pyrimidine;
2-methylsulfonyl-4-amino-5-nitro-6- (3-ethoxy-5-cyanophenoxy) pyrimidine;
2-methylsulfonyl-4-amino-5-nitro-6- (2-phenoxy-5-cyanophenoxy) pyrimidine;
2-methylsulfonyl-4-amino-5-nitro-6- (3-phenoxy-5-cyanophenoxy) pyrimidine;
2-methylsulfonyl-4-amino-5-nitro-6- (2-chloro-5-cyanophenoxy) pyrimidine;
2-methylsulfonyl-4-amino-5-nitro-6- (3-bromo-5-cyanophenoxy) pyrimidine;
2-methylsulfonyl-4-amino-5-nitro-6- (2-methyl-5-cyanophenoxy) pyrimidine;
2-methylsulfonyl-4-amino-5-nitro-6- (2-methyl-5-cyanophenoxy) pyrimidine;
2-methylsulfonyl-4-amino-5-nitro-6- (3-methyl-4-cyanophenoxy) pyrimidine;
2-methylsulfonyl-4-amino-5-nitro-6- (2-nitro-5-cyanophenoxy) pyrimidine;
2-methylsulfonyl-4-amino-5-nitro-6- (3-nitro-4-cyanophenoxy) pyrimidine;
2-methylsulfonyl-4-amino-5-nitro-6- (2-carboxy-5-cyanophenoxy) pyrimidine;
2-methylsulfonyl-4-amino-5-nitro-6- (3-carboxy-4-cyanophenoxy) pyrimidine;
2-methylsulfonyl-4-amino-5-nitro-6- (2-tert-butoxycarbonyl-5-cyanophenoxy) pyrimidine;
2-methylsulfonyl-4-amino-5-nitro-6- (tert-butoxycarbonyl-4-cyanophenoxy) pyrimidine;
2-methylsulfonyl-4-amino-5-nitro-6- (2-aminocarbonyl-5-cyanophenoxy) pyrimidine;
2-methylsulfonyl-4-amino-5-nitro-6- (3-aminocarbonyl-4-cyanophenoxy) pyrimidine;
2-methylsulfonyl-4-amino-5-nitro-6- (2-dimethylamino-5-cyanophenoxy) pyrimidine;
2-methylsulfonyl-4-amino-5-nitro-6- (3-dimethylamino-4-cyanophenoxy) pyrimidine;
2-methylsulfonyl-4-amino-5-nitro-6- (2-dimethylamino-5-cyanophenoxy) pyrimidine;
2-methylsulfonyl-4-amino-5-nitro-6- (3-dimethylamino-4-cyanophenoxy) pyrimidine;
2-methylsulfonyl-4- (1-carboxyethyl) amino-5-nitro-6- (3-bromo-5-cyanophenoxy) pyrimidine;
2-methylsulfonyl-4- (1-carboxy-2-methylpropyl) amino-5-nitro-6- (2-methyl-5-cyanophenoxy) pyrimidine;
2-methylsulfonyl-4- (1-carboxy-3-methylpropyl) amino-5-nitro-6- (2-methyl-5-cyanophenoxy) pyrimidine;
2-methylsulfonyl-4- (1-carboxy-2-methylbutyl) amino-5-nitro-6- (3-methyl-4-cyanophenoxy) pyrimidine;
2-methylsulfonyl-4- (1-carboxy-2-phenylethyl) amino-5-nitro-6- (2-nitro-5-cyanophenoxy) pyrimidine;
2-methylsulfonyl-4- (1-carboxy-2- (4-sulfonylphenyl) ethyl) amino-5-nitro-6- (3-nitro-4-cyanophenoxy) pyrimidine;
2-methylsulfonyl-4- (1-carboxy-3- (methylsulfonyl) propyl) amino-5-nitro-6- (2-carboxy-5-cyanophenoxy) pyrimidine;
2-methylsulfonyl-4- (1-carboxy-2- (imidazol-4-yl) ethyl) amino-5-nitro-6- (3-carboxy-4-cyanophenoxy) pyrimidine;
2-methylsulfonyl-4- (1-carboxy-2-hydroxyethyl) amino-5-nitro-6- (2-tert-butoxycarbonyl-5-cyanophenoxy) pyrimidine;
2-methylsulfonyl-4- (1-carboxy-2-hydroxypropyl) amino-5-nitro-6- (tert-butoxycarbonyl-4-cyanophenoxy) pyrimidine;
2-methylsulfonyl-4- (1-carboxy-2- (aminocarbonyl) ethyl) amino-5-nitro-6- (2-aminocarbonyl-5-cyanophenoxy) pyrimidine;
2-methylsulfonyl-4- (1-carboxy-2- (aminocarbonyl) propyl) amino-5-nitro-6- (3-aminocarbonyl-4-cyanophenoxy) pyrimidine;
2-methylsulfonyl-4- (1,2-dicarboxyethyl) amino-5-nitro-6- (2-dimethylamino-5-cyanophenoxy) pyrimidine;
2-methylsulfonyl-4- (1,3-dicarboxypropyl) amino-5-nitro-6- (3-dimethylamino-4-cyanophenoxy) pyrimidine;
2-methylsulfonyl-4- (1-carboxy-5-aminopentyl) amino-5-nitro-6- (2-dimethylamino-5-cyanophenoxy) pyrimidine; And
2-methylsulfonyl-4- (1-carboxy-4-guanidinobutyl) amino-5-nitro-6- (3-dimethylamino-4-cyanophenoxy) pyrimidine.
E. In a similar manner, 2-methylthio-4- (ethoxycarbonyl) methoxy-5-nitro-6- (3-dimethylaminocarbonylphenoxy) pyrimidine, ie the compound of formula Q, Prepare methylsulfonyl-4- (ethoxycarbonyl) methoxy-5-nitro-6- (3-dimethylaminocarbonylphenoxy) pyrimidine, ie a compound of formula R.
F. In a similar manner, compounds of formula R are prepared:
2-methylsulfonyl-4- (ethoxycarbonyl) methoxy-5-nitro-6- (3- (diethylaminocarbonyl) phenoxy) pyrimidine;
2-methylsulfonyl-4- (ethoxycarbonyl) methoxy-5-nitro-6- (5-methyl-3- (dimethylaminocarbonyl) phenoxy) pyrimidine;
2-methylsulfonyl-4- (ethoxycarbonyl) methoxy-5-nitro-6- (5-trifluoromethyl-3- (dimethylaminocarbonyl) phenoxy) pyrimidine;
2-methylsulfonyl-4- (ethoxycarbonyl) methoxy-5-nitro-6- (5-methoxy-3- (dimethylaminocarbonyl) phenoxy) pyrimidine;
2-methylsulfonyl-4- (ethoxycarbonyl) methoxy-5-nitro-6- (5-carboxy-3- (dimethylaminocarbonyl) phenoxy) pyrimidine;
2-methylsulfonyl-4- (ethoxycarbonyl) methoxy-5-nitro-6- (5-ethoxycarbonyl-3- (dimethylaminocarbonyl) phenoxy) pyrimidine;
2-methylsulfonyl-4- (ethoxycarbonyl) methoxy-5-nitro-6- (5-dimethylamino-3- (imidazolin-2-yl) phenoxy) pyrimidine;
2-methylsulfonyl-4- (ethoxycarbonyl) methoxy-5-nitro-6- (5- (dimethylaminocarbonyl) methyl-3- (imidazolin-2-yl) phenoxy) pyrimidine ;
2-methylsulfonyl-4- (ethoxycarbonyl) methoxy-5-nitro-6- (5- (dimethylaminoethyl) -3- (dimethylaminocarbonyl) phenoxy) pyrimidine;
2-methylsulfonyl-4- (ethoxycarbonyl) methoxy-5-nitro-6- (5- (2-ethoxycarbonylethyl) -3- (tetrahydropyrimidin-2-yl) phenoxy ) Pyrimidine;
2-methylsulfonyl-4- (1-carboxyethoxy) -5-nitro-6- (3- (diethylaminocarbonyl) phenoxy) pyrimidine;
2-methylsulfonyl-4- (1-carboxy-2-methylpropoxy) -5-nitro-6- (5-methyl-3- (dimethylaminocarbonyl) phenoxy) pyrimidine;
2-methylsulfonyl-4- (1-carboxy-3-methylbutoxy) -5-nitro-6- (5-trifluoromethyl-3- (dimethylaminocarbonyl) phenoxy) pyrimidine;
2-methylsulfonyl-4- (1-carboxy-2-methylbutoxy) -5-nitro-6- (5-methoxy-3- (dimethylaminocarbonyl) phenoxy) pyrimidine;
2-methylsulfonyl-4- (1-carboxy-2-phenylethoxy) -5-nitro-6- (5-carboxy-3- (dimethylaminocarbonyl) phenoxy) pyrimidine;
2-methylsulfonyl-4- (1-carboxy-2- (4-sulfonylphenyl) ethoxy) -5-nitro-6- (5-ethoxycarbonyl-3-methylphenoxy) pyrimidine;
2-methylsulfonyl-4- (1-carboxy-3- (methylsulfonyl) propoxy) -5-nitro-6- (5-dimethylamino-3- (imidazolin-2-yl) phenoxy) Pyrimidine;
2-methylsulfonyl-4- (1-carboxy-2-sulfonylethoxy) -5-nitro-6- (5- (dimethylaminocarbonyl) methyl-3- (imidazol-2-yl) phenoxy ) Pyrimidine;
2-methylsulfonyl-4- (1-carboxy-2- (indolin-3-yl) ethoxy) -5-nitro-6- (5- (dimethylaminoethyl-3- (dimethylaminocarbonyl) phenoxy C) pyrimidine;
2-methylsulfonyl-4- (1-carboxy-2- (imidazol-4-yl) ethoxy) -5-nitro-6- (5- (2-ethoxycarbonylethyl) -3- (tetra Hydropyrimidin-2-yl) phenoxy) pyrimidine;
2-methylsulfonyl-4- (1-carboxy-2-hydroxyethoxy) -5-nitro-6- (5-carboxy-3- (dimethylaminocarbonyl) phenoxy) pyrimidine;
2-methylsulfonyl-4- (1-carboxy-2-hydroxypropoxy) -5-nitro-6- (5-ethoxycarbonyl-3-methylphenoxy) pyrimidine;
2-methylsulfonyl-4- (1-carboxy-2- (aminocarbonyl) ethoxy) -5-nitro-6- (5-dimethylamino-3- (imidazolin-2-yl) phenoxy) Pyrimidine;
2-methylsulfonyl-4- (1-carboxy-3- (aminocarbonyl) propoxy) -5-nitro-6- (5-dimethylaminocarbonyl) methyl-3- (imidazol-2-yl) Phenoxy) pyrimidine;
2-methylsulfonyl-4- (1,2-dicarboxyethoxy) -5-nitro-6- (5- (dimethylaminoethyl-3- (dimethylaminocarbonyl) phenoxy) pyrimidine;
2-methylsulfonyl-4- (1,3-dicarboxypropoxy) -5-nitro-6- (5- (2-ethoxycarbonylethyl) -3- (tetrahydropyrimidin-2-yl) Phenoxy) pyrimidine;
2-methylsulfonyl-4- (1-carboxy-5-aminopentoxy) -5-nitro-6- (5- (dimethylaminocarbonyl) methyl-3- (imidazol-2-yl) phenoxy) pyri) Midine; And
2-methylsulfonyl-4- (1-carboxy-4-guanidinobutoxy) -5-nitro-6- (5- (dimethylaminoethyl-3- (dimethylaminocarbonyl) phenoxy) pyrimidine.
G. In a similar manner, 2-methylsulfonyl-4- (ethoxycarbonyl) methoxy-5-nitro-6- (2-benzyloxy-5-cyanophenoxy) pyrimidine, ie a compound of formula U Is oxidized to give 2-methylsulfonyl-4- (ethoxycarbonyl) methoxy-5-nitro-6- (2-benzyloxy-5-cyanophenoxy) pyrimidine, ie a compound of formula V .
H. In a similar manner, compounds of formula V are prepared:
2-methylsulfonyl-4- (ethoxycarbonyl) methoxy-5-nitro-6- (2-methoxy-5-cyanophenoxy) pyrimidine;
2-methylsulfonyl-4- (ethoxycarbonyl) methoxy-5-nitro-6- (2-ethoxy-5-cyanophenoxy) pyrimidine;
2-methylsulfonyl-4- (ethoxycarbonyl) methoxy-5-nitro-6- (3-methoxy-5-cyanophenoxy) pyrimidine;
2-methylsulfonyl-4- (ethoxycarbonyl) methoxy-5-nitro-6- (3-ethoxy-5-cyanophenoxy) pyrimidine;
2-methylsulfonyl-4- (ethoxycarbonyl) methoxy-5-nitro-6- (2-phenoxy-5-cyanophenoxy) pyrimidine;
2-methylsulfonyl-4- (ethoxycarbonyl) methoxy-5-nitro-6- (3-phenoxy-5-cyanophenoxy) pyrimidine;
2-methylsulfonyl-4- (ethoxycarbonyl) methoxy-5-nitro-6- (2-chloro-5-cyanophenoxy) pyrimidine;
2-methylsulfonyl-4- (ethoxycarbonyl) methoxy-5-nitro-6- (3-bromo-5-cyanophenoxy) pyrimidine;
2-methylsulfonyl-4- (ethoxycarbonyl) methoxy-5-nitro-6- (2-methyl-5-cyanophenoxy) pyrimidine;
2-methylsulfonyl-4- (ethoxycarbonyl) methoxy-5-nitro-6- (2-methyl-5-cyanophenoxy) pyrimidine;
2-methylsulfonyl-4- (ethoxycarbonyl) methoxy-5-nitro-6- (3-methyl-5-cyanophenoxy) pyrimidine;
2-methylsulfonyl-4- (ethoxycarbonyl) methoxy-5-nitro-6- (2-nitro-5-cyanophenoxy) pyrimidine;
2-methylsulfonyl-4- (ethoxycarbonyl) methoxy-5-nitro-6- (3-nitro-4-cyanophenoxy) pyrimidine;
2-methylsulfonyl-4- (ethoxycarbonyl) methoxy-5-nitro-6- (2-carboxy-5-cyanophenoxy) pyrimidine;
2-methylsulfonyl-4- (ethoxycarbonyl) methoxy-5-nitro-6- (3-carboxy-4-cyanophenoxy) pyrimidine;
2-methylsulfonyl-4- (ethoxycarbonyl) methoxy-5-nitro-6- (tert-butoxycarbonyl-5-cyanophenoxy) pyrimidine;
2-methylsulfonyl-4- (ethoxycarbonyl) methoxy-5-nitro-6- (3-tert-butoxycarbonyl-4-cyanophenoxy) pyrimidine;
2-methylsulfonyl-4- (ethoxycarbonyl) methoxy-5-nitro-6- (2-aminocarbonyl-5-cyanophenoxy) pyrimidine;
2-methylsulfonyl-4- (ethoxycarbonyl) methoxy-5-nitro-6- (3-aminocarbonyl-4-cyanophenoxy) pyrimidine;
2-methylsulfonyl-4- (ethoxycarbonyl) methoxy-5-nitro-6- (2-dimethylamino-5-cyanophenoxy) pyrimidine;
2-methylsulfonyl-4- (ethoxycarbonyl) methoxy-5-nitro-6- (3-dimethylamino-4-cyanophenoxy) pyrimidine;
2-methylsulfonyl-4- (ethoxycarbonyl) methoxy-5-nitro-6- (2-dimethylamino-5-cyanophenoxy) pyrimidine;
2-methylsulfonyl-4- (ethoxycarbonyl) methoxy-5-nitro-6- (3-dimethylamino-4-cyanophenoxy) pyrimidine;
2-methylsulfonyl-4- (1-carboxyethoxy) -5-nitro-6- (3-bromo-5-cyanophenoxy) pyrimidine;
2-methylsulfonyl-4- (1-carboxy-2-methylpropoxy) -5-nitro-6- (2-methyl-5-cyanophenoxy) pyrimidine;
2-methylsulfonyl-4- (1-carboxy-3-methylbutoxy) -5-nitro-6- (2-methyl-5-cyanophenoxy) pyrimidine;
2-methylsulfonyl-4- (1-carboxy-2-methylbutoxy) -5-nitro-6- (3-methyl-4-cyanophenoxy) pyrimidine;
2-methylsulfonyl-4- (1-carboxy-2-phenylethoxy) -5-nitro-6- (2-methyl-5-cyanophenoxy) pyrimidine;
2-methylsulfonyl-4- (1-carboxy-2- (4-sulfonylphenyl) ethoxy) -5-nitro-6- (3-nitro-4-cyanophenoxy) pyrimidine;
2-methylsulfonyl-4- (1-carboxy-3- (methylsulfonyl) propoxy) -5-nitro-6- (2-carboxy-5-cyanophenoxy) pyrimidine;
2-methylsulfonyl-4- (1-carboxy-2- (imidazol-4-yl) ethoxy) -5-nitro-6- (3-carboxy-4-cyanophenoxy) pyrimidine;
2-methylsulfonyl-4- (1-carboxy-2-hydroxyethoxy) -5-nitro-6- (2-tert-butoxycarbonyl-5-cyanophenoxy) pyrimidine;
2-methylsulfonyl-4- (1-carboxy-2-hydroxypropoxy) -5-nitro-6- (tert-butoxycarbonyl-4-cyanophenoxy) pyrimidine;
2-methylsulfonyl-4- (1-carboxy-2- (aminocarbonyl) ethoxy) -5-nitro-6- (2-aminocarbonyl-5-cyanophenoxy) pyrimidine;
2-methylsulfonyl-4- (1-carboxy-2- (aminocarbonyl) ethoxy) -5-nitro-6- (3-aminocarbonyl-4-cyanophenoxy) pyrimidine;
2-methylsulfonyl-4- (1,2-dicarboxyethoxy) -5-nitro-6- (2-dimethylamino-5-cyanophenoxy) pyrimidine;
2-methylsulfonyl-4- (1,3-dicarboxyethoxy) -5-nitro-6- (3-dimethylamino-5-cyanophenoxy) pyrimidine;
2-methylsulfonyl-4- (1-carboxy-5-aminopentoxy) -5-nitro-6- (2-dimethylamino-5-cyanophenoxy) pyrimidine; And
2-methylsulfonyl-4- (1-carboxy-4-guanidinobutoxy) -5-nitro-6- (3-dimethylamino-4-cyanophenoxy) pyrimidine.
<Manufacturing Method 5>
<Compounds of Formula H, Formula K, and Formula S>
A. 2-methylsulfonyl-4- (ethoxycarbonylmethyl) amino-5-nitro-6- (3- (dimethylaminocarbonyl) phenoxypyrimidine (3.5 g, 7.49 mmol) in 80 mL acetonitrile ), Ie cesium carbonate (3.17 g, 9.73 mmol) at 0 ° C., followed by 2-benzyloxy-5-cyanophenol (1.6 g, 7.49 mmol). The mixture was stirred for 15 minutes The volatiles were evaporated and the residue was chromatographed on silica (CH ₂ Cl ₂ / ethyl acetate, 10: 1, then 5: 1) to give 2.1 g (46% yield) of 2- (2 Obtain -benzyloxy-5-cyanophenoxy) -4- (ethoxycarbonylmethyl) amino-5-nitro-6- (3- (dimethylaminocarbonyl) phenoxypyrimidine, ie the compound of formula H It was.
B. In a similar manner, compounds of formula H are prepared:
2- (2-benzyloxy-5-cyanophenoxy) -4- (ethoxycarbonylmethyl) amino-5-nitro-6- (3- (diethylaminocarbonyl) phenoxy) pyrimidine;
2- (2-methoxy-5-cyanophenoxy) -4- (ethoxycarbonylmethyl) amino-5-nitro-6- (5-methyl-3- (dimethylaminocarbonyl) phenoxy) pyridine Midine;
2- (2-ethoxy-5-cyanophenoxy) -4- (ethoxycarbonylmethyl) amino-5-nitro-6- (5-trifluoromethyl-3- (dimethylaminocarbonyl) phenoxy C) pyrimidine;
2- (2-phenoxy-5-cyanophenoxy) -4- (ethoxycarbonylmethyl) amino-5-nitro-6- (5-methoxy-3- (dimethylaminocarbonyl) phenoxy) Pyrimidine;
2- (2-chloro-5-cyanophenoxy) -4- (ethoxycarbonylmethyl) amino-5-nitro-6- (5-carboxy-3- (dimethylaminocarbonyl) phenoxy) pyrimidine ;
2- (2-methyl-5-cyanophenoxy) -4- (ethoxycarbonylmethyl) amino-5-nitro-6- (5-ethoxycarbonyl-3-methylphenoxy) pyrimidine;
2- (2-tert-butyl-5-cyanophenoxy) -4- (ethoxycarbonylmethyl) amino-5-nitro-6- (5-dimethylamino-3- (imidazolin-2-yl ) Phenoxy) pyrimidine;
2- (2-nitro-5-cyanophenoxy) -4- (ethoxycarbonylmethyl) amino-5-nitro-6- (5-dimethylaminocarbonyl) methyl-3- (imidazoline-2 -Yl) phenoxy) pyrimidine;
2- (2-carboxy-5-cyanophenoxy) -4- (ethoxycarbonylmethyl) amino-5-nitro-6- (5-dimethylaminoethyl-3- (dimethylaminocarbonyl) phenoxy) Pyrimidine;
2- (2-benzyloxycarbonyl-5-cyanophenoxy) -4- (ethoxycarbonylmethyl) amino-5-nitro-6- (5- (2-ethoxycarbonylethyl) -3- (Tetrahydroxypyrimidin-2-yl) phenoxy) pyrimidine;
2- (2-diethylaminocarbonyl-5-cyanophenoxy) -4- (1-carboxyethyl) amino-5-nitro-6- (3- (diethylaminocarbonyl) phenoxy) pyrimidine ;
2- (2-amino-5-cyanophenoxy) -4- (1-carboxy-2-methylpropyl) amino-5-nitro-6- (5-methyl-3- (dimethylaminocarbonyl) phenoxy ) Pyrimidine;
2- (2-benzyloxy-5-cyanophenoxy) -4- (1-carboxy-3-methylbutyl) amino-5-nitro-6- (5-trifluoromethyl-3- (dimethylaminocar Carbonyl) phenoxy) pyrimidine;
2- (2-methoxy-5-cyanophenoxy) -4- (1-carboxy-2-methylbutyl) amino-5-nitro-6- (5-methoxy-3- (dimethylaminocarbonyl) Phenoxy) pyrimidine;
2- (2-ethoxy-5-cyanophenoxy) -4- (1-carboxy-2-phenylethyl) amino-5-nitro-6- (5-carboxy-3- (dimethylaminocarbonyl) phenoxy C) pyrimidine;
2- (2-phenoxy-5-cyanophenoxy) -4- (1-carboxy-2- (4-sulfonylphenyl) ethyl) amino-5-nitro-6- (5-ethoxycarbonyl- 3-methylphenoxy) pyrimidine;
2- (2-chloro-5-cyanophenoxy) -4- (1-carboxy-3-propyl) amino-5-nitro-6- (5-dimethylamino-3- (imidazolin-2-yl ) Phenoxy) pyrimidine;
2- (2-methyl-5-cyanophenoxy) -4- (1-carboxy-2-sulfonylethyl) amino-5-nitro-6- (5- (dimethylaminocarbonyl) methyl-3- ( Imidazol-2-yl) phenoxy) pyrimidine;
2- (2-tert-butyl-5-cyanophenoxy) -4- (1-carboxy-2- (indolin-3-yl) ethyl) amino-5-nitro-6- (5-dimethylaminoethyl -3- (dimethylaminocarbonyl) phenoxy) pyrimidine;
2- (2-nitro-5-cyanophenoxy) -4- (1-carboxy-2- (imidazol-4-yl) ethyl) amino-5-nitro-6- (5- (2-ethoxy Carbonylethyl) -3- (tetrahydropyrimidin-2-yl) phenoxy) pyrimidine;
2- (2-carboxy-5-cyanophenoxy) -4- (1-carboxy-2-hydroxyethyl) amino-5-nitro-6- (5-carboxy-3- (dimethylaminocarbonyl) phenoxy C) pyrimidine;
2- (2-benzyloxycarbonyl-5-cyanophenoxy) -4- (1-carboxy-2-hydroxypropyl) amino-5-nitro-6- (5-ethoxycarbonyl-3-methyl Phenoxy) pyrimidine;
2- (2-Diethylaminocarbonyl-5-cyanophenoxy) -4- (1-carboxy-2- (aminocarbonyl) ethyl) amino-5-nitro-6- (5-dimethylaminoethyl- 3- (imidazolin-2-yl) phenoxy) pyrimidine;
2- (2-amino-5-cyanophenoxy) -4- (1-carboxy-3- (aminocarbonyl) propyl) amino-5-nitro-6- (5- (dimethylaminocarbonyl) methyl- 3- (imidazol-2-yl) phenoxy) pyrimidine;
2- (2-benzyloxy-5-cyanophenoxy) -4- (1,2-dicarboxyethyl) amino-5-nitro-6- (5- (dimethylaminoethyl-3- (dimethylaminocarbonyl ) Phenoxy) pyrimidine;
2- (2-benzyloxy-5-cyanophenoxy) -4- (1,3-dicarboxypropyl) amino-5-nitro-6- (5- (2-ethoxycarbonylethyl) -3- (Tetrahydropyrimidin-2-yl) phenoxy) pyrimidine;
2- (2-benzyloxy-5-cyanophenoxy) -4- (1-carboxy-5-aminopentyl) amino-5-nitro-6- (5- (dimethylaminocarbonyl) methyl- (3- (Imidazol-2-yl) phenoxy) pyrimidine; and
2- (2-benzyloxy-5-cyanophenoxy) -4- (1-carboxy-4-guanidinobutyl) amino-5-nitro-6- (5- (dimethylaminoethyl-3- (dimethyl Aminocarbonyl) phenoxy) pyrimidine.
C. In a similar manner, 2-methylthio-4,6-dichloro-5-nitropyrimidine, i.e., a compound of formula A, is treated with 2-benzyloxy-5-cyanophenol, yielding 2-methylthio-4 -Chloro-5-nitro-6- (2-benzyloxy-5-cyanophenoxy) pyrimidine, a compound of formula
D. In a similar manner, compounds of formula K are prepared:
2-methylthio-4-chloro-5-nitro-6- (2-methoxy-5-cyanophenoxy) pyrimidine;
2-methylthio-4-chloro-5-nitro-6- (2-ethoxy-5-cyanophenoxy) pyrimidine;
2-methylthio-4-chloro-5-nitro-6- (3-methoxy-5-cyanophenoxy) pyrimidine;
2-methylthio-4-chloro-5-nitro-6- (3-ethoxy-5-cyanophenoxy) pyrimidine;
2-methylthio-4-chloro-5-nitro-6- (2-phenoxy-5-cyanophenoxy) pyrimidine;
2-methylthio-4-chloro-5-nitro-6- (3-phenoxy-5-cyanophenoxy) pyrimidine;
2-methylthio-4-chloro-5-nitro-6- (2-chloro-5-cyanophenoxy) pyrimidine;
2-methylthio-4-chloro-5-nitro-6- (3-bromo-5-cyanophenoxy) pyrimidine;
2-methylthio-4-chloro-5-nitro-6- (2-methyl-5-cyanophenoxy) pyrimidine;
2-methylthio-4-chloro-5-nitro-6- (3-methyl-4-cyanophenoxy) pyrimidine;
2-methylthio-4-chloro-5-nitro-6- (2-nitro-5-cyanophenoxy) pyrimidine;
2-methylthio-4-chloro-5-nitro-6- (3-nitro-4-cyanophenoxy) pyrimidine;
2-methylthio-4-chloro-5-nitro-6- (2-carboxy-5-cyanophenoxy) pyrimidine;
2-methylthio-4-chloro-5-nitro-6- (3-carboxy-4-cyanophenoxy) pyrimidine;
2-methylthio-4-chloro-5-nitro-6- (2-tert-butoxycarbonyl-5-cyanophenoxy) pyrimidine;
2-methylthio-4-chloro-5-nitro-6- (tert-butoxycarbonyl-4-cyanophenoxy) pyrimidine;
2-methylthio-4-chloro-5-nitro-6- (2-aminocarbonyl-5-cyanophenoxy) pyrimidine;
2-methylthio-4-chloro-5-nitro-6- (3-aminocarbonyl-4-cyanophenoxy) pyrimidine;
2-methylthio-4-chloro-5-nitro-6- (2-dimethylamino-5-cyanophenoxy) pyrimidine;
2-methylthio-4-chloro-5-nitro-6- (3-dimethylamino-4-cyanophenoxy) pyrimidine;
2-methylthio-4-chloro-5-nitro-6- (2-dimethylamino-5-cyanophenoxy) pyrimidine; And
2-methylthio-4-chloro-5-nitro-6- (3-dimethylamino-4-cyanophenoxy) pyrimidine.
E. In a similar manner, 2-methylsulfonyl-4- (ethoxycarbonyl) methoxy-5-nitro-6- (3-dimethylaminocarbonylphenoxy) pyrimidine, i.e. 2- Treatment with benzyloxy-5-cyanophenol to yield 2- (2-benzyloxy-5-cyanophenoxy) -4- (ethoxycarbonyl) methoxy-5-nitro-6- (3-dimethylamino Carbonylphenoxy) pyrimidine, i.e., a compound of Formula S, was prepared.
F. In a similar manner, compounds of formula S are prepared:
2- (2-benzyloxy-5-cyanophenoxy) -4- (ethoxycarbonyl) methoxy-5-nitro-6- (3- (dimethylaminocarbonyl) phenoxy) pyrimidine;
2- (2-methoxy-5-cyanophenoxy) -4- (ethoxycarbonyl) methoxy-5-nitro-6- (5-methyl-3- (dimethylaminocarbonyl) phenoxy) pyridine Midine;
2- (2-ethoxy-5-cyanophenoxy) -4- (ethoxycarbonyl) methoxy-5-nitro-6- (5-trifluoromethyl-3- (dimethylaminocarbonyl) phenoxy C) pyrimidine;
2- (2-phenoxy-5-cyanophenoxy) -4- (ethoxycarbonyl) methoxy-5-nitro-6- (5-methoxy-3- (dimethylaminocarbonyl) phenoxy) Pyrimidine;
2- (2-chloro-5-cyanophenoxy) -4- (ethoxycarbonyl) methoxy-5-nitro-6- (5-carboxy-3- (dimethylaminocarbonyl) phenoxy) pyrimidine ;
2- (2-methyl-5-cyanophenoxy) -4- (ethoxycarbonyl) methoxy-5-nitro-6- (5-ethoxycarbonyl-3-methylphenoxy) pyrimidine;
2- (2-tert-butyl-5-cyanophenoxy) -4- (ethoxycarbonyl) methoxy-5-nitro-6- (5-dimethylamino-3- (imidazolin-2-yl ) Phenoxy) pyrimidine;
2- (2-nitro-5-cyanophenoxy) -4- (ethoxycarbonyl) methoxy-5-nitro-6- (5- (dimethylaminocarbonyl) methyl-3- (imidazole-2 -Yl) phenoxy) pyrimidine;
2- (2-carboxy-5-cyanophenoxy) -4- (ethoxycarbonyl) methoxy-5-nitro-6- (5- (dimethylaminoethyl-3- (dimethylaminocarbonyl) phenoxy ) Pyrimidine;
2- (2-benzyloxycarbonyl-5-cyanophenoxy) -4- (ethoxycarbonyl) methoxy-5-nitro-6- (5- (2-ethoxycarbonylethyl) -3- (Tetrahydropyrimidin-2-yl) phenoxy) pyrimidine;
2- (2-diethylaminocarbonyl-5-cyanophenoxy) -4- (1-carboxyethoxy) -5-nitro-6- (3- (diethylaminocarbonyl) phenoxy) pyrimidine ;
2- (2-amino-5-cyanophenoxy) -4- (1-carboxy-2-methylpropoxy) -5-nitro-6- (5-methyl-3- (dimethylaminocarbonyl) phenoxy ) Pyrimidine;
2- (2-benzyloxy-5-cyanophenoxy) -4- (1-carboxy-3-methylbutoxy) -5-nitro-6- (5-trifluoromethyl-3- (dimethylaminocar Carbonyl) phenoxy) pyrimidine;
2- (2-methoxy-5-cyanophenoxy) -4- (1-carboxy-2-methylbutoxy) -5-nitro-6- (5-methoxy-3- (dimethylaminocarbonyl) Phenoxy) pyrimidine;
2- (2-ethoxy-5-cyanophenoxy) -4- (1-carboxy-2-phenylethoxy) -5-nitro-6- (5-carboxy-3- (dimethylaminocarbonyl) phenoxy C) pyrimidine;
2- (2-phenoxy-5-cyanophenoxy) -4- (1-carboxy-2- (4-sulfonylphenyl) ethoxy) -5-nitro-6- (5-ethoxycarbonyl- 3-methylphenoxy) pyrimidine;
2- (2-chloro-5-cyanophenoxy) -4- (1-carboxy-3- (methylsulfonyl) propoxy) -5-nitro-6- (5-dimethylamino-3- (imida) Zolin-2-yl) phenoxy) pyrimidine;
2- (2-methyl-5-cyanophenoxy) -4- (1-carboxy-2-sulfonylethoxy) -5-nitro-6- (5-dimethylaminocarbonyl) methyl-3- (already Dazol-2-yl) phenoxy) pyrimidine;
2- (2-tert-butyl-5-cyanophenoxy) -4- (1-carboxy-2- (indolin-3-yl) ethoxy) -5-nitro-6- (5- (dimethylamino Ethyl-3- (dimethylaminocarbonyl) phenoxy) pyrimidine;
2- (2-nitro-5-cyanophenoxy) -4- (1-carboxy-2- (imidazol-4-yl) ethoxy) -5-nitro-6- (5- (2-ethoxy Carbonylethyl) -3- (tetrahydropyrimidin-2-yl) phenoxy) pyrimidine;
2- (2-carboxy-5-cyanophenoxy) -4- (1-carboxy-2-hydroxyethoxy) -5-nitro-6- (5-carboxy-3- (dimethylaminocarbonyl) phenoxy C) pyrimidine;
2- (2-benzyloxycarbonyl-5-cyanophenoxy) -4- (1-carboxy-2-hydroxypropoxy) -5-nitro-6- (5-ethoxycarbonyl-3-methyl Phenoxy) pyrimidine;
2- (2-Diethylaminocarbonyl-5-cyanophenoxy) -4- (1-carboxy-2- (aminocarbonyl) ethoxy) -5-nitro-6- (5-dimethylamino-3 -(Imidazolin-2-yl) phenoxy) pyrimidine;
2- (2-amino-5-cyanophenoxy) -4- (1-carboxy-3- (aminocarbonyl) propoxy) -5-nitro-6- (5-dimethylaminocarbonyl) methyl-3 -(Imidazolin-2-yl) phenoxy) pyrimidine;
2- (2-benzyloxy-5-cyanophenoxy) -4- (1,2-dicarboxyethoxy) -5-nitro-6- (5-dimethylaminoethyl-3- (dimethylaminocarbonyl) Phenoxy) pyrimidine;
2- (2-benzyloxy-5-cyanophenoxy) -4- (1,3-dicarboxypropoxy) -5-nitro-6- (5- (2-ethoxycarbonylethyl) -3- (Tetrahydropyrimidin-2-yl) phenoxy) pyrimidine;
2- (2-benzyloxy-5-cyanophenoxy) -4- (1-carboxy-5-aminopentoxy) -5-nitro-6- (5- (dimethylaminocarbonyl) methyl- (3- ( Imidazol-2-yl) phenoxy) pyrimidine; and
2- (2-benzyloxy-5-cyanophenoxy) -4- (1-carboxy-4-guanidinobutoxy) -5-nitro-6- (5- (dimethylaminoethyl-3- (dimethyl Aminocarbonyl) phenoxy) pyrimidine.
<Manufacturing Method 6>
<Compound of Formula J, Formula O, Formula T and Formula X>
A. 2- (2-benzyloxy-5-cyanophenoxy) -4- (ethoxycarbonylmethyl) amino-5-nitro-6- (3- (dimethylaminocarbonyl) phenoxy) pyrimidine ( 1.1 g, 1.80 mmol), ie compound of formula H and granular zinc (0.5 g), were mixed with tetrahydrofuran (50 mL) and 10% aqueous HCl solution (10 mL). The reaction mixture was heated at 70 ° C for 30 minutes. The volatiles were evaporated. A saturated aqueous NaHCO ₃ solution was added and the solution was extracted with ethyl acetate (300 mL). The organic layer was dried (Na ₂ SO ₄ ) and evaporated to 1.35 g of 2- (2-benzyloxy-5-cyanophenoxy) -4- (3- (dimethylaminocarbonyl) phenoxy) -1,7- Dihydro-6 (5H) -pteridinone, ie the compound of formula J, was obtained.
B. In a similar manner, compounds of formula J are prepared:
2- (2-benzyloxy-5-cyanophenoxy) -4- (3- (diethylaminocarbonyl) phenoxy) -1,7-dihydro-6 (5H) -putridinone;
2- (2-methoxy-5-cyanophenoxy) -4- (5-methyl-3- (dimethylaminocarbonyl) phenoxy) -1,7-dihydro-6 (5H) -ptenedinone ;
2- (2-ethoxy-5-cyanophenoxy) -4- (5-trifluoromethyl-3- (dimethylaminocarbonyl) phenoxy) -1,7-dihydro-6 (5H)- Putridinone;
2- (2-phenoxy-5-cyanophenoxy) -4- (5-methoxy-3- (dimethylaminocarbonyl) phenoxy) -1,7-dihydro-6 (5H) -pteri Dinons;
2- (2-chloro-5-cyanophenoxy) -4- (5-carboxy-3- (dimethylaminocarbonyl) phenoxy) -1,7-dihydro-6 (5H) -pteridinone;
2- (2-Methyl-5-cyanophenoxy) -4- (5-ethoxycarbonyl-3-methylphenoxy) -1,7-dihydro-6 (5H)-putridinone;
2- (2-tert-butoxy-5-cyanophenoxy) -4- (5-dimethylamino-3- (imidazolin-2-yl) phenoxy) -1,7-dihydro-6 ( 5H) -pteridinone;
2- (2-amino-5-cyanophenoxy) -4- (5-dimethylaminocarbonyl) methyl-3- (imidazol-2-yl) phenoxy) -1,7-dihydro-6 ( 5H) -pteridinone;
2- (2-carboxy-5-cyanophenoxy) -4- (5-dimethylaminoethyl-3- (dimethylaminocarbonyl) phenoxy) -1,7-dihydro-6 (5H)-puteri Dinons;
2- (2-benzyloxycarbonyl-5-cyanophenoxy) -4- (5- (2-ethoxycarbonylethyl) -3- (tetrahydropyrimidin-2-yl) phenoxy) -1 , 7-dihydro-6 (5H) -pteridinone;
2- (2-diethylaminocarbonyl-5-cyanophenoxy) -4- (3- (diethylaminocarbonyl) phenoxy) -7-methyl-1,7-dihydro-6 (5H) -Putridinone;
2- (2-amino-5-cyanophenoxy) -4- (5-methyl-3- (dimethylaminocarbonyl) phenoxy) -7- (1-methylethyl) -1,7-dihydro- 6 (5H) -pteridinone;
2- (2-benzyloxy-5-cyanophenoxy) -4- (5-trifluoromethyl-3- (dimethylaminocarbonyl) phenoxy) -7- (2-methylpropyl) -1,7 -Dihydro-6 (5H)-putridinone;
2- (2-methoxy-5-cyanophenoxy) -4- (5-methoxy-3- (dimethylaminocarbonyl) phenoxy) -7- (1-methylpropyl) -1,7-di Hydro-6 (5H) -putridinone;
2- (2-ethoxy-5-cyanophenoxy) -4- (5-carboxy-3- (dimethylaminocarbonyl) phenoxy) -7-benzyl-1,7-dihydro-6 (5H) -Putridinone;
2- (2-phenoxy-5-cyanophenoxy) -4- (5-ethoxycarbonyl-3-methylphenoxy) -7- (4-sulfonylphenyl) methyl-1,7-dihydro -6 (5H) -pteridinone;
2- (2-chloro-5-cyanophenoxy) -4- (5-dimethylamino-3- (imidazolin-2-yl) phenoxy) -7- (2-methylsulfonyl) ethyl-1 , 7-dihydro-6 (5H) -pteridinone;
2- (2-methyl-5-cyanophenoxy) -4- (5- (dimethylaminocarbonyl) methyl-3- (imidazol-2-yl) phenoxy) -7- (sulfonylmethyl)- 1,7-dihydro-6 (5H) -pteridinone;
2- (2-tert-butyl-5-cyanophenoxy) -4- (5- (dimethylaminoethyl-3- (dimethylaminocarbonyl) phenoxy) -7- (indolin-3-yl) methyl -1,7-dihydro-6 (5H)-putridinone;
2- (2-amino-5-cyanophenoxy) -4- (5- (2-ethoxycarbonylethyl) -3- (tetrahydropyrimidin-2-yl) phenoxy) -7- (already Dazol-4-yl) methyl-1,7-dihydro-6 (5H) -putridinone;
2- (2-carboxy-5-cyanophenoxy) -4- (5- (carboxy-3- (dimethylaminocarbonyl) phenoxy) -7- (hydroxymethyl) -1,7-dihydro- 6 (5H) -pteridinone;
2- (2-benzyloxycarbonyl-5-cyanophenoxy) -5-amino-4- (5-ethoxycarbonyl-3-methylphenoxy) -7- (1-hydroxyethyl) -1 , 7-dihydro-6 (5H) -pteridinone;
2- (2-Diethylaminocarbonyl-5-cyanophenoxy) -5-amino-4- (5-dimethylamino-3- (imidazolin-2-yl) phenoxy) -7- (amino Carbonylmethyl) -1,7-dihydro-6 (5H) -putridinone;
2- (2-amino-5-cyanophenoxy) -4- (5- (dimethylaminocarbonyl) methyl-3- (imidazol-2-yl) phenoxy) -7- (2- (aminocar Carbonyl) ethyl) -1,7-dihydro-6 (5H) -phthalinone;
2- (2-benzyloxy-5-cyanophenoxy) -4- (5- (dimethylaminoethyl-3- (dimethylaminocarbonyl) phenoxy) -7- (carboxymethyl) -1,7-di Hydro-6 (5H) -putridinone;
2- (2-benzyloxy-5-cyanophenoxy) -4- (5- (2-ethoxycarbonylethyl) -3- (tetrahydropyrimidin-2-yl) phenoxy) -7- ( 2-carboxyethyl) -1,7-dihydro-6 (5H) -putridinone;
2- (2-benzyloxy-5-cyanophenoxy) -4- (5- (dimethylaminocarbonyl) methyl- (3- (imidazol-2-yl) phenoxy) -7- (4-amino Butyl) -1,7-dihydro-6 (5H) -pteridinone; and
2- (2-benzyloxy-5-cyanophenoxy) -4- (5- (dimethylaminoethyl-3- (dimethylaminocarbonyl) phenoxy) -7- (3-guanidinopropyl) -1 , 7-dihydro-6 (5H) -pteridinone.
C. In a similar manner, 2- (3-dimethylaminocarbonylphenoxy) -4- (ethoxycarbonylmethyl) amino-5-nitro-6- (2-benzyloxy-5-cyanophenoxy) pyridine The midine, i.e., the compound of formula N, was reduced and closed to yield 2- (3-dimethylaminocarbonylphenoxy) -4- (2-benzyloxy-5-cyanophenoxy) -1,7-dihydro-6 5H) -Pteridinone, ie a compound of Formula (O), was prepared.
D. In a similar manner, compounds of formula O are prepared:
2- (3-dimethylphenoxy) -4- (2-methoxy-5-cyanophenoxy) -1,7-dihydro-6 (5H) -ptenedinone;
2- (3-Chloro-5-methoxyphenoxy) -4- (2-ethoxy-5-cyanophenoxy) -1,7-dihydro-6 (5H)-putridinone;
2- (4-trifluoromethylphenoxy) -4- (3-methoxy-5-cyanophenoxy) -l, 7-dihydro-6 (5H)-putridinone;
2- (3,5-diaminophenoxy) -4- (3-ethoxy-5-cyanophenoxy) -1,7-dihydro-6 (5H) -phthalinone;
2- (3-guanidino-5-methylphenoxy) -4- (2-phenoxy-5-cyanophenoxy) -1,7-dihydro-6 (5H) -ptenedinone;
2- (3-ureidophenoxy) -4- (3-phenoxy-5-cyanophenoxy) -1,7-dihydro-6 (5H)-putridinone;
2- (3- (2-Chloroethyl) -5-methylphenoxy) -4- (2-chloro-5-cyanophenoxy) -1,7-dihydro-6 (5H)-putridinone;
2- (3-dimethylaminocarbonylphenoxy) -4- (3-bromo-5-cyanophenoxy) -1,7-dihydro-6 (5H) -ptenedinone;
2- (4-ethoxycarbonylphenoxy) -4- (2-methyl-5-cyanophenoxy) -1,7-dihydro-6 (5H) -ptenedinone;
2- (3- (1-methylimidazol-2-yl) phenoxy) -4- (2-methyl-5-cyanophenoxy) -1,7-dihydro-6 (5H) -pteri Dinons;
2- (3-dimethylaminophenoxy) -4- (3-methyl-4-cyanophenoxy) -1,7-dihydro-6 (5H) -ptenedinone;
2- (3- (1-methylimidazolin-2-yl) phenoxy) -4- (2-amino-5-cyanophenoxy) -1,7-dihydro-6 (5H) -pteri Dinons;
2- (3-tert-butoxycarbonylphenoxy) -4- (3-amino-4-cyanophenoxy) -1,7-dihydro-6 (5H)-putridinone;
2- (3- (1-methylimidazolin-2-yl) phenoxy) -4- (2-carboxy-5-cyanophenoxy) -1,7-dihydro-6 (5H) -pteri Dinons;
2- (3- (1-methylimidazolin-2-yl) phenoxy) -4- (3-carboxy-4-cyanophenoxy) -1,7-dihydro-6 (5H) -pteri Dinons;
2- (3- (1-methylimidazolin-2-yl) phenoxy) -4- (tert-butoxycarbonyl-5-cyanophenoxy) -1,7-dihydro-6 ( 5H) -pteridinone;
2- (3- (1-methylimidazolin-2-yl) phenoxy) -4- (tert-butoxycarbonyl-5-cyanophenoxy) -1,7-dihydro-6 ( 5H) -pteridinone;
2- (3- (1-methylimidazolin-2-yl) phenoxy) -4- (2-aminocarbonyl-5-cyanophenoxy) -1,7-dihydro-6 (5H)- Putridinone;
2- (3- (1-methylimidazolin-2-yl) phenoxy) -4- (3-aminocarbonyl-4-cyanophenoxy) -1,7-dihydro-6 (5H)- Putridinone;
2- (3- (1-methylimidazolin-2-yl) phenoxy) -4- (2-dimethylamino-5-cyanophenoxy) -1,7-dihydro-6 (5H) -prop Teridinone;
2- (3- (1-methylimidazolin-2-yl) phenoxy) -4- (3-dimethylamino-4-cyanophenoxy) -1,7-dihydro-6 (5H) -prop Teridinone;
2- (3- (1-methylimidazolin-2-yl) phenoxy) -4- (2-dimethylamino-5-cyanophenoxy) -1,7-dihydro-6 (5H) -prop Teridinone;
2- (3- (1-methylimidazolin-2-yl) phenoxy) -4- (3-dimethylamino-4-cyanophenoxy) -1,7-dihydro-6 (5H) -prop Teridinone;
2- (3- (1-methylimidazolin-2-yl) phenoxy) -4- (2-methoxy-5-cyanophenoxy) -1,7-dihydro-6 (5H) -prop Teridinone;
2- (3- (1-methylimidazolin-2-yl) phenoxy) -4- (2-ethoxy-4-cyanophenoxy) -1,7-dihydro-6 (5H) -prop Teridinone;
2- (3- (1-methylimidazolin-2-yl) phenoxy) -4- (3-methoxy-5-cyanophenoxy) -1,7-dihydro-6 (5H) -prop Teridinone;
2- (3- (1-methylimidazolin-2-yl) phenoxy) -4- (3-ethoxy-5-cyanophenoxy) -1,7-dihydro-6 (5H) -prop Teridinone;
2- (3- (1-methylimidazolin-2-yl) phenoxy) -4- (2-phenoxy-5-cyanophenoxy) -1,7-dihydro-6 (5H) -prop Teridinone;
2- (3-dimethylimidazolin-2-yl) phenoxy) -4- (3-phenoxy-5-cyanophenoxy) -1,7-dihydro-6 (5H) -putridinone;
2- (3-dimethylimidazolin-2-yl) phenoxy) -4- (2-chloro-5-cyanophenoxy) -1,7-dihydro-6 (5H) -putridinone;
2- (3-dimethylimidazolin-2-yl) phenoxy) -4- (3-bromo-5-cyanophenoxy) -1,7-dihydro-6 (5H) -ptenedinone;
2- (3-dimethylimidazolin-2-yl) phenoxy) -4- (2-methyl-5-cyanophenoxy) -1,7-dihydro-6 (5H) -ptenedinone;
2- (3-dimethylimidazolin-2-yl) phenoxy) -4- (2-methyl-5-cyanophenoxy) -1,7-dihydro-6 (5H) -ptenedinone;
2- (3-dimethylimidazolin-2-yl) phenoxy) -4- (3-methyl-4-cyanophenoxy) -1,7-dihydro-6 (5H) -ptenedinone;
2- (3-dimethylimidazolin-2-yl) phenoxy) -4- (2-amino-5-cyanophenoxy) -1,7-dihydro-6 (5H) -putridinone;
2- (3-dimethylimidazolin-2-yl) phenoxy) -4- (3-amino-4-cyanophenoxy) -1,7-dihydro-6 (5H) -putridinone;
2- (3-guanidinophenoxy) -4- (2-carboxy-5-cyanophenoxy) -1,7-dihydro-6 (5H)-putridinone;
2- (3-guanidinophenoxy) -4- (3-carboxy-4-cyanophenoxy) -1,7-dihydro-6 (5H) -ptenedinone;
2- (3-guanidinophenoxy) -4- (2-tert-butoxycarbonyl-5-cyanophenoxy) -1,7-dihydro-6 (5H) -ptenedinone;
2- (3-guanidinophenoxy) -4- (3-tert-butoxycarbonyl-4-cyanophenoxy) -1,7-dihydro-6 (5H) -ptenedinone;
2- (3-guanidinophenoxy) -4- (2-aminocarbonyl-5-cyanophenoxy) -1,7-dihydro-6 (5H)-putridinone;
2- (3-guanidinophenoxy) -4- (3-aminocarbonyl-4-cyanophenoxy) -1,7-dihydro-6 (5H)-putridinone;
2- (3-guanidinophenoxy) -4- (3-dimethylamino-4-cyanophenoxy) -1,7-dihydro-6 (5H)-putridinone;
2- (3-guanidinophenoxy) -4- (2-dimethylamino-5-cyanophenoxy) -7-methyl-1,7-dihydro-6 (5H) -ptenedinone;
2- (3-Guanidinophenoxy) -4- (3-dimethylamino-4-cyanophenoxy) -7- (1-methylethyl) -1,7-dihydro-6 (5H) -prop Teridinone;
2- (3-dimethylaminocarbonylphenoxy) -4- (3-bromo-5-cyanophenoxy) -7- (2-methylpropyl) -1,7-dihydro-6 (5H)- Putridinone;
2- (3-dimethylaminocarbonylphenoxy) -4- (2-methyl-5-cyanophenoxy) -7- (1-methylpropyl) -1,7-dihydro-6 (5H) -prop Teridinone;
2- (3-dimethylaminocarbonylphenoxy) -4- (2-methyl-5-cyanophenoxy) -7-benzyl-1,7-dihydro-6 (5H) -ptenedinone;
2- (3-dimethylaminocarbonylphenoxy) -4- (3-methyl-4-cyanophenoxy) -7- (4-sulfonylphenyl) methyl-1,7-dihydro-6 (5H) -Putridinone;
2- (3-dimethylaminocarbonylphenoxy) -4- (2-amino-5-cyanophenoxy) -7- (2-methylsulfonyl) ethyl-1,7-dihydro-6 (5H) -Putridinone;
2- (3-dimethylaminocarbonylphenoxy) -4- (3-amino-4-cyanophenoxy) -7- (sulfonylmethyl) -1,7-dihydro-6 (5H) -pteri Dinons;
2- (3-guanidinophenoxy) -4- (2-carboxy-5-cyanophenoxy) -7- (indolin-3-yl) methyl-1,7-dihydro-6 (5H) -Putridinone;
2- (3-guanidinophenoxy) -4- (3-carboxy-4-cyanophenoxy) -7- (imidazol-4-yl) methyl-1,7-dihydro-6 (5H) -Putridinone;
2- (3-guanidinophenoxy) -4- (tert-butoxycarbonyl-5-cyanophenoxy) -7- (hydroxymethyl) -1,7-dihydro-6 (5H ) -Pteridinone;
2- (3-guanidinophenoxy) -4- (3-tert-butoxycarbonyl-4-cyanophenoxy) -7- (1-hydroxyethyl) -1,7-dihydro-6 (5H) -pteridinone;
2- (3-guanidinophenoxy) -4- (2-aminocarbonyl-5-cyanophenoxy) -7- (aminocarbonylmethyl) -1,7-dihydro-6 (5H)- Putridinone;
2- (3-guanidinophenoxy) -4- (3-aminocarbonyl-4-cyanophenoxy) -7- (2- (aminocarbonyl) ethyl) -1,7-dihydro-6 (5H) -pteridinone;
2- (3-Guanidinophenoxy) -4- (2-dimethylamino-5-cyanophenoxy) -7- (carboxymethyl) -1,7-dihydro-6 (5H) -ptenedinone ;
2- (3-guanidinophenoxy) -4- (3-dimethylamino-4-cyanophenoxy) -7- (2-carboxyethyl) -1,7-dihydro-6 (5H) -prop Teridinone;
2- (3-Guanidinophenoxy) -4- (2-dimethylamino-5-cyanophenoxy) -7- (4-aminobutyl) -1,7-dihydro-6 (5H) -prop Teridinone; And
2- (3-guanidinophenoxy) -4- (3-dimethylamino-4-cyanophenoxy) -7- (3-guanidinopropyl) -1,7-dihydro-6 (5H) -Pteridinone.
E. In a similar manner, 2- (2-benzyloxy-5-cyanophenoxy) -4- (ethoxycarbonyl) methoxy-5-nitro-6- (3-dimethylaminocarbonylphenoxy) pyridine Midine, i.e., the compound of formula S, was reduced and closed to yield 2- (2-benzyloxy-5-cyanophenoxy) -4- (3- (dimethylaminocarbonyl) phenoxy) -5H-pyrimido [4, 5-b] [1,4] oxazin-6 (7H) -one, ie a compound of formula T, was prepared.
F. In a similar manner, compounds of formula T are prepared:
2- (2-benzyloxy-5-cyanophenoxy) -4- (3- (diethylaminocarbonyl) phenoxy) -5H-pyrimido [4,5-b] [1,4] oxazine -6 (7H) -one;
2- (2-methoxy-5-cyanophenoxy) -4- (5-methyl-3- (dimethylaminocarbonyl) phenoxy) -5H-pyrimido [4,5-b] [1,4 ] Oxazine-6 (7H) -one;
2- (2-ethoxy-5-cyanophenoxy) -4- (5-trifluoromethyl-3- (dimethylaminocarbonyl) phenoxy) -5H-pyrimido [4,5-b] [ 1,4] oxazine-6 (7H) -one;
2- (2-phenoxy-5-cyanophenoxy) -4- (5-methoxy-3- (dimethylaminocarbonyl) phenoxy) -5H-pyrimido [4,5-b] [1, 4] oxazine-6 (7H) -one;
2- (2-chloro-5-cyanophenoxy) -4- (5-carboxy-3- (dimethylaminocarbonyl) phenoxy) -5H-pyrimido [4,5-b] [1,4] Oxazine-6 (7H) -one;
2- (2-methyl-5-cyanophenoxy) -4- (5-ethoxycarbonyl-3-methylphenoxy) -5H-pyrimido [4,5-b] [1,4] oxazine -6 (7H) -one;
2- (2-tert-butyl-5-cyanophenoxy) -4- (5-dimethylamino-3- (imidazolin-2-yl) phenoxy) -5H-pyrimido [4,5-b ] [1,4] oxazine-6 (7H) -one;
2- (2-amino-5-cyanophenoxy) -4- (5- (dimethylaminocarbonyl) methyl-3- (imidazol-2-yl) phenoxy) -5H-pyrimido [4,5 -b] [1,4] oxazin-6 (7H) -one;
2- (2-carboxy-5-cyanophenoxy) -4- (5- (dimethylaminoethyl-3- (dimethylaminocarbonyl) phenoxy) -5H-pyrimido [4,5-b] [1 , 4] oxazine-6 (7H) -one;
2- (2-benzyloxycarbonyl-5-cyanophenoxy) -4- (5- (2-ethoxycarbonylethyl) -3- (tetrahydropyrimidin-2-yl) phenoxy) -5H -Pyrimido [4,5-b] [1,4] oxazin-6 (7H) -one;
2- (2-diethylaminocarbonyl-5-cyanophenoxy) -4- (3- (diethylaminocarbonyl) phenoxy) -5H-pyrimido [4,5-b] [1,4 ] Oxazine-6 (7H) -one;
2- (2-amino-5-cyanophenoxy) -4- (5-methyl-3- (dimethylaminocarbonyl) phenoxy) -7-methyl-5H-pyrimido [4,5-b] [ 1,4] oxazine-6 (7H) -one;
2- (2-benzyloxy-5-cyanophenoxy) -4- (5-trifluoromethyl-3- (dimethylaminocarbonyl) phenoxy) -7- (1-methylethyl) -5H-pyri Mino [4,5-b] [1,4] oxazine-6 (7H) -one;
2- (2-methoxy-5-cyanophenoxy) -4- (5-methoxy-3- (dimethylaminocarbonyl) phenoxy) -7- (2-methylpropyl) -5H-pyrimido [ 4,5-b] [1,4] oxazin-6 (7H) -one;
2- (2-ethoxy-5-cyanophenoxy) -4- (5-carboxy-3- (dimethylaminocarbonyl) phenoxy) -7- (1-methylpropyl) -5H-pyrimido [4 , 5-b] [1,4] oxazin-6 (7H) -one;
2- (2-phenoxy-5-cyanophenoxy) -4- (5-ethoxycarbonyl-3-methylphenoxy) -7-benzyl-5H-pyrimido [4,5-b] [1 , 4] oxazine-6 (7H) -one;
2- (2-chloro-5-cyanophenoxy) -4- (5-dimethylamino-3- (imidazolin-2-yl) phenoxy) -7- (4-sulfonylphenyl) methyl-5H -Pyrimido [4,5-b] [1,4] oxazin-6 (7H) -one;
2- (2-methyl-5-cyanophenoxy) -4- (5- (dimethylaminocarbonyl) methyl-3- (imidazol-2-yl) phenoxy) -7- (sulfonylmethyl)- 5H-pyrimido [4,5-b] [1,4] oxazin-6 (7H) -one;
2- (2-tert-butyl-5-cyanophenoxy) -4- (5- (dimethylaminoethyl-3- (dimethylaminocarbonyl) phenoxy) -7- (indolin-3-yl) methyl ) -5H-pyrimido [4,5-b] [1,4] oxazin-6 (7H) -one;
2- (2-amino-5-cyanophenoxy) -4- (5- (2-ethoxycarbonylethyl) -3- (tetrahydropyrimidin-2-yl) phenoxy) -7- (already Dazol-4-yl) methyl-5H-pyrimido [4,5-b] [1,4] oxazin-6 (7H) -one;
2- (2-carboxy-5-cyanophenoxy) -4- (5- (carboxy-3- (dimethylaminocarbonyl) phenoxy) -7- (hydroxymethyl) -5H-pyrimido [4, 5-b] [1,4] oxazin-6 (7H) -one;
2- (2-benzyloxycarbonyl-5-cyanophenoxy) -4- (5-ethoxycarbonyl-3-methylphenoxy) -7- (1-hydroxyethyl) -5H-pyrimido [ 4,5-b] [1,4] oxazin-6 (7H) -one;
2- (2-diethylaminocarbonyl-5-cyanophenoxy) -4- (5-dimethylamino-3- (imidazolin-2-yl) phenoxy) -7- (aminocarbonylmethyl) -5H-pyrimido [4,5-b] [1,4] oxazin-6 (7H) -one;
2- (2-amino-5-cyanophenoxy) -4- (5- (dimethylaminocarbonyl) methyl-3- (imidazol-2-yl) phenoxy) -7- (2- (aminocar Carbonyl) ethyl) -5H-pyrimido [4,5-b] [1,4] oxazin-6 (7H) -one;
2- (2-benzyloxy-5-cyanophenoxy) -4- (5- (dimethylaminoethyl-3- (dimethylaminocarbonyl) phenoxy) -7- (carboxymethyl) -5H-pyrimido [ 4,5-b] [1,4] oxazin-6 (7H) -one;
2- (2-benzyloxy-5-cyanophenoxy) -4- (5- (2-ethoxycarbonylethyl) -3- (tetrahydropyrimidin-2-yl) phenoxy) -7- ( 2-carboxyethyl) -5H-pyrimido [4,5-b] [1,4] oxazin-6 (7H) -one;
2- (2-benzyloxy-5-cyanophenoxy) -4- (5- (dimethylaminocarbonyl) methyl-3- (imidazol-2-yl) phenoxy) -7- (4-aminobutyl ) -5H-pyrimido [4,5-b] [1,4] oxazin-6 (7H) -one; And
2- (2-benzyloxy-5-cyanophenoxy) -4- (5- (dimethylaminoethyl-3- (dimethylaminocarbonyl) phenoxy) -7- (3-guanidinopropyl) -5H -Pyrimido [4,5-b] [1,4] oxazine-6 (7H) -one.
G. In a similar manner, 2- (3-dimethylaminocarbonylphenoxy) -4- (ethoxycarbonyl) methoxy-5-nitro-6- (2-benzyloxy-5-cyanophenoxy) pyridine Midine, i.e., the compound of formula W, was reduced and closed to yield 2- (3-dimethylaminocarbonylphenoxy) -4- (2-benzyloxy-5-cyanophenoxy) -5H-pyrimido [4,5- b] [1,4] oxazin-6 (7H) -one, ie a compound of formula X, was prepared.
H. In a similar manner, compounds of formula X are prepared:
2- (3-methylphenoxy) -4- (2-benzyloxy-5-cyanophenoxy) -5H-pyrimido [4,5-b] [1,4] oxazine-6 (7H)- On;
2- (3-chloro-5-methoxyphenoxy) -4- (2-ethoxy-5-cyanophenoxy) -5H-pyrimidido [4,5-b] [1,4] oxazine -6 (7H) -one;
2- (4-trifluoromethylphenoxy) -4- (3-methoxy-5-cyanophenoxy) -5H-pyrimidido [4,5-b] [1,4] oxazine-6 (7H) -one;
2- (3,5-diaminophenoxy) -4- (3-ethoxy-5-cyanophenoxy) -5H-pyrimidido [4,5-b] [1,4] oxazine-6 (7H) -one;
2- (3-guanidino-5-methylphenoxy) -4- (2-phenoxy-5-cyanophenoxy) -5H-pyrimidido [4,5-b] [1,4] jade Photo-6 (7H) -on;
2- (3-ureidophenoxy) -4- (3-phenoxy-5-cyanophenoxy) -5H-pyrimidido [4,5-b] [1,4] oxazine-6 (7H )-On;
2- (3- (2-chloroethyl) -5-methylphenoxy) -4- (2-chloro-5-cyanophenoxy) -5H-pyrimidido [4,5-b] [1,4 ] Oxazine-6 (7H) -one;
2- (3-dimethylaminocarbonylphenoxy) -4- (3-bromo-5-cyanophenoxy) -5H-pyrimidido [4,5-b] [1,4] oxazine-6 (7H) -one;
2- (4-ethoxycarbonylphenoxy) -4- (2-methyl-5-cyanophenoxy) -5H-pyrimidido [4,5-b] [1,4] oxazine-6 ( 7H) -one;
2- (3- (1-methylimidazol-2-yl) phenoxy) -4- (2-methyl-5-cyanophenoxy) -5H-pyrimidido [4,5-b] [1 , 4] oxazine-6 (7H) -one;
2- (3-dimethylaminophenoxy) -4- (3-methyl-4-cyanophenoxy) -5H-pyrimidido [4,5-b] [1,4] oxazine-6 (7H) -On;
2- (3- (1-methylimidazolin-2-yl) phenoxy) -4- (2-amino-5-cyanophenoxy) -5H-pyrimidido [4,5-b] [1 , 4] oxazine-6 (7H) -one;
2- (3-tert-butoxycarbonylphenoxy) -4- (3-amino-4-cyanophenoxy) -5H-pyrimidido [4,5-b] [1,4] oxazine- 6 (7H) -one;
2- (3- (1-methylimidazolin-2-yl) phenoxy) -4- (2-carboxy-5-cyanophenoxy) -5H-pyrimidido [4,5-b] [1 , 4] oxazine-6 (7H) -one;
2- (3- (1-methylimidazolin-2-yl) phenoxy) -4- (3-carboxy-4-cyanophenoxy) -5H-pyrimidido [4,5-b] [1 , 4] oxazine-6 (7H) -one;
2- (3- (1-methylimidazolin-2-yl) phenoxy) -4- (tert-butoxycarbonyl-5-cyanophenoxy) -5H-pyrimidido [4,5 -b] [1,4] oxazin-6 (7H) -one;
2- (3- (1-methylimidazolin-2-yl) phenoxy) -4- (3-tert-butoxycarbonyl-4-cyanophenoxy) -5H-pyrimidido [4,5 -b] [1,4] oxazin-6 (7H) -one;
2- (3- (1-methylimidazolin-2-yl) phenoxy) -4- (2-aminocarbonyl-5-cyanophenoxy) -5H-pyrimidido [4,5-b] [1,4] oxazine-6 (7H) -one;
2- (3- (1-methylimidazolin-2-yl) phenoxy) -4- (3-aminocarbonyl-4-cyanophenoxy) -5H-pyrimidido [4,5-b] [1,4] oxazine-6 (7H) -one;
2- (3- (1-methylimidazolin-2-yl) phenoxy) -4- (2-dimethylamino-5-cyanophenoxy) -5H-pyrimidido [4,5-b] [ 1,4] oxazine-6 (7H) -one;
2- (3- (1-methylimidazolin-2-yl) phenoxy) -4- (3-dimethylamino-4-cyanophenoxy) -5H-pyrimidido [4,5-b] [ 1,4] oxazine-6 (7H) -one;
2- (3- (1-methylimidazolin-2-yl) phenoxy) -4- (2-dimethylamino-5-cyanophenoxy) -7-methyl-5H-pyrimidido [4,5 -b] [1,4] oxazin-6 (7H) -one;
2- (3- (1-methylimidazolin-2-yl) phenoxy) -4- (3-dimethylamino-4-cyanophenoxy) -7- (1-methylethyl) -5H-pyrimidy Do [4,5-b] [1,4] oxazine-6 (7H) -one;
2- (3-dimethylaminocarbonylphenoxy) -4- (3-bromo-5-cyanophenoxy) -7- (2-methylpropyl) -5H-pyrimidido [4,5-b] [1,4] oxazine-6 (7H) -one;
2- (3-dimethylaminocarbonylphenoxy) -4- (2-methyl-5-cyanophenoxy) -7- (1-methylpropyl) -5H-pyrimidido [4,5-b] [ 1,4] oxazine-6 (7H) -one;
2- (3-dimethylaminocarbonylphenoxy) -4- (2-methyl-5-cyanophenoxy) -7-benzyl-5H-pyrimidido [4,5-b] [1,4] jade Photo-6 (7H) -on;
2- (3-dimethylaminocarbonylphenoxy) -4- (3-methyl-4-cyanophenoxy) -7- (4-sulfonylphenyl) methyl-5H-pyrimidido [4,5-b ] [1,4] oxazine-6 (7H) -one;
2- (3-dimethylaminocarbonylphenoxy) -4- (2-amino-5-cyanophenoxy) -7- (2-methylsulfonyl) ethyl-5H-pyrimidido [4,5-b ] [1,4] oxazine-6 (7H) -one;
2- (3-dimethylaminocarbonylphenoxy) -4- (3-amino-4-cyanophenoxy) -7- (sulfonylmethyl) -5H-pyrimidido [4,5-b] [1 , 4] oxazine-6 (7H) -one;
2- (3-guanidinophenoxy) -4- (2-carboxy-5-cyanophenoxy) -7- (indolin-3-yl) methyl-5H-pyrimidido [4,5-b ] [1,4] oxazine-6 (7H) -one;
2- (3-guanidinophenoxy) -4- (3-carboxy-4-cyanophenoxy) -7- (imidazol-4-yl) methyl-5H-pyrimidido [4,5-b ] [1,4] oxazine-6 (7H) -one;
2- (3-guanidinophenoxy) -4- (tert-butoxycarbonyl-5-cyanophenoxy) -7- (hydroxymethyl) -5H-pyrimidido [4,5- b] [1,4] oxazin-6 (7H) -one;
2- (3-guanidinophenoxy) -4- (3-tert-butoxycarbonyl-4-cyanophenoxy) -7- (1-hydroxyethyl) -5H-pyrimidido [4, 5-b] [1,4] oxazin-6 (7H) -one;
2- (3-guanidinophenoxy) -4- (2-aminocarbonyl-5-cyanophenoxy) -7- (aminocarbonylmethyl) -5H-pyrimidido [4,5-b] [1,4] oxazine-6 (7H) -one;
2- (3-guanidinophenoxy) -4- (3-aminocarbonyl-4-cyanophenoxy) -7- (2- (aminocarbonyl) ethyl) -5H-pyrimidido [4, 5-b] [1,4] oxazin-6 (7H) -one;
2- (3-guanidinophenoxy) -4- (2-dimethylamino-5-cyanophenoxy) -7- (carboxymethyl) -5H-pyrimidido [4,5-b] [1, 4] oxazine-6 (7H) -one;
2- (3-guanidinophenoxy) -4- (3-dimethylamino-4-cyanophenoxy) -7- (2-carboxyethyl) -5H-pyrimidido [4,5-b] [ 1,4] oxazine-6 (7H) -one;
2- (3-guanidinophenoxy) -4- (2-dimethylamino-5-cyanophenoxy) -7- (4-aminobutyl) -5H-pyrimidido [4,5-b] [ 1,4] oxazine-6 (7H) -one; And
2- (3-guanidinophenoxy) -4- (3-dimethylamino-4-cyanophenoxy) -7- (3-guanidinopropyl) -5H-pyrimidido [4,5-b ] [1,4] oxazine-6 (7H) -one.
<Example 1>
<Compounds of Formula Ia, Formula IIa, Formula Ib, and Formula IIb>
A. 2- (2-benzyloxy-5-cyanophenoxy) -4- (3- (dimethylaminocarbonyl) phenoxy) -1,7-dihydro-6 (5H) -ptenedinone (1.35 g, 2.52 mmol), ie the compound of formula J, were dissolved in ethanol (60 mL) in a pressure vessel at 0 ° C. and saturated with HCl gas. The reaction was sealed and warmed to ambient temperature over 16 hours. The reaction mixture was then concentrated to about 20 mL and ether was added to precipitate ethyl imidate. Imidate was dissolved in ethanol (30 mL) and cooled to 0 ° C. and ammonia gas was bubbled through the solution for 10 minutes. The reaction was sealed and heated at 60 ° C. for 2 hours. The reaction was cooled and the tube was carefully opened and the volatiles evaporated to yield 1.0 g of brown residue. The residue (300 mg) was hydrogenated over 10% Pd / C in ethanol and then 6N HCl (8.0 mL) was added and heated to 100 ° C. The reaction was filtered and the filtrate was evaporated to yield 120 mg of crude product. Purification by preparative HPLC gave 60 mg of 2- (2-hydroxy-5-amidinophenoxy) -4- (3- (dimethylaminocarbonyl) phenoxy) -1,7-dihydro-6 (5H) -Putteridone, ie a compound of formula la. NMR (DMSO-d ₆ ) 10.30 (brs, 1), 9.00 (brs, 2), 8.80 (brs, 2), 8.00 (br, 1), 7.60 (m, 2), 7.60 (dd, 1), 7.20 -7.30 (m, 4), 7.00 (d, 1), 4.00 (s, 2), 2.90 (s, 3), 3.00 (s, 3).
B. In a similar manner, compounds of formula la are prepared:
2- (2-hydroxy-5-amidinophenoxy) -4- (3- (diethylaminocarbonyl) phenoxy) -1,7-dihydro-6 (5H) -putridinone;
2- (2-methoxy-5-amidinophenoxy) -4- (5-methyl-3- (dimethylaminocarbonyl) phenoxy) -1,7-dihydro-6 (5H) -pteridinone ;
2- (2-ethoxy-5-amidinophenoxy) -4- (5-trifluoromethyl-3- (dimethylaminocarbonyl) phenoxy) -1,7-dihydro-6 (5H)- Putridinone;
2- (2-phenoxy-5-amidinophenoxy) -4- (5-methoxy-3- (dimethylaminocarbonyl) phenoxy) -1,7-dihydro-6 (5H) -pteri Dinons;
2- (2-Chloro-5-amidinophenoxy) -4- (5-carboxy-3- (dimethylaminocarbonyl) phenoxy) -1,7-dihydro-6 (5H)-putridinone;
2- (2-methyl-5-amidinophenoxy) -4- (5-ethoxycarbonyl-3-methylphenoxy) -1,7-dihydro-6 (5H) -ptenedinone;
2- (2-tert-butyl-5-amidinophenoxy) -4- (5-dimethylamino-3- (imidazolin-2-yl) phenoxy) -1,7-dihydro-6 (5H ) -Pteridinone;
2- (2-amino-5-amidinophenoxy) -4- (5- (dimethylaminocarbonyl) methyl-3- (imidazol-2-yl) phenoxy) -1,7-dihydro-6 (5H) -pteridinone;
2- (2-carboxy-5-amidinophenoxy) -4- (5- (dimethylaminoethyl-3- (dimethylaminocarbonyl) phenoxy) -1,7-dihydro-6 (5H) -prop Teridinone;
2- (2-benzyloxycarbonyl-5-amidinophenoxy) -4- (5- (2-ethoxycarbonylethyl) -3- (tetrahydropyrimidin-2-yl) phenoxy) -1 , 7-dihydro-6 (5H) -pteridinone;
2- (2-diethylaminocarbonyl-5-amidinophenoxy) -4- (3- (diethylaminocarbonyl) phenoxy) -7-methyl-1,7-dihydro-6 (5H) -Putridinone;
2- (2-amino-5-amidinophenoxy) -4- (5-methyl-3- (dimethylaminocarbonyl) phenoxy) -7- (1-methylethyl) -1,7-dihydro- 6 (5H) -pteridinone;
2- (2-hydroxy-5-amidinophenoxy) -4- (5-trifluoromethyl-3- (dimethylaminocarbonyl) phenoxy) -7- (2-methylpropyl) -1,7 -Dihydro-6 (5H)-putridinone;
2- (2-methoxy-5-amidinophenoxy) -4- (5-methoxy-3- (dimethylaminocarbonyl) phenoxy) -7- (1-methylpropyl) -1,7-di Hydro-6 (5H) -putridinone;
2- (2-ethoxy-5-amidinophenoxy) -4- (5-carboxy-3- (dimethylaminocarbonyl) phenoxy) -7-benzyl-1,7-dihydro-6 (5H) -Putridinone;
2- (2-phenoxy-5-amidinophenoxy) -4- (5-ethoxycarbonyl-3-methylphenoxy) -7- (4-sulfonylphenyl) methyl-1,7-dihydro -6 (5H) -pteridinone;
2- (2-chloro-5-amidinophenoxy) -4- (5-dimethylamino-3- (imidazolin-2-yl) phenoxy) -7- (2-methylsulfonyl) ethyl-1 , 7-dihydro-6 (5H) -pteridinone;
2- (2-methyl-5-amidinophenoxy) -4- (5- (dimethylaminocarbonyl) methyl-3- (imidazol-2-yl) phenoxy) -7- (sulfonylmethyl)- 1,7-dihydro-6 (5H) -pteridinone;
2- (2-tert-butyl-5-amidinophenoxy) -4- (5- (dimethylaminoethyl-3- (dimethylaminocarbonyl) phenoxy) -7- (indolin-3-yl) methyl -1,7-dihydro-6 (5H)-putridinone;
2- (2-amino-5-amidinophenoxy) -4- (5- (2-ethoxycarbonylethyl) -3- (tetrahydropyrimidin-2-yl) phenoxy) -7- (already Dazol-4-yl) methyl-1,7-dihydro-6 (5H) -putridinone;
2- (2-carboxy-5-amidinophenoxy) -4- (5-carboxy-3- (dimethylaminocarbonyl) phenoxy) -7- (hydroxymethyl) -1,7-dihydro-6 (5H) -pteridinone;
2- (2-benzyloxycarbonyl-5-amidinophenoxy) -5-amino-4- (5-ethoxycarbonyl-3-methylphenoxy) -7- (1-hydroxyethyl) -1 , 7-dihydro-6 (5H) -pteridinone;
2- (2-diethylaminocarbonyl-5-amidinophenoxy) -5-amino-4- (5-dimethylamino-3- (imidazolin-2-yl) phenoxy) -7- (amino Carbonylmethyl) -1,7-dihydro-6 (5H) -putridinone;
2- (2-amino-5-amidinophenoxy) -4- (5- (dimethylaminocarbonyl) methyl-3- (imidazol-2-yl) phenoxy) -7- (2- (aminocar Carbonyl) ethyl) -1,7-dihydro-6 (5H) -phthalinone;
2- (2-hydroxy-5-amidinophenoxy) -4- (5- (dimethylaminoethyl-3- (dimethylaminocarbonyl) phenoxy) -7- (carboxymethyl) -1,7-di Hydro-6 (5H) -putridinone;
2- (2-hydroxy-5-amidinophenoxy) -4- (5- (2-ethoxycarbonylethyl) -3- (tetrahydropyrimidin-2-yl) phenoxy) -7- ( 2-carboxyethyl) -1,7-dihydro-6 (5H) -putridinone;
2- (2-hydroxy-5-amidinophenoxy) -4- (5- (dimethylaminocarbonyl) methyl) -3- (imidazol-2-yl) phenoxy) -7- (4-amino Butyl) -1,7-dihydro-6 (5H) -putridinone; And
2- (2-hydroxy-5-amidinophenoxy) -4- (5- (dimethylaminoethyl-3- (dimethylaminocarbonyl) phenoxy) -7- (3-guanidinopropyl) -1 , 7-dihydro-6 (5H) -pteridinone.
C. In a similar manner, 2- (3-dimethylaminocarbonylphenoxy) -4- (2-benzyloxy-5-amidinophenoxy) -1,7-dihydro-6 (5H) -ptenedinone I.e., by treating a compound of formula (O) with 0.10 g of 2- (3-dimethylaminocarbonylphenoxy) -4- (2-hydroxy-5-amidinophenoxy) -1,7-dihydro-6 ( 5H) -pteridone, ie a compound of formula IIa, was obtained. NMR (DMSO-d ₆ ) 9.10 (brs, 2), 8.80 (brs, 2), 7.70 (m, 2), 7.50 (dd, 1), 7.20-7.40 (m, 4), 7.10 (d, 1) , 4.90 (s, 2), 3.00 (s, 3), 2.90 (s, 3), 2.70 (s, 3).
D. In a similar manner, compounds of formula IIa are prepared:
2- (3-methylphenoxy) -4- (2-methoxy-5-amidinophenoxy) -1,7-dihydro-6 (5H) -phthalinone;
2- (3-Chloro-5-methoxyphenoxy) -4- (2-ethoxy-5-amidinophenoxy) -1,7-dihydro-6 (5H)-putridinone;
2- (4-trifluoromethylphenoxy) -4- (3-methoxy-5-amidinophenoxy) -1,7-dihydro-6 (5H) -pteridione;
2- (3,5-diaminophenoxy) -4- (3-ethoxy-5-amidinophenoxy) -1,7-dihydro-6 (5H)-putridinone;
2- (3-guanidino-5-methylphenoxy) -4- (2-phenoxy-5-amidinophenoxy) -1,7-dihydro-6 (5H) -pteridinone;
2- (3-ureidophenoxy) -4- (3-phenoxy-5-amidinophenoxy) -1,7-dihydro-6 (5H)-putridinone;
2- (3- (2-Chloroethyl) -5-methylphenoxy) -4- (2-chloro-5-amidinophenoxy) -1,7-dihydro-6 (5H)-putridinone;
2- (3-dimethylaminocarbonylphenoxy) -4- (3-bromo-5-amidinophenoxy) -1,7-dihydro-6 (5H) -ptenedinone;
2- (4-ethoxycarbonylphenoxy) -4- (2-methyl-5-amidinophenoxy) -1,7-dihydro-6 (5H)-putridinone;
2- (3- (1-methylimidazol-2-yl) phenoxy) -4- (2-methyl-5-amidinophenoxy) -1,7-dihydro-6 (5H) -pteri Dinons;
2- (3-dimethylaminophenoxy) -4- (3-methyl-4-amidinophenoxy) -1,7-dihydro-6 (5H) -ptenedinone;
2- (3- (1-methylimidazolin-2-yl) phenoxy) -4- (2-amino-5-amidinophenoxy) -1,7-dihydro-6 (5H) -pteri Dinons;
2- (3-tert-butoxycarbonylphenoxy) -4- (3-amino-4-amidinophenoxy) -1,7-dihydro-6 (5H)-putridinone;
2- (3- (1-methylimidazolin-2-yl) phenoxy) -4- (2-carboxy-5-amidinophenoxy) -1,7-dihydro-6 (5H) -pteri Dinons;
2- (3- (1-methylimidazolin-2-yl) phenoxy) -4- (3-carboxy-4-amidinophenoxy) -1,7-dihydro-6 (5H) -pteri Dinons;
2- (3- (1-methylimidazolin-2-yl) phenoxy) -4- (tert-butoxycarbonyl-5-amidinophenoxy) -1,7-dihydro-6 ( 5H) -pteridinone;
2- (3- (1-methylimidazolin-2-yl) phenoxy) -4- (tert-butoxycarbonyl-4-amidinophenoxy) -1,7-dihydro-6 ( 5H) -pteridinone;
2- (3- (1-methylimidazolin-2-yl) phenoxy) -4- (2-aminocarbonyl-5-amidinophenoxy) -1,7-dihydro-6 (5H)- Putridinone;
2- (3- (1-methylimidazolin-2-yl) phenoxy) -4- (3-aminocarbonyl-4-amidinophenoxy) -1,7-dihydro-6 (5H)- Putridinone;
2- (3- (1-methylimidazolin-2-yl) phenoxy) -4- (2-dimethylamino-5-amidinophenoxy) -1,7-dihydro-6 (5H) -prop Teridinone;
2- (3- (1-methylimidazolin-2-yl) phenoxy) -4- (3-dimethylamino-4-amidinophenoxy) -1,7-dihydro-6 (5H) -prop Teridinone;
2- (3- (1-methylimidazolin-2-yl) phenoxy) -4- (2-dimethylamino-5-amidinophenoxy) -1,7-dihydro-6 (5H) -prop Teridinone;
2- (3- (1-methylimidazolin-2-yl) phenoxy) -4- (3-dimethylamino-4-amidinophenoxy) -1,7-dihydro-6 (5H) -prop Teridinone;
2- (3- (1-methylimidazolin-2-yl) phenoxy) -4- (2-methoxy-5-amidinophenoxy) -1,7-dihydro-6 (5H) -prop Teridinone;
2- (3- (1-methylimidazolin-2-yl) phenoxy) -4- (2-ethoxy-5-amidinophenoxy) -1,7-dihydro-6 (5H) -prop Teridinone;
2- (3- (1-methylimidazolin-2-yl) phenoxy) -4- (3-methoxy-5-amidinophenoxy) -1,7-dihydro-6 (5H) -prop Teridinone;
2- (3- (1-methylimidazolin-2-yl) phenoxy) -4- (3-ethoxy-5-amidinophenoxy) -1,7-dihydro-6 (5H) -prop Teridinone;
2- (3- (1-methylimidazolin-2-yl) phenoxy) -4- (2-phenoxy-5-amidinophenoxy) -1,7-dihydro-6 (5H) -prop Teridinone;
2- (3-dimethylaminocarbonylphenoxy) -4- (3-phenoxy-5-amidinophenoxy) -1,7-dihydro-6 (5H) -pteridinone;
2- (3-dimethylaminocarbonylphenoxy) -4- (2-chloro-5-amidinophenoxy) -1,7-dihydro-6 (5H)-putridinone;
2- (3-dimethylaminocarbonylphenoxy) -4- (3-bromo-5-amidinophenoxy) -1,7-dihydro-6 (5H) -ptenedinone;
2- (3-dimethylaminocarbonylphenoxy) -4- (2-methyl-5-amidinophenoxy) -1,7-dihydro-6 (5H) -pteridinone;
2- (3-dimethylaminocarbonylphenoxy) -4- (2-methyl-5-amidinophenoxy) -1,7-dihydro-6 (5H) -pteridinone;
2- (3-dimethylaminocarbonylphenoxy) -4- (3-methyl-4-amidinophenoxy) -1,7-dihydro-6 (5H) -phthalinone;
2- (3-dimethylaminocarbonylphenoxy) -4- (2-amino-5-amidinophenoxy) -1,7-dihydro-6 (5H)-putridinone;
2- (3-dimethylaminocarbonylphenoxy) -4- (3-amino-4-amidinophenoxy) -1,7-dihydro-6 (5H) -ptenedinone;
2- (3-guanidinophenoxy) -4- (2-carboxy-5-amidinophenoxy) -1,7-dihydro-6 (5H)-putridinone;
2- (3-guanidinophenoxy) -4- (3-carboxy-4-amidinophenoxy) -1,7-dihydro-6 (5H) -ptenedinone;
2- (3-guanidinophenoxy) -4- (2-tert-butoxycarbonyl-5-amidinophenoxy) -1,7-dihydro-6 (5H) -pteridinone;
2- (3-guanidinophenoxy) -4- (3-tert-butoxycarbonyl-4-amidinophenoxy) -1,7-dihydro-6 (5H) -ptenedinone;
2- (3-guanidinophenoxy) -4- (2-aminocarbonyl-5-amidinophenoxy) -1,7-dihydro-6 (5H) -ptenedinone;
2- (3-guanidinophenoxy) -4- (3-aminocarbonyl-4-amidinophenoxy) -1,7-dihydro-6 (5H) -putridinone;
2- (3-guanidinophenoxy) -4- (3-dimethylamino-4-amidinophenoxy) -1,7-dihydro-6 (5H)-putridinone;
2- (3-guanidinophenoxy) -4- (2-dimethylamino-5-amidinophenoxy) -7-methyl-1,7-dihydro-6 (5H) -ptenedinone;
2- (3-Guanidinophenoxy) -4- (3-dimethylamino-4-amidinophenoxy) -7- (1-methylethyl) -1,7-dihydro-6 (5H) -prop Teridinone;
2- (3-dimethylaminocarbonylphenoxy) -4- (3-bromo-5-amidinophenoxy) -7- (2-methylpropyl) -1,7-dihydro-6 (5H)- Putridinone;
2- (3-dimethylaminocarbonylphenoxy) -4- (2-methyl-5-amidinophenoxy) -7- (1-methylpropyl) -1,7-dihydro-6 (5H) -prop Teridinone;
2- (3-dimethylaminocarbonylphenoxy) -4- (2-methyl-5-amidinophenoxy) -7-benzyl-1,7-dihydro-6 (5H) -pteridinone;
2- (3-dimethylaminocarbonylphenoxy) -4- (3-methyl-4-amidinophenoxy) -7- (4-sulfonylphenyl) methyl-1,7-dihydro-6 (5H) -Putridinone;
2- (3-dimethylaminocarbonylphenoxy) -4- (2-amino-5-amidinophenoxy) -7- (2-methylsulfonyl) ethyl-1,7-dihydro-6 (5H) -Putridinone;
2- (3-dimethylaminocarbonylphenoxy) -4- (3-amino-4-amidinophenoxy) -7- (sulfonylmethyl-1,7-dihydro-6 (5H) -phthalinone ;
2- (3-guanidinophenoxy) -4- (2-carboxy-5-amidinophenoxy) -7- (indolin-3-yl) methyl-1,7-dihydro-6 (5H) -Putridinone;
2- (3-guanidinophenoxy) -4- (3-carboxy-4-amidinophenoxy) -7- (imidazol-4-yl) methyl-1,7-dihydro-6 (5H) -Putridinone;
2- (3-guanidinophenoxy) -4- (tert-butoxycarbonyl-5-amidinophenoxy) -7- (hydroxymethyl) -1,7-dihydro-6 (5H )-Putridinone;
2- (3-guanidinophenoxy) -4- (3-tert-butoxycarbonyl-4-amidinophenoxy) -7- (1-hydroxyethyl) -1,7-dihydro-6 (5H) -pteridinone;
2- (3-guanidinophenoxy) -4- (2-aminocarbonyl-5-amidinophenoxy) -7- (aminocarbonylmethyl) -1,7-dihydro-6 (5H)- Putridinone;
2- (3-guanidinophenoxy) -4- (3-aminocarbonyl-4-amidinophenoxy) -7- (2- (aminocarbonyl) ethyl) -1,7-dihydro-6 (5H) -pteridinone;
2- (3-Guanidinophenoxy) -4- (2-dimethylamino-5-amidinophenoxy) -7- (carboxymethyl) -1,7-dihydro-6 (5H) -ptenedinone ;
2- (3-Guanidinophenoxy) -4- (3-dimethylamino-4-amidinophenoxy) -7- (2-carboxyethyl) -1,7-dihydro-6 (5H) -prop Teridinone;
2- (3-Guanidinophenoxy) -4- (2-dimethylamino-5-amidinophenoxy) -7- (4-aminobutyl) -1,7-dihydro-6 (5H) -prop Teridinone; And
2- (3-guanidinophenoxy) -4- (3-dimethylamino-4-amidinophenoxy) -7- (3-guanidinopropyl) -1,7-dihydro-6 (5H) -Pteridinone.
E. In a similar manner, 2- (2-benzyloxy-5-aminophenoxy) -4- (3- (dimethylaminocarbonyl) phenoxy) -5H-pyrimido [4,5-b] [1, 4] oxazine-6 (7H) -one (0.11 g, 0.18 mmol), i.e., 0.10 g of 2- (2-hydroxy-5-amidinophenoxy) -4- (3 by treatment with a compound of formula T -(Dimethylaminocarbonyl) phenoxy) -5H-pyrimido [4,5-b] [1,4] oxazin-6 (7H) -one, ie a compound of formula (Ib). NMR (DMSO-d ₆ ) 9.10 (brs, 2), 8.80 (brs, 2), 7.70 (m, 2), 7.50 (dd, 1), 7.20-7.40 (m, 4), 7.10 (d, 12) , 4.90 (s, 2), 3.00 (s, 3), 2.90 (s, 3).
F. In a similar manner, compounds of formula (Ib) are prepared:
2- (2-hydroxy-5-amidinophenoxy) -4- (3- (diethylaminocarbonyl) phenoxy) -5H-pyrimido [4,5-b] [1,4] oxazine -6 (7H) -one;
2- (2-methoxy-5-amidinophenoxy) -4- (5-methyl-3- (dimethylaminocarbonyl) phenoxy) -5H-pyrimido [4,5-b] [1,4 ] Oxazine-6 (7H) -one;
2- (2-ethoxy-5-amidinophenoxy) -4- (5-trifluoromethyl-3- (dimethylaminocarbonyl) phenoxy) -5H-pyrimido [4,5-b] [ 1,4] oxazine-6 (7H) -one;
2- (2-phenoxy-5-amidinophenoxy) -4- (5-methoxy-3- (dimethylaminocarbonyl) phenoxy) -5H-pyrimido [4,5-b] [1, 4] oxazine-6 (7H) -one;
2- (2-chloro-5-amidinophenoxy) -4- (5-carboxy-3- (dimethylaminocarbonyl) phenoxy) -5H-pyrimido [4,5-b] [1,4] Oxazine-6 (7H) -one;
2- (2-methyl-5-amidinophenoxy) -4- (5-ethoxycarbonyl-3-methylphenoxy) -5H-pyrimido [4,5-b] [1,4] oxazine -6 (7H) -one;
2- (2-tert-butyl-5-amidinophenoxy) -4- (5-dimethylamino-3- (imidazolin-2-yl) phenoxy) -5H-pyrimido [4,5-b ] [1,4] oxazine-6 (7H) -one;
2- (2-amino-5-amidinophenoxy) -4- (5- (dimethylaminocarbonyl) methyl-3- (imidazol-2-yl) phenoxy) -5H-pyrimido [4,5 -b] [1,4] oxazin-6 (7H) -one;
2- (2-carboxy-5-amidinophenoxy) -4- (5- (dimethylaminoethyl-3- (diaminoaminocarbonyl) phenoxy) -5H-pyrimido [4,5-b ] [1,4] oxazine-6 (7H) -one;
2- (2-benzyloxycarbonyl-5-amidinophenoxy) -4- (5- (2-ethoxycarbonylethyl) -3- (tetrahydropyrimidin-2-yl) phenoxy) -5H -Pyrimido [4,5-b] [1,4] oxazin-6 (7H) -one;
2- (2-diethylaminocarbonyl-5-amidinophenoxy) -4- (3- (diethylaminocarbonyl) phenoxy) -5H-pyrimido [4,5-b] [1,4 ] Oxazine-6 (7H) -one;
2- (2-amino-5-amidinophenoxy) -4- (5-methyl-3- (dimethylaminocarbonyl) phenoxy) -7-methyl-5H-pyrimido [4,5-b] [ 1,4] oxazine-6 (7H) -one;
2- (2-hydroxy-5-amidinophenoxy) -4- (5-trifluoromethyl-3- (dimethylaminocarbonyl) phenoxy) -7- (1-methylethyl) -5H-pyri Mino [4,5-b] [1,4] oxazine-6 (7H) -one;
2- (2-methoxy-5-amidinophenoxy) -4- (5-methoxy-3- (dimethylaminocarbonyl) phenoxy) -7- (2-methoxypropyl) -5H-pyrimido [4,5-b] [1,4] oxazine-6 (7H) -one;
2- (2-ethoxy-5-amidinophenoxy) -4- (5-carboxy-3- (dimethylaminocarbonyl) phenoxy) -7- (1-methylpropyl) -5H-pyrimido [4 , 5-b] [1,4] oxazin-6 (7H) -one;
2- (2-phenoxy-5-amidinophenoxy) -4- (5-ethoxycarbonyl-3-methylphenoxy) -7-benzyl-5H-pyrimido [4,5-b] [1 , 4] oxazine-6 (7H) -one;
2- (2-chloro-5-amidinophenoxy) -4- (5-dimethylamino-3- (imidazolin-2-yl) phenoxy) -7- (4-sulfonylphenyl) methyl-5H -Pyrimido [4,5-b] [1,4] oxazin-6 (7H) -one;
2- (2-methyl-5-amidinophenoxy) -4- (5- (dimethylaminocarbonyl) methyl-3- (imidazol-2-yl) phenoxy) -7- (sulfonylmethyl)- 5H-pyrimido [4,5-b] [1,4] oxazin-6 (7H) -one;
2- (2-tert-butyl-5-amidinophenoxy) -4- (5- (dimethylaminoethyl-3- (dimethylaminocarbonyl) phenoxy) -7- (indolin-3-yl) methyl -5H-pyrimido [4,5-b] [1,4] oxazin-6 (7H) -one;
2- (2-amino-5-amidinophenoxy) -4- (5- (2-ethoxycarbonylethyl) -3- (tetrahydropyrimidin-2-yl) phenoxy) -7- (already Dazol-4-yl) methyl-5H-pyrimido [4,5-b] [1,4] oxazin-6 (7H) -one;
2- (2-carboxy-5-amidinophenoxy) -4- (5-carboxy-3- (dimethylaminocarbonyl) phenoxy) -7- (hydroxymethyl) -5H-pyrimido [4,5 -b] [1,4] oxazin-6 (7H) -one;
2- (2-benzyloxycarbonyl-5-amidinophenoxy) -4- (5-ethoxycarbonyl-3-methylphenoxy) -7- (1-hydroxyethyl) -5H-pyrimido [ 4,5-b] [1,4] oxazin-6 (7H) -one;
2- (2-diethylaminocarbonyl-5-amidinophenoxy) -4- (5-dimethylamino-3- (imidazolin-2-yl) phenoxy) -7- (aminocarbonylmethyl) -5H-pyrimido [4,5-b] [1,4] oxazin-6 (7H) -one;
2- (2-amino-5-amidinophenoxy) -4- (5- (dimethylaminocarbonyl) methyl-3- (imidazol-2-yl) phenoxy) -7- (2- (aminocar Carbonyl) ethyl) -5H-pyrimido [4,5-b] [1,4] oxazin-6 (7H) -one;
2- (2-hydroxy-5-amidinophenoxy) -4- (5- (dimethylaminoethyl-3- (dimethylaminocarbonyl) phenoxy) -7- (carboxymethyl) -5H-pyrimido [ 4,5-b] [1,4] oxazin-6 (7H) -one;
2- (2-hydroxy-5-amidinophenoxy) -4- (5- (2-ethoxycarbonylethyl) -3- (tetrahydropyrimidin-2-yl) phenoxy) -7- ( 2-carboxyethyl) -5H-pyrimido [4,5-b] [1,4] oxazin-6 (7H) -one;
2- (2-hydroxy-5-amidinophenoxy) -4- (5- (dimethylaminocarbonyl) methyl- (3- (imidazol-2-yl) phenoxy) -7- (4-amino Butyl) -5H-pyrimido [4,5-b] [1,4] oxazin-6 (7H) -one; and
2- (2-hydroxy-5-amidinophenoxy) -4- (5- (dimethylaminoethyl-3- (dimethylaminocarbonyl) phenoxy) -7- (3-guanidinopropyl) -5H -Pyrimido [4,5-b] [1,4] oxazine-6 (7H) -one.
G. In a similar manner, 2- (3-dimethylaminocarbonylphenoxy) -4- (2-benzyloxy-5-amidinophenoxy) -5H-pyrimido [4,5-b] [1,4 ] Oxazin-6 (7H) -one, i.e. 2- (3-dimethylaminocarbonylphenoxy) -4- (2-hydroxy-5-amidinophenoxy) -5H- A pyrimido [4,5-b] [1,4] oxazin-6 (7H) -one, ie a compound of formula IIb, was obtained.
H. In a similar manner, compounds of formula IIb are prepared:
2- (3-methylphenoxy) -4- (2-methoxy-5-amidinophenoxy) -5H-pyrimido [4,5-b] [1,4] oxazine-6 (7H)- On;
2- (3-chloro-5-methoxyphenoxy) -4- (2-ethoxy-5-amidinophenoxy) -5H-pyrimido [4,5-b] [1,4] oxazine- 6 (7H) -one;
2- (3-trifluoromethylphenoxy) -4- (3-methoxy-5-amidinophenoxy) -5H-pyrimido [4,5-b] [1,4] oxazine-6 ( 7H) -one;
2- (3,5-diaminophenoxy) -4- (3-ethoxy-5-amidinophenoxy) -5H-pyrimido [4,5-b] [1,4] oxazine-6 ( 7H) -one;
2- (3-guanidino-5-methylphenoxy) -4- (2-phenoxy-5-amidinophenoxy) -5H-pyrimido [4,5-b] [1,4] oxazine -6 (7H) -one;
2- (3-ureidophenoxy) -4- (3-phenoxy-5-amidinophenoxy) -5H-pyrimido [4,5-b] [1,4] oxazine-6 (7H) -On;
2- (3- (2-chloroethyl) -5-methylphenoxy) -4- (2-chloro-5-amidinophenoxy) -5H-pyrimido [4,5-b] [1,4] Oxazine-6 (7H) -one;
2- (3-dimethylaminocarbonylphenoxy) -4- (3-bromo-5-amidinophenoxy) -5H-pyrimido [4,5-b] [1,4] oxazine-6 ( 7H) -one;
2- (4-ethoxycarbonylphenoxy) -4- (2-methyl-5-amidinophenoxy) -5H-pyrimido [4,5-b] [1,4] oxazine-6 (7H )-On;
2- (3- (1-methylimidazol-2-yl) phenoxy) -4- (2-methyl-5-amidinophenoxy) -5H-pyrimido [4,5-b] [1, 4] oxazine-6 (7H) -one;
2- (3-dimethylaminophenoxy) -4- (3-methyl-4-amidinophenoxy) -5H-pyrimido [4,5-b] [1,4] oxazine-6 (7H)- On;
2- (3- (1-methylimidazolin-2-yl) phenoxy) -4- (2-amino-5-amidinophenoxy) -5H-pyrimido [4,5-b] [1, 4] oxazine-6 (7H) -one;
2- (3-tert-butoxycarbonylphenoxy) -4- (3-amino-4-amidinophenoxy) -5H-pyrimido [4,5-b] [1,4] oxazine-6 (7H) -one;
2- (3- (1-methylimidazolin-2-yl) phenoxy) -4- (2-carboxy-5-amidinophenoxy) -5H-pyrimido [4,5-b] [1, 4] oxazine-6 (7H) -one;
2- (3- (1-methylimidazolin-2-yl) phenoxy) -4- (3-carboxy-4-amidinophenoxy) -5H-pyrimido [4,5-b] [1, 4] oxazine-6 (7H) -one;
2- (3- (1-methylimidazolin-2-yl) phenoxy) -4- (tert-butoxycarbonyl-5-amidinophenoxy) -5H-pyrimido [4,5- b] [1,4] oxazin-6 (7H) -one;
2- (3- (1-methylimidazolin-2-yl) phenoxy) -4- (tert-butoxycarbonyl-4-amidinophenoxy) -5H-pyrimido [4,5- b] [1,4] oxazin-6 (7H) -one;
2- (3- (1-methylimidazolin-2-yl) phenoxy) -4- (2-aminocarbonyl-5-amidinophenoxy) -5H-pyrimido [4,5-b] [ 1,4] oxazine-6 (7H) -one;
2- (3- (1-methylimidazolin-2-yl) phenoxy) -4- (3-aminocarbonyl-4-amidinophenoxy) -5H-pyrimido [4,5-b] [ 1,4] oxazine-6 (7H) -one;
2- (3- (1-methylimidazolin-2-yl) phenoxy) -4- (2-dimethylamino-5-amidinophenoxy) -5H-pyrimido [4,5-b] [1 , 4] oxazine-6 (7H) -one;
2- (3- (1-methylimidazolin-2-yl) phenoxy) -4- (3-dimethylamino-4-amidinophenoxy) -5H-pyrimido [4,5-b] [1 , 4] oxazine-6 (7H) -one;
2- (3- (1-methylimidazolin-2-yl) phenoxy) -4- (2-dimethylamino-5-amidinophenoxy) -7-methyl-5H-pyrimido [4,5- b] [1,4] oxazin-6 (7H) -one;
2- (3- (1-methylimidazolin-2-yl) phenoxy) -4- (3-dimethylamino-4-amidinophenoxy) -7- (1-methylethyl) -5H-pyrimido [4,5-b] [1,4] oxazine-6 (7H) -one;
2- (3-dimethylaminocarbonylphenoxy) -4- (3-bromo-5-amidinophenoxy) -7- (2-methylpropyl) -5H-pyrimido [4,5-b] [ 1,4] oxazine-6 (7H) -one;
2- (3-dimethylaminocarbonylphenoxy) -4- (2-methyl-5-amidinophenoxy) -7- (1-methylpropyl) -5H-pyrimido [4,5-b] [1 , 4] oxazine-6 (7H) -one;
2- (3-dimethylaminocarbonylphenoxy) -4- (2-methyl-5-amidinophenoxy) -7-benzyl-5H-pyrimido [4,5-b] [1,4] oxazine -6 (7H) -one;
2- (3-dimethylaminocarbonylphenoxy) -4- (3-methyl-4-amidinophenoxy) -7- (4-sulfonylphenyl) methyl-5H-pyrimido [4,5-b] [1,4] oxazine-6 (7H) -one;
2- (3-dimethylaminocarbonylphenoxy) -4- (2-amino-5-amidinophenoxy) -7- (2-methylsulfonyl) ethyl-5H-pyrimido [4,5-b] [1,4] oxazine-6 (7H) -one;
2- (3-dimethylaminocarbonylphenoxy) -4- (3-amino-4-amidinophenoxy) -7- (sulfonylmethyl) -5H-pyrimido [4,5-b] [1, 4] oxazine-6 (7H) -one;
2- (3-guanidinophenoxy) -4- (2-carboxy-5-amidinophenoxy) -7- (indolin-3-yl) methyl-5H-pyrimido [4,5-b] [1,4] oxazine-6 (7H) -one;
2- (3-guanidinophenoxy) -4- (3-carboxy-4-amidinophenoxy) -7- (imidazol-4-yl) methyl-5H-pyrimido [4,5-b] [1,4] oxazine-6 (7H) -one;
2- (3-guanidinophenoxy) -4- (tert-butoxycarbonyl-5-amidinophenoxy) -7- (hydroxymethyl) -5H-pyrimido [4,5-b ] [1,4] oxazine-6 (7H) -one;
2- (3-guanidinophenoxy) -4- (3-tert-butoxycarbonyl-4-amidinophenoxy) -7- (1-hydroxyethyl) -5H-pyrimido [4,5 -b] [1,4] oxazin-6 (7H) -one;
2- (3-guanidinophenoxy) -4- (2-aminocarbonyl-5-amidinophenoxy) -7- (aminocarbonylmethyl) -5H-pyrimido [4,5-b] [ 1,4] oxazine-6 (7H) -one;
2- (3-guanidinophenoxy) -4- (3-aminocarbonyl-4-amidinophenoxy) -7- (2- (aminocarbonyl) ethyl) -5H-pyrimido [4,5 -b] [1,4] oxazin-6 (7H) -one;
2- (3-guanidinophenoxy) -4- (2-dimethylamino-5-amidinophenoxy) -7- (carboxymethyl) -5H-pyrimido [4,5-b] [1,4 ] Oxazine-6 (7H) -one;
2- (3-guanidinophenoxy) -4- (3-dimethylamino-4-amidinophenoxy) -7- (2-carboxyethyl) -5H-pyrimido [4,5-b] [1 , 4] oxazine-6 (7H) -one;
2- (3-guanidinophenoxy) -4- (2-dimethylamino-5-amidinophenoxy) -7- (4-aminobutyl) -5H-pyrimido [4,5-b] [1 , 4] oxazine-6 (7H) -one; And
2- (3-Guanidinophenoxy) -4- (3-dimethylamino-4-amidinophenoxy) -7- (3-guanidinopropyl) -5H-pyrimido [4,5-b] [1,4] oxazine-6 (7H) -one.
<Example 2>
This example provides a compound of the invention or a pharmaceutically acceptable salt thereof, for example 2- (2-hydroxy-5-amidinophenoxy) -4- (3- (dimethylaminocarbonyl) phenoxy)- The preparation of a typical pharmaceutical composition for oral administration containing 1,7-dihydro-6 (5H) -pteridinone is described:
A.
ingredient% By weight Compounds of the Invention20% Lactose７９．5% Magnesium stearate５．5%
The ingredients are mixed and dispersed into hard-shell gelatin capsules containing 100 mg each.
B.
ingredientWt% / weight Compound of the Invention20.0% Magnesium stearate0.9% Starch8.6% Lactose79.6% PVP (polyvinylpyrrolidine)0.9%
The above ingredients except magnesium stearate are mixed and granulated using water as a granulation liquid. The formulation is then dried, mixed with magnesium stearate and shaped into tablets with a suitable tablet press.
C.
ingredientCompound of the Invention0.1 g Propylene glycol20.0 g Polyethylene Glycol 40020.0 g Polysorbate 801.0 g waterAppropriate amount up to 100 ml
Compounds of the invention are dissolved in propylene glycol, polyethylene glycol 400 and polysorbate 80. Subsequently, a sufficient amount of water is added under stirring to obtain 100 ml of the solution which is filtered and placed in a bottle.
D.
ingredientWt% / weight Compound of the Invention20.0% Peanut oil78.0% Span 602.0%
The components are melted and mixed to fill with soft elastic capsules.
E.
ingredientWt% / weight Compound of the Invention1.0% Methyl or carboxymethyl cellulose2.0% 0.9% brineAppropriate amount up to 100 ml
The compounds of the present invention are dissolved in cellulose / brine solution, filtered and used in bottles.
<Example 3>
This example provides a compound of the invention or a pharmaceutically acceptable salt thereof, for example 2- (2-hydroxy-5-amidinophenoxy) -4- (3- (dimethylaminocarbonyl) phenoxy)- The preparation of a typical pharmaceutical composition for parenteral administration containing 1,7-dihydro-6 (5H) -pteridinone is described.
ingredientCompound of the Invention0.02 g Propylene glycol20.0 g Polyethylene Glycol 40020.0 g Polysorbate 801.0 g 0.9% saline solutionAppropriate amount up to 100 ml
Compounds of the invention are dissolved in propylene glycol, polyethylene glycol 400 and polysorbate 80. Subsequently, a sufficient amount of 0.9% saline solution is added under stirring to obtain 100 ml of intravenous solution, filtered through a 0.2 μ membrane filter and packaged under aseptic conditions.
<Example 4>
This example provides a compound of the invention or a pharmaceutically acceptable salt thereof, for example 2- (2-hydroxy-5-amidinophenoxy) -4- (3- (dimethylaminocarbonyl) phenoxy)- Described is the preparation of a typical pharmaceutical composition of suppository formulations containing 1,7-dihydro-6 (5H) -pteridinone:
ingredientWt% / weight Compound of the Invention1.0% Polyethylene Glycol 100074.5% Polyethylene Glycol 400024.5%
The components are melted together and mixed in a steam bath and poured into molds with a total weight of 2.5 g.
<Example 5>
The present examples include compounds of the invention or pharmaceutically acceptable salts such as 2- (3-dimethylaminocarbonylphenoxy) -4- (2-hydroxy-5-amidinophenoxy) -1,7 Explain the preparation of typical pharmaceutical compositions for inhalation containing dihydro-6 (5H) -pteridinone:
ingredientWt% / weight Finely divided compound of the present invention1.0% Differentiated Lactose99.0%
The ingredients are ground and mixed and packaged in an inhaler with a pump for administration.
<Example 6>
This example provides a compound of the invention or a pharmaceutically acceptable salt, for example 2- (3-dimethylaminocarbonylphenoxy) -4- (2-hydroxy-5-amidinophenoxy) -1,7 Described is the preparation of a typical pharmaceutical composition of a spray formulation containing -dihydro-6 (5H) -putridinone:
ingredientWt% / weight Compound of the Invention0.005% water89.995% ethanol10.000%
Compounds of the invention are dissolved in ethanol and blended with water. The composition is then packaged in a nebulizer with a pump for administration.
<Example 7>
This example provides a compound of the present invention or a pharmaceutically acceptable salt thereof, for example 2- (3-dimethylaminocarbonylphenoxy) -4- (2-hydroxy-5-amidinophenoxy) -1, Described is the preparation of a typical pharmaceutical composition of an aerosol formulation containing 7-dihydro-6 (5H) -putridinone:
ingredientWt% / weight Compound of the Invention0.10% Propellant 11/1298.90% Oleic acid1.00%
Compounds of the invention are dispersed in oleic acid and propellant. The resulting mixture is then poured into an aerosol container equipped with a metering valve.
<Example 8>
(In vitro analysis of factor Xa, thrombin and tissue plasminogen activator)
This assay shows the activity of the factor Xa, thrombin and tissue plasminogen activators of the compounds of the invention. Activity was determined as the initial cleavage rate of peptide p-nitroanilide by the enzyme. The split product p-nitroaniline absorbs at 405 nm with a molar absorbance coefficient of 9,920 M ⁻¹ cm ⁻¹ .
<Reagents and Solutions>
Dimethyl sulfoxide (DMSO) (grade analyzed by Baker).
Assay Buffer:
50 mM TrisHCl, 150 mM NaCl, 2.5 mM CaCl ₂ and 0.1% polyethylene glycol 6000 at pH 7.5.
Enzyme Research Lab .:
1. Human Factor Xa Stock: 0.281 mg / mL in Assay Buffer, stored at −80 ° C. (Working Solution (2 ×): 106 ng / mL or 2 nM in Assay Buffer, prepared before use).
2. Human thrombin stock: stored at −80 ° C. (working solution (2 ×): 1,200 ng / ml or 40 nM in assay buffer prepared before use).
3. Human Tissue Plasminogen Activator (tPA) (Two Chains, Sigma) Stock: 1 mg / ml (working solution (2X): 1,361 ng / ml in assay buffer, prepared before use) stored at −80 ° C.
Pigmentable Substrate (Pharmacia Hepar Inc.):
1. S2222 (FXa assay) stock: 6 mM in dH ₂ O (working solution (4 ×): 656 μΜ in assay buffer) stored at 4 ° C.
2. S2302 (Thrombin Assay) Stock: 10 mM in dH ₂ O, stored at 4 ° C. (Working solution (4 ×): 1200 μM in Assay Buffer).
3. S2288 (tPA assay) Stock: 10 mM in dH ₂ O (working solution (4 ×): 1484 μM in assay buffer) stored at 4 ° C.
(All substrate working solutions were prepared on day 5 of analysis).
Standard Inhibitor Compound Stocks:
5 mM in DMSO, stored at -20 ° C.
Test Compound (Compound of the Invention)
10 mM in DMSO, stored at -20 ° C.
Analysis Procedure
The wells were analyzed in 96 well microtiter plates in 200 μl total volume. The final concentration of the assay components was 50 mM TrisHCl, 150 mM NaCl, 2.5 mM CaCl ₂ , 0.1% polyethylene glycol 6000, pH 7.5, with or without the following concentrations of standard inhibitors or test compounds and enzymes and substrates: 1) 1 nM factor Xa and 164 μM S2222; (2) 20 nM thrombin and 300 μM S2302; And (3) 10 nM tPA and 371 μM S2288. The concentration of standard inhibitor compound in the assay was 5 to 0.021 μΜ at 1 to 3 dilutions. The concentration of test compound in the assay was typically 10-0.041 μΜ at one to three dilutions. For potential test compounds, the concentration used in the Factor Xa assay was further diluted 100-fold (100-0.41 nM) or 1,000-fold (10-0.041 nM). All substrate concentrations used are identical to their K _m values under this assay condition. Analysis at ambient temperature.
The first step of the assay was followed by preparation of 10 mM test compound stock in DMSO (for potential test compounds, the 10 mM stock was further diluted to 0.1 mM or 0.01 mM for Factor Xa analysis), followed by 96 Preparation of test compound working solution (4 ×) by serial 10 mM stock dilution with Biomek 1000 (or Multiprobe 204) in deep well plates:
(a) A 40 μM working solution is prepared in two steps by diluting the 10 mM stock from 1 to 250 in assay buffer: 1 to 100 and 1 to 2.5.
(b) Prepare another series of five dilutions (1: 3) of 40 μM solution (600 μl for each concentration). A total of six diluted test compound solutions were used in the analysis. Standard inhibitor compounds (5 mM stock) or DMSO (control) were performed via the same dilution steps as described above for the test compounds.
The next step in the analysis was to disperse 50 μl of test compound working solution (4 ×) (40 to 0.164 μM) twice to microtiter the plate with Biomek or MP204. To this was added 100 μl of enzyme working solution (2 ×) with Biomek or MP204. The resulting solution was incubated at ambient temperature for 10 minutes.
To the solution was added 50 μl of substrate working solution (4 ×) with Biomek or MP204.
Enzyme power was measured at 405 nm at 10 second intervals for 5 minutes at THERMO max plate reader at ambient temperature.
<K _i calculation of test compound>
Enzyme rates were calculated as mOD / min based on the first 2 minutes reading. IC ₅₀ values were measured according to log-logit equations (linear) or Morrison equations (non-linear) with EXCEL spreadsheets. The K _i value was then obtained by dividing the IC ₅₀ by two. Optionally, K _i (factor Xa) values of less than 3 nM were calculated from the Morrison equation.
Compounds of the invention, when tested in this assay, exhibited the selective ability to inhibit human factor Xa and human thrombin.
<Example 9>
(In vitro analysis of human prothrombinase)
This assay shows the ability of the compounds of the present invention to inhibit prothrombinase. Prothrombinase (PTase) catalyzes the activation of prothrombin, producing thrombin with fragment 1.2 + majorthrombin as intermediate. This analysis is an end point analysis. The activity of prothrombinase is measured by the activity of thrombin (one reaction product) or time (nM vs mOD / min) based on the thrombin amount / thrombin standard curve formed. For the determination of IC ₅₀ (PTase) of the compounds of the present invention, PTase activity is expressed as thrombin activity (mOD / min).
<material>
enzyme:
1. Human Factor Va (Haematologic Technologies Inc., Cat # HCVA-0110) Working Solution: 1.0 mg / ml (2 mM CaCl ₂ ) in 50% glycerol, stored at −20 ° C.
2. Human Factor Xa (Enzyme Res. Lab. Cat # HFXa 1011) Working Solution: 0.281 mg / ml in assay buffer (without BSA) stored at −80 ° C.
3. Human Prothrombin (FII) (Enzyme Res. Lab., Cat # HP1002) Working Solution: FII diluted to 4.85 mg / ml in assay buffer (without BSA) stored at -80 ° C.
Phospholipid (PCPS) Packets:
PCPS vesicles (80% PC, 20% PS) are described in Barenholz et al., Biochemistry (1977), Vol. 16, pp. 2806-2810, and modified by the method reported.
Phosphatidylserine (Avanti Polar Lipids, Inc., Cat # 840032): 10 mg / ml in chloroform, purified from brine and stored at −20 ° C. under nitrogen or argon.
Phosphatidyl Choline (Avanti Polar Lipids, Inc., Cat # 850457): 50 mg / ml (synthetic 16: 0 to 18: 1 palmitoyl-oleoyl) in chloroform, stored at −20 ° C. under nitrogen or argon.
Spectrozyme-TH (American Diagnostica Inc., Cat # 238L, 50 μmol stored at room temperature) Working solution: 50 μmol dissolved in 10 ml of dH ₂ O.
BSA (Sigma Chem Co., Cat # A-7888, FractionV, RIA grade).
Assay buffer: 50 mM TrisHCl, pH 7.5, 150 mM NaCl, 2.5 mM CaCl ₂ , 0.1% PEG 6000 (BDH), 0.05% BSA (Sigma, Fr. V, RIA grade).
〈Analytic Analysis of One Edition〉
For one plate analysis, prepare the following working solutions:
1.Prothrombinase Complexes:
(a) 100 μM PCPS (27.5 μl PCPS stock (4.36 mM) diluted to final 1,200 μl in assay buffer).
(b) 25 nM human factor Va: 5.08 μl of Va stock (1 mg / ml) was diluted with assay buffer to final 1,200 μl.
(c) 5 pM human factor Xa: Xa stock (0.281 mg / ml) is diluted 1: 1,220,000 in assay buffer. Prepare at least 1,200 μl.
Dynamic volumes (1,100 μl) of each component are mixed in the order of PCPS, Va and Xa. Allow to stand for 5-10 minutes at ambient temperature and use immediately or store in ice (to allow ambient temperature before use).
2. 6 μΜ human prothrombin (FII): Dilute 124 μΙ_ of FII stock solution (4.85 mg / mL) with assay buffer to final 1400 μΙ_.
3. 20 mM EDTA / assay buffer: 0.8 ml 0.5M EDTA (pH 8.5) + 19.2 ml assay buffer.
4. 0.2 mM Spectrozyme-TH / EDTA buffer: 0.44 mL SPTH stock solution (5 mM) + 10.56 mL 20 mM EDTA / assay buffer.
5. Test Compound (Compound of the Invention): A working solution (5X) is prepared from 10 mM stock solution (DMSO) to prepare a series of 1: 3 dilutions. Compounds were analyzed twice in six concentrates.
<Analysis Conditions and Procedures>
The prothrombinase reaction was performed with a final 50 μl mixture containing PTase (20 μM PCPS, 5 nM hFVa and 1 pM hFXa), 1.2 μM human factor II and varying concentrations of test compound (5-0.021 μM or lower). Range). The reaction was initiated by the addition of PTase and incubated for 6 minutes at room temperature. The reaction was stopped by adding EDTA / buffer to the final 10 mM. The activity of thrombin (product) was then measured for 5 minutes (10 second intervals) at ambient temperature in a THEROmax microplate reader at 405 nm in the presence of 0.1 mM spectrozyme-TH as substrate. The reaction was carried out in 96 well microtiter plates.
In the first step of the assay, 10 μl of diluted test compound (5 ×) or buffer was added to the plate twice. 10 μl of prothrombin (hFII) (5 ×) was then added to each well. Then 30 μl of PTase was added to each well and mixed for about 30 seconds. The plate was then incubated at ambient temperature for 6 minutes.
In a subsequent step, 50 μl of 20 mM EDTA (in assay buffer) was added to each well to stop the reaction. The resulting solution was then mixed for about 10 seconds. 100 μl of 0.2 mM spectrozyme was then added to each well. The thrombin reaction rate was then measured at 405 nm for 5 minutes at 10 second intervals in a molecular device microplate reader.
<Calculation>
The thrombin reaction rate is expressed in mOD / min using the OD reading from the 5 minute reaction. IC ₅₀ values were calculated with a log-logit curve fit program.
Compounds of the present invention showed the ability to inhibit prothrombinase when tested in this assay.
<Example 10>
(In vivo analysis)
The following assay shows the ability of a compound to act as an anticoagulant.
Male rats (250-330 g) were anesthetized with sodium pentobarbital (90 mg / kg, intraperitoneally) and prepared for surgery. The left carotid artery was intubated for blood pressure measurements and blood sample collection to monitor the hemolysis parameters (prothrombin time (PT) and activated partial thromboplastin time (aPTT)). The tail vein was intubated for administration of the test compound (ie, compounds and standards of the invention) and thromboplastin injection. The abdomen was opened through a midline incision and the abdominal vena cava separated for 2-3 cm distal to the renal vein. All venous branches were ligated in this 2-3 cm segment of the abdominal vena cava. After all surgery, rats were stabilized and the experiments started. Test compounds were administered as an intravenous antagonist (t = 0). Three minutes later (t = 3), 5 minutes of thromboplastin injection was initiated. At 2 minutes (t = 5) of injection, the abdominal vena cava was ligated at both the proximal and distal ends. The vessel was left on its left side for 60 minutes, then excised from the rat and lengthened to open, and carefully measured by removing blood clots (if present). Statistical analysis of the results was performed using the rank test labeled Wilcoxin matched pair.
Compounds of the present invention, when tested in this assay, exhibited the ability to inhibit blood clotting.
Although the present invention has been described with reference to specific embodiments thereof, those skilled in the art should understand that the present invention may be variously changed and equivalents may be substituted without departing from the true spirit and scope of the present invention. In addition, various modifications may be made and equivalents may be substituted without departing from the true spirit and scope of the invention. In addition, various modifications may be made to adapt a particular situation, material, or composition, of a material, method, or process step (s) to the objects, spirit, and scope of the present invention. All such modifications are intended to be within the scope of the claims appended hereto.

权利要求:
Claims (13)
[1" claim-type="Currently amended] A compound or a pharmaceutically acceptable salt thereof as a single stereoisomer or mixture thereof selected from the group consisting of the following formulas (I) and (II).
<Formula I>

<Formula II>

Where
A is -O-, -N (R ⁵ )-or -S (O) _n- , where n is 0, 1 or 2;
Z ¹ and Z ² are independently —O—, —N (R ⁵ ) — or —OCH ₂ —;
R ¹ and R ⁴ are each independently hydrogen, halo, alkyl, -OR ⁸ , -C (O) OR ⁸ , -C (O) N (R ⁸ ) R ⁹ , -N (R ⁸ ) R ⁹ ,- N (R ⁸ ) C (O) R ⁹ or —N (H) S (O) ₂ R ¹¹ ;
R ² is -C (NH) NH ₂ , -C (NH) N (H) OR ⁸ , -C (NH) N (H) C (O) OR ¹¹ , -C (NH) N (H) C ( O) R ⁸ , -C (NH) N (H) S (O) ₂ R ¹¹ or -C (NH) N (H) C (O) N (H) R ⁸ ;
R ³ is halo, alkyl, haloalkyl, haloalkoxy, cyano, ureido, guanidino, -OR ⁸ , -C (NH) NH ₂ , -C (NH) N (H) OR ⁸ , -C ( O) N (R ⁸ ) R ⁹ , -R ¹⁰ -C (O) N (R ⁸ ) R ⁹ , -CH (OH) C (O) N (R ⁸ ) R ⁹ , -N (R ⁸ ) R ⁹ , -R ¹⁰ -N (R ⁸ ) R ⁹ , -C (O) OR ⁸ , -R ¹⁰ -C (O) OR ⁸ , -N (R ⁸ ) C (O) R ⁸ , (1,2 ) -Tetrahydropyrimidinyl (optionally substituted by alkyl), (1,2) -imidazolyl (optionally substituted by alkyl) or (1,2) -imidazolinyl (optionally substituted by alkyl) );
R ⁵ is hydrogen, alkyl, aryl (halo, alkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl or dialkyl, respectively) Optionally substituted by aminocarbonyl) or aralkyl (halo, alkyl, aryl, hydroxy, alkoxy, aralkyl, amino, dialkylamino, monoalkylamino, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylamino Carbonyl or optionally substituted by dialkylaminocarbonyl);
R ⁶ is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, cycloalkyl, cycloalkylalkyl, -C (O) OR ⁸ , -R ¹⁰ -C (O) OR ⁸ , -R ^10- C (O) N (R ⁸ ) R ⁹ , -C (O) -R ¹⁰ -N (R ⁸ ) R ⁹ , -R ¹⁰ -C (O) R ⁸ , -R ¹⁰ -C (O) N ( R ⁸ ) N (R ⁸ ) R ⁹ , -R ¹⁰ -C (R ⁸ ) (OR ⁹ ) -R ¹⁰ -N (R ⁸ ) (R ⁹ ), -C (R ⁸ ) (OR ⁸ ) C ( O) OR ⁹ , -R ¹⁰ -C (R ⁸ ) (C (O) OR ⁹ ) ₂ , -C (R ⁸ ) (N (R ⁸ ) R ⁹ ) C (O) OR ⁸ , -R ^10- C (R ⁸ ) (N (R ⁸ ) R ⁹ ) C (O) OR ⁸ , -C (R ⁸ ) (OR ⁸ ) R ⁹ , -R ¹⁰ -N (R ⁸ ) R ⁹ , -R ^10- N (R ⁸ ) C (O) OR ¹¹ , -R ¹⁰ -N (R ⁸ ) C (0) R ⁹ , -R ¹⁰ -N (R ⁸ ) C (NR ⁸ ) R ¹¹ , -R ¹⁰ -N (R ⁸ ) S (O) ₂ R ¹¹ , -R ¹⁰ -N (R ⁸ ) C (O) N (R ⁸ ) R ⁹ , -R ¹⁰ -N (R ⁸ ) C (NR ⁸ ) N (R ⁸ ) R ⁹ , -R ¹⁰ -N (R ⁸ ) C (NR ⁸ ) N (R ⁸ ) N (R ⁸ ) R ⁹ , -R ¹⁰ -N (R ⁸ ) -R ¹⁰ -C (R ⁸ ) (N (R ⁸ ) R ⁹ ) C (O) OR ⁸ , -R ¹⁰ -N (R ⁸ ) S (O) R ⁹ , -R ¹⁰ OR ⁸ , -R ¹⁰ -ON (R ⁸ ) C (NR ⁸ ) N (R ⁸ ) R ⁹ , -R ¹⁰ -OS (O) ₂ OR ⁸ , -R ¹⁰ -P (O) (OR ⁸ ) R ⁹ , -R ¹⁰ -OP (O) (OR ⁸ ) ₂ , -R ¹⁰ -P (O) (OR ⁸ ) ₂ , -R ¹⁰ -SR ⁸ , -R ¹⁰ -SR ¹⁰ -C (O) OR ⁸ , -R ¹⁰ -SR ¹⁰ -N (R ⁸ ) R ⁹ , -R ¹⁰ -SR ¹⁰ -C (R ⁸ ) (N (R ⁸ ) R ⁹ ) C (O) OR ⁸ , -R ¹⁰ -SR ¹⁰ -N (R ⁸ ) C (O) OR ⁸ , -R ¹⁰ -SR ¹⁰ -N (R ⁸ ) C (O) R ⁸ , -R ¹⁰ -SSR ¹⁰ -C (R ⁸ ) (N (R ⁸ ) R ⁹ ) C (O) OR ⁸ , -R ¹⁰ -SC (O) N (R ⁸ ) R ⁹ , -R ¹⁰ -SC (S) N (R ⁸ ) R ⁹ , -R ^10- S (O) R ⁸ , -R ¹⁰ -S (O) ₂ R ¹¹ , -R ¹⁰ -S (O) OR ⁸ , -R ¹⁰ -S (O) ₂ OR ⁸ , -R ¹⁰ -S (O) ₂ N (R ⁸ ) R ⁹ or —R ¹⁰ —S (O) (NR ⁸ ) R ⁹ ; or
R ⁶ is aryl (alkyl, halo, haloalkyl, haloalkoxy, -OR ⁸ , -SR ⁸ , -N (R ⁸ ) R ⁹ , -C (O) OR ⁸ , -C (O) N (R ⁸ ) R ⁹ , -S (O) ₂ OR ⁸ and -OP (O) (OR ⁸ ) ₂ optionally substituted with one or more substituents selected from the group consisting of; or
R ⁶ is aralkyl (alkyl, halo, haloalkyl, haloalkoxy, -OR ⁸ , -SR ⁸ , -N (R ⁸ ) R ⁹ , -C (O) OR ⁸ , -C (O) N (R ⁸ ) R ⁹ , -S (O) ₂ OR ⁸ and -OP (O) (OR ⁸ ) ₂ optionally substituted with one or more substituents selected from the group consisting of; or
R ⁶ is heterocyclyl (alkyl, halo, haloalkyl, haloalkoxy, aralkyl, -OR ⁸ , -C (O) OR ⁸ , -N (R ⁸ ) R ⁹ , -C (O) N (R ⁸ ) R ⁹ , -S (O) ₂ OR ⁸ and -OP (O) (OR ⁸ ) ₂ optionally substituted with one or more substituents selected from the group consisting of; or
R ⁶ is heterocyclylalkyl (the heterocyclyl radical is alkyl, halo, haloalkyl, haloalkoxy, aralkyl, -OR ⁸ , -SR ⁸ , -C (O) OR ⁸ , -N (R ⁸ ) R ⁹ , -C (O) N (R ⁸ ) R ⁹ , -S (O) ₂ OR ⁸ and -OP (O) (OR ⁸ ) ₂ optionally substituted with one or more substituents selected from the group consisting of; or
R ⁶ is adamantyl (alkyl, halo, haloalkyl, haloalkoxy, -OR ⁸ , -SR ⁸ , -C (O) OR ⁸ , -N (R ⁸ ) R ⁹ , -C (O) N (R ⁸ ) R ⁹ , -S (O) ₂ OR ⁸ and -OP (O) (OR ⁸ ) ₂ optionally substituted; or
R ⁶ is adamantylalkyl (the adamantyl radicals are alkyl, halo, haloalkyl, haloalkoxy, -OR ⁸ , -SR ⁸ , -C (O) OR ⁸ , -N (R ⁸ ) R ⁹ ,- C (O) N (R ⁸ ) R ⁹ , optionally substituted by —S (O) ₂ OR ⁸ and —OP (O) (OR ⁸ ) ₂ ;
R ⁷ is hydrogen, alkyl, cycloalkyl, aralkyl or aryl;
R ⁸ and R ⁹ are each independently hydrogen, alkyl, aryl (halo, alkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylamino Optionally substituted by carbonyl or dialkylaminocarbonyl) or aralkyl (halo, alkyl, aryl, hydroxy, alkoxy, aralkyl, amino, dialkylamino, monoalkylamino, carboxy, alkoxycarbonyl, aminocarbon Optionally substituted by carbonyl, monoalkylaminocarbonyl or dialkylaminocarbonyl);
R ¹⁰ is a straight or branched alkylene chain;
R ¹¹ is alkyl, aryl (halo, alkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl or dialkylaminocarbonyl Optionally substituted by) or aralkyl (halo, alkyl, aryl, hydroxy, alkoxy, aralkyl, amino, dialkylamino, monoalkylamino, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl or Optionally substituted with dialkylaminocarbonyl).
[2" claim-type="Currently amended] The method of claim 1,
A is -O-, -N (R ⁵ )-;
Z ¹ and Z ² are both —O—;
R ¹ and R ⁴ are each independently hydrogen, halo or -OR ⁸ ;
R ² is —C (NH) NH ₂ , —C (NH) N (H) S (O) ₂ R ¹¹ or —C (NH) N (H) C (O) N (H) R ⁸ ;
R ³ is ureido, guanidino, -OR ⁸ , -C (O) N (R ⁸ ) R ⁹ , -N (R ⁸ ) R ⁸ , -C (O) OR ⁸ , -N (R ⁸ ) C (O) R ⁸ , (1,2) -tetrahydropyrimidinyl (optionally substituted by alkyl), (1,2) -imidazolyl (optionally substituted by alkyl) or (1,2) Imidazolinyl (optionally substituted by alkyl);
R ⁵ is each hydrogen, alkyl, aryl (optionally substituted by halo) or aralkyl (optionally substituted by halo);
R ⁶ is hydrogen, alkyl, -R ¹⁰ -C (O) OR ⁸ , -R ¹⁰ -C (O) N (R ⁸ ) R ⁹ , -R ¹⁰ -C (R ⁸ ) (C (O) OR ⁹ ) ₂ , -R ¹⁰ -N (R ⁸ ) R ⁹ , -R ¹⁰ -N (R ⁸ ) C (NR ⁸ ) R ¹¹ , -R ¹⁰ -N (R ⁸ ) C (O) N (R ⁸ ) R ⁹ , -R ¹⁰ -N (R ⁸ ) C (NR ⁸ ) N (R ⁸ ) R ⁹ , -R ¹⁰ OR ⁸ , -R ¹⁰ -OP (O) (OR ⁸ ) ₂ , -R ¹⁰ -SR ⁸ or -R ¹⁰ -S (O) ₂ R ¹¹ ; or
R ⁶ is aryl (optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, haloalkoxy and -OR ⁸ ); or
R ⁶ is aralkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, haloalkoxy and -OR ⁸ ); or
R ⁶ is heterocyclyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, haloalkoxy and -OR ⁸ ); or
R ⁶ is heterocyclylalkyl, wherein said heterocyclyl radical is optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, haloalkoxy or -OR ⁸ ;
R ⁷ is hydrogen, alkyl, cycloalkyl, aralkyl or aryl;
R ⁸ and R ⁹ are each independently hydrogen, alkyl, aryl (optionally substituted by halo, alkyl, hydroxy or alkoxy) or aralkyl (optionally substituted by halo, alkyl, hydroxy or alkoxy);
R ¹⁰ is a straight or branched alkylene chain;
R ¹¹ is alkyl, aryl (optionally substituted by halo, alkyl, hydroxy or alkoxy) or aralkyl (optionally substituted by halo, alkyl, hydroxy or alkoxy)
compound.
[3" claim-type="Currently amended] The method of claim 2,
A is -N (R ⁵ )-;
Z ¹ and Z ² are both —O—;
R ¹ and R ⁴ are each independently hydrogen or —OR ⁸ ;
R ² is —C (NH) NH ₂ ;
R ³ is -C (O) N (R ⁸ ) R ⁹ , (1,2) -tetrahydropyrimidinyl (optionally substituted by alkyl), (1,2) -imidazolyl (optionally by alkyl Substituted) or (1,2) -imidazolinyl (optionally substituted by alkyl);
R ⁵ is each hydrogen, alkyl, aryl (optionally substituted by halo) or aralkyl (optionally substituted by halo);
R ⁶ is hydrogen, alkyl, -R ¹⁰ -C (O) OR ⁸ , -R ¹⁰ -C (O) N (R ⁸ ) R ⁹ , -R ¹⁰ -C (R ⁸ ) (C (O) OR ⁹ ) ₂ , -R ¹⁰ -N (R ⁸ ) R ⁹ , -R ¹⁰ -N (R ⁸ ) C (NR ⁸ ) R ¹¹ , -R ¹⁰ -N (R ⁸ ) C (O) N (R ⁸ ) R ⁹ , -R ¹⁰ -N (R ⁸ ) C (NR ⁸ ) N (R ⁸ ) R ⁹ , -R ¹⁰ OR ⁸ , -R ¹⁰ -OP (O) (OR ⁸ ) ₂ , -R ¹⁰ -SR ⁸ or -R ¹⁰ -S (O) ₂ R ¹¹ ; or
R ⁶ is aralkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, haloalkoxy and -OR ⁸ ); or
R ⁶ is imidazolylalkyl or indolylalkyl;
R ⁷ is hydrogen or alkyl;
R ⁸ and R ⁹ are each independently hydrogen, alkyl, aryl or aralkyl;
R ¹⁰ is a straight or branched alkylene chain;
R ¹¹ is alkyl or aryl
compound.
[4" claim-type="Currently amended] The method of claim 3,
R ¹ is -OR ⁸ ;
R ² is —C (NH) NH ₂ ;
R ³ is -C (O) N (R ⁸ ) R ⁹ , (1,2) -imidazolyl (optionally substituted by methyl) or (1,2) -imidazolinyl (optionally substituted by methyl );
Each R ⁵ is hydrogen, alkyl, aryl or aralkyl;
R ⁶ is hydrogen, alkyl, -R ¹⁰ -C (O) OR ⁸ , -R ¹⁰ -C (O) N (R ⁸ ) R ⁹ , -R ¹⁰ -C (R ⁸ ) (C (O) OR ⁹ ) ₂ , -R ¹⁰ -N (R ⁸ ) R ⁹ , -R ¹⁰ -N (R ⁸ ) C (NR ⁸ ) R ¹¹ , -R ¹⁰ -N (R ⁸ ) C (O) N (R ⁸ ) R ⁹ , -R ¹⁰ -N (R ⁸ ) C (NR ⁸ ) N (R ⁸ ) R ⁹ , -R ¹⁰ OR ⁸ , -R ¹⁰ -OP (O) (OR ⁸ ) ₂ , -R ¹⁰ -SR ⁸ or -R ¹⁰ -S (O) ₂ R ¹¹ ; or
R ⁶ is aralkyl (optionally substituted by one or more substituents selected from the group consisting of methyl and hydroxy); or
R ⁶ is imidazolylalkyl or indolylalkyl;
R ⁷ is hydrogen or alkyl;
R ⁸ and R ⁹ are each independently hydrogen, alkyl, aryl or aralkyl;
R ¹⁰ is a straight or branched alkylene chain;
R ¹¹ is alkyl or aryl
compound.
[5" claim-type="Currently amended] The compound of claim 4, wherein A is —N (H) —; Z ¹ and Z ² are both —O—; R ¹ is hydroxy; R ² is —C (NH) NH ₂ ; R ³ is —C (O) N (CH ₃ ) ₂ ; R ⁴ , R ⁵ , R ⁶ and R ⁷ are hydrogen.
[6" claim-type="Currently amended] A compound according to claim 5, selected from formula I 2- (2-hydroxy-5-amidinophenoxy) -4- (3- (dimethylaminocarbonyl) phenoxy) -1,7-dihydro-6 (5H) -pteridone.
[7" claim-type="Currently amended] A compound according to claim 5, selected from formula II: 2- (3-dimethylaminocarbonylphenoxy) -4- (2-hydroxy-5-amidinophenoxy) -1,7-dihydro-6 (5H ) -Pteridone.
[8" claim-type="Currently amended] The method of claim 2,
A is -O-;
Z ¹ and Z ² are both —O—;
R ¹ and R ⁴ are each independently hydrogen or —OR ⁸ ;
R ² is —C (NH) NH ₂ ;
R ³ is -C (O) N (R ⁸ ) R ⁹ , (1,2) -tetrahydropyrimidinyl (optionally substituted by alkyl), (1,2) -imidazolyl (optionally by alkyl Substituted) or (1,2) -imidazolinyl (optionally substituted by alkyl);
R ⁵ is hydrogen, alkyl, aryl (optionally substituted by halo) or aralkyl (optionally substituted by halo);
R ⁶ is hydrogen, alkyl, -R ¹⁰ -C (O) OR ⁸ , -R ¹⁰ -C (O) N (R ⁸ ) R ⁹ , -R ¹⁰ -C (R ⁸ ) (C (O) OR ⁹ ) ₂ , -R ¹⁰ -N (R ⁸ ) R ⁹ , -R ¹⁰ -N (R ⁸ ) C (NR ⁸ ) R ¹¹ , -R ¹⁰ -N (R ⁸ ) C (O) N (R ⁸ ) R ⁹ , -R ¹⁰ -N (R ⁸ ) C (NR ⁸ ) N (R ⁸ ) R ⁹ , -R ¹⁰ OR ⁸ , -R ¹⁰ -OP (O) (OR ⁸ ) ₂ , -R ¹⁰ -SR ⁸ or -R ¹⁰ -S (O) ₂ R ¹¹ ; or
R ⁶ is aralkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, haloalkoxy and -OR ⁸ ); or
R ⁶ is imidazolylalkyl or indolylalkyl;
R ⁷ is hydrogen or alkyl;
R ⁸ and R ⁹ are each independently hydrogen, alkyl, aryl or aralkyl;
R ¹⁰ is a straight or branched alkylene chain;
R ¹¹ is alkyl or aryl
compound.
[9" claim-type="Currently amended] The method of claim 8,
R ¹ is -OR ⁸ ;
R ² is —C (NH) NH ₂ ;
R ³ is -C (O) N (R ⁸ ) R ⁹ , (1,2) -imidazolyl (optionally substituted by methyl) or (1,2) -imidazolinyl (optionally substituted by methyl );
R ⁵ is hydrogen, alkyl, aryl or aralkyl;
R ⁶ is hydrogen, alkyl, -R ¹⁰ -C (O) OR ⁸ , -R ¹⁰ -C (O) N (R ⁸ ) R ⁹ , -R ¹⁰ -C (R ⁸ ) (C (O) OR ⁹ ) ₂ , -R ¹⁰ -N (R ⁸ ) R ⁹ , -R ¹⁰ -N (R ⁸ ) C (NR ⁸ ) R ¹¹ , -R ¹⁰ -N (R ⁸ ) C (O) N (R ⁸ ) R ⁹ , -R ¹⁰ -N (R ⁸ ) C (NR ⁸ ) N (R ⁸ ) R ⁹ , -R ¹⁰ OR ⁸ , -R ¹⁰ -OP (O) (OR ⁸ ) ₂ , -R ¹⁰ -SR ⁸ or -R ¹⁰ -S (O) ₂ R ¹¹ ; or
R ⁶ is aralkyl (optionally substituted by one or more substituents selected from the group consisting of methyl and hydroxy); or
R ⁶ is imidazolylalkyl or indolylalkyl;
R ⁷ is hydrogen or alkyl;
R ⁸ and R ⁹ are each independently hydrogen, alkyl, aryl or aralkyl;
R ¹⁰ is a straight or branched alkylene chain;
R ¹¹ is alkyl or aryl
compound.
[10" claim-type="Currently amended] The compound of claim 9, wherein A is —O—; Z ¹ and Z ² are both —O—; R ¹ is hydroxy; R ² is —C (NH) NH ₂ ; R ³ is —C (O) N (CH ₃ ) ₂ ; R ⁴ , R ⁵ , R ⁶ and R ⁷ are hydrogen.
[11" claim-type="Currently amended] A compound according to claim 10, selected from formula I 2- (2-hydroxy-5-amidinophenoxy) -4- (3- (dimethylaminocarbonyl) phenoxy) -5H-pyrimido [4,5 -b] [1,4] oxazine-6 (7H) -one.
[12" claim-type="Currently amended] With a disease characterized by thrombotic activity, comprising a therapeutically effective amount of a compound as a single stereoisomer or mixture thereof, selected from the group consisting of Formulas I and II, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient thereof Pharmaceutical compositions useful in the treatment of humans.
<Formula I>

<Formula II>

Where
A is -O-, -N (R ⁵ )-or -S (O) _n- , where n is 0, 1 or 2;
Z ¹ and Z ² are independently —O—, —N (R ⁵ ) — or —OCH ₂ —;
R ¹ and R ⁴ are each independently hydrogen, halo, alkyl, -OR ⁸ , -C (O) OR ⁸ , -C (O) N (R ⁸ ) R ⁹ , -N (R ⁸ ) R ⁹ ,- N (R ⁸ ) C (O) R ⁹ or —N (H) S (O) ₂ R ¹¹ ;
R ² is -C (NH) NH ₂ , -C (NH) N (H) OR ⁸ , -C (NH) N (H) C (O) OR ¹¹ , -C (NH) N (H) C ( O) R ⁸ , -C (NH) N (H) S (O) ₂ R ¹¹ or -C (NH) N (H) C (O) N (H) R ⁸ ;
R ³ is halo, alkyl, haloalkyl, haloalkoxy, cyano, ureido, guanidino, -OR ⁸ , -C (NH) NH ₂ , -C (NH) N (H) OR ⁸ , -C ( O) N (R ⁸ ) R ⁹ , -R ¹⁰ -C (O) N (R ⁸ ) R ⁹ , -CH (OH) C (O) N (R ⁸ ) R ⁹ , -N (R ⁸ ) R ⁹ , -R ¹⁰ -N (R ⁸ ) R ⁹ , -C (O) OR ⁸ , -R ¹⁰ -C (O) OR ⁸ , -N (R ⁸ ) C (O) R ⁸ , (1,2 ) -Tetrahydropyrimidinyl (optionally substituted by alkyl), (1,2) -imidazolyl (optionally substituted by alkyl) or (1,2) -imidazolinyl (optionally substituted by alkyl) );
R ⁵ is hydrogen, alkyl, aryl (halo, alkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl or dialkyl, respectively) Optionally substituted by aminocarbonyl) or aralkyl (halo, alkyl, aryl, hydroxy, alkoxy, aralkyl, amino, dialkylamino, monoalkylamino, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylamino Carbonyl or optionally substituted by dialkylaminocarbonyl);
R ⁶ is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, cycloalkyl, cycloalkylalkyl, -C (O) OR ⁸ , -R ¹⁰ -C (O) OR ⁸ , -R ^10- C (O) N (R ⁸ ) R ⁹ , -C (O) -R ¹⁰ -N (R ⁸ ) R ⁹ , -R ¹⁰ -C (O) R ⁸ , -R ¹⁰ -C (O) N ( R ⁸ ) N (R ⁸ ) R ⁹ , -R ¹⁰ -C (R ⁸ ) (OR ⁹ ) -R ¹⁰ -N (R ⁸ ) (R ⁹ ), -C (R ⁸ ) (OR ⁸ ) C ( O) OR ⁹ , -R ¹⁰ -C (R ⁸ ) (C (O) OR ⁹ ) ₂ , -C (R ⁸ ) (N (R ⁸ ) R ⁹ ) C (O) OR ⁸ , -R ^10- C (R ⁸ ) (N (R ⁸ ) R ⁹ ) C (O) OR ⁸ , -C (R ⁸ ) (OR ⁸ ) R ⁹ , -R ¹⁰ -N (R ⁸ ) R ⁹ , -R ^10- N (R ⁸ ) C (O) OR ¹¹ , -R ¹⁰ -N (R ⁸ ) C (0) R ⁹ , -R ¹⁰ -N (R ⁸ ) C (NR ⁸ ) R ¹¹ , -R ¹⁰ -N (R ⁸ ) S (O) ₂ R ¹¹ , -R ¹⁰ -N (R ⁸ ) C (O) N (R ⁸ ) R ⁹ , -R ¹⁰ -N (R ⁸ ) C (NR ⁸ ) N (R ⁸ ) R ⁹ , -R ¹⁰ -N (R ⁸ ) C (NR ⁸ ) N (R ⁸ ) N (R ⁸ ) R ⁹ , -R ¹⁰ -N (R ⁸ ) -R ¹⁰ -C (R ⁸ ) (N (R ⁸ ) R ⁹ ) C (O) OR ⁸ , -R ¹⁰ -N (R ⁸ ) S (O) R ⁹ , -R ¹⁰ OR ⁸ , -R ¹⁰ -ON (R ⁸ ) C (NR ⁸ ) N (R ⁸ ) R ⁹ , -R ¹⁰ -OS (O) ₂ OR ⁸ , -R ¹⁰ -P (O) (OR ⁸ ) R ⁹ , -R ¹⁰ -OP (O) (OR ⁸ ) ₂ , -R ¹⁰ -P (O) (OR ⁸ ) ₂ , -R ¹⁰ -SR ⁸ , -R ¹⁰ -SR ¹⁰ -C (O) OR ⁸ , -R ¹⁰ -SR ¹⁰ -N (R ⁸ ) R ⁹ , -R ¹⁰ -SR ¹⁰ -C (R ⁸ ) (N (R ⁸ ) R ⁹ ) C (O) OR ⁸ , -R ¹⁰ -SR ¹⁰ -N (R ⁸ ) C (O) OR ⁸ , -R ¹⁰ -SR ¹⁰ -N (R ⁸ ) C (O) R ⁸ , -R ¹⁰ -SSR ¹⁰ -C (R ⁸ ) (N (R ⁸ ) R ⁹ ) C (O) OR ⁸ , -R ¹⁰ -SC (O) N (R ⁸ ) R ⁹ , -R ¹⁰ -SC (S) N (R ⁸ ) R ⁹ , -R ^10- S (O) R ⁸ , -R ¹⁰ -S (O) ₂ R ¹¹ , -R ¹⁰ -S (O) OR ⁸ , -R ¹⁰ -S (O) ₂ OR ⁸ , -R ¹⁰ -S (O) ₂ N (R ⁸ ) R ⁹ or —R ¹⁰ —S (O) (NR ⁸ ) R ⁹ ; or
R ⁶ is aryl (alkyl, halo, haloalkyl, haloalkoxy, -OR ⁸ , -SR ⁸ , -N (R ⁸ ) R ⁹ , -C (O) OR ⁸ , -C (O) N (R ⁸ ) R ⁹ , -S (O) ₂ OR ⁸ and -OP (O) (OR ⁸ ) ₂ optionally substituted with one or more substituents selected from the group consisting of; or
R ⁶ is aralkyl (alkyl, halo, haloalkyl, haloalkoxy, -OR ⁸ , -SR ⁸ , -N (R ⁸ ) R ⁹ , -C (O) OR ⁸ , -C (O) N (R ⁸ ) R ⁹ , -S (O) ₂ OR ⁸ and -OP (O) (OR ⁸ ) ₂ optionally substituted with one or more substituents selected from the group consisting of; or
R ⁶ is heterocyclyl (alkyl, halo, haloalkyl, haloalkoxy, aralkyl, -OR ⁸ , -C (O) OR ⁸ , -N (R ⁸ ) R ⁹ , -C (O) N (R ⁸ ) R ⁹ , -S (O) ₂ OR ⁸ and -OP (O) (OR ⁸ ) ₂ optionally substituted with one or more substituents selected from the group consisting of; or
R ⁶ is heterocyclylalkyl (the heterocyclyl radical is alkyl, halo, haloalkyl, haloalkoxy, aralkyl, -OR ⁸ , -SR ⁸ , -C (O) OR ⁸ , -N (R ⁸ ) R ⁹ , -C (O) N (R ⁸ ) R ⁹ , -S (O) ₂ OR ⁸ and -OP (O) (OR ⁸ ) ₂ optionally substituted with one or more substituents selected from the group consisting of; or
R ⁶ is adamantyl (alkyl, halo, haloalkyl, haloalkoxy, -OR ⁸ , -SR ⁸ , -C (O) OR ⁸ , -N (R ⁸ ) R ⁹ , -C (O) N (R ⁸ ) R ⁹ , -S (O) ₂ OR ⁸ and -OP (O) (OR ⁸ ) ₂ optionally substituted; or
R ⁶ is adamantylalkyl (the adamantyl radicals are alkyl, halo, haloalkyl, haloalkoxy, -OR ⁸ , -SR ⁸ , -C (O) OR ⁸ , -N (R ⁸ ) R ⁹ ,- C (O) N (R ⁸ ) R ⁹ , optionally substituted by —S (O) ₂ OR ⁸ and —OP (O) (OR ⁸ ) ₂ ;
R ⁷ is hydrogen, alkyl, cycloalkyl, aralkyl or aryl;
R ⁸ and R ⁹ are each independently hydrogen, alkyl, aryl (halo, alkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylamino Optionally substituted by carbonyl or dialkylaminocarbonyl) or aralkyl (halo, alkyl, aryl, hydroxy, alkoxy, aralkyl, amino, dialkylamino, monoalkylamino, carboxy, alkoxycarbonyl, aminocarbon Optionally substituted by carbonyl, monoalkylaminocarbonyl or dialkylaminocarbonyl);
R ¹⁰ is a straight or branched alkylene chain;
R ¹¹ is alkyl, aryl (halo, alkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl or dialkylaminocarbonyl Optionally substituted by) or aralkyl (halo, alkyl, aryl, hydroxy, alkoxy, aralkyl, amino, dialkylamino, monoalkylamino, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl or Optionally substituted with dialkylaminocarbonyl).
[13" claim-type="Currently amended] Humans with a disease characterized by thrombotic activity, comprising administering to a human being in need thereof a compound or a pharmaceutically acceptable salt thereof as a single stereoisomer or mixture thereof selected from the group consisting of Formulas I and II Method of treatment.
<Formula I>

<Formula II>

Where
A is -O-, -N (R ⁵ )-or -S (O) _n- , where n is 0, 1 or 2;
Z ¹ and Z ² are independently —O—, —N (R ⁵ ) — or —OCH ₂ —;
R ¹ and R ⁴ are each independently hydrogen, halo, alkyl, -OR ⁸ , -C (O) OR ⁸ , -C (O) N (R ⁸ ) R ⁹ , -N (R ⁸ ) R ⁹ ,- N (R ⁸ ) C (O) R ⁹ or —N (H) S (O) ₂ R ¹¹ ;
R ² is -C (NH) NH ₂ , -C (NH) N (H) OR ⁸ , -C (NH) N (H) C (O) OR ¹¹ , -C (NH) N (H) C ( O) R ⁸ , -C (NH) N (H) S (O) ₂ R ¹¹ or -C (NH) N (H) C (O) N (H) R ⁸ ;
R ³ is halo, alkyl, haloalkyl, haloalkoxy, cyano, ureido, guanidino, -OR ⁸ , -C (NH) NH ₂ , -C (NH) N (H) OR ⁸ , -C ( O) N (R ⁸ ) R ⁹ , -R ¹⁰ -C (O) N (R ⁸ ) R ⁹ , -CH (OH) C (O) N (R ⁸ ) R ⁹ , -N (R ⁸ ) R ⁹ , -R ¹⁰ -N (R ⁸ ) R ⁹ , -C (O) OR ⁸ , -R ¹⁰ -C (O) OR ⁸ , -N (R ⁸ ) C (O) R ⁸ , (1,2 ) -Tetrahydropyrimidinyl (optionally substituted by alkyl), (1,2) -imidazolyl (optionally substituted by alkyl) or (1,2) -imidazolinyl (optionally substituted by alkyl) );
R ⁵ is hydrogen, alkyl, aryl (halo, alkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl or dialkyl, respectively) Optionally substituted by aminocarbonyl) or aralkyl (halo, alkyl, aryl, hydroxy, alkoxy, aralkyl, amino, dialkylamino, monoalkylamino, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylamino Carbonyl or optionally substituted by dialkylaminocarbonyl);
R ⁶ is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, cycloalkyl, cycloalkylalkyl, -C (O) OR ⁸ , -R ¹⁰ -C (O) OR ⁸ , -R ^10- C (O) N (R ⁸ ) R ⁹ , -C (O) -R ¹⁰ -N (R ⁸ ) R ⁹ , -R ¹⁰ -C (O) R ⁸ , -R ¹⁰ -C (O) N ( R ⁸ ) N (R ⁸ ) R ⁹ , -R ¹⁰ -C (R ⁸ ) (OR ⁹ ) -R ¹⁰ -N (R ⁸ ) (R ⁹ ), -C (R ⁸ ) (OR ⁸ ) C ( O) OR ⁹ , -R ¹⁰ -C (R ⁸ ) (C (O) OR ⁹ ) ₂ , -C (R ⁸ ) (N (R ⁸ ) R ⁹ ) C (O) OR ⁸ , -R ^10- C (R ⁸ ) (N (R ⁸ ) R ⁹ ) C (O) OR ⁸ , -C (R ⁸ ) (OR ⁸ ) R ⁹ , -R ¹⁰ -N (R ⁸ ) R ⁹ , -R ^10- N (R ⁸ ) C (O) OR ¹¹ , -R ¹⁰ -N (R ⁸ ) C (0) R ⁹ , -R ¹⁰ -N (R ⁸ ) C (NR ⁸ ) R ¹¹ , -R ¹⁰ -N (R ⁸ ) S (O) ₂ R ¹¹ , -R ¹⁰ -N (R ⁸ ) C (O) N (R ⁸ ) R ⁹ , -R ¹⁰ -N (R ⁸ ) C (NR ⁸ ) N (R ⁸ ) R ⁹ , -R ¹⁰ -N (R ⁸ ) C (NR ⁸ ) N (R ⁸ ) N (R ⁸ ) R ⁹ , -R ¹⁰ -N (R ⁸ ) -R ¹⁰ -C (R ⁸ ) (N (R ⁸ ) R ⁹ ) C (O) OR ⁸ , -R ¹⁰ -N (R ⁸ ) S (O) R ⁹ , -R ¹⁰ OR ⁸ , -R ¹⁰ -ON (R ⁸ ) C (NR ⁸ ) N (R ⁸ ) R ⁹ , -R ¹⁰ -OS (O) ₂ OR ⁸ , -R ¹⁰ -P (O) (OR ⁸ ) R ⁹ , -R ¹⁰ -OP (O) (OR ⁸ ) ₂ , -R ¹⁰ -P (O) (OR ⁸ ) ₂ , -R ¹⁰ -SR ⁸ , -R ¹⁰ -SR ¹⁰ -C (O) OR ⁸ , -R ¹⁰ -SR ¹⁰ -N (R ⁸ ) R ⁹ , -R ¹⁰ -SR ¹⁰ -C (R ⁸ ) (N (R ⁸ ) R ⁹ ) C (O) OR ⁸ , -R ¹⁰ -SR ¹⁰ -N (R ⁸ ) C (O) OR ⁸ , -R ¹⁰ -SR ¹⁰ -N (R ⁸ ) C (O) R ⁸ , -R ¹⁰ -SSR ¹⁰ -C (R ⁸ ) (N (R ⁸ ) R ⁹ ) C (O) OR ⁸ , -R ¹⁰ -SC (O) N (R ⁸ ) R ⁹ , -R ¹⁰ -SC (S) N (R ⁸ ) R ⁹ , -R ^10- S (O) R ⁸ , -R ¹⁰ -S (O) ₂ R ¹¹ , -R ¹⁰ -S (O) OR ⁸ , -R ¹⁰ -S (O) ₂ OR ⁸ , -R ¹⁰ -S (O) ₂ N (R ⁸ ) R ⁹ or —R ¹⁰ —S (O) (NR ⁸ ) R ⁹ ; or
R ⁶ is aryl (alkyl, halo, haloalkyl, haloalkoxy, -OR ⁸ , -SR ⁸ , -N (R ⁸ ) R ⁹ , -C (O) OR ⁸ , -C (O) N (R ⁸ ) R ⁹ , -S (O) ₂ OR ⁸ and -OP (O) (OR ⁸ ) ₂ optionally substituted with one or more substituents selected from the group consisting of; or
R ⁶ is aralkyl (alkyl, halo, haloalkyl, haloalkoxy, -OR ⁸ , -SR ⁸ , -N (R ⁸ ) R ⁹ , -C (O) OR ⁸ , -C (O) N (R ⁸ ) R ⁹ , -S (O) ₂ OR ⁸ and -OP (O) (OR ⁸ ) ₂ optionally substituted with one or more substituents selected from the group consisting of; or
R ⁶ is heterocyclyl (alkyl, halo, haloalkyl, haloalkoxy, aralkyl, -OR ⁸ , -C (O) OR ⁸ , -N (R ⁸ ) R ⁹ , -C (O) N (R ⁸ ) R ⁹ , -S (O) ₂ OR ⁸ and -OP (O) (OR ⁸ ) ₂ optionally substituted with one or more substituents selected from the group consisting of; or
R ⁶ is heterocyclylalkyl (the heterocyclyl radical is alkyl, halo, haloalkyl, haloalkoxy, aralkyl, -OR ⁸ , -SR ⁸ , -C (O) OR ⁸ , -N (R ⁸ ) R ⁹ , -C (O) N (R ⁸ ) R ⁹ , -S (O) ₂ OR ⁸ and -OP (O) (OR ⁸ ) ₂ optionally substituted with one or more substituents selected from the group consisting of; or
R ⁶ is adamantyl (alkyl, halo, haloalkyl, haloalkoxy, -OR ⁸ , -SR ⁸ , -C (O) OR ⁸ , -N (R ⁸ ) R ⁹ , -C (O) N (R ⁸ ) R ⁹ , -S (O) ₂ OR ⁸ and -OP (O) (OR ⁸ ) ₂ optionally substituted; or
R ⁶ is adamantylalkyl (the adamantyl radicals are alkyl, halo, haloalkyl, haloalkoxy, -OR ⁸ , -SR ⁸ , -C (O) OR ⁸ , -N (R ⁸ ) R ⁹ ,- C (O) N (R ⁸ ) R ⁹ , optionally substituted by —S (O) ₂ OR ⁸ and —OP (O) (OR ⁸ ) ₂ ;
R ⁷ is hydrogen, alkyl, cycloalkyl, aralkyl or aryl;
R ⁸ and R ⁹ are each independently hydrogen, alkyl, aryl (halo, alkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylamino Optionally substituted by carbonyl or dialkylaminocarbonyl) or aralkyl (halo, alkyl, aryl, hydroxy, alkoxy, aralkyl, amino, dialkylamino, monoalkylamino, carboxy, alkoxycarbonyl, aminocarbon Optionally substituted by carbonyl, monoalkylaminocarbonyl or dialkylaminocarbonyl);
R ¹⁰ is a straight or branched alkylene chain;
R ¹¹ is alkyl, aryl (halo, alkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl or dialkylaminocarbonyl Optionally substituted by) or aralkyl (halo, alkyl, aryl, hydroxy, alkoxy, aralkyl, amino, dialkylamino, monoalkylamino, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl or Optionally substituted with dialkylaminocarbonyl).

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引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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法律状态:
1996-08-16|Priority to US08/699,372

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1996-08-16|Priority to US8/699,372

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1997-08-14|Application filed by 에바-마리아 시마-메이어, 얼설라 멜져, 마거, 하르트만, 쉐링 악티엔게젤샤프트

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2000-11-25|Publication of KR20000068173A

优先权:

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申请号 | 申请日 | 专利标题

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US08/699,372|US5693641A|1996-08-16|1996-08-16|Bicyclic pyrimidine derivatives and their use as anti-coagulants|

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US8/699,372|1996-08-16|