HK1018615A

HK1018615A - Benzamidine derivatives substituted by amino acid and hydroxy acid derivatives and their use as anti-coagulants

Info

Publication number: HK1018615A
Application number: HK99103677.6A
Authority: HK
Inventors: 莫妮卡‧科昌尼; 拉居‧莫汉; 迈克尔‧M‧莫里西; 霍华德‧P‧额; 卫嘉‧恽
Original assignee: 伯莱克斯实验室公司
Priority date: 1996-02-12
Filing date: 1997-02-07
Publication date: 1999-12-30

Description

Benzamidine derivatives substituted with amino acid and hydroxy acid derivatives and their use as anticoagulants

Technical Field

The present invention relates to monocyclic N-heterocyclic compounds substituted with amino acid and hydroxy acid derivatives and pharmaceutically acceptable salts thereof which inhibit the enzyme, factor xa, and are therefore useful as anticoagulants. The invention also relates to pharmaceutical compositions comprising the derivatives or pharmaceutically acceptable salts thereof, and methods of use thereof.

Background

Factor xa is an enzyme of the trypsin-like serine protease class. One-to-one binding of factors xa and va with calcium ions and phospholipids forms the prothrombinase complex, which converts prothrombin to thrombin. Thrombin in turn converts fibrinogen to fibrin, which polymerizes to form insoluble fibrin.

In the coagulation cascade, the prothrombinase complex is the point of convergence of the intrinsic (surface activated) and extrinsic (damaged vascular tissue factor) pathways (Biochemistry, (1991), Vol.30, p.10363; and Cell (1998), Vol.53, pp.505-518). The pattern of the coagulation cascade has also been further refined with the discovery of the mode of activation of Tissue Factor Pathway Inhibitor (TFPI) (sensiars in hematology (1992), Vol.29, pp.159-161). TFPI is a cyclic multi-domain serine protease inhibitor with three Kuniz-type domains that competes with factor va for free factor xa. Once formed, the binary complex of factor xa with TFPI becomes a potential inhibitor of the factor vila and tissue factor complex.

Factor Xa is activated by two different complexes, the tissue factor VIIa complex via the "Xa burst" pathway and the factor IX a-VIII a complex (TENase) via the "Xa persistence" pathway of the blood coagulation cascade. Following vascular injury, the "xa burst" pathway is activated by Tissue Factor (TF). Upregulation of the coagulation cascade occurs via the "xa-persistent" pathway through factor xa production. Down-regulation of the coagulation cascade then occurs with the formation of the factor Xa-TFPI complex, which not only removes factor Xa but further inhibits factor formation via the "Xa burst" pathway. Thus, the coagulation cascade is naturally regulated by factor xa.

The main advantage of factor xa inhibition of thrombin to prevent coagulation is that factor xa plays an important role in a variety of functions of thrombin. Thrombin not only catalyzes the conversion of fibrinogen to fibrin, factor viii to factor viii a, factor v to factor va, factor xi to factor xia, but also activates platelets which are single-cell chemokines and mitogens for lymphocytes and smooth muscle cells. When bound to thrombomodulin, thrombin activates the anticoagulant inactivators of protein C, factors va and viia in vivo. In circulation, antithrombin III (AT III) and heparin cofactor II (HC II) rapidly inactivate thrombin in a reaction catalyzed by heparin or other proteoglycan-associated glycosaminoglycans, and thrombin in the tissue is thereby inactivated by proteases, ligans. Thrombin performs its multi-Cell activation function through a unique "tethered ligand" thrombin receptor (Cell (1991),/vol.64, p.1057), which requires the same anionic binding site and active site for fibrinogen binding and cleavage and activation by thrombomodulin and protein C. Thus, another group of in vivo molecular targets compete for binding to thrombin, and the subsequent proteolytic events will have completely different physiological consequences depending on the type of cell and what receptor, modulator, substrate or inhibitor binds to thrombin.

Published data on protein anti-stasis (antistasin) and Tick Anticoagulant Peptide (TAP) indicate that factor Xa inhibitors are potent anticoagulants (Thrombosis and Haemostasis (1992), Vol.67, pp.371-376; and Science (1990), vol.248, pp.593-596).

The active site of factor xa can be blocked by two binding inhibitors, one being a mechanistic-based (mechanism-based) binding inhibitor and the other being a compact (light) binding inhibitor (compact binding inhibitors differ from mechanistic binding inhibitors by lacking the covalent bond between the enzyme and the inhibitor). There are two types of known mechanistic binding inhibitors, reversible and irreversible, which are readily distinguished by hydrolysis of the enzyme-inhibitor bond (Thrombosils 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 compact binding inhibitors (Thrombosils Res (1980), Vol.19, pp.339-349). Arylsulfonyl-arginine-piperidinecarboxylic acid derivatives have also been shown to be compact binding inhibitors of thrombin (Biochem. (1984), Vol.23, pp.85-90), as well as a series of arylamidine-containing compounds, including 3-amidinophenylaryl derivatives (Thrombosils Res (1983), Vol.29, pp.635-642) and bis (amidino) benzylcyclic ketones (Thrombosils Res (1980), Vol.17, pp.545-548). However, these compounds are less selective for factor xa.

EP 0540051A (Nagahara et al) discloses aromatic amidine derivatives which are believed to exhibit a strong anticoagulant effect as a result of reversible inhibition of factor Xa.

Methods for the synthesis of α, α '-bis (amidinobenzylidene) cyclic ketones and α, α' -bis (amidinobenzylidene) cyclic ketones are disclosed in Pharmazie (1977), Vol.32, No.3, pp 141-145. These compounds are serine protease inhibitors.

Summary of The Invention

The present invention relates to compounds which inhibit factor xa, or a pharmaceutically acceptable salt thereof, and which are accordingly useful as pharmaceutical agents for the treatment of diseases characterised by thrombotic activity.

Accordingly, in one aspect, the present invention provides a compound selected from compounds having the formula:wherein:

a is-C (R)⁸) or-N =;

Z¹and Z²Independently is-O-, -N (R)¹³) -, -S-or-OCH₂-；

R¹And R⁴Independently of one another, hydrogen, halogen, alkyl, nitro, -OR¹³、-C(O)OR¹³、-C(O)N(R¹³)R¹⁴、-N(R¹³)R¹⁴、-N(R¹³)C(O)R¹³or-N (H) S (O)₂R¹⁶；

R²is-C (NH) NH₂、-C(NH)N(H)OR¹³、-C(NH)N(H)C(O)OR¹⁶、-C(NH)N(H)C(O)R¹³、-C(NH)N(H)S(O)₂R¹⁶or-C (NH) N (H) C (O) N (H) R¹³；

R³Is halogen, alkyl, haloalkyl, nitro, amino, ureido, guanidino, -OR¹³、-C(NH)NH₂、-C(NH)N(H)OR¹³、-C(O)N(R¹³)R¹⁴、-R¹⁵-C(O)N(R¹³)R¹⁴、-CH(OH)C(O)N(R¹³)R¹⁴、-N(R¹³)R¹⁴、-R¹⁵-N(R¹³)R¹⁴、-C(O)OR¹³、-R¹⁵-C(O)OR¹³、-N(R¹³)C(O)R¹³(1,2) -tetrahydropyrimidinyl (optionally substituted with alkyl), (1,2) -imidazolyl (optionally substituted with alkyl)Alkyl substituted) or (1,2) -imidazolinyl (optionally substituted with alkyl);

R⁵and R⁶Independently of one another, hydrogen, halogen, alkyl, haloalkyl, nitro, -N (R)¹³)R¹⁴、-C(O)OR¹³、-C(O)N(R¹³)R¹⁴、-C(O)N(R¹³)CH₂C(O)N(R¹³)R¹⁴、-N(R¹³)C(O)N(R¹³)R¹⁴、-N(R¹³)C(O)R¹⁴、-N(R¹³)S(O)₂R¹⁶or-N (R)¹³)C(O)N(R¹³)CH₂C(O)N(R¹³)R¹⁴；

R⁷is-N (R)⁹)-(C(R¹⁰)(R¹¹))_n-R¹²(wherein n is 1-4) or-O- (C (R)¹⁰)(R¹¹))_n-R¹²(wherein n is 1 to 6);

R⁸is hydrogen, alkyl or halogen;

R⁹is hydrogen, alkyl, aryl, aralkyl, -R¹⁵-C(O)OR¹³、-R¹⁵-C(O)N(R¹³)R¹⁴、-R¹⁵-N(R¹³)R¹⁴、-R¹⁵-CH(N(R¹³)R¹⁴)C(O)OR¹³Or- (R)¹⁵)S(O)₂R¹⁶；

R¹⁰Each independently is alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, cycloalkyl, cycloalkylalkyl, -C (O) OR¹³、-R¹⁵-C(O)OR¹³、-R¹⁵-C(O)N(R¹³)R¹⁴、-C(O)R¹⁵-N(R¹³)R¹⁴、-R¹⁵-C(O)R¹³、-R¹⁵-C(O)N(R¹³)N(R¹³)R¹⁴、-R¹⁵-C(R¹³)(OR¹³)-R¹⁵-N(R¹³)(R¹⁴)、-C(R¹³)(OR¹³)C(O)OR¹⁴、R¹⁵-C(R¹³)(C(O)OR¹³)₂、-C(R¹³)(NR¹³)(R¹⁴)C(O)OR¹³、-R¹⁵-C(R¹³)(N(R¹³)R¹⁴)C(O)OR¹³、-C(R¹³)(OR¹³)R¹⁴、-R¹⁵-N(R¹³)(R¹⁴)、-R¹⁵-N(R¹³)C(O)OR¹⁶、-R¹⁵-N(R¹³)C(O)OR¹⁴、-R¹⁵-N(R¹³)C(NR¹³)R¹⁶、-R¹⁵-N(R¹³)S(O)₂R¹⁶、-R¹⁵-N(R¹³)C(O)N(R¹³)R¹⁴、-R¹⁵-N(R¹³)C(NR¹³)N(R¹³)R¹⁴、-R¹⁵-N(R¹³)C(NR¹³)N(R¹³)N(R¹³)R¹⁴、-R¹⁵-N(R¹³)-R¹⁵-C(R¹³)(N(R¹³)R¹⁴)C(O)OR¹³、-R¹⁵-N(R¹³)S(O)R¹⁴、-R¹⁵OR¹³、-R¹⁵-ON(R¹³)C(NR¹³)N(R¹³)R¹⁴、-R¹⁵-OS(O)₂OR¹³、-R¹⁵-P(O)(OR¹³)R¹⁴、-R¹⁵-OP(O)(OR¹³)₂、-R¹⁵P(O)(OR¹³)₂、-R¹⁵-SR¹³、-R¹⁵-S-R¹⁵-C(O)OR¹³、-R¹⁵-S-R¹⁵-N(R¹³)R¹⁴、-R¹⁵-S-R¹⁵-C(R¹³)(N(R¹³)R¹⁴)C(O)OR¹³、-R¹⁵-S-R¹⁵-N(R¹³)C(O)R¹³、-R¹⁵-S-R¹⁵-N(R¹³)C(O)R¹³、-R¹⁵-S-S-R¹⁵-C(R¹³)(N(R¹³)R¹⁴)C(O)OR¹³、-R¹⁵-SC(O)N(R¹³)R¹⁴、-R¹⁵-SC(S)N(R¹³)R¹⁴、-R¹⁵-S(O)R¹³、-R¹⁵-S(O)₂R¹⁶、-R¹⁵-S(O)OR¹³、-R¹⁵-S(O)₂OR¹³、-R¹⁵-S(O)₂N(R¹³)R¹⁴、-R¹⁵-S(O)(NR¹³)R¹⁴；

Or R¹⁰Each is aryl (optionally substituted with one OR more substituents selected from alkyl, halogen, haloalkyl, haloalkoxy, nitro, -OR¹³、-SR¹³、-N(R¹³)R¹⁴、-C(O)OR¹³、-C(O)N(R¹³)R¹⁴、-S(O)₂OR¹³and-OP (O) (OR)¹³)₂)；

Or R¹⁰Each is aralkyl (optionally substituted with one OR more substituents selected from the group consisting of alkyl, halogen, haloalkyl, haloalkoxy, cyano, nitro, -OR¹³、-SR¹³、-N(R¹³)R¹⁴、-C(O)OR¹³、-C(O)N(R¹³)R¹⁴、-S(O)₂OR¹³and-OP (O) (OR)¹³)₂)；

Or R¹⁰Each is a heterocyclic group (optionally substituted by one OR more substituents selected from the group consisting of alkyl, halogen, haloalkyl, haloalkoxy, aralkyl, -OR¹³、-C(O)OR¹³、-N(R¹³)R¹⁴、-C(O)N(R¹³)R¹⁴、-S(O)₂OR¹³and-OP (O) (OR)¹³)₂)；

Or R¹⁰Each is heterocyclylalkyl (wherein the heterocyclyl is optionally substituted with one OR more substituents selected from the group consisting of alkyl, halo, haloalkyl, haloalkoxy, aralkyl, -OR¹³、-SR¹³、-C(O)OR¹³、-N(R¹³)R¹⁴、-C(O)N(R¹³)R¹⁴、-S(O)₂OR¹³and-OP (O) (OR)¹³)₂)；

Or R¹⁰Each adamantyl (optionally substituted with substituents selected from alkyl, halogen, haloalkyl, haloalkoxy, -OR¹³、-SR¹³、-C(O)OR¹³、-N(R¹³)R¹⁴、-C(O)N(R¹³)R¹⁴、-S(O)₂OR¹³and-OP (O) (OR)¹³)₂)；

Or R¹⁰Each is adamantylalkyl (wherein adamantylalkyl is optionally substituted with substituents selected from the group consisting of alkyl, halogen, haloalkyl, haloalkoxy, -OR¹³、-SR¹³、-C(O)OR¹³、-N(R¹³)R¹⁴、-C(O)N(R¹³)R¹⁴、-S(O)₂OR¹³and-OP (O) (OR)¹³)₂)；

R¹¹Independently of one another, hydrogen, alkyl, cycloalkyl or aryl;

R¹²is-C (O) OR¹³or-C (O) N (R)¹³)R¹⁴；

R¹³And R¹⁴Independently of one another, hydrogen, alkyl, aryl (optionally substituted with halogen, alkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, cyano, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl), or aralkyl (optionally substituted with halogen, alkyl, aryl, hydroxy, alkoxy, aralkyl, amino, dialkylamino, monoalkylamino, nitro, cyano, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl);

R¹⁵is a linear or branched alkylene group; and

R¹⁶is alkyl, aryl (optionally substituted with halogen, alkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, cyano, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl or dialkylaminocarbonyl), or aralkyl (optionally substituted with halogen, alkyl, aryl, hydroxy, alkoxy, aralkyl, amino, dialkylamino, monoalkylaminocarbonyl or dialkylaminocarbonyl)Nitro, cyano, carboxyl, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl or dialkylaminocarbonyl).

In another aspect, the present invention provides a pharmaceutical composition for treating a disease characterized by thrombotic activity in a human, which composition comprises a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, as described above, and a pharmaceutically acceptable excipient.

In another aspect, the invention provides a method for treating a disease characterized by thrombotic activity in a human, which method comprises administering to a patient a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, as described above.

In another aspect, the invention provides a method of treatment of a human subject suffering from a disease state mediated by inhibition of factor xa, which method comprises administering to the subject a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, as hereinbefore described.

In another aspect, the invention provides a method of inhibiting factor xa in vitro or in vivo by administering a compound of the invention.

Detailed Description

Definition of

Unless otherwise indicated, the following terms used in the description and claims of the present invention have the following meanings:

"alkyl" means a straight or branched chain monovalent or divalent group having 1 to 6 carbon atoms consisting of only carbon and hydrogen atoms, containing no unsaturated bonds, such as methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1-dimethylethyl (tert-butyl), and the like.

"alkenyl" means a straight or branched chain monovalent or divalent group of 2 to 6 carbon atoms consisting only of carbon and hydrogen atoms containing at least one double bond, such as vinyl, prop-1-enyl, but-1-enyl, pent-1, 4-dienyl, and the like.

"alkynyl" means a straight or branched, monovalent or divalent group of 2 to 6 carbon atoms consisting solely of carbon and hydrogen atoms containing at least one triple bond, e.g., ethynyl, prop-1-yne, but-1-yne, pent-3-yne, and the like.

"alkoxy" refers to a group of formula-ORa, wherein R_aIs an alkyl group as defined above, such as methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, n-pentoxy, 1-dimethylethoxy (tert-butoxy), and the like.

"alkylene" means a straight or branched divalent group of 1 to 6 carbon atoms consisting only of carbon and hydrogen atoms, containing no unsaturated bonds, such as methylene, ethylene, propylene, n-butylene, and the like.

"aryl" refers to phenyl or naphthyl.

"aralkyl" means a group of the formula-R_aR_bWherein R is_aIs alkyl as previously defined, R_bAryl as previously defined, such as benzyl.

"aryloxy" means a group of the formula-OR_bWherein R is_bAryl as defined above, such as phenoxy, naphthoxy.

"aralkoxy" means a compound of the formula-OR_cWherein R is_cAralkyl as defined above, such as benzyloxy and the like.

"alkoxyalkyl" means a group of the formula-R_aOR_aWherein each R is_aIndependently an alkyl group as previously defined, such as methoxyethyl, ethoxymethyl, propoxymethyl, propoxyethyl, and the like.

"Alkoxyalkenyl" means a group of the formula-R_dOR_aWherein R is_aIs alkyl as previously defined, R_dIs alkenyl as previously defined, e.g. methoxyethylAlkenyl, methoxyprop-1-enyl, ethoxybut-1-enyl, propoxypent-1-enyl, ethoxypenta-1, 4-dienyl, and the like.

"Alkoxyalkynyl" means a compound of the formula-R_eOR_aWherein R is_aIs alkyl as previously defined, R_eIs alkynyl as previously defined, such as ethoxyethynyl, methoxyprop-1-ynyl, propoxybut-1-ynyl, ethoxypent-1-ynyl, methoxypent-1, 4-diynyl, and the like.

"Alkoxycarbonylalkenyl" means a compound of the formula-R_dC(O)OR_aWherein R is_aIs alkyl as previously defined, R_dAlkenyl as previously defined such as ethoxycarbonylvinyl, 3-methoxycarbonylprop-1-enyl, 4-tert-butoxycarbonylbut-1-enyl, 5-ethoxycarbonylpent-1-enyl, 5-tert-butoxycarbonylpenta-1, 4-dienyl and the like.

"Alkoxycarbonylalkynyl" means a group of the formula-R_eC(O)OR_aWherein R is_aIs alkyl as previously defined, R_eAlkynyl as previously defined, such as 3-methoxycarbonylprop-1-ynyl, 4-tert-butoxycarbonylbut-1-ynyl, 5-ethoxycarbonylpent-1-ynyl, 5-tert-butoxycarbonylpent-3-ynyl and the like.

"Aryloxycarbonylalkenyl" means a compound of the formula-R_dC(O)OR_bWherein R is_bIs aryl as previously defined, R_dIs an alkenyl group as defined above, such as phenoxycarbonylvinyl, phenoxycarbonylprop-1-enyl, 4-phenoxycarbonylbut-1-enyl, 5-naphthoxycarbonylpent-1-enyl, 5-phenoxycarbonylpent-1, 4-dienyl, and the like.

"Aryloxycarbonyl alkynyl" means a compound of the formula-R_eC(O)OR_bWherein R is_bIs aryl as previously defined, R_eAlkynyl as defined previously, such as 3-phenoxycarbonylprop-1-ynyl, 4-phenoxycarbonylbut-1-ynyl, 5-phenoxycarbonylpent-3-ynyl and the like.

"amidino" refers to the group-C (NH) -NH₂。

"carboxyalkenyl" means an alkenyl group as previously defined substituted with a carboxyl group, such as 3-carboxyprop-1-enyl, 4-carboxybut-1-enyl, 4-carboxypent-1-enyl, 5-carboxypent-1, 4-dienyl, and the like.

"carboxyalkynyl" refers to alkynyl groups as previously defined substituted with a carboxyl group, such as 3-carboxyprop-1-ynyl, 4-carboxybut-1-ynyl, 5-carboxypent-3-ynyl, and the like.

"cycloalkyl" refers to a saturated cyclic group consisting of only carbon and hydrogen atoms having a 3-7 membered monocyclic ring, such as propyl, cyclobutyl, cyclohexyl, and the like.

"dialkylamino" means a compound of the formula-NR_aR_aWherein R is_aIndependently an alkyl group as previously defined, such as dimethylamino, methylethylamino, diethylamino, dipropylamino, ethylpropylamino, and the like.

"Dialkylaminocarbonyl" means a compound of the formula-C (O) NR_aR_aWherein R is_aIndependently an alkyl group as previously defined, such as dimethylaminocarbonyl, methylethylaminocarbonyl, diethylaminocarbonyl, dipropylaminocarbonyl, ethylpropylaminocarbonyl and the like.

"halogen" means bromine, chlorine or fluorine.

"haloalkyl" means an alkyl group as defined above substituted with one or more halogens as defined above, e.g., trifluoromethyl, difluoromethyl, trichloromethyl, 2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, 3-bromo-2-fluoropropyl, 1-bromomethyl-2-bromoethyl, and the like.

"haloalkoxy" means a compound of the formula-OR_fWherein R is_fIs haloalkyl as defined hereinbefore such as trifluoromethoxy, difluoromethoxy, trichloromethoxy, 2-trifluoroethoxy, 1-fluoromethyl-2-fluoroethoxy, 3-bromo-2-fluoropropoxy, 1-bromomethyl-2-bromoethoxy and the like.

"haloalkenyl" means an alkenyl group as previously defined which is substituted with one or more halogens as previously defined, e.g., bromovinyl, 3-trifluoroprop-1-enyl, bromobut-1-enyl, chloropent-1-enyl, bromopenta-1, 4-dienyl, and the like.

"haloalkynyl" means an alkynyl group as defined previously which is substituted with one or more halogens as defined previously, e.g., bromoethynyl, 3-trifluoroprop-1-ynyl, bromobut-1-ynyl, chloropent-1-ynyl, bromopent-1, 4-diynyl, and the like.

"haloalkoxyalkyl" means a compound of the formula-R_aOR_aWherein R is_aIs an alkyl group as defined above which is substituted on the alkoxy group by one or more halogens as defined above, such as bromomethoxyethyl, chloroethoxymethyl, 3-trifluoropropoxymethyl, bromopropoxyethyl, and the like.

"haloalkoxyalkenyl" means a compound of the formula-R_dOR_aWherein R is_aIs alkyl as previously defined, R_dIs alkenyl as defined hereinbefore which is substituted by one or more halogen as defined hereinbefore, e.g. bromomethoxyvinyl, chloromethoxyprop-1-enyl, chloroethoxyethbut-1-enyl, 3-trifluoropropoxypent-1-enyl, chloroethoxyethpent-1, 4-dienyl, etc.

"haloalkoxyalkynyl" means a group of the formula-R_eOR_aWherein R is_aIs alkyl as previously defined, R_eIs alkynyl as previously defined which is substituted with one or more halogens as previously defined, e.g., bromomethoxyethynyl, chloromethoxyprop-1-ynyl, 3-trifluoropropoxybut-1-ynyl, bromoethoxypent-1-ynyl, chloromethoxypent-3-ynyl, and the like.

"hydroxyalkenyl" means an alkenyl group as previously defined which is substituted with a hydroxy group, such as 3-hydroxyprop-1-enyl, 4-hydroxybut-1-enyl, 4-hydroxypent-1-enyl, 5-hydroxypent-1, 4-dienyl, and the like.

"Hydroxyalkynyl" means an alkynyl group as previously defined substituted with a hydroxyl group, such as 3-hydroxyprop-1-ynyl, 4-hydroxybut-1-ynyl, 5-hydroxypent-1, 4-diynyl, and the like.

"haloalkoxycarbonylalkyl" means a compound of the formula-R_aC(O)OR_aWherein R is_aIndependently an alkyl group as previously defined wherein the terminal alkyl group is substituted with 1 or more halogens, such as bromoethoxycarbonylethyl, 3-chloropropyloxycarbonylethyl, 4-bromobutoxycarbonylethyl and the like.

"haloalkoxycarbonylalkenyl" means a compound of formula-R_dC(O)OR_aWherein R is_aIs alkyl as defined above, substituted by 1 or more halogens, R_dAlkenyl as previously defined such as bromomethoxycarbonylvinyl, 3-chloroethoxycarbonylpropyl-1-enyl, 4- (2-bromoethoxycarbonyl) but-1-enyl, 5- (3-chloropropoxycarbonyl) pent-1-enyl and the like.

"haloalkoxycarbonyl alkynyl" means a compound of the formula-R_eC(O)OR_aWherein R is_aIs alkyl as defined above, substituted by 1 or more halogens, R_eAlkynyl as previously defined, such as bromomethoxycarbonylethynyl, 3- (2-chloroethoxycarbonyl) prop-1-ynyl, 4- (3-chloropropoxycarbonyl) but-1-ynyl, 5- (2-bromoethoxycarbonyl) pent-1-ynyl and the like.

"Heterocyclyl" means a stable 3-to 10-membered monocyclic or bicyclic group, which may be saturated or unsaturated, consisting of carbon atoms and 1 to 3 atoms selected from nitrogen, oxygen and sulfur atoms, which may be optionally oxidized, and which may be optionally quaternized. The heterocyclic group may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure. Examples of such heterocyclic groups include, but are not limited to: piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, thiazolyl, indanyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, silanyl, isothiazolidinyl, indolyl, isoindolyl, indolinyl, isoindolyl, octahydroisoindolyl, quinolyl, isoquinolyl, decahydroisoquinolyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl, tetrahydrofuranyl, tetrahydropyranyl, thienyl, benzothienyl, pyrrolyl, oxazolyl, furyl, thiazolyl, oxazolyl, thiazolyl, and the like, Thiomorpholinyl, thiomorpholinyl sulfoxide (thiomorpholinyl sulfoxide), thiomorpholinyl sulfone, and oxadiazolyl. Preferred heterocyclic groups in the context of the present invention are indolyl, imidazolyl, thiazolyl, isoxazolyl, pyridyl, thienyl, furyl, and 3, 4-dihydro-2, 3-dioxo-1 (2H) pyrimidinyl.

"Heterocyclylalkyl" means a compound of the formula-R_aR_gWherein R is_aIs alkyl as previously defined, R_gIs a heterocyclic group as previously defined, such as indolylmethyl or imidazolylmethyl and the like.

"(1, 2) -imidazolyl" means an imidazolyl group attached at position 1 or position 2.

"(1, 2) -imidazolinyl" means a 4, 5-dihydroimidazolyl group attached at the 1-or 2-position.

"monoalkylamino" refers to the formula-NHR_aWherein R is_aAlkyl as previously defined, such as methylamino, ethylamino, propylamino, and the like.

"Monoalkylaminocarbonyl" refers to the formula-C (O) NHR_aWherein R is_aAlkyl as previously defined, such as methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl and the like.

"(1, 2) -tetrahydropyrimidinyl" means a tetrahydropyrimidinyl group attached at the 1-or 2-position.

"adamantyl" means a compound of the formula-R_aR_hWherein R is_aIs alkyl as previously defined, R_hAdamantyl radicals such as adamantylmethyl, 2-adamantylethyl and the like.

"Selective" or "optional" means that the subsequently described event can or can not occur, and that the definition includes both possibilities of occurrence or nonoccurrence of the described event. For example, "optionally substituted aryl" means that the aryl group may be substituted or unsubstituted, and this definition includes both substituted aryl groups and unsubstituted aryl groups.

"pharmaceutically acceptable salts" include acid addition salts and base addition salts.

"pharmaceutically acceptable acid addition salts" refers to those salts that retain their biological effectiveness and free basic properties, without producing biologically or otherwise undesirable properties. The salts are formed with mineral acids, examples of which are: hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, and the like, or with organic acids, examples of which are: acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, propylene glycol, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.

"pharmaceutically acceptable base addition salts" refers to those salts that retain their biological potency and free acidic properties, without producing biologically or otherwise undesirable properties. These salts can be prepared by addition of an inorganic or 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 ammonium, sodium, potassium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, the following: primary, secondary, tertiary amines, substituted amines include naturally substituted amines, cyclic amines and basic ion exchange resins such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, trimethylamine (trimethamine), dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine G, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine (trimethamine), dicyclohexylamine, choline and caffeine.

By "therapeutically effective amount" is meant an amount of a compound of formula (I) which, when administered to a human, is sufficient to effect treatment of a condition characterized by thrombotic activity as described below. The amount of the compound of formula (i) which constitutes a "therapeutically effective amount" will vary depending on the compound, the disease and its severity, the age of the patient, etc., but will be determined by those skilled in the art in light of its general knowledge and the teachings of the present invention.

"treating" or "treatment" herein encompasses the treatment of a disease in a human, which disease is characterized by thrombotic activity, including:

preventing the onset of a disease in a human, particularly when the patient has been infected with the disease but has not yet been diagnosed;

(ii) control of the disease, i.e. arrest of progression of the disease; or

(iii) alleviating the disease, i.e. causing regression of the disease.

The yield of the reaction described herein is expressed as a percentage of the theoretical yield.

The compound of the present invention or a pharmaceutically acceptable salt thereof may have an asymmetric carbon atom in its structure. Thus, a compound of the present invention, or a pharmaceutically acceptable salt thereof, may comprise stereoisomers, racemates and mixtures of enantiomers and diastereomers in single form. The present invention encompasses all of these single stereoisomers, racemates and mixtures thereof.

The nomenclature adopted by the present invention is modified from the i.u.p.a.c. system, wherein the compounds of the present invention are named benzamidine derivatives. For example, the compounds of the general formula (I) according to the invention, i.e.

Wherein, A is-N =; z¹And Z²Independently is-O-; r¹Is a hydroxyl group;R²is-C (NH) NH₂；R³Is 1-methylimidazolin-2-yl; r⁴Is hydrogen; r⁵And R⁶Are both fluorine; r⁷is-N (R)⁹)-(C(R¹⁰)(R¹¹))_n-R¹²(wherein n is 1); r⁹Is methyl; r¹⁰Is methyl; r¹¹Is methyl; r¹²is-C (O) OR¹³；R¹³Is hydrogen, the compound is named: 4-hydroxy-3- [ (4- (N- (1-carboxy-5-aminopentyl) amino) -6- (3- (1-methyl) imidazolin-2-yl) phenoxy) -3, 5-difluoropyridin-2-yl) oxy]Benzamidine.

Use and administration

A. Use of

The compounds of the invention are inhibitors of factor xa and are therefore useful in diseases characterised by thrombosis, based on the action of factor xa in the coagulation cascade (see background of the invention section above). The main indication for the compounds of the invention is the prevention of long-term risk after myocardial infarction. Other indications are the prevention of Deep Vein Thrombosis (DVT) after orthopaedic surgery or the prevention of patients after transient ischemic attacks. The compounds of the invention are also useful in indications where coumarin is currently employed, such as DVT or other types of surgical interventions such as coronary artery bypass grafting and percutaneous transluminal coronary angioplasty. The compounds of the present invention are also useful in the treatment of thrombotic complications associated with acute promyelocytic leukemia, diabetes, multiple myeloma, disseminated intravascular coagulation associated with septic shock, infection-related purpura, adult respiratory distress syndrome, unstable angina, and thrombotic complications associated with aortic valve or vascular repair. The compounds of the invention are also useful in the prevention of thrombotic disorders, particularly in patients at high risk for such disorders.

Furthermore, the compounds of the invention are useful as in vitro and in vivo diagnostic agents for the selective inhibition of factor xa without inhibiting other components of the coagulation cascade.

B. Test of

The main biological assay used to show the inhibitory effect of the compounds of the invention on factor Xa is a simple chromogenic assay comprising only the serine protease, the experimental compounds of the invention, the substrate and the buffer (cf.: Thrombosis Res. (1979), Vol.16, pp.245-254). For example, four tissue human serine proteases are used in major biological experiments, namely free factor Xa, prothrombinase, thrombin (IIa) and tissue plasminogen activator (tPA). Experiments with tPA were successfully performed before unwanted side effects in the inhibition of the fibrinolytic process occurred (see: J.Med.chem. (1993), Vol.36, pp.314-319).

Another biological experiment illustrating the utility of the compounds of the invention for inhibiting factor Xa shows the efficacy of the compounds on free factor Xa in citrate-added plasma. For example, the anti-coagulant effect of the compounds of the invention is measured by the Prethrombin Time (PT) or the activated partial thromboplastin time (aPTT), while the selectivity of the compounds is measured by the Thrombin Clotting Time (TCT) assay. K in the major enzyme experiments_iValues associated with K for the dissociation of factor Xa in citrate-added plasma_iThe relationship between the values will screen for compounds that act with or are activated by other plasma components. And K_iThe relationship of the extension of the values with PT is an essential in vitro demonstration that the potency in the free factor Xa inhibition assay translates into that of the clinical coagulation assay. Furthermore, extension of PT in citrate-added plasma can be used to measure the duration of activity in subsequent pharmacokinetic studies.

Further details of the experiments which demonstrate the activity of the compounds of the invention can be found in: 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 mode of administration

The compounds of the present invention or pharmaceutically acceptable salts thereof may be administered as pure compounds or as suitable pharmaceutical compositions, in any acceptable manner of administration or by means of agents for similar uses. Thus, administration may be selected from solid, semi-solid, lyophilized powder or liquid dosage forms for oral, nasal, parenteral, topical, dermal or rectal administration, e.g., tablets, suppositories, pills, soft elastic and hard gelatin capsules, powders, solutions, suspensions or aerosols, and the like, preferably in unit dosage form, suitable for simple administration of precise dosages. The composition may contain a conventional pharmaceutical carrier or excipient and the compound of the present invention as an active ingredient, and may further contain other agents, carriers, auxiliaries and the like.

Generally, depending on the desired mode of administration, a pharmaceutically acceptable composition will comprise from about 1 to about 99% by weight of a compound of the present invention or a pharmaceutically acceptable salt thereof, and from about 99 to about 1% by weight of a suitable pharmaceutical excipient. Preferably, the composition comprises 5-75% by weight of a compound of the invention or a pharmaceutically acceptable salt thereof, the remainder being suitable pharmaceutical excipients.

The preferred mode of administration is oral, using a conventional daily dosage regimen which may be adjusted depending on the severity of the disease. For oral administration, the pharmaceutical composition comprising the compound of the present invention or a pharmaceutically acceptable salt thereof is formed by adding commonly used excipients, examples of which are pharmaceutical grades of mannitol, lactose, starch, pregelatinized starch, magnesium stearate, sodium saccharin, talcum, cellulose ether derivatives, glucose, gelatin, sucrose, citrate, propyl gallate and the like. Such compositions may take the form of solutions, suspensions, formulations, tablets, pills, capsules, powders, sustained release formulations and the like.

Preferably the composition is in the form of a capsule, caplet or tablet, and thus it may further comprise a diluent 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 invention or pharmaceutically acceptable salts thereof may also be formulated as a suppository, for example by distributing about 0.5 to 50% of the active ingredient in a carrier which is slowly soluble in the body, such as polyoxyethylene glycol and polyethylene glycol (PEG), such as PEG 1000 (96%) and PEG 4000 (4%).

For the pharmaceutical composition of the present invention, which can be administered in liquid form, for example, the composition or a pharmaceutically acceptable salt thereof (about 0.5 to 20%) and optionally a pharmaceutically acceptable auxiliary agent can be dissolved or dispersed by means of dissolution, dispersion or the like in a carrier, for example, water, saline, aqueous glucose, glycerol, ethanol or the like, to form a solution or suspension.

If desired, the pharmaceutical compositions of the present invention may also contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents, antioxidants and the like, for example: citric acid, sorbitan monolaurate, triethanolamine oleate, butylated hydroxybenzene, and the like.

The actual preparation of such dosage forms is known or obvious to the person skilled in the art, for example, see the following documents: remington's Pharmaceutical Sciences,18th ed. (Mack Publishing Company, Easton, Pennsylvania, 1990). In any event, in accordance with the techniques of this invention, the compositions administered will contain a therapeutically effective amount of a compound of this invention, or a pharmaceutically acceptable salt thereof, for the treatment of diseases which are alleviated by the inhibition of factor xa.

The compounds of the present invention, or pharmaceutically acceptable salts thereof, are administered in a therapeutically effective amount which will vary depending upon a variety of factors including the activity of the particular compound employed, the metabolic stability, and the length of activity of the compound, the age, body weight, health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular disease and the subject being treated. Generally, a therapeutically effective daily dose will be about 0.14-14.3mg of a compound of the invention or a pharmaceutically acceptable salt thereof per kg of body weight per day, preferably about 0.7-10mg/kg of body weight per day, most preferably 1.4-7.2mg/kg of body weight per day. For example, the dosage range for a human weighing 70kg is about 10mg to 1.0g of the compound of the present invention or a pharmaceutically acceptable salt thereof per day, preferably about 50 to 700mg per day, and most preferably about 100 to 500mg per day.

Description of the preferred embodiments

Of the compounds of the invention set forth in the summary of the invention above, several groups of compounds are preferred.

One group of preferred compounds comprises those selected from the following formula (i), which are compounds in the form of single stereoisomers or mixtures thereof or pharmaceutically acceptable salts thereof:

within this group of compounds, preference is given to compounds of the following subgroups: wherein

A is-N =;

Z¹and Z²Independently is-O-, -S-or-OCH₂-；

R¹And R⁴Independently of one another, hydrogen, halogen OR-OR¹³；

R²is-C (NH) NH₂、-C(NH)N(H)S(O)₂R¹⁶or-C (NH) N (H) C (O) N (H) R¹³；

R³Is ureido, guanidino, -N (R)¹³)R¹⁴、-N(H)C(O)R¹³(1,2) -tetrahydropyrimidinyl (optionally substituted with alkyl), (1,2) -imidazolyl (optionally substituted with alkyl) or (1,2) -imidazolinyl (optionally substituted with alkyl);

R⁵and R⁶Independently of one another, hydrogen, halogen, alkyl, haloalkyl;

R⁷is-N (R)⁹)-(C(R¹⁰)(R¹¹))_n-R¹²(wherein n is 4);

R⁹hydrogen, alkyl, aryl, aralkyl;

R¹⁰each independently is alkyl, -R¹⁵-N(R¹³)C(O)N(R¹³)R¹⁴、-R¹⁵-N(R¹³)C(NR¹³)N(R¹³)R¹⁴、-R¹⁵-N(R¹³)C(NR¹³)R¹⁶、-R¹⁵-C(O)OR¹³、-R¹⁵-C(O)N(R¹³)R¹⁴、R¹⁵-C(R¹³)(C(O)OR¹³)₂、-R¹⁵-N(R¹³)R¹⁴、-R¹⁵SR¹³、-R¹⁵OR¹³、-R¹⁵-S(O)₂OR¹⁶、-R¹⁵-OP(O)(OR¹³)₂；

Or R¹⁰Each is aralkyl (optionally substituted with one OR more substituents selected from the group consisting of alkyl, halogen, haloalkyl, haloalkoxy, cyano, -OR¹³、-N(R¹³)R¹⁴、-C(O)OR¹³、-C(O)N(R¹³)R¹⁴、-SR¹³、-S(O)₂OR¹⁶and-OP (O) (OR)¹³)₂)；

Or R¹⁰Each is heterocyclylalkyl (wherein the heterocyclyl is optionally substituted with one OR more substituents selected from alkyl, halo, haloalkyl, haloalkoxy, cyano, -OR¹³、-N(R¹³)R¹⁴、-C(O)OR¹³、-C(O)N(R¹³)R¹⁴、-SR¹³、-S(O)₂OR¹³and-OP (O) (OR)¹³)₂)；

R¹¹Independently of one another, hydrogen or alkyl;

R¹²is-C (O) OR¹³or-C (O) N (R)¹³)R¹⁴；

R¹³And R¹⁴Independently of one another, hydrogen, alkyl, aryl (optionally substituted by halogen, alkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, mono-or di-alkylamino)Alkylamino, nitro, cyano, carboxyl, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl or dialkylaminocarbonyl), or aralkyl (optionally substituted with: halogen, alkyl, aryl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, cyano, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl);

R¹⁵is a linear or branched alkylene group; and

R¹⁶is alkyl, aryl (optionally substituted with halogen, alkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, cyano, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl or dialkylaminocarbonyl), or aralkyl (optionally substituted with halogen, alkyl, aryl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, cyano, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl or dialkylaminocarbonyl).

Among this subgroup of compounds, more preferred are the following compounds, among which:

Z¹and Z²Independently is-O-;

R¹is hydrogen OR OR¹³；

R²is-C (NH) NH₂；

R³Is (1,2) -tetrahydropyrimidinyl (optionally substituted with methyl), (1,2) -imidazolyl (optionally substituted with methyl) or (1,2) -imidazolinyl (optionally substituted with methyl);

R⁴is hydrogen;

R⁵and R⁶Independently of one another, halogen;

R⁷is-N (R)⁹)-(C(R¹⁰)(R¹¹))_n-R¹²(wherein n is 1);

R⁹is hydrogen, alkyl, aryl or aralkyl;

R¹⁰is alkyl, -R¹⁵-N(R¹³)C(O)N(R¹³)R¹⁴、-R¹⁵-N(R¹³)C(NR¹³)N(R¹³)R¹⁴、-R¹⁵-N(R¹³)C(NR¹³)R¹⁶、-R¹⁵-C(O)OR¹³、-R¹⁵-C(O)N(R¹³)R14、R¹⁵-C(R¹³)(C(O)OR¹³)₂、-R¹⁵-N(R¹³)R¹⁴、-R¹⁵SR¹³、-R¹⁵OR¹³、-R¹⁵-S(O)₂OR¹⁶、-R¹⁵-OP(O)(OR¹³)₂；

Or R¹⁰Is aralkyl (optionally substituted with one OR more substituents selected from halogen, haloalkyl, hydroxy OR-OP (O) (OR)¹³)₂)；

Or R¹⁰Is imidazolyl alkyl or indolyl alkyl;

R¹¹is hydrogen or alkyl;

R¹²is-C (O) OR¹³or-C (O) N (R)¹³)R¹⁴；

R¹³And R¹⁴Independently of one another, hydrogen or alkyl;

R¹⁵is a linear or branched alkylene group; and

R¹⁶is alkyl or aryl.

Of this group of compounds, the following compounds are preferred, among others:

R¹is OR¹³；

R³Is (1,2) -imidazolyl (optionally substituted with methyl) or (1,2) -imidazolinyl (optionally substituted with methyl);

R⁵and R⁶Are both fluorine;

R⁹is hydrogen or alkyl;

R¹⁰is alkyl, -R¹⁵-N(R¹³)C(O)N(R¹³)R¹⁴、-R¹⁵-N(R¹³)C(NR¹³)R¹⁶or-R¹⁵-N(R¹³)C(NR¹³)N(R¹³)R¹⁴；

R¹¹Is hydrogen or alkyl;

R¹²is-C (O) OR¹³。

A preferred specific compound of this group is selected from the following compounds:

4-hydroxy-3- [ (4- (N-methyl-N- (1-ethoxycarbonyl-1-methylethyl) amino) -6- (3- (1-methylimidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzamidine;

4-hydroxy-3- [ (4- (N- (1-carboxy-5-guanidinopentyl) amino) -6- (3- (1-methylimidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzamidine;

4-hydroxy-3- [ (4- (N-methyl-N- (1-ethoxycarbonylethyl) amino) -6- (3- (1-methylimidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzamidine;

4-hydroxy-3- [ (4- (N-methyl-N- (1-carboxy-1-methylethyl) amino) -6- (3- (1-methylimidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzamidine;

4-hydroxy-3- [ (4- (N-methyl-N- (1-carboxyethyl) amino) -6- (3- (1-methylimidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzamidine;

4-hydroxy-3- [ (4- (N- (1-carboxy-5-aminopentyl) amino) -6- (3- (1-methylimidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzamidine;

4-hydroxy-3- [ (4- (N- (1-carboxy-5-guanidinopentyl) amino) -6- (3- (1-methylimidazol-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzamidine;

4-hydroxy-3- [ (4- (N- (1-carboxy-5- (N- (1-iminoethyl) amino) pentyl) amino) -6- (3- (1-methylimidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzamidine, and

4-hydroxy-3- [ (4- (N- (1-carboxy-5- (N- (1-iminoethyl) amino) pentyl) amino) -6- (3- (1-methylimidazol-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzamidine.

Another group of preferred compounds is the subgroup wherein:

a is-N =;

Z¹and Z²Independently is-O-, -S-or-OCH₂-；

R¹And R⁴Independently of one another, hydrogen, halogen OR-OR¹³；

R⁵and R⁶Independently of one another, hydrogen, halogen, alkyl, haloalkyl;

R⁷is-O- (C (R)¹⁰)(R¹¹))_n-R¹²(wherein n is 1 to 6);

R¹⁰each independently is alkyl, -R¹⁵-N(R¹³)C(O)N(R¹³)R¹⁴、-R¹⁵-N(R¹³)C(NR¹³)N(R¹³)R¹⁴、-R¹⁵-N(R¹³)C(NR¹³)R¹⁶、-R¹⁵-C(O)OR¹³、-R¹⁵-C(O)N(R¹³)R¹⁴、-R¹⁵-C(R¹³)(C(O)OR¹³)₂、-R¹⁵-N(R¹³)R¹⁴、-R¹⁵SR¹³、-R¹⁵OR¹³、-R¹⁵-S(O)₂OR¹⁶、-R¹⁵-Op(O)(OR¹³)₂；

Or R¹⁰Each independently is aralkyl (optionally substituted with one OR more substituents selected from the group consisting of alkyl, halogen, haloalkyl, haloalkoxy, cyano, -OR¹³、-C(O)OR¹³、-N(R¹³)R¹⁴、-C(O)OR¹³、-C(O)N(R¹³)R¹⁴、-SR¹³、-S(O)₂OR¹⁶and-OP (O) (OR)¹³)₂)；

R¹¹Independently of one another, hydrogen or alkyl;

R¹²is-C (O) OR¹³or-C (O) N (R)¹³)R¹⁴；

R¹³And R¹⁴Independently of one another, hydrogen, alkyl, aryl (optionally substituted by halogen, alkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, cyano, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl or dialkylaminocarbonyl), or aralkyl (optionally substituted by halogen, alkyl, aryl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, cyano, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl or dialkylaminocarbonyl)An alkylaminocarbonyl group);

R¹⁵is a linear or branched alkylene group; and

Z¹and Z²Independently is-O-;

R¹is hydrogen OR-OR¹³；

R²is-C (NH) NH₂；

R³Is (1,2) tetrahydropyrimidinyl (optionally substituted with methyl), (1,2) -imidazolyl (optionally substituted with methyl) or (1,2) -imidazolinyl (optionally substituted with methyl);

R⁴is hydrogen;

R⁵and R⁶Independently of one another, halogen;

R⁷is-O- (C (R)¹⁰)(R¹¹))_n-R¹²(wherein n is 1 to 6);

R¹⁰is alkyl, -R¹⁵-N(R¹³)C(O)N(R¹³)R¹⁴、-R¹⁵-N(R¹³)C(NR¹³)N(R¹³)R¹⁴、-R¹⁵-N(R¹³)C(NR¹³)R¹⁶、-R¹⁵-C(O)OR¹³、-R¹⁵-C(O)N(R¹³)R¹⁴、R¹⁵-C(R¹³)(C(O)OR¹³)₂、-R¹⁵-N(R¹³)R¹⁴、-R¹⁵SR¹³、-R¹⁵OR¹³、-R¹⁵-S(O)₂OR¹⁶、-R¹⁵-OP(O)(OR¹³)₂；

Or R¹⁰Is imidazolyl alkyl or indolyl alkyl;

R¹¹is hydrogen or alkyl;

R¹²is-C (O) OR¹³or-C (O) N (R)¹³)R¹⁴；

R¹³And R¹⁴Independently of one another, hydrogen or alkyl;

R¹⁵is a linear or branched alkylene group; and

R¹⁶is alkyl or aryl.

R¹is OR¹³；

R⁵and R⁶Are both fluorine;

R⁹is hydrogen or alkyl;

R¹¹Is hydrogen or alkyl;

R¹²is-C (O) OR¹³。

4-hydroxy-3- [ (4- (1-ethoxycarbonyl-3-methylbutoxy) -6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzamidine; and

4-hydroxy-3- [ (4- (1-carboxy-3-methylbutoxy) -6- (3- (1-methylimidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzamidine.

Preparation of the Compounds of the invention

For convenience, the following description of the preparation of the compounds of the present invention will be directed to the preparation of the compounds of formula (i) wherein a is-N = only. However, it will be appreciated that analogous synthetic methods may be employed to prepare compounds of formulae (II), (III), (IV), (V), (VI) and (VII). It is also understood that in the following description, combinations of substituents and/or variables (e.g., R) in the schematic diagrams¹⁰And R¹¹) Are permissible provided such combination results in a stable compound.

A. Preparation of Compounds of formula (Ia) and (Ib)

The compounds of formulae (la) and (lb) are compounds of the invention described in the summary of the invention, which can be prepared according to the following reaction scheme, wherein X is halogen; y is bromine, chlorine or iodine; r¹³Is alkyl or aralkyl (optionally substituted with halogen, alkyl, aryl, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, cyano, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl or dialkylaminocarbonyl); r¹、R³、R⁴、R⁵、R⁶、R⁹、R¹⁰And R¹¹Are as described in the summary of the invention (only in R)¹⁰And R¹¹In the description of (1) R¹³Is not provided withAryl): p19

Reaction scheme 1P20

Reaction scheme (continuation)

Amino acids in the formula are commercially available from, for example, Aldrich Chemical Co., Sigma Chemical Co., or ICN Biomedicals, Inc. The compounds of formulae (B), (D), (F), (H) and (K) are commercially available, for example, from Aldrich Chemical co, or can be prepared according to methods well known to those skilled in the art.

In general, the compounds of formulae (Ia) and (Ib) are prepared by:

first, the compound of formula (A) is treated with the compound of formula (B) under standard esterification conditions, for example at-100 to 50℃, preferably at room temperature, in the presence of a strong mineral acid such as hydrogen chloride (gas) to give the compound of formula (C), which is isolated from the reaction mixture by removing the solvent using standard techniques, for example in vacuo.

The compound of formula (C) formed is then treated with the compound of formula (D) in an aprotic solvent, such as DMSO, in the presence of a base, such as triethylamine, at a temperature of 20-50 deg.C, preferably at room temperature, for a period of 20-40 hours. The compound of formula (E) is isolated from the reaction mixture by standard techniques such as extraction, filtration and removal of the solvent in vacuo.

Thereafter, the resulting compound of formula (E) is treated with the compound of formula (F) under standard alkylation conditions, for example in an aprotic solvent such as acetonitrile, in the presence of a base such as sodium hydride at room temperature for a period of from 1 to 24 hours, preferably about 2 hours. The compound of formula (G) is isolated from the reaction mixture by standard techniques such as extraction, removal of the solvent in vacuo and flash chromatography.

Thereafter, the compound of formula (G) formed in the aprotic solvent, e.g. acetonitrile, is treated with an equimolar amount of the compound of formula (H) in the presence of a base, e.g. cesium carbonate, at 20-120 ℃, preferably at room temperature, for a time sufficient to complete the desired reaction, which is monitored by Thin Layer Chromatography (TLC). The compound of formula (J) is then isolated from the reaction mixture using standard separation techniques such as extraction, solvent removal in vacuo and flash chromatography.

Thereafter, the compound of formula (J) formed in the aprotic solvent, e.g. DMSO, is treated with an equimolar amount of the compound of formula (K) in the presence of a base, e.g. cesium carbonate, at 20-120 ℃, preferably 35 ℃, for a time sufficient to complete the desired reaction, e.g. for about 13 hours. The reaction mixture is cooled to room temperature and the compound of formula (L) is then isolated from the reaction mixture using standard separation techniques such as extraction, solvent removal in vacuo and flash chromatography.

The compound of formula (L) formed is dissolved in an anhydrous alkanol, preferably ethanol, treated with a mineral acid, preferably hydrochloric acid, while maintaining the reaction mixture at about-78 ℃ to room temperature for a period of 2-24 hours, and when the reaction is complete, as detected (e.g. by TLC), the temperature is raised to room temperature. The solvent is removed in vacuo and the resulting residue is dissolved in a new anhydrous alkanol, preferably ethanol, and then treated with anhydrous ammonia at room temperature to 100 ℃ for about 1-5 hours, preferably about 2 hours. The compound of formula (ia) is then isolated from the reaction mixture using standard separation techniques such as solvent removal in vacuo and flash chromatography and purified by High Pressure Liquid Chromatography (HPLC).

In addition, in the above-mentioned treatment of the residue formed with anhydrous ammonia, there may be used NH of the formula₂OR¹³In place of ammonia, to give the corresponding compound of formula (Ia), wherein R²is-C (NH) N (H) OR¹³。

The resulting compound of formula (Ia) is then hydrolyzed under acidic conditions, for example by treatment with a strong mineral acid such as hydrochloric acid, to produce a compound of formula (Ib). Furthermore, during this step, any of the produced ester-containing substituents R¹、R³、R⁴、R⁵、R⁶、R¹⁰、R¹¹、R¹³Or R¹⁴The compounds of formula (Ia) can be hydrolyzed to compounds containing the corresponding acid substituents.

Alternatively, the compounds of formula (Ia) may be prepared by using a compound of formula R under standard transesterification conditions¹³Alcoholic treatment of OH, wherein R¹³R is aryl (optionally substituted by halogen, alkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, cyano, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl or dialkylaminocarbonyl) to yield R¹³A compound of the invention which is an optionally substituted aryl group.

R³is-C (NH) NH₂OR-C (NH) N (H) OR¹³The compounds of formula (Ia) can be prepared in a similar manner to the compounds of formula (L) described above from the corresponding cyano compounds.

In addition, R can be reacted under acidic conditions¹、R³、R⁴、R⁵、R⁶、R⁹、R¹⁰Or R¹¹comprising-C (O) N (R)¹³)R¹⁴OR-C (O) OR¹³A compound of formula (Ia) wherein R¹³And R¹⁴Independently of one another, alkyl, optionally substituted aryl or optionally substituted aralkyl) to give the corresponding R¹、R³、R⁴、R⁵、R⁵、R⁹、R¹⁰Or R¹¹Compounds of the present invention comprising-C (O) OH.

In addition, R may be reacted under standard amidation conditions¹、R³、R⁴、R⁵、R⁶、R⁹、R¹⁰Or R¹¹comprising-C (O) OR¹³A compound of formula (Ia) wherein R¹³Hydrogen, alkyl, optionally substituted aryl or optionally substituted aralkyl) to yield the corresponding R¹、R³、R⁴、R⁵、R⁶、R⁹、R¹⁰Or R¹¹comprising-C (O) N (R)¹³)R¹⁴Of the group of the compounds of the invention, wherein R¹³And R¹⁴Independently of one another, hydrogen, alkyl, optionally substituted aryl or optionally substituted aralkyl.

In addition, under standard conditions, R can be treated¹、R³、R⁴、R⁵、R⁶Or R¹⁰Reduction of compounds of formula (Ia) containing a nitro group to give the corresponding R¹、R³、R⁴、R⁵、R⁶Or R¹⁰Compounds of formula (Ia) containing an amino group, which can be treated with a suitable alkylating agent to give the corresponding R¹、R³、R⁴、R⁵、R⁶Or R¹⁰comprising-N (R)¹³)R¹⁴or-N (R)¹³)C(O)R¹⁴A compound of formula (Ia) wherein R¹³And R¹⁴Independently of one another, hydrogen, alkyl, optionally substituted aryl or optionally substituted aralkyl.

The compound of formula (Ia) may be further treated with a suitable acid halide, preferably an acid chloride, or with a suitable acid anhydride or equivalent to give R²is-C (NH) N (H) C (O) R¹³Wherein R is¹³Is hydrogen, alkyl, optionally substituted aryl or optionally substituted aralkyl. Alternatively, the compound of formula (Ia) may be further treated with carbamoyl chloride or an equivalent thereof to give R²is-C (NH) N (H) C (O) OR¹⁶Wherein R is¹⁶As described in the summary of the invention.

Alternatively, the compound of formula (Ia) may be further treated with a compound of formula R in a polar solvent such as dichloromethane at room temperature¹⁶-S(O)₂Imidazole (wherein R¹⁶As described in the summary of the invention) to give R²is-C (NH) N (H) S (O)₂R¹⁶The compound of the present invention.

Alternatively, the compound of formula (Ia) may be further treated with the appropriate N-R in a polar solvent such as dichloromethane at room temperature¹³Substituted phenylThe carbamate is treated for a time of about 6 to 24 hours, preferably about 12 hours, to provide R²is-C (NH) N (H) C (O) N (H) R¹³The compound of the present invention.

Furthermore, if the compound of formula (A) has been represented by R as described in the summary of the invention⁹The substituent is substituted for the amino group, and the compound does not require the alkylation process of step 3 as illustrated in scheme 1.

B. Preparation of the Compound of formula (N)

Compounds of formula (N) are intermediates in the preparation of compounds of the present invention, the preparation of which is illustrated in scheme 2 below, wherein X is halogen; r¹³Is alkyl or aralkyl (optionally substituted with halogen, alkyl, aryl, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, cyano, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl or dialkylaminocarbonyl); r⁵、R⁶、R¹⁰And R¹¹Are as described in the summary of the invention (only in R)¹⁰And R¹¹In the description of (1) R¹³Is not aryl):

reaction scheme 2

Hydroxy acids of formula (M) are commercially available from, for example, Aldrich Chemical co, Sigma Chemical co, or IcN Biomedicals, inc, or can be prepared according to methods well known to those skilled in the art. The compounds of formula (D) are commercially available, for example, from Aldrich Chemical co, or can be prepared according to methods well known to those skilled in the art.

Typically, the compound of formula (N) is prepared by: the compound of formula (M) is treated with compound (D) in an aprotic solvent such as DMF in the presence of a base such as cesium carbonate at from room temperature to 50 ℃, preferably about 45 ℃. The reaction mixture is stirred at this temperature for about 24 to 72 hours, preferably about 72 hours. The compound of formula (N) is then isolated from the reaction mixture using standard separation techniques such as extraction, solvent removal in vacuo and chromatography.

The compounds of formula (N) can then be treated in a manner analogous to that described for compound (E) in scheme 1 above to give the compounds of the invention, including those R¹³Corresponding compounds which are hydrogen or aryl (by hydrolysis or transesterification).

C. Preparation of Compounds of formula (Q)

Compounds of formula (Q), wherein X is halogen and R is R, are useful as intermediates in the preparation of compounds of the invention, as shown in scheme 3¹、R³、R⁴、R⁹、R¹¹、R¹³And R¹⁴As described in the summary of the invention, R¹⁷Is alkyl, aryl or aralkyl:

reaction scheme 3

P25

The compound of formula (O) is prepared according to the process of scheme 1 above. The compound of formula (P) may be commercially available from, for example, Aldrich Chemical co, or may be prepared according to methods well known to those skilled in the art.

Typically, the compound of formula (Q) is prepared by: first, the compound of formula (O) is dissolved in an aprotic solvent such as dichloromethane in the presence of an organic acid such as trifluoroacetic acid (TFA), and the resulting solution is stirred at room temperature for about 1 to 10 hours, preferably about 1.5 hours; the solvent is then removed and the residue formed is dissolved in an aqueous alkanol solution, preferably methanol/water, in the presence of a base such as potassium carbonate until a pH of 10-12, preferably 11, is obtained. The resulting solution is then treated with the compound of formula (P) and the resulting mixture is stirred at room temperature until the reaction is complete, for example by HPLC analysis of an aliquot of the desired product. The compound of formula (Q) is then isolated from the reaction mixture by standard separation techniques such as extraction, filtration and removal of the solvent in vacuo and chromatography.

Other amidino acids of formula (P) can be used in this reaction scheme to produce the corresponding compounds of formula (Q).

The compounds of formula (Q) can be processed in a similar manner to the compounds of formula (L) in scheme 1 above to give the corresponding compounds of the invention.

D. Preparation of Compounds of formulae (ic) and (id)

Compounds of the formulae (ic) and (id), wherein X is halogen and R is as shown in scheme 4, are compounds of the present invention¹、R³、R⁴、R⁹、R¹¹、R¹³、R¹⁴、R¹⁵And R¹⁶As described in the summary of the invention, R¹⁷Is alkyl, aryl or aralkyl:

reaction scheme 4

The compound of formula (O) is prepared according to the method described in scheme 1 above.

In general, the preparation of the compounds of the formulae (ic) and (id) is such that: first, the compound of formula (O) is dissolved in an aprotic solvent/alkanol, e.g. ethanol/dichloromethane, and the solution is then reduced at-20 to 0℃, preferably about-10℃, and treated with a mineral acid such as hydrochloric acid for about 15 minutes to 1 hour, preferably about 15 minutes. Thereafter, the reaction mixture is stirred at room temperature for about 10-20 hours, preferably 20 hours. The volatile solvent is removed in vacuo and the resulting residue redissolved in an alcohol, preferably absolute ethanol. The resulting solution is then cooled to about-20 ℃ to about 0 ℃, preferably about-10 ℃, and treated with anhydrous ammonia gas at room temperature for about 15 minutes to about 1 hour, preferably about 15 minutes. Thereafter, the resulting mixture is heated to reflux for about 1-3 hours, preferably about 2 hours, cooled to room temperature, and concentrated. The resulting residue is dissolved in an aqueous solution of an inorganic acid, such as hydrochloric acid, and heated under reflux for about 2 to 4 hours, preferably about 4 hours. The compound of formula (ic) is then isolated from the reaction mixture using standard separation techniques, such as purification by HPLC.

The compound of formula (ic) is then dissolved in an aqueous alcoholic solvent, for example methanol/water. To the resulting solution is added an alkyl imidoacetate (preferably ethyl imidoacetate) in the presence of a strong organic base such as potassium carbonate. The resulting reaction mixture is stirred at room temperature for about 1-3 hours, preferably about 1 hour. The compound of formula (id) is then isolated from the reaction mixture using standard separation techniques such as filtration and chromatography.

Furthermore, all compounds of the invention in free base form or in free acid form can be converted into their pharmaceutically acceptable salts by treatment with suitable inorganic or organic acids or by suitable inorganic or organic bases. Salts of the compounds of the invention may also be converted into the free base form or the free acid form or another salt form.

The following specific preparations and examples are provided as guidance to assist in the practice of the invention, but they are not intended to limit the scope of the invention.

Preparation example 1

A compound of formula (C)

A. A solution of 2-aminoisobutyric acid (3.3g, 32mmol) in absolute ethanol (100ml) was cooled to-78 deg.C and bubbled with HCl (g) for 10 minutes. The flask was sealed with a septum and stirred at room temperature. After 14 hours, the mixture was concentrated in vacuo to give 5.3g (yield 99%) of ethyl 2-aminoisobutyrate as a white solid; NMR (CDCl)₃)8.9(brs,3),4.1(q,2),1.7(s,6),1.3(t,3)ppm。

B. In a similar manner, the following compounds were prepared:

2-N-methyl-2-aminopropionic acid ethyl ester.

C. In a similar manner, the following compounds were prepared:

2-methyl-2-aminopropionic acid ethyl ester;

2-methylethyl-2-aminopropionic acid ethyl ester;

2- (2-methylpropyl) -2-aminopropionic acid ethyl ester;

2- (1-methylpropyl) -2-aminopropionic acid ethyl ester;

2- (hydroxymethyl) -2-aminopropionic acid ethyl ester;

2- (1-hydroxyethyl) -2-aminopropionic acid ethyl ester;

2- (mercaptomethyl) -2-aminopropionic acid ethyl ester;

2- (methylthioethyl) -2-aminopropionic acid ethyl ester;

2- (carboxymethyl) -2-aminopropionic acid ethyl ester;

2- (aminocarbonylmethyl) -2-aminopropionic acid ethyl ester;

2- (2-carboxyethyl) -2-aminopropionic acid ethyl ester;

2- (aminocarbonylethyl) -2-aminopropionic acid ethyl ester;

2- (3-guanidinopropyl) -2-aminopropionic acid ethyl ester;

2- (4-guanidinopropyl) -2-aminopropionic acid ethyl ester;

2- (4-aminobutyl) -2-aminopropionic acid ethyl ester;

2- (4-amino-3-hydroxybutyl) -2-aminopropionic acid ethyl ester;

2- (4- (N-tert-butoxycarbonylamino) butyl) -2-aminopropionic acid methyl ester;

2- (imidazol-4-ylmethyl) -2-aminopropionic acid methyl ester;

2- (phenylmethyl) -2-aminopropionic acid methyl ester;

2- ((4-hydroxyphenyl) methyl) -2-aminopropionic acid methyl ester;

2- (indol-3-ylmethyl) -2-aminopropionic acid methyl ester;

2- (2-mercaptoethyl) -2-aminopropionic acid methyl ester;

2- (2-hydroxyethyl) -2-aminopropionic acid methyl ester;

2- (3-aminopropyl) -2-aminopropionic acid methyl ester;

2- (3-ureidopropyl) -2-aminopropionic acid methyl ester; and

2- (2, 2-Dicarboxyethyl) -2-aminopropionic acid methyl ester.

Preparation example 2

A compound of formula (E)

A. To a solution of ethyl 2-aminoisobutyrate (92.0g,12mmol) in anhydrous DMSO (125ml) were added pentafluoropyridine (1.6ml,2.4g,14.4mmol) and triethylamine (8.3ml,6.1g,60 mmol). The resulting mixture was stirred at room temperature for 40 hours, and then poured into 300ml of water and 300ml of ethyl acetate. The aqueous layer was separated and extracted with 100ml of ethyl acetate. And the combined extracts were washed with water (250ml), then brine (250ml), MgSO₄Drying, filtration and concentration in vacuo afforded 3.5g (92% yield) of 4-N- (1-ethoxycarbonyl-1-methylethyl) amino-2, 3,5, 6-tetrafluoropyridine as a crystalline solid: NMR (CDCl)₃)5.0(brs,1),4.2(q,2),1.7(s,6),1.3(t,3)ppm。

B. In a similar manner, the following compounds were prepared:

4-N- (1-tert-butoxycarbonyl-5- (N-tert-butoxycarbonyl) aminopent-1-yl) amino-2, 3,5, 6-tetrafluoropyridine; and

4-N-methyl-N- (1-ethoxycarbonylethyl) amino-2, 3,5, 6-tetrafluoropyridine.

C. In a similar manner, the following compounds were prepared:

4-N- (1-ethoxycarbonyl-3-methylbutyl) amino-2, 3,5, 6-tetrafluoropyridine;

4-N- (1-ethoxycarbonyl-2-methylpropyl) amino-2, 3,5, 6-tetrafluoropyridine;

4-N- (1-ethoxycarbonyl-2-methylbutyl) amino-2, 3,5, 6-tetrafluoropyridine;

4-N- (1-ethoxycarbonyl-2-mercaptoethyl) amino-2, 3,5, 6-tetrafluoropyridine;

4-N- (1-ethoxycarbonyl-3-methylthiopropyl) amino-2, 3,5, 6-tetrafluoropyridine;

4-N- (1-ethoxycarbonyl-2-hydroxyethyl) amino-2, 3,5, 6-tetrafluoropyridine;

4-N- (1-ethoxycarbonyl-2-hydroxypropyl) amino-2, 3,5, 6-tetrafluoropyridine;

4-N- (1-ethoxycarbonyl-2-carboxyethyl) amino-2, 3,5, 6-tetrafluoropyridine;

4-N- (1-ethoxycarbonyl-2-aminocarbonylethyl) amino-2, 3,5, 6-tetrafluoropyridine;

4-N- (1-ethoxycarbonyl-3-carboxypropyl) amino-2, 3,5, 6-tetrafluoropyridine;

4-N- (1-ethoxycarbonyl-3-aminocarbonylpropyl) amino-2, 3,5, 6-tetrafluoropyridine;

4-N- (1-ethoxycarbonyl-2-imidazol-4-ylethyl) amino-2, 3,5, 6-tetrafluoropyridine;

4-N- (1-ethoxycarbonyl-2-phenylmethyl ethyl) amino-2, 3,5, 6-tetrafluoropyridine;

4-N- (1-ethoxycarbonyl-2-indol-3-ylethyl) amino-2, 3,5, 6-tetrafluoropyridine;

4-N- (1-ethoxycarbonyl-4-guanidinobutyl) amino-2, 3,5, 6-tetrafluoropyridine; and

4-N- (1-ethoxycarbonyl-4-aminobutyl) amino-2, 3,5, 6-tetrafluoropyridine.

Preparation example 3

A compound of formula (G)

A. To 4-N- (1-ethoxycarbonyl-1-methylethyl) amino-2, 3,5, 6-tetrafluoropyridine (3.1g, 9)8mmol) in acetonitrile (70ml) was added sodium hydride (0.8g,20mmol, 60% dispersion in mineral oil). After the evolution of gas had ceased methyl iodide (1.25ml,2.8g,20mmol) was added and the resulting mixture was stirred at room temperature for 2 hours. The mixture was then poured into 200ml of water and 200ml of ethyl acetate. The aqueous layer was separated and extracted with 100ml of ethyl acetate. The combined organic extracts were washed with MgSO₄Drying, filtering and vacuum concentrating to obtain a brown oil. Purification by flash chromatography on silica gel gave 2.2g (68% yield) of 4-N-methyl-N- (1-ethoxycarbonyl-1-methylethyl) amino-2, 3,5, 6-tetrafluoropyridine as a clear colorless liquid: NMR (CDCl)₃)4.2(q,2),3.1(s.3),1.6(s,6),1.3(t,3)ppm。

B. In a similar manner, the following compounds were prepared:

4-N-ethyl-N- (1-ethoxycarbonyl-1-methylethyl) amino-2, 3,5, 6-tetrafluoropyridine;

4-N-propyl-N- (1-ethoxycarbonyl-1-methylethyl) amino-2, 3,5, 6-tetrafluoropyridine;

4-N-butyl-N- (1-ethoxycarbonyl-1-methylethyl) amino-2, 3,5, 6-tetrafluoropyridine;

4-N-phenyl-N- (1-ethoxycarbonyl-1-methylethyl) amino-2, 3,5, 6-tetrafluoropyridine;

4-N-benzyl-N- (1-ethoxycarbonyl-1-methylethyl) amino-2, 3,5, 6-tetrafluoropyridine;

4-N- (3-ethoxycarbonyl) propyl-N- (1-ethoxycarbonyl-1-methylethyl) amino-2, 3,5, 6-tetrafluoropyridine;

4-N- (4-dimethylaminocarbonyl) butyl-N- (1-ethoxycarbonyl-1-methylethyl) amino-2, 3,5, 6-tetrafluoropyridine;

4-N- (4-dimethylaminobutyl) -N- (1-ethoxycarbonyl-1-methylethyl) amino-2, 3,5, 6-tetrafluoropyridine;

4-N-propyl-N- (1-ethoxycarbonyl-3-methylbutyl) amino-2, 3,5, 6-tetrafluoropyridine;

4-N-methyl-N- (1-ethoxycarbonyl-2-methylpropyl) amino-2, 3,5, 6-tetrafluoropyridine;

4-N-methyl-N- (1-ethoxycarbonyl-2-methylbutyl) amino-2, 3,5, 6-tetrafluoropyridine;

4-N-methyl-N- (1-ethoxycarbonyl-2-mercaptoethyl) amino-2, 3,5, 6-tetrafluoropyridine;

4-N-methyl-N- (1-ethoxycarbonyl-3-methylthiopropyl) amino-2, 3,5, 6-tetrafluoropyridine;

4-N-methyl-N- (1-ethoxycarbonyl-2-hydroxyethyl) amino-2, 3,5, 6-tetrafluoropyridine;

4-N-methyl-N- (1-ethoxycarbonyl-2-hydroxypropyl) amino-2, 3,5, 6-tetrafluoropyridine;

4-N-methyl-N- (1-ethoxycarbonyl-2-carboxyethyl) amino-2, 3,5, 6-tetrafluoropyridine;

4-N-methyl-N- (1-ethoxycarbonyl-2-aminocarbonylethyl) amino-2, 3,5, 6-tetrafluoropyridine;

4-N-methyl-N- (1-ethoxycarbonyl-3-carboxypropyl) amino-2, 3,5, 6-tetrafluoropyridine;

4-N-methyl-N- (1-ethoxycarbonyl-3-aminocarbonylpropyl) amino-2, 3,5, 6-tetrafluoropyridine;

4-N-methyl-N- (1-ethoxycarbonyl-2-imidazol-4-ylethyl) amino-2, 3,5, 6-tetrafluoropyridine;

4-N-methyl-N- (1-ethoxycarbonyl-2-phenylmethyl ethyl) amino-2, 3,5, 6-tetrafluoropyridine;

4-N-methyl-N- (1-ethoxycarbonyl-2-indol-3-ylethyl) amino-2, 3,5, 6-tetrafluoropyridine;

4-N-methyl-N- (1-ethoxycarbonyl-4-guanidinobutyl) amino-2, 3,5, 6-tetrafluoropyridine; and

4-N-methyl-N- (1-ethoxycarbonyl-4-aminobutyl) amino-2, 3,5, 6-tetrafluoropyridine.

Preparation example 4

A compound of formula (J)

A. To 4- [ N-methyl-N- (1-ethoxycarbonyl-1-methylethyl) amino]To a solution of 2,3,5, 6-tetrafluoropyridine (2.2g,6.6mmol) in acetonitrile (60ml) were added 2-benzyloxy-5-cyanophenol (1.5g,6.6mmol) and cesium carbonate (2.8g,8.6 mmol). The resulting mixture was stirred at 40 ℃ for 2 days. The mixture was then cooled to room temperature and poured into 200ml of 0.5M aqueous KOH and 200ml of ethyl acetate. The aqueous layer was separated and extracted with 100ml of ethyl acetate. The combined organic extracts were washed with 0.5M aqueous KOH (200ml), then brine (200ml), and MgSO₄Drying, filtering, and vacuum concentrating to obtain yellow oil, which solidifies after standing. Recrystallization from 30% ethyl acetate/hexane gave 2.4g (68% yield) of 4-benzyloxy-3- [ (4-methyl-N- (1-ethoxycarbonyl-1-methylethyl) amino) -3,5, 6-trifluoropyridin-2-yl) oxy]Benzonitrile, as white crystalline solid: NMR (CDCl)₃)7.6-7.1(m,8),5.2(s,2),4.2(q,2),3.1(s,3),1.6(s,6),1.3(t,3)ppm。

B. In a similar manner, the following compounds were prepared:

4-benzyloxy-3- [ (4-N- (1-tert-butoxycarbonylamino-5- (N-tert-butoxycarbonylamino) pentyl) amino) -3,5, 6-trifluoropyridin-2-yl) oxy ] benzonitrile; and

4-benzyloxy-3- [ (4- (N-methyl-N- (1-ethoxycarbonyl) ethylamino) -3,5, 6-trifluoropyridin-2-yl) oxy ] benzonitrile.

C. In a similar manner, the following compounds were prepared:

4-benzyloxy-3- [ (4- (N-ethyl-N- (1-ethoxycarbonyl-1-methylethyl) amino) -3,5, 6-trifluoropyridin-2-yl) oxy ] benzonitrile;

4-benzyloxy-3- [ (4- (N-propyl-N- (1-ethoxycarbonyl-1-methylethyl) amino) -3,5, 6-trifluoropyridin-2-yl) oxy ] benzonitrile;

4-benzyloxy-3- [ (4- (N-butyl-N- (1-ethoxycarbonyl-1-methylethyl) amino) -3,5, 6-trifluoropyridin-2-yl) oxy ] benzonitrile;

4-benzyloxy-3- [ (4- (N-phenyl-N- (1-ethoxycarbonyl-1-methylethyl) amino) -3,5, 6-trifluoropyridin-2-yl) oxy ] benzonitrile;

4-benzyloxy-3- [ (4- (N-benzyl-N- (1-ethoxycarbonyl-1-methylethyl) amino) -3,5, 6-trifluoropyridin-2-yl) oxy ] benzonitrile;

4-benzyloxy-3- [ (4- (N- (3-ethoxycarbonylpropyl) -N- (1-ethoxycarbonyl-1-methylethyl) amino) -3,5, 6-trifluoropyridin-2-yl) oxy ] benzonitrile;

4-benzyloxy-3- [ (4- (N- (4-aminocarbonylbutyl) -N- (1-ethoxycarbonyl-1-methylethyl) amino) -3,5, 6-trifluoropyridin-2-yl) oxy ] benzonitrile;

4-benzyloxy-3- [ (4- (N- (4-aminobutyl) -N- (1-ethoxycarbonyl-1-methylethyl) amino) -3,5, 6-trifluoropyridin-2-yl) oxy ] benzonitrile;

4-benzyloxy-3- [ (4- (N-propyl-N- (1-ethoxycarbonyl-3-methylbutyl) amino) -3,5, 6-trifluoropyridin-2-yl) oxy ] benzonitrile;

4-benzyloxy-3- [ (4- (N-methyl-N- (1-ethoxycarbonyl-2-methylpropyl) amino) -3,5, 6-trifluoropyridin-2-yl) oxy ] benzonitrile;

4-benzyloxy-3- [ (4- (N-methyl-N- (1-ethoxycarbonyl-2-methylbutyl) amino) -3,5, 6-trifluoropyridin-2-yl) oxy ] benzonitrile;

4-benzyloxy-3- [ (4- (N-methyl-N- (1-ethoxycarbonyl-2-mercaptoethyl) amino) -3,5, 6-trifluoropyridin-2-yl) oxy ] benzonitrile;

4-benzyloxy-3- [ (4- (N-methyl-N- (1-ethoxycarbonyl-3-methylthiopropyl) amino) -3,5, 6-trifluoropyridin-2-yl) oxy ] benzonitrile;

4-benzyloxy-3- [ (4- (N-methyl-N- (1-ethoxycarbonyl-2-hydroxyethyl) amino) -3,5, 6-trifluoropyridin-2-yl) oxy ] benzonitrile;

4-benzyloxy-3- [ (4- (N-methyl-N- (1-ethoxycarbonyl-2-hydroxypropyl) amino) -3,5, 6-trifluoropyridin-2-yl) oxy ] benzonitrile;

4-benzyloxy-3- [ (4- (N-methyl-N- (1-ethoxycarbonyl-2-carboxyethyl) amino) -3,5, 6-trifluoropyridin-2-yl) oxy ] benzonitrile;

4-benzyloxy-3- [ (4- (N-methyl-N- (1-ethoxycarbonyl-2-aminocarbonylethyl) amino) -3,5, 6-trifluoropyridin-2-yl) oxy ] benzonitrile;

4-benzyloxy-3- [ (4- (N-methyl-N- (1-ethoxycarbonyl-3-carboxypropyl) amino) -3,5, 6-trifluoropyridin-2-yl) oxy ] benzonitrile;

4-benzyloxy-3- [ (4- (N-methyl-N- (1-ethoxycarbonyl-3-aminocarbonylpropyl) amino) -3,5, 6-trifluoropyridin-2-yl) oxy ] benzonitrile;

4-benzyloxy-3- [ (4- (N-methyl-N- (1-ethoxycarbonyl-2-imidazol-4-ylethyl) amino) -3,5, 6-trifluoropyridin-2-yl) oxy ] benzonitrile;

4-benzyloxy-3- [ (4- (N-methyl-N- (1-ethoxycarbonyl-2-phenylmethyl) amino) -3,5, 6-trifluoropyridin-2-yl) oxy ] benzonitrile;

4-benzyloxy-3- [ (4- (N-methyl-N- (1-ethoxycarbonyl-2-indol-3-ylethyl) amino) -3,5, 6-trifluoropyridin-2-yl) oxy ] benzonitrile;

4-benzyloxy-3- [ (4- (N-methyl-N- (1-ethoxycarbonyl-4-guanidinobutyl) amino) -3,5, 6-trifluoropyridin-2-yl) oxy ] benzonitrile;

4-benzyloxy-3- [ (4- (1-ethoxycarbonyl-4-guanidinobutoxy) -3,5, 6-trifluoropyridin-2-yl) oxy ] benzonitrile;

4-benzyloxy-3- [ (4- (1-ethoxycarbonyl-1-methylethoxy) -3,5, 6-trifluoropyridin-2-yl) oxy ] benzonitrile;

4-benzyloxy-3- [ (4- (1-ethoxycarbonyl-1-methylethoxy) amino) -3,5, 6-trifluoropyridin-2-yl) oxy ] benzonitrile;

4-benzyloxy-3- [ (4- (1-ethoxycarbonyl-3-methylbutoxy) -3,5, 6-trifluoropyridin-2-yl) oxy ] benzonitrile;

4-benzyloxy-3- [ (4- (1-ethoxycarbonyl-2-methylpropoxy) -3,5, 6-trifluoropyridin-2-yl) oxy ] benzonitrile;

4-benzyloxy-3- [ (4- (1-ethoxycarbonyl-2-methylbutoxy) -3,5, 6-trifluoropyridin-2-yl) oxy ] benzonitrile;

4-benzyloxy-3- [ (4- (1-ethoxycarbonyl-2-mercaptoethoxy) -3,5, 6-trifluoropyridin-2-yl) oxy ] benzonitrile;

4-benzyloxy-3- [ (4- (1-ethoxycarbonyl-3-methylthiopropoxy) -3,5, 6-trifluoropyridin-2-yl) oxy ] benzonitrile;

4-benzyloxy-3- [ (4- (1-ethoxycarbonyl-2-hydroxyethoxy) -3,5, 6-trifluoropyridin-2-yl) oxy ] benzonitrile;

4-benzyloxy-3- [ (4- (1-ethoxycarbonyl-2-hydroxypropoxy) -3,5, 6-trifluoropyridin-2-yl) oxy ] benzonitrile;

4-benzyloxy-3- [ (4- (1-ethoxycarbonyl-2-carboxyethoxy) -3,5, 6-trifluoropyridin-2-yl) oxy ] benzonitrile;

4-benzyloxy-3- [ (4- (1-ethoxycarbonyl-2-aminocarbonylethoxy) -3,5, 6-trifluoropyridin-2-yl) oxy ] benzonitrile;

4-benzyloxy-3- [ (4- (1-ethoxycarbonyl-3-carboxypropoxy) -3,5, 6-trifluoropyridin-2-yl) oxy ] benzonitrile;

4-benzyloxy-3- [ (4- (1-ethoxycarbonyl-3-aminocarbonylpropoxy) -3,5, 6-trifluoropyridin-2-yl) oxy ] benzonitrile;

4-benzyloxy-3- [ (4- (1-ethoxycarbonyl-2-imidazol-4-ylethoxy) -3,5, 6-trifluoropyridin-2-yl) oxy ] benzonitrile;

4-benzyloxy-3- [ (4- (1-ethoxycarbonyl-2-phenylmethylethoxy) -3,5, 6-trifluoropyridin-2-yl) oxy ] benzonitrile;

4-benzyloxy-3- [ (4- (1-ethoxycarbonyl-2-indo-3-ylethoxy) -3,5, 6-trifluoropyridin-2-yl) oxy ] benzonitrile; and

4-benzyloxy-3- [ (4- (1-ethoxycarbonyl-4-guanidinobutoxy) -3,5, 6-trifluoropyridin-2-yl) oxy ] benzonitrile.

Preparation example 5

A compound of formula (L)

A. To 4-benzyloxy-3- [ (4-methyl-N- (1-ethoxycarbonyl-1-methylethyl) amino) -3,5, 6-trifluoropyridin-2-yl) oxy]To a solution of benzonitrile (2.4g,4.5mmol) in DMSO (50ml) were added 3- ((1-methyl) imidazolin-2-yl) phenol (0.8g,4.5mmol) and cesium carbonate (1.9g,5.8 mmol). The resulting mixture was stirred at 35 ℃. After 13 hours, the mixture was cooled to room temperature and poured into 200ml of water and 200ml of ethyl acetate. The aqueous layer was separated and extracted with 100ml of ethyl acetate. The combined organic extracts were washed with 0.5M KOH solution (200ml), then brine (200ml), and MgSO₄Drying, filtering, and vacuum concentrating to obtain 4-benzyloxy-3- [ (4- (N-methyl-N- (1-ethoxycarbonyl-1-methylethyl) amino) -6- (3- (1-methylimidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy]Benzonitrile, as solid foam: NMR (CDCl)₃)7.4-7.0(m,12),5.0(s,2),4.2(q,2),3.9(t,2),3.5(t,2),3.1(s,3),2.8(s,3),1.6(s,6),1.3(t,3)ppm。

B. In a similar manner, the following compounds were prepared:

4-benzyloxy-3- [ (4-N- (1-tert-butoxycarbonyl-5- (N-tert-butoxycarbonylaminopentan-1-yl) amino) -6- (3- (1-methylimidazol-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzonitrile;

4-benzyloxy-3- [ (4-N- (1-tert-butoxycarbonyl-5- (N-tert-butoxycarbonylaminopentan-1-yl) amino) -6- (3- (1-methylimidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzonitrile, and

4-benzyloxy-3- [ (4- (N-methyl-N- (1-ethoxycarbonyl) ethylamino) -6- (3- (1-methylimidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzonitrile.

C. In a similar manner, the following compounds were prepared:

4-benzyloxy-3- [ (4- (N-ethyl-N- (1-ethoxycarbonyl-1-methylethyl) amino) -6- (3- (1-methylimidazol-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzonitrile;

4-benzyloxy-3- [ (4- (N-propyl-N- (1-ethoxycarbonyl-1-methylethyl) amino) -6- (3- (1-methylimidazol-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzonitrile;

4-benzyloxy-3- [ (4- (N-butyl-N- (1-ethoxycarbonyl-1-methylethyl) amino) -6- (3- (1-methylimidazol-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzonitrile;

4-benzyloxy-3- [ (4- (N-phenyl-N- (1-ethoxycarbonyl-1-methylethyl) amino) -6- (3- (1-methylimidazol-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzonitrile;

4-benzyloxy-3- [ (4- (N-benzyl-N- (1-ethoxycarbonyl-1-methylethyl) amino) -6- (3- (1-methylimidazol-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzonitrile;

4-benzyloxy-3- [ (4- (N- (3-ethoxycarbonylpropyl) -N- (1-ethoxycarbonyl-1-methylethyl) amino) -6- (3- (1-methylimidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzonitrile;

4-benzyloxy-3- [ (4- (N- (4-aminocarbonylbutyl) -N- (1-ethoxycarbonyl-1-methylethyl) amino) -6- (3- (1-methylimidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzonitrile;

4-benzyloxy-3- [ (4- (N- (4-aminobutyl) -N- (1-ethoxycarbonyl-1-methylethyl) amino) -6- (3- (1-methylimidazol-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzonitrile;

4-benzyloxy-3- [ (4- (N-propyl-N- (1-ethoxycarbonyl-3-methylbutyl) amino) -6- (3- (1-methylimidazol-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzonitrile;

4-benzyloxy-3- [ (4- (N-methyl-N- (1-ethoxycarbonyl-2-methylpropyl) amino) -6- (3- (1-methylimidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzonitrile;

4-benzyloxy-3- [ (4- (N-methyl-N- (1-ethoxycarbonyl-2-methylbutyl) amino) -6- (3- (1-methylimidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzonitrile;

4-benzyloxy-3- [ (4- (N-methyl-N- (1-ethoxycarbonyl-2-mercaptoethyl) amino) -6- (3- (1-methylimidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzonitrile;

4-benzyloxy-3- [ (4- (N-methyl-N- (1-ethoxycarbonyl-3-methylthiopropyl) amino) -6- (3- (1-methylimidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzonitrile;

4-benzyloxy-3- [ (4- (N-methyl-N- (1-ethoxycarbonyl-2-hydroxyethyl) amino) -6- (3- (1-methylimidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzonitrile;

4-benzyloxy-3- [ (4- (N-methyl-N- (1-ethoxycarbonyl-2-hydroxypropyl) amino) -6- (3- (1-methylimidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzonitrile;

4-benzyloxy-3- [ (4- (N-methyl-N- (1-ethoxycarbonyl-2-carboxyethyl) amino) -6- (3- (1-methylimidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzonitrile;

4-benzyloxy-3- [ (4- (N-methyl-N- (1-ethoxycarbonyl-2-aminocarbonylethyl) amino) -6- (3- (1-methylimidazol-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzonitrile;

4-benzyloxy-3- [ (4- (N-methyl-N- (1-ethoxycarbonyl-3-carboxypropyl) amino) -6- (3- (1-methylimidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzonitrile;

4-benzyloxy-3- [ (4- (N-methyl-N- (1-ethoxycarbonyl-3-aminocarbonylpropyl) amino) -6- (3- (1-methylimidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzonitrile;

4-benzyloxy-3- [ (4- (N-methyl-N- (1-ethoxycarbonyl-2-imidazol-4-ylethyl) amino) -6- (3- (1-methylimidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzonitrile;

4-benzyloxy-3- [ (4- (N-methyl-N- (1-ethoxycarbonyl-2-phenylmethyl) ethyl) amino) -6- (3- (1-methylimidazol-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzonitrile;

4-benzyloxy-3- [ (4- (N-methyl-N- (1-ethoxycarbonyl-2-indol-3-ylethyl) amino) -6- (3- (1-methylimidazol-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzonitrile;

4-benzyloxy-3- [ (4- (N-methyl-N- (1-ethoxycarbonyl-4-guanidinobutyl) amino) -6- (3- (1-methylimidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzonitrile;

4-benzyloxy-3- [ (4- (N-methyl-N- (1-ethoxycarbonyl-4-guanidinobutyl) amino) -6- (3- (1-methylimidazol-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzonitrile;

4-benzyloxy-3- [ (4- (1-ethoxycarbonyl-1-methylethoxy) -6- (3- (1-methylimidazol-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzonitrile;

4-benzyloxy-3- [ (4- (1-ethoxycarbonyl-1-methylethoxy) -6- (3- (1-methylimidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzonitrile;

4-benzyloxy-3- [ (4- (1-ethoxycarbonyl-3-methylbutoxy) -6- (3- (1-methylimidazol-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzonitrile;

4-benzyloxy-3- [ (4- (1-ethoxycarbonyl-2-methylpropoxy) -6- (3- (1-methylimidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzonitrile;

4-benzyloxy-3- [ (4- (1-ethoxycarbonyl-2-methylbutoxy) -6- (3- (1-methylimidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzonitrile;

4-benzyloxy-3- [ (4- (1-ethoxycarbonyl-2-mercaptoethoxy) -6- (3- (1-methylimidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzonitrile;

4-benzyloxy-3- [ (4- (1-ethoxycarbonyl-3-methylthiopropoxy) -6- (3- (1-methylimidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzonitrile;

4-benzyloxy-3- [ (4- (1-ethoxycarbonyl-2-hydroxyethoxy) -6- (3- (1-methylimidazol-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzonitrile;

4-benzyloxy-3- [ (4- (1-ethoxycarbonyl-2-hydroxypropoxy) -6- (3- (1-methylimidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzonitrile;

4-benzyloxy-3- [ (4- (1-ethoxycarbonyl-2-carboxyethoxy) -6- (3- (1-methylimidazol-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzonitrile;

4-benzyloxy-3- [ (4- (1-ethoxycarbonyl-2-aminocarbonylethoxy) -6- (3- (1-methylimidazol-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzonitrile;

4-benzyloxy-3- [ (4- (1-ethoxycarbonyl-3-carboxypropoxy) -6- (3- (1-methylimidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzonitrile;

4-benzyloxy-3- [ (4- (1-ethoxycarbonyl-3-aminocarbonylpropoxy) -6- (3- (1-methylimidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzonitrile;

4-benzyloxy-3- [ (4- (1-ethoxycarbonyl-2-imidazol-4-ylethoxy) -6- (3- (1-methylimidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzonitrile;

4-benzyloxy-3- [ (4- (1-ethoxycarbonyl-2-phenylmethylethoxy) -6- (3- (1-methylimidazol-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzonitrile;

4-benzyloxy-3- [ (4- (1-ethoxycarbonyl-2-indol-3-ylethoxy) -6- (3- (1-methylimidazol-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzonitrile;

4-benzyloxy-3- [ (4- (1-ethoxycarbonyl-4-guanidinobutoxy) -6- (3- (1-methylimidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzonitrile, and

4-benzyloxy-3- [ (4- (1-ethoxycarbonyl-4-guanidinobutoxy) -6- (3- (1-methylimidazol-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzonitrile.

Preparation example 6

A compound of formula (N)

A. To a solution of ethyl 2-hydroxy-4-methylpentanoate (0.50g,2.5mmol) in anhydrous DMF (25ml) were added pentafluoropyridine (0.31ml,0.47g,2.8mmol) and cesium carbonate (1.1g,3.3 mmol). The resulting mixture was heated to 45 ℃ and stirred at this temperature for 10 days, then poured into 100ml of water and 100ml of ethyl acetate. The aqueous layer was separated and extracted with 500ml of ethyl acetate. The combined extracts were washed with water (100ml), then brine (100ml), and MgSO₄Drying, filtration and concentration in vacuo gave 0.87g (99% yield) of 4- (1-ethoxycarbonyl-3-methylbutyl) oxy-2, 3,5, 6-tetrafluoropyridine as a clear yellow solution: NMR (CDCl)₃)5.2(d,1),4.3-4.1(m,3),2.0(m,1),1.8(m,1),1.3(m,3),1.0(m,6)ppm。

B. In a similar manner, the following compounds were prepared:

4- (1-ethoxycarbonyl-3-methylbutyl) oxy-2, 3,5, 6-tetrafluoropyridine;

4- (1-ethoxycarbonyl-2-methylpropyl) oxy-2, 3,5, 6-tetrafluoropyridine;

4- (1-ethoxycarbonyl-2-methylbutyl) oxy-2, 3,5, 6-tetrafluoropyridine;

4- (1-ethoxycarbonyl-2-mercaptoethyl) oxy-2, 3,5, 6-tetrafluoropyridine;

4- (1-ethoxycarbonyl-3-methylthiopropyl) oxy-2, 3,5, 6-tetrafluoropyridine;

4- (1-ethoxycarbonyl-2-hydroxyethyl) oxy-2, 3,5, 6-tetrafluoropyridine;

4- (1-ethoxycarbonyl-2-hydroxypropyl) oxy-2, 3,5, 6-tetrafluoropyridine;

4- (1-ethoxycarbonyl-2-carboxyethyl) oxy-2, 3,5, 6-tetrafluoropyridine;

4- (1-ethoxycarbonyl-2-aminocarbonylethyl) oxy-2, 3,5, 6-tetrafluoropyridine;

4- (1-ethoxycarbonyl-3-carboxypropyl) oxy-2, 3,5, 6-tetrafluoropyridine;

4- (1-ethoxycarbonyl-3-aminocarbonylpropyl) oxy-2, 3,5, 6-tetrafluoropyridine;

4- (1-ethoxycarbonyl-2-imidazol-4-ylethyl) oxy-2, 3,5, 6-tetrafluoropyridine;

4- (1-ethoxycarbonyl-2-phenylmethyl ethyl) oxy-2, 3,5, 6-tetrafluoropyridine;

4- (1-ethoxycarbonyl-2-indol-3-ylethyl) oxy-2, 3,5, 6-tetrafluoropyridine;

4- (1-ethoxycarbonyl-4-guanidinobutyl) oxy-2, 3,5, 6-tetrafluoropyridine; and

4- (1-ethoxycarbonyl-4-aminobutyl) oxy-2, 3,5, 6-tetrafluoropyridine.

Preparation example 7

A compound of formula (Q)

A. To 4-benzyloxy-3- [ (4- (N- (1-tert-butoxycarbonyl-5- (N-tert-butoxycarbonylamino) pentyl) amino-6- (3- (1-methylimidazol-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy group]Benzonitrile (600mg,0.74mmol) in dichloromethane (25ml) was added 25ml of TFA. The resulting mixture was stirred at room temperature for 1.5 hours, then all volatile components were removed in vacuo. The residue is dissolved in 25ml of a 3: 2 methanol/water mixture and K is added₂CO₃To a pH of 11(1.05g, 7.4mmol) was added amidino sulfonic acid (275mg,2.22 mmol). After 30 minutes, the unit fractions were withdrawn and analyzed by HPLC using a C18Dynamax column and eluted with a gradient of 0.1% trifluoroacetic acid in 20-80% acetonitrile in water to show complete reaction. The reaction mixture was concentrated in vacuo to remove the solvent, and the residual aqueous solution was extracted 3 times with acetonitrile. The combined organic layers were washed with brine, filtered through a column of Celite and concentrated to give 800mg of 4-benzyloxy-3- [ (4- (N- (carboxy-5-guanidinopentyl) amino) -6- (3- (1-methyl) imidazol-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy]Benzonitrile, an oil.

B. In a similar manner, the following compounds were prepared:

4-benzyloxy-3- [ (4- (N- (carboxy-5-guanidinopentyl) amino) -6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzonitrile.

C. In a similar manner, the following compounds were prepared:

4-benzyloxy-3- [ (4- (N-methyl-N- (carboxy-5-guanidinopentyl) amino) -6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzonitrile.

Example 1

A compound of formula (Ia)

A. 4-benzyloxy-3- [ (4- (N-methyl-N- (1-ethoxycarbonyl-1-methylethyl) amino) -6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy]A solution of benzonitrile (0.98g, 1.46mmol) in absolute ethanol (40ml) was cooled to-78 deg.C and HCl (gas) was bubbled through the mixture for 15 min. The resulting mixture was stirred at room temperature for 20 hours and then concentrated in vacuo without heating to give a white foam. The foam was dissolved in absolute ethanol (40ml) and heated to reflux with NH₃Gently (gas) bubbled through the mixture. After 2 hours, the mixture was cooled to room temperature and concentrated in vacuo. HPLC purification on a C18Dynamax column with a gradient elution using 20-80% acetonitrile in water containing 0.1% trifluoroacetic acid to give 4-hydroxy-3- [ (4- (N-methyl-N- (1-ethoxycarbonyl-1-methylethyl) amino) -6- (3- (1-methylimidazolin-2-yl) phenoxy) -3, 5-difluoropyridin-2-yl) oxy]Trifluoroacetate salt of benzamidine as white solid: NMR (DMSO-d)₆)10.2(br s,1),9.0(br s,2),8.7(br s,2),7.3-7.6(m,6),7.0(d,2),3.9-4.2(m,6),3.0(s,3),2.9(s,3),1.5(s,3),1.1(t,3)ppm。

B. In a similar manner, the following compounds were prepared:

4-hydroxy-3- [ (4- (N- (1-carboxy-5-guanidinopentyl) amino) -6- (3- (1-methylimidazolin-2-yl) phenoxy) -3, 5-difluoropyridin-2-yl) oxy]Benzamidine; NMR (DMSO-d)₆)11.1(br s,1),10.3(br s,1),9.1(br s,2),8.9(br s,2),7.0-7.7(m,10),6.6(d,1),4.3(m,1),4.0(m,2),3.9(m,2),3.1(m,2),3.0(s,3),1.8(m,2),1.5(m,4)ppm；

4-hydroxy-3- [ (4- (1-ethoxycarbonyl-3-methylbutoxy) -6- (3- (1-methylimidazolin-2-yl) phenoxy) -3, 5-difluoropyridin-2-yl) oxy]Benzamidine; NMR (DMSO-d)₆)10.2(br s,1),9.0(brs,2),8.8(br s,2),7.3-7.6(m,6),7.0(d,1),5.2(m,1),4.2(q,2),3.9-4.1(m,4),2.9(s,3),1.7-2.0(m,3),1.2(t,3),1.0(s,3),0.95(s,3)ppm；

4-hydroxy-3- [ (4- (N-methyl-N- (1-ethoxycarbonylethyl) amino) -6- (3- (1-methylimidazolin-2-yl) phenoxy) -3, 5-difluoropyridin-2-yl) oxy]Benzamidine; NMR (DMSO-d)₆)10.2(br s,1),9.0(br s,2),8.8(br s,2),7.3-7.6(m,6),7.0(d,2),4.4(q,2),3.8-4.2(m,5),3.0(s,3),2.9(s,3),1.4(d,3),1.2(t,3)ppm。

C. In a similar manner, the following compounds were prepared:

4-hydroxy-3- [ (4- (N-ethyl-N- (1-ethoxycarbonyl-1-methylethyl) amino) -6- (3- (1-methylimidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzamidine;

4-hydroxy-3- [ (4- (N-propyl-N- (1-ethoxycarbonyl-1-methylethyl) amino) -6- (3- (1-methylimidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzamidine;

4-hydroxy-3- [ (4- (N-butyl-N- (1-ethoxycarbonyl-1-methylethyl) amino) -6- (3- (1-methylimidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzamidine;

4-hydroxy-3- [ (4- (N-phenyl-N- (1-ethoxycarbonyl-1-methylethyl) amino) -6- (3- (1-methylimidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzamidine;

4-hydroxy-3- [ (4- (N-benzyl-N- (1-ethoxycarbonyl-1-methylethyl) amino) -6- (3- (1-methylimidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzamidine;

4-hydroxy-3- [ (4- (N- (3-ethoxycarbonylpropyl) -N- (1-ethoxycarbonyl-1-methylethyl) amino) -6- (3- (1-methylimidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzamidine;

4-hydroxy-3- [ (4- (N- (4-aminocarbonylbutyl) -N- (1-ethoxycarbonyl-1-methylethyl) amino) -6- (3- (1-methylimidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzamidine;

4-hydroxy-3- [ (4- (N- (4-aminobutyl) -N- (1-ethoxycarbonyl-1-methylethyl) amino) -6- (3- (1-methylimidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzamidine;

4-hydroxy-3- [ (4- (N-propyl-N- (1-ethoxycarbonyl-3-methylbutyl) amino) -6- (3- (1-methylimidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzamidine;

4-hydroxy-3- [ (4- (N-methyl-N- (1-ethoxycarbonyl-2-methylpropyl) amino) -6- (3- (1-methylimidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzamidine;

4-hydroxy-3- [ (4- (N-methyl-N- (1-ethoxycarbonyl-2-methylbutyl) amino) -6- (3- (1-methylimidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzamidine;

4-hydroxy-3- [ (4- (N-methyl-N- (1-ethoxycarbonyl-2-mercaptoethyl) amino) -6- (3- (1-methylimidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzamidine;

4-hydroxy-3- [ (4- (N-methyl-N- (1-ethoxycarbonyl-3-methylthiopropyl) amino) -6- (3- (1-methylimidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzamidine;

4-hydroxy-3- [ (4- (N-methyl-N- (1-ethoxycarbonyl-2-hydroxyethyl) amino) -6- (3- (1-methylimidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzamidine;

4-hydroxy-3- [ (4- (N-methyl-N- (1-ethoxycarbonyl-2-hydroxypropyl) amino) -6- (3- (1-methylimidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzamidine;

4-hydroxy-3- [ (4- (N-methyl-N- (1-ethoxycarbonyl-2-carboxyethyl) amino) -6- (3- (1-methylimidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzamidine;

4-hydroxy-3- [ (4- (N-methyl-N- (1-ethoxycarbonyl-2-aminocarbonylethyl) amino) -6- (3- (1-methylimidazol-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzamidine;

4-hydroxy-3- [ (4- (N-methyl-N- (1-ethoxycarbonyl-3-carboxypropyl) amino) -6- (3- (1-methylimidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzamidine;

4-hydroxy-3- [ (4- (N-methyl-N- (1-ethoxycarbonyl-3-aminocarbonylpropyl) amino) -6- (3- (1-methylimidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzamidine;

4-hydroxy-3- [ (4- (N-methyl-N- (1-ethoxycarbonyl-2-imidazol-4-ylethyl) amino) -6- (3- (1-methylimidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzamidine;

4-hydroxy-3- [ (4- (N-methyl-N- (1-ethoxycarbonyl-2-phenylmethyl) ethyl) amino) -6- (3- (1-methylimidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzamidine;

4-hydroxy-3- [ (4- (N-methyl-N- (1-ethoxycarbonyl-2-indol-3-ylethyl) amino) -6- (3- (1-methylimidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzamidine;

4-hydroxy-3- [ (4- (N-methyl-N- (1-ethoxycarbonyl-4-guanidinobutyl) amino) -6- (3- (1-methylimidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzamidine;

4-hydroxy-3- [ (4- (1-ethoxycarbonyl-1-methylethoxy) -6- (3- (1-methylimidazol-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzamidine;

4-hydroxy-3- [ (4- (1-ethoxycarbonyl-1-methylethoxy) -6- (3- (1-methylimidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzamidine;

4-hydroxy-3- [ (4- (1-ethoxycarbonyl-3-methylbutoxy) -6- (3- (1-methylimidazol-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzamidine;

4-hydroxy-3- [ (4- (1-ethoxycarbonyl-2-methylpropoxy) -6- (3- (1-methylimidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzamidine;

4-hydroxy-3- [ (4- (1-ethoxycarbonyl-2-methylbutoxy) -6- (3- (1-methylimidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzamidine;

4-hydroxy-3- [ (4- (1-ethoxycarbonyl-2-mercaptoethoxy) -6- (3- (1-methylimidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzamidine;

4-hydroxy-3- [ (4- (1-ethoxycarbonyl-3-methylthiopropoxy) -6- (3- (1-methylimidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzamidine;

4-hydroxy-3- [ (4- (1-ethoxycarbonyl-2-hydroxyethoxy) -6- (3- (1-methylimidazol-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzamidine;

4-hydroxy-3- [ (4- (1-ethoxycarbonyl-2-hydroxypropoxy) -6- (3- (1-methylimidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzamidine;

4-hydroxy-3- [ (4- (1-ethoxycarbonyl-2-carboxyethoxy) -6- (3- (1-methylimidazol-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzamidine;

4-hydroxy-3- [ (4- (1-ethoxycarbonyl-2-aminocarbonylethoxy) -6- (3- (1-methylimidazol-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzamidine;

4-hydroxy-3- [ (4- (1-ethoxycarbonyl-3-carboxypropoxy) -6- (3- (1-methylimidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzamidine;

4-hydroxy-3- [ (4- (1-ethoxycarbonyl-3-aminocarbonylpropoxy) -6- (3- (1-methylimidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzamidine;

4-hydroxy-3- [ (4- (1-ethoxycarbonyl-2-imidazol-4-ylethoxy) -6- (3- (1-methylimidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzamidine;

4-hydroxy-3- [ (4- (1-ethoxycarbonyl-2-phenylmethylethoxy) -6- (3- (1-methylimidazol-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzamidine;

4-hydroxy-3- [ (4- (1-ethoxycarbonyl-2-indol-3-ylethoxy) -6- (3- (1-methylimidazol-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzamidine;

4-hydroxy-3- [ (4- (1-ethoxycarbonyl-4-guanidinobutoxy) -6- (3- (1-methylimidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzamidine, and

4-hydroxy-3- [ (4- (1-ethoxycarbonyl-4-guanidinobutoxy) -6- (3- (1-methylimidazol-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzamidine.

Example 2

Compounds of formula (Ib)

A. 4-hydroxy-3- [ (4- (N-methyl-N- (1-ethoxycarbonyl-1-methylethyl) amino) -6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy]Benzamidine trifluoroacetate salt (0.10g,0.11mmol) in 6N aqueous HCl (12ml) was stirred at 65 ℃ for 1 hour. Then, it was cooled to room temperature, diluted with acetonitrile and trifluoroacetic acid, purified by HPLC using a C18Dynamax column, and subjected to gradient elution using a 20-80% acetonitrile aqueous solution containing 0.1% trifluoroacetic acid to give 4-hydroxy-3- [ (4- (N-methyl-N- (1-carboxy-1-methylethyl) amino) -6- (3- (1-methylimidazolin-2-yl) phenoxy) -3, 5-difluoropyridin-2-yl) oxy]Trifluoroacetate salt of benzamidine as white solid: NMR ((DMSO-d)₆)/TFA)10.2(br s,1),9.0(br s,2),8.8(br s,2),7.3-7.6(m,6),7.0(d,2),4.1m,2),3.9(m,2),3.0(s,3),2.9(s,3),1.4(s,3)ppm。

B. In a similar manner, the following compounds were prepared:

4-hydroxy-3- [ (4- (1-carboxy-3-methylbutoxy) -6- (3- (1-methylimidazolin-2-yl) phenoxy) -3, 5-difluoropyridin-2-yl) oxy]Benzamidine: NMR (DMSO-d)₆)9.0(br s,2),8.8(br s,2),7.0-7.7(m,6),7/0(d,1),5.2(m,1),3.9-4.1(m,4),2.9(s,3),3.0(s,3),1.7-2.0(m,3),1.0(s,3),0.95(s,3)ppm；

4-hydroxy-3- [ (4- (N-methyl-N- (1-carboxyethyl) amino) -6- (3- (1-methylimidazolin-2-yl) phenoxy) -3, 5-difluoropyridin-2-yl) oxy]Trifluoroacetate salt of benzamidine as white solid: NMR (DMSO-d)₆)10.2(br s,1),9.0(br s,2),8.8(br s,2),7.3-7.6(m,6),7.0(d,2),4.3(q,2),4.1(m,2),3.9(m,2),3.0(s,3),2.9(s,3),1.4(d,3)ppm。

C. In a similar manner, the following compounds were prepared:

4-hydroxy-3- [ (4- (N-ethyl-N- (1-carboxy-1-methylethyl) amino) -6- (3- (1-methylimidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzamidine;

4-hydroxy-3- [ (4- (N-propyl-N- (1-carboxy-1-methylethyl) amino) -6- (3- (1-methylimidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzamidine;

4-hydroxy-3- [ (4- (N-butyl-N- (1-carboxy-1-methylethyl) amino) -6- (3- (1-methylimidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzamidine;

4-hydroxy-3- [ (4- (N-phenyl-N- (1-carboxy-1-methylethyl) amino) -6- (3- (1-methylimidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzamidine;

4-hydroxy-3- [ (4- (N-benzyl-N- (1-carboxy-1-methylethyl) amino) -6- (3- (1-methylimidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzamidine;

4-hydroxy-3- [ (4- (N- (3-carboxypropyl) -N- (1-carboxy-1-methylethyl) amino) -6- (3- (1-methylimidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzamidine;

4-hydroxy-3- [ (4- (N- (4-aminocarbonylbutyl) -N- (1-carboxy-1-methylethyl) amino) -6- (3- (1-methylimidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzamidine;

4-hydroxy-3- [ (4- (N- (4-aminobutyl) -N- (1-carboxy-1-methylethyl) amino) -6- (3- (1-methylimidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzamidine;

4-hydroxy-3- [ (4- (N-propyl-N- (1-carboxy-3-methylbutyl) amino) -6- (3- (1-methylimidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzamidine;

4-hydroxy-3- [ (4- (N-methyl-N- (1-carboxy-2-methylpropyl) amino) -6- (3- (1-methylimidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzamidine;

4-hydroxy-3- [ (4- (N-methyl-N- (1-carboxy-2-methylbutyl) amino) -6- (3- (1-methylimidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzamidine;

4-hydroxy-3- [ (4- (N-methyl-N- (1-carboxy-2-mercaptoethyl) amino) -6- (3- (1-methylimidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzamidine;

4-hydroxy-3- [ (4- (N-methyl-N- (1-carboxy-3-methylthiopropyl) amino) -6- (3- (1-methylimidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzamidine;

4-hydroxy-3- [ (4- (N-methyl-N- (1-carboxy-2-hydroxyethyl) amino) -6- (3- (1-methylimidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzamidine;

4-hydroxy-3- [ (4- (N-methyl-N- (1-carboxy-2-hydroxypropyl) amino) -6- (3- (1-methylimidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzamidine;

4-hydroxy-3- [ (4- (N-methyl-N- (1-carboxy-2-carboxyethyl) amino) -6- (3- (1-methylimidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzamidine;

4-hydroxy-3- [ (4- (N-methyl-N- (1-carboxy-2-aminocarbonylethyl) amino) -6- (3- (1-methylimidazol-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzamidine;

4-hydroxy-3- [ (4- (N-methyl-N- (1-carboxy-3-carboxypropyl) amino) -6- (3- (1-methylimidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzamidine;

4-hydroxy-3- [ (4- (N-methyl-N- (1-carboxy-3-aminocarbonylpropyl) amino) -6- (3- (1-methylimidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzamidine;

4-hydroxy-3- [ (4- (N-methyl-N- (1-carboxy-2-imidazol-4-ylethyl) amino) -6- (3- (1-methylimidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzamidine;

4-hydroxy-3- [ (4- (N-methyl-N- (1-carboxy-2-phenylmethyl) ethyl) amino) -6- (3- (1-methylimidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzamidine;

4-hydroxy-3- [ (4- (N-methyl-N- (1-carboxy-2-indol-3-ylethyl) amino) -6- (3- (1-methylimidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzamidine;

4-hydroxy-3- [ (4- (N-methyl-N- (1-carboxy-4-guanidinobutyl) amino) -6- (3- (1-methylimidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzamidine;

4-hydroxy-3- [ (4- (1-carboxy-1-methylethoxy) -6- (3- (1-methylimidazol-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzamidine;

4-hydroxy-3- [ (4- (1-carboxy-1-methylethoxy) -6- (3- (1-methylimidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzamidine;

4-hydroxy-3- [ (4- (1-carboxy-3-methylbutoxy) -6- (3- (1-methylimidazol-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzamidine;

4-hydroxy-3- [ (4- (1-carboxy-2-methylpropoxy) -6- (3- (1-methylimidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzamidine;

4-hydroxy-3- [ (4- (1-carboxy-2-methylbutoxy) -6- (3- (1-methylimidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzamidine;

4-hydroxy-3- [ (4- (1-carboxy-2-mercaptoethoxy) -6- (3- (1-methylimidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzamidine;

4-hydroxy-3- [ (4- (1-carboxy-3-methylthiopropoxy) -6- (3- (1-methylimidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzamidine;

4-hydroxy-3- [ (4- (1-carboxy-2-hydroxyethoxy) -6- (3- (1-methylimidazol-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzamidine;

4-hydroxy-3- [ (4- (1-carboxy-2-hydroxypropoxy) -6- (3- (1-methylimidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzamidine;

4-hydroxy-3- [ (4- (1-carboxy-2-carboxyethoxy) -6- (3- (1-methylimidazol-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzamidine;

4-hydroxy-3- [ (4- (1-carboxy-2-aminocarbonylethoxy) -6- (3- (1-methylimidazol-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzamidine;

4-hydroxy-3- [ (4- (1-carboxy-3-carboxypropoxy) -6- (3- (1-methylimidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzamidine;

4-hydroxy-3- [ (4- (1-carboxy-3-aminocarbonylpropoxy) -6- (3- (1-methylimidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzamidine;

4-hydroxy-3- [ (4- (1-carboxy-2-imidazol-4-ylethoxy) -6- (3- (1-methylimidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzamidine;

4-hydroxy-3- [ (4- (1-carboxy-2-phenylmethylethoxy) -6- (3- (1-methylimidazol-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzamidine;

4-hydroxy-3- [ (4- (1-carboxy-2-indol-3-ylethoxy) -6- (3- (1-methylimidazol-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzamidine;

4-hydroxy-3- [ (4- (1-carboxy-4-guanidinobutoxy) -6- (3- (1-methylimidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzamidine, and

4-hydroxy-3- [ (4- (1-carboxy-4-guanidinobutoxy) -6- (3- (1-methylimidazol-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzamidine.

Example 3

A compound of formula (ic)

A. 4-benzyloxy-3- [ (4- (N- (1-tert-butoxycarbonyl-5- (N-tert-butoxycarbonyl) amino) pentyl) amino) -6- (3- (1-methyl) imidazol-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy]A solution (15ml) of benzonitrile (890mg,1.1mmol) in a 1: 1 mixture of ethanol/dichloromethane was cooled to-10 ℃ and HCl (gas) was bubbled through the mixture for 15 minutes. The resulting mixture was stirred at room temperature for 20 hours and then concentrated in vacuo without heating to remove all volatiles to give a white foamy solid. Dissolving the foam in anhydrous ethanol (40ml), cooling to-10 deg.C while using NH₃Gently (gas) bubble through the mixture for 15 minutes. The mixture was then heated at 65 ℃ for 2 hours, cooled to room temperature and concentrated in vacuo. The resulting residue was dissolved in 6N aqueous HCl (10ml) and heated at 85 ℃ for 4 hours. The mixture was cooled to room temperature and purified by HPLC using a C18Dynamax column, and eluted with a gradient of 0.1% trifluoroacetic acid in 20-80% acetonitrile in water to give 4-hydroxy-3- [ (4- (N- (1-carboxy-5-amino) pentyl) amino) -6- (3- (1-methylimidazol-2-yl) phenoxy) -3, 5-difluoropyridin-2-yl) oxy]Benzamidine; NMR (DMSO-d)₆)8.9(br s,2),8.6(br s,2),7.7-7.2(m,12),6.8-7.7(m,9),6.5(br s,1),4.4(m,1),3.7(s,3),2.8(m,2),1.9(m,2),1.5(m,4)ppm。

B. In a similar manner, the following compounds were prepared:

4-hydroxy-3- [ (4- (N- (1-carboxy-5-guanidinopentyl) amino) -6- (3- (1-methylimidazol-2-yl) phenoxy) -3, 5-difluoropyridin-2-yl) oxy]Benzamidine: NMR (DMSO-d)₆)8.9(br s,2),6.3-7.7(m,17),4.4(m,1),3.7(s,3),3.1(m,2),1.9(m,2),1.5(m,4)ppm；

C. In a similar manner, the following compounds were prepared:

4-hydroxy-3- [ (4- (N- (1-carboxy-5-aminopentyl) amino) -6- (3- (1-methylimidazolin-2-yl) phenoxy) -3, 5-difluoropyridin-2-yl) oxy ] benzamidine.

Example 4

A compound of formula (Id)

A. To 4-hydroxy-3- [ (4- (N- (1-carboxy-5-aminopentyl) amino) -6- (3- (1-methyl) imidazol-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy]To a solution of benzamidine (271mg,0.47mmol) in a 4: 1 methanol/water mixture (12ml) was added K₂CO₃(193mg,1.4mmol, pH8-9) and Ethylimidoacetate (172mg,1.4 mmol). After stirring for 1 hour, the mixture was filtered and purified by preparative HPLC on a C18Dynamax column, eluting with a gradient of 20-80% acetonitrile in water containing 0.1% trifluoroacetic acid to give 4-hydroxy-3- [ (4- (N- (1-carboxy-5- (N- (1-iminoethyl) amino) pentyl) amino) -6- (3- (1-methylimidazolin-2-yl) phenoxy) -3, 5-difluoropyridin-2-yl) oxy]Benzamidine; NMR ((DMSO-d)₆))9.3(br s,1),8.9(br s,3),8.6(br s,2),8.4(br s,2),7.4-7.7(m,9),7.2(d,1),6.8(d,1),4.4(m,1),3.7(s,3),3.2(m,2),2.1(s,3),1.9(m,2),1.5(m,4)ppm。

B. In a similar manner, the following compounds were prepared:

4-hydroxy-3- [ (4- (1-carboxy-5- (N- (1-iminoethyl) amino) pentyl) amino) -6- (3- (1-methylimidazolin-2-yl) phenoxy) -3, 5-difluoropyridin-2-yl) oxy]Benzamidine: NMR (DMSO-d)₆)10.3(br s,1),9.4(br s,1),9.0(br s,3),8.7(br s,2),8.5(br s,2),7.0-7.7(m,9),6.3(br s,1),4.4(m,1),4.1(m,2),3.9(m,2),3.3(m,2),3.0(s,3),2.2(s,3),1.8(m,2),1.5(m,4)ppm。

Example 5

This example illustrates the preparation of a representative oral pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, e.g., 4-hydroxy-3- [ (4-N-methyl-N- (1-carboxy-1-methylethyl) amino) -6- (3- (1-methylimidazolin-2-yl) phenoxy) -3, 5-difluoropyridin-2-yl) oxy ] benzamidine:

A. composition% by weight

Compound of the invention 20.0%

Lactose 79.5%

Magnesium stearate 0.5%

The above ingredients were mixed and filled into hard shell gelatin capsules, each containing 100mg, each capsule for approximately one day of dosage.

B. Composition% by weight

Compound of the invention 20.0%

0.9 percent of magnesium stearate

8.6 percent of starch

Lactose 79.6%

PVP (polyvinylpyrrolidone) 0.5%

The ingredients other than magnesium stearate were combined and granulated with water as the granulation liquid. It is then dried and mixed with magnesium stearate and formed into tablets using a suitable tablet press.

C. Weight of ingredients

Compound of the invention 0.1g

Polyethylene glycol 20.0g

Polyethylene glycol 40020.0 g

Polysorbate 801.0 g

Water to 100ml

The compounds of the invention were dissolved in ethylene glycol, ethylene glycol 400 and polysorbate 80. Sufficient water was then added with stirring to give a 100ml solution which was filtered and bottled.

D. Composition% by weight

Compound of the invention 20.0%

Peanut oil 78.0%

Span 602.0%

Melting the above materials, mixing, and encapsulating.

E. Composition% by weight

Compound 1.0% of the present invention

2.0 percent of methyl or carboxymethyl cellulose

0.9% saline to 100ml

Example 6

This example illustrates the preparation of a representative parenterally administered pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, for example, 4-hydroxy-3- [ (4- (N-methyl-N- (1-ethoxycarbonyl-1-methylethyl) amino) -6- (3- (1-methylimidazolin-2-yl) phenoxy) -3, 5-difluoropyridin-2-yl) oxy ] benzamidine:

composition (I)

Compound of the invention 0.02g

Polyethylene glycol 20.0g

Polyethylene glycol 40020.0 g

Polysorbate 801.0 g

0.9% saline solution to 100ml

The compounds of the invention were dissolved in ethylene glycol, ethylene glycol 400 and polysorbate 80. Sufficient 0.9% saline solution was then added with stirring to give 100ml of intravenous solution, which was filtered through 0.2 μ of membrane filter and packaged under sterile conditions.

Example 7

This example illustrates the preparation of a representative pharmaceutical composition in the form of a suppository, containing a compound of the present invention, or a pharmaceutically acceptable salt thereof, e.g., 4-hydroxy-3- [ (4- (N-methyl-N- (1-ethoxycarbonyl-1-methylethyl) amino) -6- (3- (1-methylimidazolin-2-yl) phenoxy) -3, 5-difluoropyridin-2-yl) oxy ] benzamidine:

composition% by weight

Compound 1.0% of the present invention

100074.5 percent of polyethylene glycol

400024.5 percent of polyethylene glycol

In a steam bath, the ingredients were melted together and mixed and poured into molds containing a total weight of 2.5 g.

Example 8

This example illustrates the preparation of a pharmaceutical composition in the form of a representative insufflation comprising a compound of the present invention or a pharmaceutically acceptable salt thereof, for example, 4-hydroxy-3- [ (4-N-methyl-N- (1-carboxy-1-methylethyl) amino) -6- (3- (1-methylimidazolin-2-yl) phenoxy) -3, 5-difluoropyridin-2-yl) oxy ] benzamidine:

composition% by weight

Micronized compound of the invention 1.0%

Micronized lactose 99.0%

The two components are ground, mixed and packaged in an insufflator equipped with a dosage pump.

Example 9

This example illustrates the preparation of a pharmaceutical composition in the form of a representative spray containing a compound of the invention, or a pharmaceutically acceptable salt thereof, for example, 4-hydroxy-3- [ (4-N- (1-carboxy-5-aminopentyl) amino) -6- (3- (1-methylimidazolin-2-yl) phenoxy) -3, 5-difluoropyridin-2-yl) oxy ] benzamidine:

composition% by weight

0.005% of the compound of the present invention

89.995 percent of water

Ethanol 10.000%

The compounds of the invention are dissolved in ethanol, admixed with water. The formulation is then packaged in a nebulizer equipped with a dosage pump.

Example 10

This example illustrates the preparation of a representative pharmaceutical composition in aerosol form comprising a compound of the invention or a pharmaceutically acceptable salt thereof, e.g., 4-hydroxy-3- [ (4-N- (1-carboxy-5-guanidinopentyl) amino) -6- (3- (1-methylimidazol-2-yl) phenoxy) -3, 5-difluoropyridin-2-yl) oxy ] benzamidine:

composition% by weight

0.10% of the compound of the present invention

98.90 percent of spraying agent

Oleic acid 1.00%

The compounds of the present invention are dispersed in oleic acid and a propellant. The resulting mixture was then poured into an aerosol container equipped with a metering valve.

Example 11

(in vitro experiments on factor Xa and Thrombin)

This experiment illustrates the activity of the compounds of the invention on factor xa, thrombin and tissue plasminogen activator. This activity is determined by the initial rate of cleavage of the paranitroanilide peptide by the enzyme. The cleavage product p-nitroaniline has absorption at 405nm and molar extinction coefficient of 9920M^-1cm^-1。

Reagents and solutions:

dimethylsulfoxide (DMSO) (Baker analytical grade).

Experiment buffer solution:

50mM TrisHCl,150mM NaCl,2.5mM CaCl₂0.1% polyethylene glycol 6000, pH 7.5.

Enzyme (Enzyme Research Lab.):

1. human factor xa stock solution: 0.281mg/ml (assay buffer as solvent), stored at-80 deg.C (working solution (2X): 106ng/ml or 2nM (assay buffer as solvent), prepared before use).

2. Human thrombin stock solution: storage at-80 deg.C (working solution (2X): 1200ng/ml or 40nM of assay buffer as solvent, prepared before use).

3. Human tissue plasminogen activator (tPA) (Two chains, Sigma) stock: 1mg/ml, stored at-80 ℃ (working solution (2X): 1361ng/ml (experimental buffer as solvent), prepared before use).

Chromogenic substrate (Pharmacia Hepar Inc.):

s2222(F Xa experiment)) Liquid storage: 6mM (dH)₂O as solvent), stored at 4 deg.C (working solution (4X): 656. mu.M (experimental buffer as solvent)).

S2302 (thrombin assay) stock: 10mM (dH)₂O as solvent), stored at 4 deg.C (working solution (4X): 1200. mu.M (experimental buffer as solvent)).

S2288(tPA experiment) stock: 10mM (dH)₂O as solvent), stored at 4 deg.C (working solution (4X): 1484. mu.M (experimental buffer as solvent)).

(all substrate working solutions were prepared on day 5 of the experiment)

Stock solutions of standard inhibitor compounds:

5mM (DMSO as solvent), stored at-20 ℃.

Test compounds (compounds of the invention) stock solutions:

10mM (DMSO as solvent), stored at-20 ℃.

The experimental process comprises the following steps:

the experiments were performed in 96-well microtiter plates with a total volume of 200. mu.L. The final concentration of the experimental components was 50mM TrisHCl, 150mM NaCl,2.5mM CaCl₂0.1% polyethylene glycol 6000, ph7.5, with or without standard inhibitors, or the concentrations of test compounds and enzymes and substrates were as follows: (1)1nM of factor Xa and 164. mu. M S2222; (2)20nM thrombin and 300. mu.MS 2302; (3)10nM tPA and 371 u M S2228. In this experiment, the concentration of the standard inhibitor compound in the 1-3 dilutions was typically 5. mu.M-0.021. mu.M. In this experiment, the concentration of the test compound in the 1-3 dilutions was typically 10. mu.M-0.041. mu.M. For the potent test compounds, the concentrations employed in the factor Xa assay had to be further diluted 100-fold (100nM to 0.41nM) or 1000-fold (10nM to 0.041 nM). Under the experimental conditions of this experiment, all substrate concentrations equal to their K were used_mThe value is obtained. The experiments were performed at room temperature.

The first step of the experiment was to prepare a 10mM stock solution of the test compound (DMSO as solvent) (for factor Xa experiments, 10mM stock solutions of potent compounds should be further diluted to 0.1-0.01mM) and then prepare test compound working solutions (4 ×) in 96-deep well plates by serial dilution of the 10mM stock solutions with Biomek 1000 (or Multiprobe 204) as follows:

(a)10 mM stock solution 1 was diluted to 250: 1 to 100, and 1 to 2.5, in two steps with assay buffer to make 40. mu.M working solution (assay buffer as solvent);

(b) five further serial dilutions (1: 3) of 40. mu.M solution were prepared (600. mu.l each at each concentration). A total of six test compound solutions were used in this experiment. Standard inhibitor compounds (5mM stock) or DMSO (control) were prepared following the same dilution procedure as described above for test compounds.

The second step of the experiment was to dispense 50. mu.l of the test compound working solution (4X) (40. mu.M-0.164. mu.M) onto a microtiter plate using Biomek or MP204, and the same procedure was repeated once. To this solution was added 100. mu.l of enzyme working solution (2X) using Biomek or MP 204. The resulting solution was incubated at room temperature for 10 minutes.

To this solution was added 50. mu.l of the substrate working solution (4X) using Biomek or MP 204.

The enzyme kinetics at 405nm were measured at room temperature in a THERMOmax plate counter at 10 second intervals for 5 minutes.

Calculating K of BX Compound_iThe value:

the enzyme rate was calculated based on the reading of the first two minutes in mOD/min. Using the spread-sheet of EXCEL, the IC is determined by fitting the data to a log-log equation (linear) or to a Morrison equation (non-linear)₅₀The value is obtained. Then, the IC is put₅₀The value is divided by 2 to give K_iThe value is obtained. And K out of 3nM was calculated incidentally from the Morrison equation_iValue (factor xa).

The compounds of the invention tested in this experiment show their selective ability to inhibit human factor xa and human thrombin.

Example 12

(in vitro assay of human prothrombinase)

This experiment demonstrates the ability of the compounds of the invention to inhibit prothrombinase. Using meizothrombin as an intermediate, prothrombinase (PTase) catalyzes the activation of prethrombin to produce fragment 1.2 and thrombin. This experiment is an end-point experiment. The prothrombinase activity is measured from the activity of thrombin (one of the reaction products) or from the amount of thrombin formed/time based on a thrombin standard curve (nM vs. mOD/min). To determine the IC of the Compounds of the invention₅₀Value (PTase), PTase activity is expressed by thrombin activity (mOD/min).

Materials:

enzyme

1. Human factor Va (Haematologic Technologies inc., Cat # HCVA-0110) working solution: 1.0mg/ml (50% glycerol as solvent), 2mM CaCl₂And storing at-20 ℃.

2. Human factor Xa (Enzyme Research Lab., Cat # HF Xa-1011) working solution: 0.281mg/ml (assay buffer as solvent) (no BSA) was stored at-80 ℃.

3. Human prethrombin (fii) (Enzyme Research lab, Cat # HP1002) working solution: f II was diluted to 4.85mg/ml (assay buffer as solvent) (BSA free) and stored at-80 ℃.

Phospholipid (PCPS) vesicles:

PCPS vesicles (80% PC, 20% PS) were prepared according to the following modification: barenhola et al, Biochemistry (1977), Vol.16, pp.2806-2810.

Phosphatidylserine (Avanti Polar Lipid, inc., Cat # 840032): 10mg/ml (chloroform as solvent), purified from brain, and stored under nitrogen or argon at-20 ℃.

Phosphatidylcholine (Avanti Polar Lipid, inc., Cat # 850457):

50mg/ml (chloroform as solvent), 16: 0-18: 1 palmitoyl-oleoyl is synthesized and stored under nitrogen or argon at-20 ℃.

Spectrozyme-TH (American Diagnostica Inc., Cat #238L, 50. mu. mol, stored at room temperature) working solution: dissolve 50. mu. mol in 10ml dH₂And (4) in O.

BSA (Sigma Chem Co., Cat # A-7888, Fraction V, grade RIA).

Experiment buffer solution:

50mM TrisHCl,pH7.5,150mM NaCl,2.5mM CaCl₂0.1% polyethylene glycol 6000(BDH), 0.05% BSA (Sigma, FrV, RIA grade).

For the single plate experiment, the following working solutions were prepared:

1. prothrombinase complex: (a)100 μ M PCPS (27.5 μ l stock solution (4.36mM) diluted to a final 1200 μ l with assay buffer). (b)25nM human factor Xa: 5.08 μ l of Va stock was diluted with assay buffer to a final 1200 μ l. (c)5pM of human factor Xa: factor Xa stock solution (0.281mg/ml) was diluted 1: 1,220,000 with assay buffer. At least 1200. mu.l was prepared.

Equal volumes (1100. mu.l) of each component were combined in the order of PCPS, Va and Xa. Left to stand at room temperature for 5-10 minutes, used immediately or stored in ice (warmed to room temperature before use).

2.6 μ M human prethrombin (FII): stock 124. mu. L F II (4.85mg/ml) was diluted with assay buffer to a final volume of 1400. mu.L.

3.20 mM EDTA/assay buffer: 0.8ml of 0.5M EDTA (pH8.5) plus 19.2ml of assay buffer.

4.0.2 mM Spectrozyme-TH/EDTA buffer: 0.44ml of SPTH stock (5mM) plus 10.56ml of 20mM EDTA/assay buffer.

5. Test compound (compound of the invention): working solutions (5X) were prepared from 10mM stock solution (DMSO) and a series of 1: 3 dilutions were made. The compound experiments were repeated at 6 concentrations.

Experimental conditions and procedures:

the prothrombinase reaction was performed in a final 50. mu.l mixture containing Ptase (20uMPCPS,5nM hFva and 1pMhF Xa), 1.2uM human factor II and various concentrations of test compounds (5. mu.M-0.021. mu.M or lower). The reaction was started by adding PTase and incubated at room temperature for 6 minutes. The reaction was stopped by adding EDTA/buffer to a final 10 mM. Then, the activity of thrombin (product) at 405nm was measured in the presence of 0.1mm of Spectrozyme-TH as a substrate in a THEROmax microtiter counter at room temperature for 5 minutes (at 10 second intervals). The reaction was performed in a 96-well microtiter plate.

In the first step of the experiment, 10 μ l of diluted test compound (5 ×) or buffer was added to the plate and the procedure was repeated once. Then, 10. mu.l of prethrombin (hFII) (5X) was added to each well. Thereafter, 30. mu.l of PTase was added to each well and mixed for about 30 seconds. The plates were then incubated at room temperature for 6 minutes.

In the second step, 50. mu.l of 20mM EDTA (assay buffer as solvent) was added to each well to stop the reaction. The resulting solution was mixed for about 10 seconds. To each well was added 100. mu.l of 0.2mM Spectrozyme. Then, the reaction rate of thrombin at 405nm was measured in a Molecular Devices microtiter plate counter at 10-second intervals for 5 minutes.

And (3) calculating:

the thrombin reaction rate is expressed in mOD/min, using the OD reading from the 5 min reaction. IC calculation by Log-log curve fitting₅₀The value is obtained.

This experiment with the compounds of the invention shows their ability to inhibit prothrombinase.

Example 13

(in vivo experiment)

The following experiments illustrate the ability of the compounds of the present invention to act as anticoagulants.

Male rats were anesthetized with sodium pentobarbital (90mg/kg, i.p.) and prepared for surgery. A cannula was inserted into the left carotid artery of the rat to measure blood pressure, and a blood sample was taken to detect clot changes (prothrombin time (PT) and activated partial thromboplastin time (aPTT)). The tail vein thereof was cannulated to supply test compounds (i.e., compounds of the invention and standards) thereto, and thromboplastin perfusion was performed. The abdomen was opened by a median incision, and the abdominal aorta was separated at a distance of 2-3cm from the renal vein. All venous branches in a 2-3cm section above the abdominal aorta were ligated. After completion of the surgery, the rats were stabilized prior to the experiment. Test compounds were administered by intravenous bolus (t = 0). After 3 minutes (t =3), 5 minutes of thromboplastin perfusion was started. After two minutes of perfusion (t =5), the abdominal aorta was ligated proximally and distally. The vessels were allowed to recover for 60 minutes, then excised from the rats, dissected, carefully removed of blood clots (if present), and weighed. Results were statistically analyzed using the Wiscoxin paired signed permutation test.

The compounds of the present invention, when subjected to this experiment, showed the ability to inhibit blood coagulation.

While the invention has been described in detail with reference to specific embodiments thereof, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the spirit and scope of the invention. In addition, many modifications may be made to adapt a particular situation, material, composition of matter, process step or steps, to the objective. All such modifications are intended to be within the scope of the claims.

Claims

1. A compound selected from compounds having the formula:

wherein:

a is-C (R)⁸) or-N =;

Z¹and Z²Independently is-O-, -N (R)¹³) -, -S-or-OCH₂-；

R¹And R⁴Independently of one another, hydrogen, halogen,Alkyl, nitro, -OR¹³、-C(O)OR¹³、-C(O)N(R¹³)R¹⁴、-N(R¹³)R¹⁴、-N(R¹³)C(O)R¹³or-N (H) S (O)₂R¹⁶；

R³Is halogen, alkyl, haloalkyl, nitro, amino, ureido, guanidino, -OR¹³、-C(NH)NH₂、-C(NH)N(H)OR¹³、-C(O)N(R¹³)R¹⁴、-R¹⁵-C(O)N(R¹³)R¹⁴、-CH(OH)C(O)N(R¹³)R¹⁴、-N(R¹³)R¹⁴、-R¹⁵-N(R¹³)R¹⁴、-C(O)OR¹³、-R¹⁵-C(O)OR¹³、-N(R¹³)C(O)R¹³(1,2) -tetrahydropyrimidinyl (optionally substituted with alkyl), (1,2) -imidazolyl (optionally substituted with alkyl) or (1,2) -imidazolinyl (optionally substituted with alkyl);

R⁸is hydrogen, alkyl or halogen;

R¹⁰Each independently is alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, cycloalkyl, cycloalkylalkyl, -C (O) OR¹³、-R¹⁵-C(O)OR¹³、-R¹⁵-C(O)N(R¹³)R¹⁴、-C(O)R¹⁵-N(R¹³)R¹⁴、-R¹⁵-C(O)R¹³、-R¹⁵-C(O)N(R¹³)N(R¹³)R¹⁴、-R¹⁵-C(R¹³)(OR¹³)-R¹⁵-N(R¹³)(R¹⁴)、-C(R¹³)(OR¹³)C(O)OR¹⁴、R¹⁵-C(R¹³)(C(O)OR¹³)₂、-C(R¹³)(N(R¹³)R¹⁴)C(O)OR¹³、-R¹⁵-C(R¹³)(N(R¹³)R¹⁴)C(O)OR¹³、-C(R¹³)(OR¹³)R¹⁴、-R¹⁵-N(R¹³)(R¹⁴)、-R¹⁵-N(R¹³)C(O)OR¹⁶、-R¹⁵-N(R¹³)C(O)OR¹⁴、-R¹⁵-N(R¹³)C(NR¹³)R¹⁶、-R¹⁵-N(R¹³)S(O)₂R¹⁶、-R¹⁵-N(R¹³)C(O)N(R¹³)R¹⁴、-R¹⁵-N(R¹³)C(NR¹³)N(R¹³)R¹⁴、-R¹⁵-N(R¹³)C(NR¹³)N(R¹³)N(R¹³)R¹⁴、-R¹⁵-N(R¹³)-R¹⁵-C(R¹³)(N(R¹³)R¹⁴)C(O)OR¹³、-R¹⁵-N(R¹³)S(O)R¹⁴、-R¹⁵OR¹³、-R¹⁵-ON(R¹³)C(NR¹³)N(R¹³)R¹⁴、-R¹⁵-OS(O)₂OR¹³、-R¹⁵-P(O)(OR¹³)R¹⁴、-R¹⁵-OP(O)(OR¹³)₂、-R¹⁵-P(O)(OR¹³)₂、-R¹⁵-SR¹³、-R¹⁵-S-R¹⁵-C(O)OR¹³、-R¹⁵-S-R¹⁵-N(R¹³)R¹⁴、-R¹⁵-S-R¹⁵-C(R¹³)(N(R¹³)R¹⁴)C(O)OR¹³、-R¹⁵-S-R¹⁵-N(R¹³)C(O)R¹³、-R¹⁵-S-R¹⁵-N(R¹³)C(O)R¹³、-R¹⁵-S-S-R¹⁵-C(R¹³)(N(R¹³)R¹⁴)C(O)OR¹³、-R¹⁵-SC(O)N(R¹³)R¹⁴、-R¹⁵-SC(S)N(R¹³)R¹⁴、-R¹⁵-S(O)R¹³、-R¹⁵-S(O)₂R¹⁶、-R¹⁵-S(O)OR¹³、-R¹⁵-S(O)₂OR¹³、-R¹⁵-S(O)₂N(R¹³)R¹⁴、-R¹⁵-S(O)(NR¹³)R¹⁴；

Or R¹⁰Each independently represents a heterocyclic group which may be substituted by one or more substituents selected from the group consisting of alkyl, halogen, haloalkyl, haloalkoxy, aralkyl, heteroaryl,-OR¹³、-C(O)OR¹³、-N(R¹³)R¹⁴、-C(O)N(R¹³)R¹⁴、-S(O)₂OR¹³and-OP (O) (OR)¹³)₂)；

Or R¹⁰Each adamantyl (optionally substituted with alkyl, halogen, haloalkyl, haloalkoxy, -OR¹³、-SR¹³、-C(O)OR¹³、-N(R¹³)R¹⁴、-C(O)N(R¹³)R¹⁴、-S(O)₂OR¹³and-OP (O) (OR)¹³)₂)；

Or R¹⁰Each is adamantylalkyl (wherein adamantylalkyl is optionally substituted with alkyl, halogen, haloalkyl, haloalkoxy, -OR¹³、-SR¹³、-C(O)OR¹³、-N(R¹³)R¹⁴、-C(O)N(R¹³)R¹⁴、-S(O)₂OR¹³and-OP (O) (OR)¹³)₂)；

R¹¹Independently of one another, hydrogen, alkyl, cycloalkyl or aryl;

R¹²is-C (O) OR¹³or-C (O) N (R)¹³)R¹⁴；

R¹³And R¹⁴Independently of each other, hydrogen, alkyl, aryl (optionally substituted by halogen, alkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, cyano, carboxy, alkoxycarbonyl, aminocarbonyl, (monoalkylaminocarbonyl or dialkylaminocarbonyl), or aralkyl (optionally substituted by halogen, alkyl, aryl; hydroxy, alkoxy, aralkyl, ammonia)A group selected from the group consisting of alkyl, dialkylamino, monoalkylamino, nitro, cyano, carboxyl, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, and dialkylaminocarbonyl);

R¹⁵is a linear or branched alkylene group; and

R¹⁶is alkyl, aryl (optionally substituted with halogen, alkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, cyano, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl or dialkylaminocarbonyl), or aralkyl (optionally substituted with halogen, aryl, alkyl, hydroxy, alkoxy, aralkyl, amino, dialkylamino, monoalkylamino, nitro, cyano, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl or dialkylaminocarbonyl).

2. A compound according to claim 1 selected from compounds having the following formula (i), being a single stereoisomer or a mixture thereof, or a pharmaceutically acceptable salt thereof:

3. a compound according to claim 2, wherein

A is-N =;

Z¹and Z²Independently is-O-, -S-or-OCH₂-；

R¹And R⁴Independently of one another, hydrogen, halogen OR-OR¹³；

R⁵and R⁶Independently of one another, hydrogen, halogen, alkyl, haloalkyl;

R⁷is-N (R)⁹)-(CR¹⁰)(R¹¹))_n-R¹²(wherein n is 4);

R⁹hydrogen, alkyl, aryl, aralkyl;

Or R¹⁰Each is heterocyclylalkyl (wherein the heterocyclyl may be optionally substituted with one OR more substituents selected from alkyl, halo, haloalkyl, haloalkoxy, cyano, -OR¹³、-C(O)OR¹³、-N(R¹³)R¹⁴、-C(O)N(R¹³)R¹⁴、-SR¹³、-S(O)₂OR¹⁶and-OP (O) (OR)¹³)₂)。

R¹¹Independently of one another, hydrogen or alkyl;

R¹²is-C (O) OR¹³or-C (O) N (R)¹³)R¹⁴；

R¹³And R¹⁴Independently of one another, hydrogen, alkyl, aryl (optionally substituted by halogen; halogen)Alkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, cyano, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl or dialkylaminocarbonyl), or aralkyl (optionally substituted with: halogen, alkyl, aryl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, cyano, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl);

R¹⁵is a linear or branched alkylene group; and

4. A compound according to claim 3, wherein:

Z¹and Z²Independently is-O-;

R¹is hydrogen OR OR¹³；

R²is-C (NH) NH₂；

R⁴is hydrogen;

R⁵and R⁶Independently of one another, halogen;

R⁷is-N (R)⁹)-(C(R¹⁰)(R¹¹))_n-R¹²(wherein n is 1);

R⁹is hydrogen, alkyl, aryl or aralkyl;

Or R¹⁰Is imidazolyl alkyl or indolyl alkyl;

R¹¹is hydrogen or alkyl;

R¹²is-C (O) OR¹³or-C (O) N (R)¹³)R¹⁴；

R¹³And R¹⁴Independently of one another, hydrogen or alkyl;

R¹⁵is a linear or branched alkylene group; and

R¹⁶is alkyl or aryl.

5. The compound according to claim 4, wherein:

R¹is-OR¹³；

R⁵and R⁶Are both fluorine;

R⁹is hydrogen or alkyl;

R¹¹Is hydrogen or alkyl;

R¹²is-C (O) OR¹³。

6. The compound according to claim 5, selected from:

7. A compound according to claim 3, wherein:

a is-N =;

Z¹and Z²Independently is-O-, -S-or-OCH₂-；

R¹And R⁴Independently of one another, hydrogen, halogen OR-OR¹³；

R⁵and R⁶Independently of one another, hydrogen, halogen, alkyl, haloalkyl;

R⁷is-O- (C (R)¹⁰)(R¹¹))_n-R¹²(wherein n is 1 to 6);

Or R¹⁰Each is aralkyl (optionally substituted with one OR more substituents selected from the group consisting of alkyl, halogen, haloalkyl, haloalkoxy, cyano, -OR¹³、-C(O)OR¹³、-N(R¹³)R¹⁴、-C(O)OR¹³、-C(O)N(R¹³)R¹⁴、-SR¹³、-S(O)₂OR¹⁶and-OP (O) (OR)¹³)₂)；

Or R¹⁰Are respectively asHeterocyclylalkyl (wherein the heterocyclyl is optionally substituted with one OR more substituents selected from the group consisting of alkyl, halogen, haloalkyl, haloalkoxy, cyano, -OR¹³、-C(O)OR¹³、-N(R¹³)R¹⁴、-C(O)N(R¹³)R¹⁴、-SR¹³、-S(O)₂OR¹³and-OP (O) (OR)¹³)₂)；

R¹¹Independently of one another, hydrogen or alkyl;

R¹²is-C (O) OR¹³or-C (O) N (R)¹³)R¹⁴；

R¹³And R¹⁴Independently of one another, hydrogen, alkyl, aryl (optionally substituted by halogen, alkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, cyano, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl or dialkylaminocarbonyl), or aralkyl (optionally substituted by halogen, alkyl, aryl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, cyano, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl or dialkylaminocarbonyl);

R¹⁵is a linear or branched alkylene group; and

8. The compound according to claim 7, wherein:

Z¹and Z²Independently is-O-;

R¹is hydrogen OR-OR¹³；

R²is-C (NH) NH₂；

R⁴is hydrogen;

R⁵and R⁶Independently of one another, halogen;

R⁷is-O- (C (R)¹⁰)(R¹¹))_n-R¹²(wherein n is 1 to 6);

Or R¹⁰Is imidazolyl alkyl or indolyl alkyl;

R¹¹is hydrogen or alkyl;

R¹²is-C (O) OR¹³or-C (O) N (R)¹³)R¹⁴；

R¹³And R¹⁴Independently of one another, hydrogen or alkyl;

R¹⁵is a linear or branched alkylene group; and

R¹⁶is alkyl or aryl.

9. A compound according to claim 8, wherein:

R¹is OR¹³；

R⁵and R⁶Are both fluorine;

R⁹is hydrogen or alkyl;

R¹¹Is hydrogen or alkyl;

R¹²is-C (O) OR¹³。

10. A compound according to claim 8, selected from:

11. A pharmaceutical composition for treating a human afflicted with a disorder characterized by thrombotic activity, which composition comprises a therapeutically effective amount of a compound selected from the group consisting of compounds having the formula:

wherein:

a is-C (R)⁸) or-N =;

Z¹and Z²Independently is-O-, -N (R)¹³) -, -S-or-OCH₂-；

R¹And R⁴Independently of one another, hydrogen, halogen, alkylNitro, -OR¹³、-C(O)OR¹³、-C(O)N(R¹³)R¹⁴、-N(R¹³)R¹⁴、-N(R¹³)C(O)R¹³or-N (H) S (O)₂R¹⁶；

R²is-C (NH) NH₂、-C(NH)N(H)OR¹⁴、-C(NH)N(H)C(O)OR¹⁶、-C(NH)N(H)C(O)R¹³、-C(NH)N(H)S(O)₂R¹⁶or-C (NH) N (H) C (O) N (H) R¹³；

R³Is halogen, alkyl, haloalkyl, nitro, amino, ureido, guanidino, -OR¹³、-C(NH)NH₂、-C(NH)N(H)OR¹³、-C(O)N(R¹³)R¹⁴、-R¹⁵-C(O)N(R¹³)R¹⁴、-CH(OH)C(O)N(R¹³)R¹⁴、-N(R¹³)R¹⁴、-R¹⁵-N(R¹³)R¹⁴、-C(O)OR¹³、-R¹⁵-C(O)OR¹³、-N(R¹³)C(O)R¹³(1,2) tetrahydropyrimidinyl (optionally substituted with alkyl), (1,2) -imidazolyl (optionally substituted with alkyl) or (1,2) -imidazolinyl (optionally substituted with alkyl);

R⁵and R⁶Independently of one another, hydrogen, halogen, alkyl, haloalkyl, nitro, -N (R)¹³)R¹⁴、-C(O)OR¹³、-C(O)N(R¹³)R¹⁴、-C(O)N(R¹³)CH₂C(O)N(R¹³)R¹⁴-N(R¹³)C(O)N(R¹³)R¹⁴、-N(R¹³)C(O)R¹⁴、-N(R¹³)S(O)₂R¹⁶or-N (R)¹³)C(O)N(R¹³)CH₂C(O)N(R¹³)R¹⁴；

R⁸is hydrogen, alkyl or halogen;

R¹⁰Each independently is alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, cycloalkyl, cycloalkylalkyl, -C (O) OR¹³、-R¹⁵-C(O)OR¹³、-R¹⁵-C(O)N(R¹³)R¹⁴、-C(O)R¹⁵-N(R¹³)R¹⁴、-R¹⁵-C(O)R¹³、-R¹⁵-C(O)N(R¹³)N(R¹³)R¹⁴、-R¹⁵-C(R¹³)(OR¹³)-R¹⁵-N(R¹³)(R¹⁴)、-C(R¹³)(OR¹³)C(O)OR¹⁴、R¹⁵-C(R¹³)(C(O)OR¹³)₂、-C(R¹³)N(R¹³)(R¹⁴)C(O)OR¹³、-R¹⁵-C(R¹³)(N(R¹³)R¹⁴)C(O)OR¹³、-C(R¹³)(OR¹³)R¹⁴、-R¹⁵-N(R¹³)(R¹⁴)、-R¹⁵-N(R¹³)C(O)OR¹⁶、-R¹⁵-N(R¹³)C(O)OR¹⁴、-R¹⁵-N(R¹³)C(NR¹³)R¹⁶、-R¹⁵-N(R¹³)S(O)₂R¹⁶、-R¹⁵-N(R¹³)C(O)N(R¹³)R¹⁴、-R¹⁵-N(R¹³)C(NR¹³)N(R¹³)R¹⁴、-R¹⁵-N(R¹³)C(NR¹³)N(R¹³)N(R¹³)R¹⁴、-R¹⁵-N(R¹³)-R¹⁵-C(R¹³)(N(R¹³)R¹⁴)C(O)OR¹³、-R¹⁵-N(R¹³)S(O)R¹⁴、-R¹⁵OR¹³、-R¹⁵-ON(R¹³)C(NR¹³)N(R¹³)R¹⁴、-R¹⁵-OS(O)₂OR¹³、-R¹⁵-P(O)(OR¹³)R¹⁴、-R¹⁵-OP(O)(OR¹³)₂、-R¹⁵-P(O)(OR¹³)₂、-R¹⁵-SR¹³、-R¹⁵-S-R¹⁵-C(O)OR¹³、-R¹⁵-S-R¹⁵-N(R¹³)R¹⁴、-R¹⁵-S-R¹⁵-C(R¹³)(N(R¹³)R¹⁴)C(O)OR¹³、-R¹⁵-S-R¹⁵-N(R¹³)C(O)R¹³、-R¹⁵-S-R¹⁵-N(R¹³)C(O)R¹³、-R¹⁵-S-S-R¹⁵-C(R¹³)(N(R¹³)R¹⁴)C(O)OR¹³、-R¹⁵-SC(O)N(R¹³)R¹⁴、-R¹⁵-SC(S)N(R¹³)R¹⁴、-R¹⁵-S(O)R¹³、-R¹⁵-S(O)₂R¹⁶、-R¹⁵-S(O)OR¹³、-R¹⁵-S(O)₂OR¹³、-R¹⁵-S(O)₂N(R¹³)R¹⁴、-R¹⁵-S(O)(NR¹³)R¹⁴；

R¹¹Independently of one another, hydrogen, alkyl, cycloalkyl or aryl;

R¹²is-C (O) OR¹³or-C (O) N (R)¹³)R¹⁴；

R¹³And R¹⁴Independently of one another, hydrogen, alkyl, aryl (optionally substituted by halogen, alkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, cyano, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl or dialkylaminocarbonyl), or aralkyl (optionally substituted by halogen, aryl, alkyl, hydroxy, alkoxy, aralkylcarbonyl)Alkoxy, amino, dialkylamino, monoalkylamino, nitro, cyano, carboxyl, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl or dialkylaminocarbonyl);

R¹⁵is a linear or branched alkylene group; and

R¹⁶is alkyl, aryl (optionally substituted with halogen, alkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, cyano, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl or dialkylaminocarbonyl), or aralkyl (optionally substituted with halogen, alkyl, aryl, hydroxy, alkoxy, aralkyl, amino, dialkylamino, monoalkylamino, nitro, cyano, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl or dialkylaminocarbonyl).

12. A method for treating a human suffering from a disorder characterized by thrombotic activity, which method comprises administering to the human a therapeutically effective amount of a compound selected from the group consisting of compounds having the formula:andwherein:

a is-C (R)⁸) or-N =;

Z¹and Z²Independently is-O-, -N (R)¹³) -, -S-or-OCH₂-；

R⁸is hydrogen, alkyl or halogen;

R¹¹Independently of one another, hydrogen, alkyl, cycloalkyl or aryl;

R¹²is-C (O) OR¹³or-C (O) N (R)¹³)R¹⁴；

R¹⁵is a linear or branched alkylene group; and

R¹⁶is alkyl, aryl (optionally substituted by halogen, alkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, cyano, carboxyAn alkyl group, an alkoxycarbonyl group, an aminocarbonyl group, a monoalkylaminocarbonyl group or a dialkylaminocarbonyl group), or an aralkyl group (optionally substituted with: halogen, alkyl, aryl, hydroxy, alkoxy, aralkyl, amino, dialkylamino, monoalkylamino, nitro, cyano, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl).