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    • 专利摘要:
    The present invention discloses benzoxazinone and benzothiazinone compounds that have an inhibitory effect on serine proteases such as Factor Xa, Thrombin, and / or Factor VIIa. The invention also discloses pharmaceutically acceptable salts of the compounds, pharmaceutically acceptable compositions comprising the compounds or salts and methods of using them as therapeutic agents for treating or preventing a disease state in a mammal characterized by abnormal thrombosis. have.
    公开号:KR20010042296A
    申请号:KR1020007010839
    申请日:1998-12-15
    公开日:2001-05-25
    发明作者:켄트 알란 베리만；데니스 마이클 다우닝；다네트 안드레아 두들리；제레미 존 에드먼즈；라크시미 수리라잔 나라심한；스테판 타라스 라푼달로
    申请人:로즈 암스트롱, 크리스틴 에이. 트러트웨인；워너-램버트 캄파니；
    IPC主号:
    专利说明:

    Benzoxazinones / Benzothiazinones as Serine Protease Inhibitors} as Serine Protease Inhibitors
    In economically developed countries, cardiovascular disease still accounts for the majority of deaths. In particular, abnormal coagulation and inadequate thrombus formation in the blood vessels promote many acute cardiovascular disease states. Although long recognized that various plasma proteins and cellular receptors, such as fibrinogen and serine protease, are involved in hemostasis, the exceptions have emerged as important factors contributing to cardiovascular disease. Thrombin can be regarded as an important and major regulatory enzyme of the coagulation cascade, which plays a variety of roles as both positive and negative feedback regulators in normal hemostasis. However, in some pathological conditions the electrons are augmented through the catalytic activity of cofactors required for thrombin generation, such as factor Xa. Factor Xa as part of a prothrombinase complex composed of the non-enzymatic cofactor Va, calcium ions and phospholipid membrane surface regulates the production of thrombin from the enzyme source prothrombin. In addition, the location of the prothrombinase complex at the point of aggregation of both endogenous and exogenous coagulation pathways may be a viable approach to limiting prothrombin activity of thrombin by controlling factor Xa and thus thrombin generation. Implied.
    Indeed, there is sufficient evidence of the role of factor Xa inhibitors as anticoagulants. Antistatin, a potent inhibitor of blood coagulation factor Xa from Mexican leeches, Haementeria officinalis, exhibits antithrombotic activity in various models of arterial and venous thrombosis (Lapatto et al., Embo. J., 1997: 5151-5161]. Other protein or polypeptide factor Xa inhibitors include recombinant tick anticoagulant peptides (rTAPs), which are known to promote recombinant tissue plasminogen activator mediated fusion and prevent acute re-occlusion of dogs, so factor Xa inhibitors are thrombolytic. It would be useful as an adjuvant of therapy (Mellott et al., Fibrinolysis, 1993: 195-202). In addition, rTAP has been described in the canine coronary artery electrolyte disorder model to reduce thrombus mass and occlusion time without sudden hemodynamic or hemostatic changes, indicating that factor Xa plays a major role in the progression of arterial thrombosis (see [ Lynch et al., Thromb. Haemostasis, 1995: 640-645; Schaffer et al., Circulation, 1991: 1741-1748]. On the venous side, it has also been described that rTAP reduces fibrin sedimentation but has little effect on tissue hemostatic parameters in a rabbit model of venous thrombosis (Fioravanti et al., Thromb. Res., 1993: 317-324). ). As well as such relatively large molecular weight proteins, which are not suitable as oral antithrombotic agents, examples of low molecular weight factor Xa inhibitors also exist. In particular, Dx9065a, a low molecular weight synthetic factor Xa inhibitor, also shows antithrombotic potential in various experimental thrombosis rat models. In both arteriovenous shunt and venous congestion models, inhibition of thrombus formation was achieved at doses that had little effect on APTT, indicating that DX9065a is therapeutically effective in preventing thrombosis and has therapeutic antithrombotic potential. Wong et al., Thromb. Res., 1996: 117-126].
    The majority of Factor Xa inhibitors known to date are already summarized in both documents (Edmunds et al., Annual Reports in Medicinal Chemistry, 1996: 51 and Kunitada and Nagahara, Curr. Pharm. Des., 1996: 531- 542]). However, it is obvious that there is still a need for more effective drugs that modulate factor Xa proteolytic activity.
    Some benzoxazinones and benzothiazinones have been reported and these compounds show significant pharmaceutical activity;
    Moriyama et al, Biol. Pharm. Bull., 1997: 701-703;
    Gezginci et al., Farmaco, 1997: 255-256;
    Sastry et al., Indian J. Chem., Sect. B, 1989: 882-884;
    US Patent No. 680718;
    Bornschein et al., Pharmazie, 1977: 695-697 and Pfeifer et al., Pharmazie, 1977: 587-592;
    Japanese Patent No. 60166674;
    European Patent No. 116368;
    Japanese Patent No. 01272524;
    US Patent No. 4,786,635;
    Fujita M. et al., L. Med. Chem., 1990: 1898;
    Japanese Patent No. 03118380;
    Japanese Patent No. 09227561;
    Shridhar et al., Indian J. Chem., Sect. B, 1985; 24B (12): 1263-1267;
    Bornschein et al., Pharmazie, 1977: 32 (11): 695-697 and 1977; 32 (10): 587-592;
    Thuillier et al., Eur. J. Med. Chem.-Chim. Ther., 1975; 10 (1): 37-42;
    German Patent No. 2044530; And
    U.S. Patent # 3401166]
    However, none of the documents described above discloses or suggests compounds that are inhibitors of serine proteases associated with the blood coagulation cascades described herein.
    Summary of the Invention
    It is an object of the present invention to provide an enzyme associated with a coagulation cascade and a serine protease inhibitor which exhibits inhibitory activity mainly against target enzymes, factor Xa, thrombin and factor VIIa.
    It is another object of the present invention to provide a serine protease inhibitor which exhibits inhibitory activity against target enzyme factor Xa and which is provided in a pharmacologically acceptable state.
    It is another object of the present invention to provide such Factor Xa inhibitors and agents as anticoagulants and the use of Factor Xa inhibitors.
    Yet another object of the present invention is to provide the use of such factor Xa inhibitors and agents for treating various thrombotic diseases.
    Another object of the present invention is the synthesis of such low molecular weight thrombin inhibitors. Enzyme inhibitors of the present invention include a compound of Formula 1 below.
    The present invention fulfills this purpose and provides novel compounds that exhibit antithrombogenic activity. More specifically, the present invention provides a novel compound represented by the following formula (1), or a pharmaceutically acceptable salt or prodrug form thereof, which exhibits antithrombotic activity by inhibiting factor Xa. The present invention also provides pharmaceutically acceptable compositions comprising the novel compounds or salts or prodrug forms thereof, and methods of using them as therapeutic agents for treating or preventing a disease state in a mammal characterized by abnormal thrombosis.
    Thus, in a first embodiment the present invention provides a novel compound of formula 1 or a stereoisomer or a pharmaceutically acceptable salt form or prodrug thereof.
    Where
    A is O, S, S (= O), S (= O) (= O), OCH 2 , CH 2 O, SCH 2 , S (= O) CH 2 , S (= O) (= O) CH 2 , CH 2 S, CH 2 S (= 0), CH 2 S (= 0) (= 0),
    B is selected from cycloalkyl, heteroalkyl, cycloalkylalkyl, heteroalkylalkyl, aryl, arylalkyl, heterocycle, heterocycloalkyl, which may be substituted with R 1 and R 2 , respectively,
    D is selected from H, alkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heteroalkylalkyl, aryl, arylalkyl, heterocycle, heterocycloalkyl, which may be substituted with R 1 and R 2 , respectively,
    E is absent or selected from O, S, NH,
    F is selected from N, NCH 2 , CH 2 N,
    G is absent or selected from alkyl, alkyl in which one or more heteroatoms are present, cycloalkyl, cycloalkyl through one or more heteroatoms,
    J is selected from aryl or heterocycle which may be absent or substituted with R 1 and R 2 , respectively,
    K is absent or selected from alkyl, which may be substituted with R 1 and R 2 , respectively, alkyl via one or more heteroatoms, cycloalkyl via one or more heteroatoms, cycloalkylalkyl via one or more heteroatoms,
    L is H, chlorine, fluorine, bromine, iodine, OH, O (alkyl), amine, alkyl, fluoroalkyl, amide, NO 2 , SH, S (O) n (alkyl), SO 3 H, SO 3 alkyl , Aldehyde, ketone, acid, ester, urea, O alkylamide, O alkyl ester, O alkyl acid, N alkyl acid, alkylamine, alkyl amide, alkyl ketone, alkyl acid, alkyl ester, alkyl urea, N alkyl amide, N Selected from alkyl esters, NC (= 0) alkyl, NC (= 0) aryl, NC (= 0) cycloalkyl, NC (= 0) cycloalkylalkyl, NC (= 0) alkylaryl, R 1 R 2 , nitrile Become,
    R 1 is H, amine, alkylamine, amide, C (= NH) NHNH 2 , alkyl C (= NH) NHNH 2 , C (= NH) NHOH, alkyl C (= NH) NHOH, NHC (= NH) NH 2 , alkyl NHC (= NH) NH 2 , C (= S) NH 2 , alkyl C (= S) NH 2 , C (= NH) alkyl, alkylC (= NH) alkyl, C (= NR 3 ) N (R 4 ) (R 5 ), alkyl C (═NR 3 ) N (R 4 ) (R 5 ),
    R 2 is H, chlorine, fluorine, bromine, iodine, OH, Oalkyl, amine, alkylaldehyde, alkylamide, alkylester, alkylketone, alkyl acid, Oalkylamide, Oalkyl acid, Oalkyl ester, nonalkyl acid , Aminealkylamides, aminealkyl esters, NC (= 0) alkyl, NC (= 0) aryl, NC (= 0) cycloalkyl, NC (= 0) alkylaryl, alkylamines, amides, aldehydes, esters, ketones, NO 2 , SH, S (O) n (C 1-10 alkyl), SO 3 H, SO 3 alkyl, CHO, acid, alkyl, C (= NH) alkyl, C (= NH) NHNH 2 , alkyl C ( = NH) NHNH 2 , C (= NH) NHOH, alkyl C (= NH) NHOH, NHC (= NH) NH 2 , alkylNHC (-NH) NH 2 , C (= S) NH 2 , alkyl C (= S) NH 2 , alkylC (= NH) alkyl, C (= NR 3 ) N (R 4 ) (R 5 ), alkylC (= NR 3 ) N (R 4 ) (R 5 ),
    R 3 , R 4 and R 5 are hydrogen atoms, alkyl groups having 1 to 4 carbon atoms which may be interrupted by one heteroatom, or R 4 and R 5 are bonded to-(CH 2 ) p -W- (CH 2 ) q- (where p and q are integers of 2 or 3), and a constant position of the methylene chain is unsubstituted or substituted by an alkyl group having 1 to 4 carbon atoms, W is a direct bond, -CH 2- , -O-, -N (R 6 )-or -S (O) r- (wherein R 6 is H or alkyl and r is 0 or 1 or 2),
    n is selected from 0, 1, 2,
    X 1 is C or N,
    X 2 is C or N,
    X 3 is C or N,
    X 4 is C or N.
    Preferred compounds of the present invention are compounds of the formula It is a drug.
    Another preferred compound is a compound of Formula 3 wherein B, G, J, K and L are as defined above, or a stereoisomer or pharmaceutically acceptable salt, ester, amide or prodrug thereof.
    Another preferred compound is a compound of formula 4 wherein B, G, J, K and L are as defined above, or a stereoisomer or pharmaceutically acceptable salt, ester, amide or prodrug thereof.
    More preferred compounds are compounds of the formula 5 wherein R 1 , R 2 , G, J, K and L are as defined above, or stereoisomers or pharmaceutically acceptable salts, esters, amides or prodrugs thereof. .
    Another more preferred compound is a compound of Formula 6 wherein R 1 , R 2 , G, J, K and L is as defined above, or a stereoisomer or pharmaceutically acceptable salt, ester, amide or precursor thereof It is a drug.
    Most preferred compounds provided by the present invention are the compounds of formulas 7 and 8 or their stereoisomers or pharmaceutically acceptable salts, esters, amides or prodrugs thereof.
    Where
    R 7 is (3-amidino) phenyl, (3-hydroxy) phenyl, [3-hydroxyamino (imino) methyl] -phenyl, [3-hydrazino (imino) methyl] -phenyl, (3 -Aminomethyl) phenyl, (3-amino) phenyl, (3-methylamino) phenyl, (3-dimethylamino) phenyl, (5-amidino-2-hydroxy) phenyl, (5-amidino-2- Methoxy) phenyl, (1-amidino) piperid-3-yl, (1-amidino) pyrrolid-3-yl, (5-amidino) thien-2-yl, (5-amidino) furan 2-yl, (5-amidino) -1,3-oxazol-2-yl, (2-amidino) -1,3-oxazol-5-yl, 1H-pyrazol-5-yl, Tetrahydro-1H-pyrazol-3-yl, (1-amidino) tetrahydro-1H-pyrazol-3-yl, (2-amidino) -1H-imidazol-4-yl, (2-amino ) -1H-imidazol-4-yl, (5-amidino) -1H-imidazol-2-yl, (5-amino) -1H-imidazol-2-yl, pyridin-3-yl, (4 -Amino) pyridin-3-yl, (4-dimethylamino) pyridin-3-yl, (6-amino) pyridin-2-yl, (6-amidino) pyridin-2-yl, (2-amino) pyridine -4-yl, (2-amidi Pyridin-4-yl, (2-amidino) pyrimid-4-yl, (2-amino) pyrimidin-4-yl, (4-amidino) pyrimid-2-yl, (4-amino) Pyrimidin-2-yl, (6-amidino) pyrazin-2-yl, (6-amino) pyrazin-2-yl, (4-amidino) -1,3,5-triazin-2-yl, (4-amino) -1,3,5-triazin-2-yl, (3-amidino) -1,2,4-triazin-5-yl, (3-amino) -1,2,4 -Triazin-5-yl, (3-amidino) benzyl, (3-amino) benzyl, (3-aminomethyl) benzyl, (1-amidino) piperid-3-ylmethyl, (1-amidino) ) Pyrrolid-3-ylmethyl, (5-amidino) thien-2-ylmethyl, (5-amidino) furan-2-ylmethyl, (5-amidino) oxazol-2-ylmethyl, ( 2-amidino) imidazol-5-ylmethyl, (5-amidino) imidazol-2-ylmethyl, (6-amidino) pyridin-2-ylmethyl, (6-amino) pyridin-2-yl Methyl, (2-amidino) pyrimidin-4-ylmethyl, (2-amino) pyrimidin-4-ylmethyl, (4-amidino) pyrimidin-2-ylmethyl, (4-amino) pyrimidine 2-ylmethyl, (6-amidino) pyrazine- 2-ylmethyl, (6-amino) pyrazin-2-ylmethyl, 3-aminocyclohexyl, 3-amidinocyclohexyl, 3-aminocyclohexylmethyl, 3-amidinocyclohexylmethyl, 3-aminocyclopentyl , 3-amidinocyclopentyl, 3-aminocyclopentylmethyl and 3-amidinocyclopentylmethyl,
    R 8 is Br, I, C 2 H 5 , H, Cl, F, SH, SMe, CF 3 , CH 3 , CO 2 H, CO 2 Me, CN, C (= NH) NH 2 , C (= NH ) NHOH, C (= NH) NHNH 2 , C (= O) NH 2 , CH 2 OH, CH 2 NH 2 , NO 2 , OH, OMe, OCH 2 Ph, OCH 2 CO 2 H, O (CH 2 ) 2 CO 2 H, O (CH 2 ) 3 CO 2 H, NHCH 2 CO 2 H, NH (CH 2 ) 2 CO 2 H, NH (CH 2 ) 3 CO 2 H, OCH 2 CH 2 OH, OCH 2 ( 1H-tetrazol-5-yl), NH 2 , NHbutyl, NMe 2 , NHPh, NHCH 2 Ph, NHC (= 0) Me, NHC (= 0) c-hexyl, NHC (= 0) CH 2 c- Hexyl, NHC (= 0) Ph, NHC (= 0) CH 2 Ph, NHS (= 0) 2 Me, NHS (= 0) 2 c-hexyl, NHS (= 0) 2 CH 2 c-hexyl, NHS ( = O) 2 Ph and NHS (= O) 2 CH 2 Ph,
    R 9 is (CH 2 ) 5 , (CH 2 ) 4 , (CH 2 ) 6 , CH 2 C (= 0) NHCH 2 CH 2 , CH 2 CH 2 NHC (= 0) CH 2 , (CH 2 ) 2 NH (CH 2 ) 2 , (CH 2 ) 2 O (CH 2 ) 2 , C 6 H 4 , CH 2 C 6 H 4 , C 6 H 4 CH 2 , C 6 H 10 , CH 2 C 6 H 10 , C 6 H 10 CH 2 , C 5 H 8 , CH 2 C 5 H 8 , C 5 H 8 CH 2 and CH 2 CH = CHCH 2 CH 2 ,
    R 10 is 2,6-dimethylpiperidinyl, 2,2,6,6-tetramethyl-piperidinyl-4-one, piperidinyl, 2,2,6,6-tetramethylpiperidinyl, ( 2-carboxy) piperidinyl, (3-carboxy) piperidinyl, (4-carboxy) piperidinyl, 3,5-dimethylpiperidinyl, (4-hydroxy) piperidinyl, (2-imino ) Piperidinyl, piperidin-4-one-yl, (2-dimethylaminomethyl) -piperidinyl, (4-dimethylamino) -piperidinyl, (4-sulfonyloxy) -piperidinyl, (2-phenyl) piperidinyl, 2,5-dimethylpyrrolidinyl, pyrrolidinyl, (2-carboxy) pyrrolidinyl, (3-N-acetyl-N-methyl) pyrrolidinyl, (3-amino Pyrrolidinyl, (2,5-bis-methoxymethyl) -pyrrolidinyl, 2-hydroxymethyl-pyrrolidinyl, 2-hydroxymethyl-5-methyl-pyrrolidinyl, diisopropylamino, Diethylamino, methylamino, 1-methyl-4,5-dihydro-1H-imidazol-2-yl, 2,5-dimethyl-1H-imidazolyl, morpholinyl, 2,6-dimethylmorpholi Neil, piperage A 2,6-dimethyl piperazinyl, 1H- pyrazolyl, tetrahydro -1H- pyrazolyl and 2,5-dimethyl-tetrahydro -1H-1- pyrazolyl.
    In one embodiment of Formulas 7 and 8, R 8 , R 9 and R 10 are as above, and R 7 is (2-hydroxy-5-amidino) phenyl. In another embodiment of Formulas 7 and 8, R 7 , R 9 and R 10 are as above and R 8 is H. In another embodiment of Formulas 7 and 8, R 7 , R 8 and R 10 are as above and R 9 is (CH 2 ) 5 . In another embodiment of Formulas 7 and 8, R 7 , R 8 and R 10 are 2,6-dimethylpiperidinyl. In another embodiment of Formulas 7 and 8, R 7 is as defined above, R 8 is H, R 9 is (CH 2 ) 5 , and R 10 is 2,6-dimethylpiperidinyl. In another embodiment of Formulas 7 and 8, R 7 is as defined above, R 8 is H, R 9 is (CH 2 ) 5 and R 10 is 2,5-dimethylpyrrolidinyl.
    Representative compounds of the invention include the following:
    3- (4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benzo Thiazin-2-yl) -4-methoxybenzenecarboximidamide,
    3- (4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benzo Thiazin-2-yl) -benzenecarboximidamide,
    4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2- (3-hydroxyphenyl) -2H-1,4-benzothiazine-3 (4H) -on,
    3- (4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benzo Thiazin-2-yl) -N-hydroxybenzenecarboximidamide,
    3- (4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benzo Thiazin-2-yl) -N-hydroxybenzenecarboximidamide,
    3- (4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benzo Thiazin-2-yl) benzenecarboximidohydrazide,
    2- [3- (aminomethyl) phenyl] -4,5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2H-1,4-benzothiazine -3 (4H) -on,
    2- (3- (aminophenyl) -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2H-1,4-benzothiazine-3 (4H) -on,
    4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2- [3- (methylamino) phenyl] -2H-1,4-benzothiazine -3 (4H) -on,
    2- [3- (dimethylamino) phenyl] -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2H-1,4-benzothiazine -3 (4H) -on,
    3- (4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benzo Thiazin-2-yl) -4-hydroxybenzenecarboximidamide,
    3- (4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benzo Thiazin-2-yl) tetrahydro-1 (2H) -pyridinecarboximidamide,
    3- (4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benzo Thiazin-2-yl) -1-pyrrolidinecarboximidamide,
    5- (4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benzo Thiazin-2-yl) -2-thiophenecarboximidamide,
    5- (4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benzo Thiazin-2-yl) -2-furancarboximidamide,
    2- (4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benzo Thiazin-2-yl) -1,3-oxazole-5-carboximidamide,
    5- (4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benzo Thiazin-2-yl) -1,3-oxazole-2-carboximidamide,
    4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2- (1H-pyrazol-5-yl) -2H-1,4-benzothia Jin-3 (4H) -one,
    5- (4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benzo Thiazin-2-yl) -1-pyrazolidinecarboximidamide,
    4- (4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benzo Thiazin-2-yl) -1H-imidazole-2-carboximidamide,
    2- (2-amino-1H-imidazol-4-yl) -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2H-1, 4-benzothiazine-3 (4H) -one,
    2- (4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benzo Thiazin-2-yl) -1H-imidazole-5-carboximidamide,
    2- (5-amino-1H-imidazol-2-yl) -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2H-1, 4-benzothiazine-3 (4H) -one,
    4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2- (3-pyridinyl) -2H-1,4-benzothiazine-3 ( 4H) -on,
    2- (4-amino-3-pyridinyl) -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2H-1,4-benzothia Jin-3 (4H) -one,
    2- [4- (dimethylamino) -3-pyridinyl] -4,5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2H-1,4 Benzothiazine-3 (4H) -one,
    2- (6-amino-2-pyridinyl) -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2H-1,4-benzothia Jin-3 (4H) -one,
    6- (4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benzo Thiazin-2-yl) -2-pyridinecarboximidamide,
    2- (2-amino-4-pyridinyl) -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2H-1,4-benzothia Jin-3 (4H) -one,
    4- (4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benzo Thiazin-2-yl) -2-pyridinecarboximidamide,
    4- (4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benzo Thiazin-2-yl) -2-pyrimidinecarboximidamide,
    2- (2-amino-4-pyrimidinyl) -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2H-1,4-benzo Thiazine-3 (4H) -one,
    2- (4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benzo Thiazin-2-yl) -4-pyrimidinecarboximidamide,
    2- (4-amino-2-pyrimidinyl) -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2H-1,4-benzo Thiazine-3 (4H) -one,
    6- (4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benzo Thiazin-2-yl) -2-pyrazinecarboximidamide,
    2- (6-amino-2-pyrazinyl) -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2H-1,4-benzothia Jin-3 (4H) -one,
    4- (4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benzo Thiazin-2-yl) -1,3,5-triazine-2-carboximidamide,
    2- (4-Amino-1,3,5-triazin-2-yl) -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl- 2H-1,4-benzothiazine-3 (4H) -one,
    5- (4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benzo Thiazin-2-yl) -1,2,4-triazine-3-carboximidamide,
    2- (3-amino-1, 2,4-triazin-5-yl) -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl- 2H-1,4-benzothiazine-3 (4H) -one,
    3-[(4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4- Benzothiazin-2-yl) methyl] benzenecarboximidamide,
    2- (3-aminobenzyl) -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2H-1,4-benzothiazine-3 ( 4H) -on,
    2-[(3-aminomethyl) benzyl) -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2H-1,4-benzothiazine -3 (4H) -on,
    3-([4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4- Benzothiazin-2-yl) methyl] tetrahydro-1 (2H) -pyridinecarboximidamide,
    3-([4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4- Benzothiazin-2-yl) methyl] -1-pyrrolidinecarboximidamide,
    5-([4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4- Benzothiazin-2-yl) methyl] -2-thiophenecarboximidamide,
    5-([4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4- Benzothiazin-2-yl) methyl] -2-furancarboximidamide,
    2-[(4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4- Benzothiazin-2-yl) methyl] -1,3-oxazole-5-carboximidamide,
    5-[(4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4- Benzothiazin-2-yl) methyl] -1 H-imidazole-2-carboximidamide,
    2-[(4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4- Benzothiazin-2-yl) methyl] -1 H-imidazole-5-carboximidamide,
    6-[(4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4- Benzothiazin-2-yl) methyl] -2-pyridinecarboximidamide,
    2-[(6-amino-2-pyridinyl) methyl] -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2H-1,4 Benzothiazine-3 (4H) -one,
    4-[(4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4- Benzothiazin-2-yl) methyl] -2-pyrimidinecarboximidamide,
    2-[(2-amino-4-pyrimidinyl) methyl] -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2H-1, 4-benzothiazine-3 (4H) -one,
    2-[(4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4- Benzothiazin-2-yl) methyl] -4-pyrimidinecarboximidamide,
    2-[(4-amino-2-pyrimidinyl) methyl] -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2H-1, 4-benzothiazine-3 (4H) -one,
    6-[(4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4- Benzothiazin-2-yl) methyl] -2-pyrazinecarboximidamide,
    2-[(6-amino-2-pyrazinyl) methyl] -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2H-1,4 Benzothiazine-3 (4H) -one,
    2- (3-aminocyclohexyl) -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2H-1,4-benzothiazine-3 (4H) -on,
    3- (4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benzo Thiazin-2-yl) cyclohexanecarboximidamide,
    2-[(3-aminocyclohexyl) methyl] -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2H-1,4-benzothia Jin-3 (4H) -one,
    3-[(4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4- Benzothiazin-2-yl) methyl] cyclohexanecarboximidamide,
    2- (3-aminocyclopentyl) -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2H-1,4-benzothiazine-3 (4H) -on,
    3- (4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benzo Thiazin-2-yl) cyclopentanecarboximidamide,
    2-[(3-aminocyclopentyl) methyl] -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2H-1,4-benzothia Jin-3 (4H) -one,
    3-[(4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4- Benzothiazin-2-yl) methyl] cyclopentanecarboximidamide,
    3- (4-4-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] butyl-3-oxo-3,4-dihydro-2H-1,4-benzo Thiazin-2-yl) benzenecarboximidamide,
    3- (4-6-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] hexyl-3-oxo-3,4-dihydro-2H-1,4-benzo Thiazin-2-yl) benzenecarboximidamide,
    2- (2-3- [amino (imino) methyl] phenyl-3-oxo-2,3-dihydro-4H-1,4-benzothiazin-4-yl) -N-2-[(2R , 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] ethylacetamide,
    3- (2-3- [amino (imino) methyl] phenyl-3-oxo-2,3-dihydro-4H-1,4-benzothiazin-4-yl) -N-2-[(2R , 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] methylpropanamide,
    3-4- [2- (2-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] ethylamino) ethyl-3-oxo-3,4-dihydro-2H -1,4-benzothiazin-2-ylbenzenecarboximidamide,
    3-4- [2-2-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] ethoxyethyl) -3-oxo-3,4-dihydro-2H- 1,4-benzothiazin-2-yl] benzenecarboximidamide,
    3- (4-4-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] phenyl-3-oxo-3,4-dihydro-2H-1,4-benzo Thiazin-2-yl) benzenecarboximidamide,
    3- (4-4-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] benzyl-3-oxo-3,4-dihydro-2H-1,4-benzo Thiazin-2-yl) benzenecarboximidamide,
    3- [4- (4-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] methylphenyl-3-oxo-3,4-dihydro-2H-1,4- Benzothiazin-2-yl] benzenecarboximidamide,
    3- (4-4-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] cyclohexyl-3-oxo-3,4-dihydro-2H-1,4- Benzothiazin-2-yl) benzenecarboximidamide,
    3- [4- (4-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] cyclohexylmethyl-3-oxo-3,4-dihydro-2H-1, 4-benzothiazin-2-yl] benzenecarboximidamide,
    3- [4- (4-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] methylcyclohexyl-3-oxo-3,4-dihydro-2H-1, 4-benzothiazin-2-yl] benzenecarboximidamide,
    3- (4-3-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] cyclopentyl-3-oxo-3,4-dihydro-2H-1,4- Benzothiazin-2-yl) benzenecarboximidamide,
    3- [4- (3-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] cyclopentylmethyl) -3-oxo-3,4-dihydro-2H-1 , 4-benzothiazin-2-yl] benzenecarboximidamide,
    3- [4- (3-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] methylcyclopentyl) -3-oxo-3,4-dihydro-2H-1 , 4-benzothiazin-2-yl] benzenecarboximidamide,
    3- (4- (E) -5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] -2-pentenyl-3-oxo-3,4-dihydro -2H-1,4-benzothiazin-2-yl) benzenecarboximidamide,
    3- [3-oxo-4- (5-piperidinopentyl) -3,4-dihydro-2H-1,4-benzothiazin-2-yl] benzenecarboximidamide,
    3-3-oxo-4- [5- (2,2,6,6-tetramethylpiperidino) pentyl] -3,4-dihydro-2H-1,4-benzothiazin-2-ylbenzene Carboximidamide,
    1- [5- (2-3- [amino (imino) methyl] phenyl-3-oxo-2,3-dihydro-4H-1,4-benzothiazin-4-yl) pentyl] -2- Piperidinecarboxylic acid,
    1- [5- (2-3- [amino (imino) methyl] phenyl-3-oxo-2,3-dihydro-4H-1,4-benzothiazin-4-yl) pentyl] -3- Ferridinecarboxylic acid,
    1- [5- (2-3- [amino (imino) methyl] phenyl-3-oxo-2,3-dihydro-4H-1,4-benzothiazin-4-yl) pentyl] -4- Piperidinecarboxylic acid,
    3-4- [5- (3,5-dimethylpiperidino) pentyl] -3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-ylbenzenecarboximidamide ,
    3-4- [5- (4-hydroxypiperidino) pentyl] -3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-ylbenzenecarboximidamide,
    3-4- [5- (2-iminopiperidino) pentyl] -3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-ylbenzenecarboximidamide,
    3-3-oxo-4- [5- (4-oxopiperidino) pentyl] -3,4-dihydro-2H-1,4-benzothiazin-2-ylbenzenecarboximidamide,
    3- [4- (5-2-[(dimethylamino) methyl] piperidinopentyl) -3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl] benzenecarbox Voximidamide,
    3- (4- (5- [4- (dimethylamino) piperidino] pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl) benzenecarboximime Damide,
    1- [5- (2,3- [amino (imino) methyl] phenyl-3-oxo-3,4-dihydro-4H-1,4-benzothiazin-4-yl) pentyl] -4- Piperidine Sulfonic Acid,
    3-3-oxo-4- [5- (2-phenylpiperidino) pentyl] -3,4-dihydro-2H-1,4-benzothiazin-2-ylbenzenecarboximidamide,
    3-4- [5- (2,5-dimethyl-1-pyrrolidinyl) pentyl] -3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-ylbenzenecarbox Imidamide,
    3-3-oxo-4- [5- (1-pyrrolidinyl) pentyl] -3,4-dihydro-2H-1,4-benzothiazin-2-ylbenzenecarboximidamide,
    1- [5- (2,3- [amino (imino) methyl] phenyl-3-oxo-3,4-dihydro-4H-1,4-benzothiazin-4-yl) pentyl] -4- Pyrrolidinecarboxylic acid,
    N-1- [5- (2,3- [amino (imino) methyl] phenyl-3-oxo-3,4-dihydro-4H-1,4-benzothiazin-4-yl) pentyl] tetra Hydro-1H-pyrrole-3-yl-N-methylacetamide,
    3-4- [5- (3-amino-1-pyrrolidinyl) pentyl] -3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-ylbenzenecarboximida mid,
    3- (4-5- [2,5-bis (methoxymethyl) -1-pyrrolidinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazine-2- (1) benzene carboximidamide,
    3- (4-5- [2- (hydroxymethyl) -1-pyrrolidinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl) benzene Carboximidamide,
    3- (4-5- [2- (hydroxymethyl) -5-methyl-1-pyrrolidinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazine-2 -Yl) benzenecarboximidamide,
    3-4- [5- (diisopropylamino) pentyl] -3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-ylbenzenecarboximidamide,
    3-4- [5- (diethylamino) pentyl] -3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-ylbenzenecarboximidamide,
    3-4- [5- (methylamino) pentyl] -3-oxo-3,4-dihydro-2H-1, 4-benzothiazin-2-ylbenzenecarboximidamide,
    3-4- [5- (1-methyl-1H-imidazol-2-yl) pentyl] -3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-ylbenzenecarba Voximidamide,
    3-4- [5- (2,5-dimethyl-1H-imidazol-1-yl) pentyl] -3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl Benzenecarboximidamide,
    3- [4- (5-morpholinopentyl) -3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl] benzenecarboximidamide,
    3-4- [5- (3,5-dimethylmorpholino) pentyl] -3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-ylbenzenecarboximidamide ,
    3- [3-oxo-4- (5-piperazinopentyl) -3,4-dihydro-2H-1,4-benzothiazin-2-yl] benzenecarboximidamide,
    3-4- [5- (2,6-dimethylpiperazino) pentyl] -3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-ylbenzenecarboximidamide ,
    3-3-oxo-4- [5- (1H-pyrazol-1-yl) pentyl] -3,4-dihydro-2H-1,4-benzothiazin-2-ylbenzenecarboximidamide ,
    3- [3-oxo-4- (5-tetrahydro-1H-pyrazol-1-ylpentyl) -3,4-dihydro-2H-1,4-benzothiazin-2-yl] benzenecarbox Imidamide,
    3-4- [5- (2,5-dimethyltetrahydro-1H-pyrazol-1-yl) pentyl] -3-oxo-3,4-dihydro-2H-1,4-benzothiazine-2 Monobenzenecarboximidamide,
    3- (6-chloro-4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1 , 4-benzothiazin-2-yl) benzenecarboximidamide,
    3- (4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-6-fluoro-3-oxo-3,4-dihydro-2H- 1,4-benzothiazin-2-yl) benzenecarboximidamide,
    3- (4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-6-sulfanyl-3,4-dihydro-2H- 1,4-benzothiazin-2-yl) benzenecarboximidamide,
    3- [4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-6- (methylsulfanyl) -3-oxo-3,4-dihydro -2H-1,4-benzothiazin-2-yl] benzenecarboximidamide,
    3- [4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-6- (trifluoromethyl) -3,4-di Hydro-2H-1,4-benzothiazin-2-yl] benzenecarboximidamide,
    3- (4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-6-methyl-3-oxo-3,4-dihydro-2H-1 , 4-benzothiazin-2-yl) benzenecarboximidamide,
    2-3- [amino (imino) methyl] phenyl-4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4 -Dihydro-2H-1,4-benzothiazine-6-carboxylic acid,
    Methyl 2-3- [amino (imino) methyl] phenyl-4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3, 4-dihydro-2H-1,4-benzothiazine-6-carboxylate,
    3- (6-cyano-4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H- 1,4-benzothiazin-2-yl) benzenecarboximidamide,
    2-3- [amino (imino) methyl] phenyl-4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4 -Dihydro-2H-1,4-benzothiazine-6-carboximidamide,
    2-3- [amino (imino) methyl] phenyl-4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-N-hydroxy-3- Oxo-3,4-dihydro-2H-1,4-benzothiazine-6-carboximidamide,
    3-4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-6- [hydrazino (imino) methyl] -3-oxo-3,4 -Dihydro-2H-1,4-benzothiazin-2-ylbenzenecarboximidamide,
    2-3- [amino (imino) methyl] phenyl-4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4 -Dihydro-2H-1,4-benzothiazine-6-carboxyamide,
    3- [4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-6- (hydroxymethyl) -3-oxo-3,4-dihydro -2H-1,4-benzothiazin-2-yl] benzenecarboximidamide,
    3- (6- (aminomethyl) -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro- 2H-1,4-benzothiazin-2-yl) benzenecarboximidamide,
    3- [4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-6-nitro-3-oxo-3,4-dihydro-2H-1 , 4-benzothiazin-2-yl) benzenecarboximidamide,
    3- (4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-6-hydroxy-3-oxo-3,4-dihydro-2H- 1,4-benzothiazin-2-yl) benzenecarboximidamide,
    3- (4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-6-methoxy-3-oxo-3,4-dihydro-2H- 1,4-benzothiazin-2-yl) benzenecarboximidamide,
    3- (6- (benzyloxy) -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro- 2H-1,4-benzothiazin-2-yl) benzenecarboximidamide,
    2-[(2-3- [amino (imino) methyl] phenyl-4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo -3,4-dihydro-2H-1,4-benzothiazin-6-yl) oxy] acetic acid,
    3-[(2-3- [amino (imino) methyl] phenyl-4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo -3,4-dihydro-2H-1,4-benzothiazin-6-yl) oxy] propanoic acid,
    4-[(2-3- [amino (imino) methyl] phenyl-4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo -3,4-dihydro-2H-1,4-benzothiazin-6-yl) oxy] butanoic acid,
    2-[(2-3- [amino (imino) methyl] phenyl-4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo -3,4-dihydro-2H-1,4-benzothiazin-6-yl) amino] acetic acid,
    3-[(2-3- [amino (imino) methyl] phenyl-4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo -3,4-dihydro-2H-1,4-benzothiazin-6-yl) amino] propanoic acid,
    4-[(2-3- [amino (imino) methyl] phenyl-4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo -3,4-dihydro-2H-1,4-benzothiazin-6-yl) amino] butanoic acid,
    3- [4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-6- (2-hydroxyethoxy) -3-oxo-3,4 -Dihydro-2H-1,4-benzothiazin-2-yl] benzenecarboximidamide,
    3- [4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-6- (2H-1,2,3,4-tetra Azole) -5-ylmethoxy) -3,4-dihydro-2H-1,4-benzothiazin-2-yl] benzenecarboximidamide,
    3- (6-amino-4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1 , 4-benzothiazin-2-yl) benzenecarboximidamide,
    3- (6- (butylamino) -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro- 2H-1,4-benzothiazin-2-yl) benzenecarboximidamide,
    3- (6- (dimethylamino) -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro- 2H-1,4-benzothiazin-2-yl) benzenecarboximidamide,
    3- (6-anilino-4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H- 1,4-benzothiazin-2-yl) benzenecarboximidamide,
    3- (6- (benzylamino) -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro- 2H-1,4-benzothiazin-2-yl) benzenecarboximidamide,
    N- (2,3- [amino (imino) methyl] phenyl-4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo- 3,4-dihydro-2H-1,4-benzothiazin-6-yl) acetamide,
    N- (2,3- [amino (imino) methyl] phenyl-4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo- 3,4-dihydro-2H-1,4-benzothiazin-6-yl) cyclohexanecarboxamide,
    N- (2,3- [amino (imino) methyl] phenyl-4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo- 3,4-dihydro-2H-1,4-benzothiazin-6-yl) -2-cyclohexylacetamide,
    N- (2,3- [amino (imino) methyl] phenyl-4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo- 3,4-dihydro-2H-1,4-benzothiazin-6-yl) benzenecarboxamide,
    N- (2,3- [amino (imino) methyl] phenyl-4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo- 3,4-dihydro-2H-1,4-benzothiazin-6-yl) -2-phenylacetamide,
    3-4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-6-[(methylsulfonyl) amino] -3-oxo-3,4- Dihydro-2H-1,4-benzothiazin-2-ylbenzenecarboximidamide,
    3- (6-[(cyclohexylsulfonyl) amino] -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3, 4-dihydro-2H-1,4-benzothiazin-2-yl) benzenecarboximidamide,
    3- (6-[(cyclohexylmethyl) sulfonyl] amino-4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3 , 4-dihydro-2H-1,4-benzothiazin-2-yl) benzenecarboximidamide,
    3-4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-6-[(phenylsulfonyl) amino] -3,4- Dihydro-2H-1,4-benzothiazin-2-ylbenzenecarboximidamide,
    3- (6- (benzylsulfonyl) amino] -4,5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4- Dihydro-2H-1,4-benzothiazin-2-yl) benzenecarboximidamide,
    3- (4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benz Oxazine-2-yl) -4-methoxybenzenecarboximidamide,
    3- (4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benz Oxazine-2-yl) -benzenecarboximidamide,
    4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2- (3-hydroxyphenyl) -2H-1,4-benzoxazine-3 (4H) -on,
    3- (4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benz Oxazin-2-yl) -N-hydroxybenzenecarboximidamide,
    3- (4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benz Oxazine-2-yl) benzenecarboximidohydrazide,
    2- [3- (aminomethyl) phenyl] -4,5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2H-1,4-benzoxazine -3 (4H) -on,
    2- (3-aminophenyl) -4,5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2H-1,4-benzoxazine-3 ( 4H) -on,
    4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2- [3- (methylamino) phenyl] -2H-1,4-benzoxazine -3 (4H) -on,
    2- [3- (dimethylamino) phenyl] -4,5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2H-1,4-benzoxazine -3 (4H) -on,
    3- (4,5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benz Oxazine-2-yl) -4-hydroxybenzenecarboximidamide,
    3- (4,5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benz Oxazin-2-yl) tetrahydro-1 (2H) -pyridinecarboximidamide,
    3- (4,5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benz Oxazine-2-yl) -1-pyrrolidinecarboximidamide,
    5- (4,5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benz Oxazine-2-yl) -2-thiophene carboximidamide,
    5- (4,5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benz Oxazine-2-yl) -2-furancarboximidamide,
    2- (4,5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benz Oxazin-2-yl) -1,3-oxazole-5-carboximidamide,
    5- (4,5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benz Oxazin-2-yl) -1,3-oxazole-2-carboximidamide,
    4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2- (1H-pyrazol-5-yl) -2H-1,4-benzox Photo-3 (4H) -On,
    4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2-tetrahydro-1H-pyrazol-3-yl-2H-1,4-benz Oxazine-3 (4H) -one,
    5- (4,5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benz Oxazine-2-yl) -1-pyrazolidinecarboximidamide,
    4- (4,5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benz Oxazine-2-yl) -1H-imidazole-2-carboximidamide,
    2- (2-amino-1H-imidazol-4-yl) -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2H-1, 4-benzoxazine-3 (4H) -one,
    2- (4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benz Oxazin-2-yl) -1H-imidazole-5-carboximidamide,
    2- (5-amino-1H-imidazol-2-yl) -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2H-1, 4-benzoxazine-3 (4H) -one,
    4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2- (3-pyridinyl) -2H-1,4-benzoxazin-3 ( 4H) -on,
    2- (4-amino-3-pyridinyl) -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2H-1,4-benzox Photo-3 (4H) -On,
    2- [4- (dimethylamino) -3-pyridinyl] -4,5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2H-1,4 Benzoxazine-3 (4H) -one,
    2- (6-amino-2-pyridinyl) -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2H-1,4-benzox Photo-3 (4H) -On,
    6- (4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benz Oxazine-2-yl) -2-pyridinecarboximidamide,
    2- (2-amino-4-pyridinyl) -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2H-1,4-benzox Photo-3 (4H) -On,
    4- (4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benz Oxazine-2-yl) -2-pyridinecarboximidamide,
    4- (4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benz Oxazine-2-yl) -2-pyrimidinecarboximidamide,
    2- (2-amino-4-pyrimidinyl) -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2H-1,4-benz Oxazine-2-yl) -3 (4H) -one,
    2- (4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benz Oxazine-2-yl) -2-pyrimidinecarboximidamide,
    2- (4-amino-2-pyrimidinyl) -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2H-1,4-benz Oxazine-3 (4H) -one,
    6- (4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benz Oxazine-2-yl) -2-pyrazinecarboximidamide,
    2- (6-amino-2-pyrazinyl) -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2H-1,4-benzox Photo-3 (4H) -On,
    4- (4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benz Oxazine-2-yl) -1,3,5-triazine-2-carboximidamide,
    2- (4-Amino-1,3,5-triazin-2-yl) -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl- 2H-1,4-benzoxazin-3 (4H) -one,
    5- (4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benz Oxazine-2-yl) -1,2,4-triazine-3-carboximidamide,
    2- (3-amino-1, 2,4-triazin-5-yl) -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl- 2H-1,4-benzoxazin-3 (4H) -one,
    3-[(4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4- Benzoxazine-2-yl) methyl] benzenecarboximidamide,
    2- (3-aminobenzyl) -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2H-1,4-benzoxazine-3 ( 4H) -on,
    2-[(3-aminomethyl) benzyl) -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2H-1,4-benzoxazine -3 (4H) -on,
    3-([4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4- Benzoxazine-2-yl) methyl] tetrahydro-1 (2H) -pyridinecarboximidamide,
    3-([4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4- Benzoxazine-2-yl) methyl] -1-pyrrolidinecarboximidamide,
    5-([4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4- Benzoxazine-2-yl) methyl] -2-thiophenecarboximidamide,
    5-([4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4- Benzoxazine-2-yl) methyl] -2-furancarboximidamide,
    2-[(4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4- Benzoxazine-2-yl) methyl] -1,3-oxazole-5-carboximidamide,
    5-[(4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4- Benzoxazine-2-yl) methyl] -1 H-imidazole-2-carboximidamide,
    2-[(4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4- Benzoxazine-2-yl) methyl] -1 H-imidazole-5-carboximidamide,
    6-[(4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4- Benzoxazine-2-yl) methyl] -2-pyridinecarboximidamide,
    2-[(6-amino-2-pyridinyl) methyl] -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2H-1,4 Benzoxazine-3 (4H) -one,
    4-[(4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4- Benzoxazine-2-yl) methyl] -2-pyrimidinecarboximidamide,
    2-[(2-amino-4-pyrimidinyl) methyl] -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2H-1, 4-benzoxazine-3 (4H) -one,
    2-[(4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4- Benzoxazine-2-yl) methyl] -4-pyrimidinecarboximidamide,
    2-[(4-amino-2-pyrimidinyl) methyl] -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2H-1, 4-benzoxazine-3 (4H) -one,
    6-[(4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4- Benzoxazine-2-yl) methyl] -2-pyrazinecarboximidamide,
    2-[(6-amino-2-pyrazinyl) methyl] -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2H-1,4 Benzoxazine-3 (4H) -one,
    2- (3-aminocyclohexyl) -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2H-1,4-benzoxazin-3 (4H) -on,
    3- (4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benz Oxazine-2-yl) cyclohexanecarboximidamide,
    2-[(3-aminocyclohexyl) methyl] -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2H-1,4-benzox Photo-3 (4H) -On,
    3-[(4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4- Benzoxazine-2-yl) methyl] cyclohexanecarboximidamide,
    2- (3-aminocyclopentyl) -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2H-1,4-benzoxazin-3 (4H) -on,
    3- (4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benz Oxazine-2-yl) cyclopentanecarboximidamide,
    2-[(3-aminocyclopentyl) methyl] -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2H-1,4-benzox Photo-3 (4H) -On,
    3-[(4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4- Benzoxazine-2-yl) methyl] cyclopentanecarboximidamide,
    3- (4-4-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] butyl-3-oxo-3,4-dihydro-2H-1,4-benz Oxazine-2-yl) benzenecarboximidamide,
    3- (4-6-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] hexyl-3-oxo-3,4-dihydro-2H-1,4-benz Oxazine-2-yl) benzenecarboximidamide,
    2- (2-3- [amino (imino) methyl] phenyl-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl) -N-2-[(2R , 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] ethylacetamide,
    3- (2-3- [amino (imino) methyl] phenyl-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl) -N-[(2R, 6S ) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] methylpropanamide,
    3-4- [2- (2-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] ethylamino) ethyl-3-oxo-3,4-dihydro-2H -1,4-benzoxazin-2-ylbenzenecarboximidamide,
    3-4- [2-2-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] ethoxyethyl) -3-oxo-3,4-dihydro-2H- 1,4-benzoxazin-2-yl] benzenecarboximidamide,
    3- (4-4-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] phenyl-3-oxo-3,4-dihydro-2H-1,4-benz Oxazine-2-yl) benzenecarboximidamide,
    3- (4-4-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] benzyl-3-oxo-3,4-dihydro-2H-1,4-benz Oxazine-2-yl) benzenecarboximidamide,
    3- [4- (4-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] methylphenyl-3-oxo-3,4-dihydro-2H-1,4- Benzoxazine-2-yl] benzenecarboximidamide,
    3- (4-4-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] cyclohexyl-3-oxo-3,4-dihydro-2H-1,4- Benzoxazine-2-yl) benzenecarboximidamide,
    3- [4- (4-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] cyclohexylmethyl-3-oxo-3,4-dihydro-2H-1, 4-benzoxazine-2-yl] benzenecarboximidamide,
    3- [4- (4-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] methylcyclohexyl-3-oxo-3,4-dihydro-2H-1, 4-benzoxazine-2-yl] benzenecarboximidamide,
    3- (4-3-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] cyclopentyl-3-oxo-3,4-dihydro-2H-1,4- Benzoxazine-2-yl) benzenecarboximidamide,
    3- [4- (3-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] cyclopentylmethyl) -3-oxo-3,4-dihydro-2H-1 , 4-benzoxazine-2-yl] benzenecarboximidamide,
    3- [4- (3-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] methylcyclopentyl) -3-oxo-3,4-dihydro-2H-1 , 4-benzoxazine-2-yl] benzenecarboximidamide,
    3- (4- (E) -5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] -2-pentenyl-3-oxo-3,4-dihydro -2H-1,4-benzoxazin-2-yl) benzenecarboximidamide,
    3- [3-oxo-4- (5-piperidinopentyl) -3,4-dihydro-2H-1,4-benzoxazin-2-yl] benzenecarboximidamide,
    3-3-oxo-4- [5- (2,2,6,6-tetramethylpiperidino) pentyl] -3,4-dihydro-2H-1,4-benzoxazin-2-ylbenzene Carboximidamide,
    1- [5- (2-3- [amino (imino) methyl] phenyl-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl) pentyl] -2- Piperidinecarboxylic acid,
    1- [5- (2-3- [amino (imino) methyl] phenyl-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl) pentyl] -3- Ferridinecarboxylic acid,
    1- [5- (2-3- [amino (imino) methyl] phenyl-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl) pentyl] -4- Piperidinecarboxylic acid,
    3-4- [5- (3,5-dimethylpiperidino) pentyl] -3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-ylbenzenecarboximidamide ,
    3-4- [5- (4-hydroxypiperidino) pentyl] -3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-ylbenzenecarboximidamide,
    3-4- [5- (2-iminopiperidino) pentyl] -3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-ylbenzenecarboximidamide,
    3-3-oxo-4- [5- (4-oxopiperidino) pentyl] -3,4-dihydro-2H-1,4-benzoxazin-2-ylbenzenecarboximidamide,
    3- [4- (5-2-[(dimethylamino) methyl] piperidinopentyl) -3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl] benzenecarbox Voximidamide,
    3- (4-5- [4- (dimethylamino) piperidino] pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl) benzenecarboximida mid,
    1- [5- (2-3- [amino (imino) methyl] phenyl-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl) pentyl] -4- Piperidine Sulfonic Acid,
    3-3-oxo-4- [5- (2-phenylpiperidino) pentyl] -3,4-dihydro-2H-1,4-benzoxazin-2-ylbenzenecarboximidamide,
    3-4- [5- (2,5-dimethyl-1-pyrrolidinyl) pentyl] -3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-ylbenzenecarbox Imidamide,
    3-3-oxo-4- [5- (1-pyrrolidinyl) pentyl] -3,4-dihydro-2H-1,4-benzoxazin-2-ylbenzenecarboximidamide,
    1- [5- (2,3- [amino (imino) methyl] phenyl-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl) pentyl] -2- Pyrrolidinecarboxylic acid,
    N-1- [5- (2-3- [amino (imino) methyl] phenyl-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl) pentyl] tetra Hydro-1H-pyrrole-3-yl-N-methylacetamide,
    3-4- [5- (3-amino-1-pyrrolidinyl) pentyl] -3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-ylbenzenecarboximida mid,
    3- (4-5- [2,5-bis (methoxymethyl) -1-pyrrolidinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2- (1) benzene carboximidamide,
    3- (4-5- [2- (hydroxymethyl) -1-pyrrolidinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl) benzene Carboximidamide,
    3- (4-5- [2- (hydroxymethyl) -5-methyl-1-pyrrolidinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2 -Yl) benzenecarboximidamide,
    3-4- [5- (diisopropylamino) pentyl] -3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-ylbenzenecarboximidamide,
    3-4- [5- (diethylamino) pentyl] -3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-ylbenzenecarboximidamide,
    3-4- [5- (methylamino) pentyl] -3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-ylbenzenecarboximidamide,
    3-4- [5- (1-methyl-1H-imidazol-2-yl) pentyl] -3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-ylbenzenecarba Voximidamide,
    3-4- [5- (2,5-dimethyl-1H-imidazol-1-yl) pentyl] -3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl Benzenecarboximidamide,
    3- [4- (5-morpholinopentyl) -3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl] benzenecarboximidamide,
    3-4- [5- (3,5-dimethylmorpholino) pentyl] -3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-ylbenzenecarboximidamide ,
    3- [3-oxo-4- (5-piperazinopentyl) -3,4-dihydro-2H-1,4-benzoxazin-2-yl] benzenecarboximidamide,
    3-4- [5- (2,6-dimethylpiperidino) pentyl] -3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-ylbenzenecarboximidamide ,
    3-3-oxo-4- [5- (1H-pyrazol-1-yl) pentyl] -3,4-dihydro-2H-1,4-benzoxazin-2-ylbenzenecarboximidamide ,
    3- [3-oxo-4- (5-tetrahydro-1H-pyrazol-1-ylpentyl) -3,4-dihydro-2H-1,4-benzoxazin-2-yl] benzenecarbox Imidamide,
    3-4- [5- (2,5-dimethyltetrahydro-1H-pyrazol-1-yl) pentyl] -3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2 Monobenzenecarboximidamide,
    3- (6-chloro-4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1 , 4-benzoxazin-2-yl) benzenecarboximidamide,
    3- (4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-6-fluoro-3-oxo-3,4-dihydro-2H- 1,4-benzoxazin-2-yl) benzenecarboximidamide,
    3- (4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-6-sulfanyl-3,4-dihydro-2H- 1,4-benzoxazin-2-yl) benzenecarboximidamide,
    3- [4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-6- (methylsulfanyl) -3-oxo-3,4-dihydro -2H-1,4-benzoxazin-2-yl] benzenecarboximidamide,
    3- [4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-6- (trifluoromethyl) -3,4-di Hydro-2H-1,4-benzoxazin-2-yl] benzenecarboximidamide,
    3- (4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-6-methyl-3-oxo-3,4-dihydro-2H-1 , 4-benzoxazin-2-yl) benzenecarboximidamide,
    2-3- [amino (imino) methyl] phenyl-4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4 -Dihydro-2H-1,4-benzoxazine-6-carboxylic acid,
    Methyl 2-3- [amino (imino) methyl] phenyl-4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3, 4-dihydro-2H-1,4-benzoxazin-6-carboxylate,
    3- (6-cyano-4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H- 1,4-benzoxazin-2-yl) benzenecarboximidamide,
    2-3- [amino (imino) methyl] phenyl-4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4 -Dihydro-2H-1,4-benzoxazine-6-carboximidamide,
    2-3- [amino (imino) methyl] phenyl-4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-N-hydroxy-3- Oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboximidamide,
    3-4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-6- [hydrazino (imino) methyl] -3-oxo-3,4 -Dihydro-2H-1,4-benzoxazin-2-ylbenzenecarboximidamide,
    2-3- [amino (imino) methyl] phenyl-4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4 -Dihydro-2H-1,4-benzoxazin-6-carboxyamide,
    3- [4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-6- (hydroxymethyl) -3-oxo-3,4-dihydro -2H-1,4-benzoxazin-2-yl] benzenecarboximidamide,
    3- (6- (aminomethyl) -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro- 2H-1,4-benzoxazin-2-yl) benzenecarboximidamide,
    3- [4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-6-nitro-3-oxo-3,4-dihydro-2H-1 , 4-benzoxazin-2-yl) benzenecarboximidamide,
    3- (4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-6-hydroxy-3-oxo-3,4-dihydro-2H- 1,4-benzoxazin-2-yl) benzenecarboximidamide,
    3- (4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-6-methoxy-3-oxo-3,4-dihydro-2H- 1,4-benzoxazin-2-yl) benzenecarboximidamide,
    3- (6- (benzyloxy) -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro- 2H-1,4-benzoxazin-2-yl) benzenecarboximidamide,
    2-[(2-3- [amino (imino) methyl] phenyl-4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo -3,4-dihydro-2H-1,4-benzoxazin-6-yl) oxy] acetic acid,
    3-[(2-3- [amino (imino) methyl] phenyl-4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo -3,4-dihydro-2H-1,4-benzoxazin-6-yl) oxy] propanoic acid,
    4-[(2-3- [amino (imino) methyl] phenyl-4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo -3,4-dihydro-2H-1,4-benzoxazin-6-yl) oxy] butanoic acid,
    2-[(2-3- [amino (imino) methyl] phenyl-4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo -3,4-dihydro-2H-1,4-benzoxazin-6-yl) amino] acetic acid,
    3-[(2-3- [amino (imino) methyl] phenyl-4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo -3,4-dihydro-2H-1,4-benzoxazin-6-yl) amino] propanoic acid,
    4-[(2-3- [amino (imino) methyl] phenyl-4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo -3,4-dihydro-2H-1,4-benzoxazin-6-yl) amino] butanoic acid,
    3- [4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-6- (2-hydroxyethoxy) -3-oxo-3,4 -Dihydro-2H-1,4-benzoxazin-2-yl] benzenecarboximidamide,
    3- [4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-6- (2H-1,2,3,4-tetra Azole) -5-ylmethoxy) -3,4-dihydro-2H-1,4-benzoxazin-2-yl] benzenecarboximidamide,
    3- (6-amino-4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1 , 4-benzoxazin-2-yl) benzenecarboximidamide,
    3- (6- (butylamino) -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro- 2H-1,4-benzoxazin-2-yl) benzenecarboximidamide,
    3- (6- (dimethylamino) -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro- 2H-1,4-benzoxazin-2-yl) benzenecarboximidamide,
    3- (6-anilino-4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H- 1,4-benzoxazin-2-yl) benzenecarboximidamide,
    3- (6- (benzylamino) -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro- 2H-1,4-benzoxazin-2-yl) benzenecarboximidamide,
    N- (2,3- [amino (imino) methyl] phenyl-4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo- 3,4-dihydro-2H-1,4-benzoxazin-6-yl) acetamide,
    N- (2,3- [amino (imino) methyl] phenyl-4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo- 3,4-dihydro-2H-1,4-benzoxazin-6-yl) cyclohexacarboxamide,
    N- (2,3- [amino (imino) methyl] phenyl-4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo- 3,4-dihydro-2H-1,4-benzoxazin-6-yl) -2-cyclohexylacetamide,
    N- (2,3- [amino (imino) methyl] phenyl-4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo- 3,4-dihydro-2H-1,4-benzoxazin-6-yl) benzenecarboxamide,
    N- (2,3- [amino (imino) methyl] phenyl-4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo- 3,4-dihydro-2H-1,4-benzoxazin-6-yl) -2-phenylacetamide,
    3-4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-6-[(methylsulfonyl) amino] -3-oxo-3,4- Dihydro-2H-1,4-benzoxazin-2-ylbenzenecarboximidamide,
    3- (6-[(cyclohexylsulfonyl) amino] -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3, 4-dihydro-2H-1,4-benzoxazin-2-yl) benzenecarboximidamide,
    3- (6-[(cyclohexylmethyl) sulfonyl] amino-4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3 , 4-dihydro-2H-1,4-benzoxazin-2-yl) benzenecarboximidamide,
    3-4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-6-[(phenylsulfonyl) amino] -3,4- Dihydro-2H-1,4-benzoxazin-2-ylbenzenecarboximidamide,
    3- (6- (benzylsulfonyl) amino] -4,5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4- Dihydro-2H-1,4-benzoxazin-2-yl) benzenecarboximidamide,
    2H-1,4-Benzoxazine-3 (4H) -one, 4- [3- (2,6-dimethyl-1-piperidinyl) propyl] -2-phenyl-,
    4- [5- (2,5-dimethyl-pyrrolidin-1-yl) -pentyl] -2-phenyl-4H-benzo [1,4] oxazin-3-one,
    2H-1,4-Benzoxazine-3 (4H) -one, 4- [5-bis (1-methylethyl) amino] pentyl] -2-phenyl-,
    2H-1,4-Benzoxazine-3 (4H) -one, 4- [3- (2,5-dimethyl-1-pyrrolidinyl) propyl] -2-phenyl-,
    2H-1,4-Benzoxazine-3 (4H) -one, 4- [3-bis (1-methylethyl) amino) propyl] -2-phenyl-,
    4- [5- (2,6-dimethyl-piperidin-1-yl) -pentyl] -2-phenyl-4H-benzo [1,4] oxazin-3-one,
    4- (5-diethylamino-pentyl) -2-phenyl-4H-benzo [1,4] oxazin-3-one,
    2-phenyl-4- (5-pyrrolidin-1-yl-pentyl) -4H-benzo [1,4] oxazin-3-one,
    2- [5- (3-oxo-2-phenyl-2,3-dihydro-benzo [1,4] oxazin-4-yl) -pentyl] -isoindole-1,3-dione,
    4- (5-imidazol-1-yl-pentyl) -2-phenyl-4H-benzo [1,4] oxazin-3-one,
    2- (4-chloro-phenyl) -4- [5- (2,6-dimethyl-piperidin-1-yl) -pentyl] -4H-benzo [1,4] oxazin-3-one,
    2- (2-chloro-phenyl) -4- [5- (2,5-dimethyl-pyrrolidin-1-yl) -pentyl] -4H-benzo [1,4] oxazin-3-one,
    2- (2-chloro-phenyl) -4- [5- (2,6-dimethyl-piperidin-1-yl) -pentyl] -4H-benzo [1,4] oxazin-3-one,
    5- (3-oxo-2-phenyl-2,3-dihydro-benzo [1,4] oxazin-4-yl) -pentaneamidine,
    2-phenyl-4- (5-piperidin-1-yl-pentyl) -4H-benzo [1,4] oxazin-3-one,
    2- (4-chloro-phenyl) -4- [5- (2,5-dimethyl-pyrrolidin-1-yl) -pentyl] -4H-benzo [1,4] oxazin-3-one,
    2-phenyl-4- (5-pyrrolidin-1-yl-pentyl) -4H-benzo [1,4] oxazin-3-one,
    Compound with trifluoro-acetic acid,
    3- (3-oxo-2-phenyl-2,3-dihydro-benzo [1,4] oxazin-4-ylmethyl) -benzonitrile,
    4- [6- (2,5-dimethyl-pyrrolidin-1-yl) -hexyl] -2-phenyl-4H-benzo [1,4] oxazin-3-one,
    3- (3-oxo-2-phenyl-2,3-dihydro-benzo [1,4] oxazin-4-ylmethyl) -benzamidine,
    2-naphthalen-2-yl-4- (5-piperidin-1-yl-pentyl) -4H-benzo [1,4] oxazin-3-one,
    4- (5-amino-pentyl) -2-phenyl-4H-benzo [1,4] -oxazin-3-one,
    4- [5- (2,6-dimethyl-piperidin-1-yl) -pentyl] -2-phenyl-4H-benzo [1,4] oxazin-3-one,
    6-methyl-2-phenyl-4- (5-piperidin-1-yl-pentyl) -4H-benzo [1,4] oxazin-3-one,
    7-methoxy-2-phenyl-4- (5-piperidin-1-yl-pentyl) -4H-benzo [1,4] oxazin-3-one,
    8-chloro-2-phenyl-4- (5-piperidin-1-yl-pentyl) -4H-benzo [1,4] oxazin-3-one,
    3-oxo-2-phenyl-4- (5-piperidin-1-yl-pentyl) -3,4-dihydro-2H-benzo [l, 4] oxazine-6-carbonitrile,
    4- (3-oxo-2-phenyl-2,3-dihydro-benzo [1,4] oxazin-4-ylmethyl) -benzamidine,
    1- [5- (3-oxo-2-phenyl-2,3-dihydro-benzo [1,4] oxazin-4-yl) -pentyl] -piperidine-2,6-dione,
    3- (3-oxo-2-phenyl-2,3-dihydro-benzo [1,4] oxazin-4-yl) -propionitrile,
    4- (3-oxo-2-phenyl-2,3-dihydro-benzo [1,4] oxazin-4-yl) -butyronitrile,
    5- (3-oxo-2-phenyl-2,3-dihydro-benzo [1,4] oxazin-4-yl) -pentanenitrile,
    N- [3- (3-oxo-2-phenyl-2,3-dihydro-benzo [1,4] oxazin-4-yl) -propyl] -guanidine,
    N- [5- (3-oxo-2-phenyl-2,3-dihydro-benzo [1,4] oxazin-4-yl) -pentyl] -guanidine,
    4- (3-oxo-2-phenyl-2,3-dihydro-benzo [1,4] oxazin-4-ylmethyl) -benzamidine,
    2- (4-methoxy-phenyl) -4- (5-piperidin-1-yl-pentyl) -4H-benzo [1,4] oxazin-3-one,
    7-methyl-2-phenyl-4- (5-piperidin-1-yl-pentyl) -4H-benzo [1,4] oxazin-3-one,
    5-methyl-2-phenyl-4- (5-piperidin-1-yl-pentyl) -4H-benzo [1,4] oxazin-3-one,
    6-methoxy-2-phenyl-4- (5-piperidin-1-yl-pentyl) -4H-benzo [1,4] oxazin-3-one,
    N-hydroxy-4- (3-oxo-2-phenyl-2,3-dihydro-benzo [1,4] oxazin-4-ylmethyl) -benzamidine,
    6-chloro-2-phenyl-4- (5-piperidin-1-yl-pentyl) -4H-benzo [1,4] oxazin-3-one,
    2- (4-methoxy-phenyl) -4- (5-piperazin-1-yl-pentyl) -4H-benzo [1,4] oxazin-3-one,
    2- (4-hydroxy-phenyl) -4- (5-piperidin-1-yl-pentyl) -4H-benzo [1,4] oxazin-3-one,
    4- [5- (2,6-dimethyl-piperidin-1-yl) -pentyl] -2- (4-hydroxy-phenyl) -4H-benzo [1,4] oxazin-3-one,
    2- (4-methoxy-phenyl) -4- [5- (4-methyl-piperazin-1-yl) -pentyl] -4H-benzo [1,4] oxazin-3-one,
    4- {4- [5- (2,6-Dimethyl-piperidin-1-yl) -pentyl] -3-oxo-3,4-dihydro-2H-benzo [1,4] oxazine-2 -Yl} -benzonitrile,
    4- {4- [5- (2,6-Dimethyl-piperidin-1-yl) -pentyl] -3-oxo-3,4-dihydro-2H-benzo [1,4] oxazine-2 -Yl} -benzoamidine,
    4- {4- [5- (2,6-Dimethyl-piperidin-1-yl) -pentyl] -3-oxo-3,4-dihydro-2H-benzo [1,4] oxazine-2 -Yl} -thiobenzamide,
    [2- (4-methoxy-phenyl) -3-oxo-2,3-dihydro-benzo [1,4] oxazin-4-yl} -acetic acid,
    4- {4- [5- (2,6-Dimethyl-piperidin-1-yl) -pentyl] -3-oxo-3,4-dihydro-2H-benzo [1,4] oxazine-2 -Yl} -N-hydroxy-benzamidine,
    Benzenecarboxyimide acid, 4- [3,4-dihydro-4- [5- (2,6-dimethyl-1-piperidinyl) pentyl] -3-oxo-2H-1,4-benzoxazine- 2-yl]-, hydrazide,
    6-amino-2-phenyl-4- (5-piperidin-1-yl-pentyl) -4H-benzo [1,4] oxazin-3-one,
    4- (5-bromo-pentyl) -2- (3,4-dimethoxy-phenyl) -4H-benzo [1,4] oxazin-3-one,
    4- (5-bromo-pentyl) -2- (3,4,5-trimethoxy-phenyl) -4H-benzo [1,4] oxazin-3-one,
    4- (5-bromo-pentyl) -2- (4-methoxy-phenyl) -4H-benzo [1,4] oxazin-3-one,
    N- [2- (2,6-Dimethyl-piperidin-1-yl) -ethyl] -2- [2- (4-methoxy-phenyl) -3-oxo-2,3-dihydro-benzo [1,4] oxazin-4-yl] -acetamide,
    4- [5- (2,6-dimethyl-piperidin-1-yl) -pentyl] -2- (3,4,5-trimethoxy-phenyl) -4H-benzo [1,4] oxazine -3-one,
    2- (3,4-Dimethoxy-phenyl) -4- [5- (2,6-dimethyl-piperidin-1-yl) -pentyl] -4H-benzo [1,4] oxazine-3- On,
    2- (4-bromo-phenyl) -4- [5- (2,6-dimethyl-piperidin-1-yl) -pentyl] -4H-benzo [1,4] oxazin-3-one,
    8-methyl-2-phenyl-4- (5-piperidin-1-yl-pentyl) -4H-benzo [1,4] oxazin-3-one,
    2- (4-benzylamino-phenyl) -4- [5- (2,6-dimethyl-piperidin-1-yl) -pentyl] -4H-benzo [1,4] oxazin-3-one,
    2- (4-methoxy-phenyl) -4- [5- (2,2,6,6-tetramethyl-piperidin-1-yl) -pentyl] -4H-benzo [1,4] oxazine -3-one,
    4- (2-bromo-ethyl) -2- (4-methoxy-phenyl) -4H-benzo [1,4] oxazin-3-one,
    4- (5-bromo-pentyl) -2- (3,4-dichloro-phenyl) -4H-benzo [1,4] oxazin-3-one,
    4- (2-hydroxy-ethyl) -2- (4-methoxy-phenyl) -4H-benzo [1,4] oxazin-3-one,
    2- (3,4-Dichloro-phenyl) -4- [5- (2,6-dimethyl-piperidin-1-yl) -pentyl] -4H-benzo [1,4] oxazin-3-one ,
    4- [3- (2,6-Dimethyl-piperidin-1-ylmethyl) -benzyl] -2- (4-methoxy-phenyl) -4H-benzo [1,4] oxazin-3-one ,
    4- (2-amino-ethyl) -2- (4-methoxy-phenyl) -4H-benzo [1,4] oxazin-3-one,
    2- (2,6-dimethyl-piperidin-1-yl) -N- {2- [2 (4-methoxy-phenyl) -3-oxo-2,3-dihydro-benzo [1,4 ] Oxazin-4-yl] -ethyl} acetamide,
    4- [5- (2,6-Dimethyl-piperidin-1-yl) -5-oxo-pentyl] -2- (4-methoxy-phenyl) -4H-benzo [1,4] oxazine- 3-on,
    3- {4- [4- (2,6-Dimethyl-piperidin-1-yl) -butyl] -3-oxo-3,4-dihydro-2H-benzo [1,4] oxazine-2 Benzamidine,
    3- {4- [6- (2,6-Dimethyl-piperidin-1-yl) -hexyl] -3-oxo-3,4-dihydro-2H-benzo [1,4] oxazine-2 Benzamidine,
    2- (5-aminomethyl-2-hydroxy-phenyl) -4- [5- (2,6-dimethyl-piperidin-1-yl) -pentyl] -4H-benzo [1,4] oxazine -3-one,
    2- (3-aminomethyl-phenyl) -4- [5- (2,6-dimethyl-piperidin-1-yl) -pentyl] -4H-benzo [1,4] oxazin-3-one,
    3- {4- [5- (2,6-Dimethyl-piperidin-1-yl) -pentyl] -7-methyl-3-oxo-3,4-dihydro-2H-benzo [1,4] Oxazine-2-yl} -benzamidine,
    3- {4- [5- (2,6-Dimethyl-piperidin-1-yl) -pentyl] -3-oxo-3,4-dihydro-2H-benzo [1,4] oxazine-2 -Yl} -4-methoxy-benzamidine,
    2- (5-aminomethyl-2-methoxy-phenyl) -4- [5- (2,6-dimethyl-piperidin-1-yl) -pentyl] -4H-benzo [1,4] oxazine -3-one,
    3- {4- [5- (2,6-Dimethyl-piperidin-1-yl) -pentyl] -3-oxo-3,4-dihydro-2H-benzo [1,4] oxazine-2 -Yl} -N-hydroxy-4-methoxy-benzamidine,
    3- {4- [5- (2,6-Dimethyl-piperidin-1-yl) -pentyl] -3-oxo-3,4-dihydro-2H-benzo [1,4] oxazine-2 -Yl} -N-hydroxy-benzamidine,
    3- {7-chloro-4- [5- (2,6-dimethyl-piperidin-1-yl) -pentyl] -3-oxo-3,4-dihydro-2H-benzo [1,4] Oxazine-2-yl} -benzamidine,
    4- (5-bromo-pentyl) -2-phenyl-4H-benzo [1,4] oxazin-3-one,
    3- [3-oxo-4- (5-piperidin-1-yl-pentyl) -3,4-dihydro-2H-benzo [1,4] oxazin-2-yl] -benzamidine,
    N- {2- (3-Carbamimidoyl-phenyl) -4- [5- (2,6-dimethyl-piperidin-1-yl) -pentyl] -3-oxo-3,4-dihydro -2H-benzo [1,4] oxazin-6-yl} -acetamide,
    3- {4- [5- (2,6-dimethyl-piperidin-1-yl) -pentyl] -2-methyl-3-oxo-3,4-dihydro-2H-benzo [1,4] Oxazin-2-yl} -N-hydroxy-benzamidine,
    3- [4- (5-Diisopropylamino-pentyl) -3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-2-yl] -benzamidine,
    3- (4- {4-[(Diisopropylamino) -methyl] -benzyl} -3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-2-yl) -benz Amidine,
    3- {4- [4- (2,6-Dimethyl-piperidin-1-ylmethyl) -benzyl] -3-oxo-3,4-dihydro-2H-benzo [1,4] oxazine- 2-yl} -benzamidine,
    3- {4- [5- (2,6-Dimethyl-piperidin-1-yl) -pentyl] -3-oxo-3,4-dihydro-2H-benzo [1,4] oxazine-2 -Yl} -4-hydroxy-benzamidine,
    3- {4- [5- (2,6-Dimethyl-piperidin-1-yl) -pentyl] -3-oxo-3,4-dihydro-2H-benzo [1,4] oxazine-2 -Yl} -N-methyl-benzamidine,
    {2- (3-Carbamimidoyl-phenyl) -4- [5- (2,6-dimethyl-piperidin-1-yl) -pentyl] -3-oxo-3,4-dihydro-2H -Benzo [1,4] oxazin-6-yl} -acetic acid,
    3- (4- {3-[(Diisopropylamino) -methyl] -benzyl} -3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-2-yl) -benz Amidine,
    3- {4- [3- (2,6-Dimethyl-piperidin-1-ylmethyl) -benzyl] -3-oxo-3,4-dihydro-2H-benzo [1,4] oxazine- 2-yl} -benzamidine,
    2- (3-Carbamimidoyl-phenyl) -4- [5- (2,6-dimethyl-piperidin-1-yl) -pentyl] -3-oxo-3,4-dihydro-2H- Benzo [1,4] oxazine-7-carboxylic acid,
    3- {3-oxo-4- [4- (pyridin-2-ylamino) -butyl] -3,4-dihydro-2H-benzo [1,4] oxazin-2-yl} -benzamidine ,
    2- (3-Carbamimidoyl-phenyl) -4- [5- (2,6-dimethyl-piperidin-1-yl) -pentyl] -3-oxo-3,4-dihydro-2H- Benzo [1,4] oxazine-7-carboxylic acid methyl ester,
    3- [4- (5-dihexylamino-pentyl) -3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-2-yl] -benzamidine,
    3- {4- [4- (Methyl-pyridin-2-yl-amino) -butyl] -3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-2-yl}- Benzamidine,
    4- [5- (2,6-Dimethyl-piperidin-1-yl) -pentyl] -2- [3- (imino-morpholin-4-yl-methyl) -phenyl] -4H-benzo [ 1,4] oxazine-3-one,
    3- {3-oxo-4- [4- (pyrimidin-2-ylamino) -butyl] -3,4-dihydro-2H-benzo [1,4] oxazin-2-yl} -benzami Dean,
    3- [4- (4-cyclohexylamino-butyl) -3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-2-yl] -benzamidine,
    3- {4- [5- (2,5-Dimethyl-pyrrolidin-1-yl) -pentyl] -3-oxo-3,4-dihydro-2H-benzo [1,4] oxazine-2 -Day] -benzamidine,
    3- [4- (5-morpholin-4-yl-pentyl) -3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-2-yl] -benzamidine,
    3- {4- [5- (2,6-Dimethyl-piperidin-1-yl) -2,3-dihydroxy-pentyl] -3-oxo-3,4-dihydro-2H-benzo [ 1,4] oxazine-2-yl} -benzamidine,
    4- [2- (3-Carbamimidoyl-phenyl) -3-oxo-2,3-dihydro-benzo [1,4] oxazin-4-ylmethyl] -N, N-dimethyl-benzamide ,
    2- (3-Carbamimidoyl-phenyl) -4- [5- (2,6-dimethyl-piperidin-1-yl) -pentyl] -3-oxo-3,4-dihydro-2H- Benzo [1,4] oxazine-6-carboxylic acid,
    3- [2- (3-Carbamimidoyl-phenyl) -3-oxo-2,3-dihydro-benzo [1,4] oxazin-4-ylmethyl] -N, N-dimethyl-benzamide ,
    3- {4- [5- (2,6-Dimethyl-piperidin-1-yl) -pent-2-enyl] -3-oxo-3,4-dihydro-2H-benzo [1,4] Oxazine-2-yl} -benzamidine,
    3- [4- (5-amino-pentyl) -3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-2-yl] -benzamidine,
    2- (3-Carbamimidoyl-phenyl) -4- [5- (2,6-dimethyl-piperidin-1-yl) -pentyl] -3-oxo-3,4-dihydro-2H- Benzo [1,4] oxazine-6-carboxylic acid methyl ester,
    4-methoxy-3- [4- (4-methoxy-benzyl) -3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-2-yl] -benzonitrile,
    3- {4- [5- (2,6-Dimethyl-piperidin-1-yl) -pent-3-enyl] -3-oxo-3,4-dihydro-2H-benzo [1,4] Oxazine-2-yl} -benzamidine,
    4- [2- (3-cyano-phenyl) -3-oxo-2,3-dihydro-benzo [1,4] oxazin-4-ylmethyl] -N, N-dimethyl-benzamide,
    3- [2- (3-carbamimidoyl-phenyl) -3-oxo-2,3-dihydro-benzo [1,4] oxazin-4-ylmethyl] -5- (2,6-dimethyl Piperidin-1-ylmethyl) -benzoic acid,
    3- {4- [5- (2,6-Dimethyl-piperidin-1-yl) -pentyl] -3-oxo-3,4-dihydro-2H-benzo [1,4] oxazine-2 -Yl} -4-hydroxy-benzamidine,
    3-acetyl-2- (2-methoxy-phenyl) -thiazolidine-4-carboxylic acid 4-cyano-2- {4- [5- (2,6-dimethyl-piperidine-1- Yl) -pentyl] -3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-2-yl} -phenyl ester,
    3- [2- (3-carbamimidoyl-phenyl) -3-oxo-2,3-dihydro-benzo [1,4] oxazin-4-ylmethyl] -5- (2,6-dimethyl -Piperidin-1-ylmethyl) -N-hydroxy-benzamide,
    4- (2-dimethylamino-ethyl) -7-nitro-2-phenyl-4H-benzo [1,4] -thiazin-3-one,
    4- (2-diethylamino-ethyl) -7-nitro-2-phenyl-4H-benzo [1,4] -thiazin-3-one,
    2H-1,4-benzothiazine-3 (4H) -one, 4- [2- (dimethylamino) ethyl] -7-nitro-2-phenyl-, monohydrochloride,
    2H-1,4-benzothiazine-3 (4H) -one, 4- [2- (diethylamino) ethyl] -7-nitro-2-phenyl-, monohydrochloride,
    4- [5- (2,6-dimethyl-piperidin-1-yl) -pentyl] -2- (4-methoxy-phenyl) -4H-benzo [1,4] thiazin-3-one,
    4- {4- [5- (2,6-Dimethyl-piperidin-1-yl) -pentyl] -3-oxo-3,4-dihydro-2H-benzo [1,4] thiazine-2 -Yl} -benzonitrile,
    4- {4- [5- (2,6-Dimethyl-piperidin-1-yl) -pentyl] -3-oxo-3,4-dihydro-2H-benzo [1,4] thiazine-2 -Yl} -thiobenzamide,
    4- [5- (2,6-dimethyl-piperidin-1-yl) -pentyl] -2- (4-methoxy-phenyl) -4H-benzo [1,4] thiazin-3-one,
    Compound with trifluoro-acetic acid,
    3- {4- [5- (2,6-Dimethyl-piperidin-1-yl) -pentyl] -3-oxo-3,4-dihydro-2H-benzo [1,4] thiazine-2 -Yl} -benzonitrile,
    3- {4- [5- (2,6-Dimethyl-piperidin-1-yl) -pentyl] -3-oxo-3,4-dihydro-2H-benzo [1,4] thiazine-2 -Yl} -benzamide,
    4- [5- (2,6-dimethyl-piperidin-1-yl) -pentyl] -2- (3-methoxy-phenyl) -2- (4-methoxy-phenyl) -4H-benzo [ 1,4] thiazin-3-one,
    4- [5- (2,6-Dimethyl-piperidin-1-yl) -pentyl] -2- (4-methoxy-phenyl) -1,1-dioxo-1,4-dihydro-2H -Benzo [1,4] thiazin-3-one,
    2- (4-benzyloxy-phenyl) -4- [5- (2,6-dimethyl-piperidin-1-yl) -pentyl] -4H-benzo [1,4-thiazin-3-one,
    2- (4-butoxy-phenyl) -4- [5- (2,6-dimethyl-piperidin-1-yl) -pentyl] -4H-benzo [1,4-thiazin-3-one,
    3- {4- [5- (2,6-Dimethyl-piperidin-1-yl) -pentyl] -3-oxo-3,4-dihydro-2H-benzo [1,4] thiazine-2 -Yl} -thiobenzamide,
    4- {4- [5- (2,6-Dimethyl-piperidin-1-yl) -pentyl] -3-oxo-3,4-dihydro-2H-benzo [1,4] thiazine-2 Benzamidine,
    3- {4- [5- (2,6-Dimethyl-piperidin-1-yl) -pentyl] -3-oxo-3,4-dihydro-2H-benzo [1,4] thiazine-2 -Yl} -N-hydroxy-benzamide,
    3- {4- [5- (2,6-Dimethyl-piperidin-1-yl) -pentyl] -3-oxo-3,4-dihydro-2H-benzo [1,4] thiazine-2 -Yl} -benzamide,
    3- {4- [5- (2-hydroxymethyl-pyrrolidin-1-yl) -pentyl] -3-oxo-3,4-dihydro-2H-benzo [1,4] thiazine-2 Benzamidine,
    4-allyl-2,2-diphenyl-4H-benzo [1,4] thiazin-3-one,
    4- (2-diethylamino-ethyl) -7-nitro-2-phenyl-4H-benzo [1,4] thiazin-3-one,
    2- (3-diethylamino-propylamino) -4-methyl-2-phenyl-4H-benzo [1,4] thiazin-3-one,
    4- (2-diethylamino-ethyl) -2,2-diphenyl-4H-benzo [1,4] thiazin-3-one,
    2-benzyl-4- (5-piperidin-1-yl-pentyl) -4H-benzo [1,4] oxazin-3-one,
    2-cyclohexyl-4- [5- (2,6-dimethyl-piperidin-1-yl) -pentyl] -4H-benzo [1,4] thiazin-3-one,
    2H-1,4-benzothiazine-3 (4H) -one, 4-methyl-2,2-diphenyl-,
    4-ethyl-2-phenyl-2-piperidin-1-yl-4H-benzo [1,4] thiazin-3-one,
    4-methyl-2-phenyl-2-piperidin-1-yl-4H-benzo [1,4] thiazin-3-one,
    3- {4- [5- (2-Dimethyl-piperidin-1-yl) -pentyl] -3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-2-yl } -Piperidine-1-carboxamidine,
    4- [5- (2,6-dimethyl-piperidin-1-yl) -pentyl] -2-piperidin-3-yl-4H-benzo [1,4] oxazin-3-one,
    3-oxo-2-phenyl-2,4-bis- (5-piperidin-1-yl-pentyl) -3,4-dihydro-2H-benzo [1,4] oxazine-6-carbonitrile ,
    4- [5- (2,6-dimethyl-piperidin-1-yl) -pentyl] -2-pyridin-2-yl-4H-benzo [1,4] oxazin-3-one,
    N-hydroxy-3-oxo-2-phenyl-4- (5-piperidin-1-yl-pentyl) -3,4-dihydro-2H-benzo [1,4] oxazine-6-carr Voxamidine,
    3-oxo-2-phenyl-4- (5-piperidin-1-yl-pentyl) -3,4-dihydro-2H-benzo [1,4] oxazine-6-carboxamidine,
    3- {4- [5- (2,6-Dimethyl-piperidin-1-yl) -pentyl] -3-oxo-3,4-dihydro-2H-benzo [1,4] oxazine-2 -Yl} -thiobenzamide,
    3- {4- [5- (Adamantan-1-ylamino) -pentyl] -3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-2-yl} -benz amides,
    2- (3-diethylamino-propylamino) -4-methyl-2-phenyl-4H-benzo [1,4] oxazin-3-one,
    4- [3- (2,6-dimethyl-1-piperidinyl) propyl] -2-phenyl-2H-1,4-benzoxazin-3 (4H) -one,
    4-methyl-2-phenyl-2H-1,4-benzoxazin-3 (4H) -one.
    In one aspect, the present invention discloses benzoxazinone and benzothiazinone compounds that have an inhibitory effect on serine proteases such as Factor Xa, Thrombin and / or Factor VIIa. The invention also provides pharmaceutically acceptable salts of the compounds, pharmaceutically acceptable compositions comprising the compounds or salts thereof, and methods of using them as therapeutic agents for treating or preventing a disease state in a mammal characterized by abnormal thrombosis. Is starting.
    The term "alkyl" means a straight, branched, saturated or unsaturated carbon chain having 1 to 20 carbon atoms. Typical alkyl groups include methyl, isobutyl, pentyl, 2-methyl-pentyl, pent-1,4-dienyl, but-1-enyl and the like.
    The term "cycloalkyl" means a saturated or unsaturated carbon chain that forms a ring having 3 to 20 carbon atoms. Typical examples include cyclopropyl, cyclohexyl and the like.
    The term "cycloalkylalkyl" means a cycloalkyl group in which "cycloalkyl" and "alkyl" are bonded to an alkyl group as described above and include, for example, cyclopropylmethyl, cyclopentylethyl and the like.
    The term “heteroalkyl” means a straight, branched, saturated or unsaturated carbon chain having 1 to 20 carbon atoms, in which one or more carbon atoms are substituted by a heteroatom selected from oxygen, nitrogen, sulfur, sulfoxide or sulfone. Typical "heteroalkyl" groups include methoxymethyl, 2-thiomethylpropyl, 2-thiomethoxyethoxymethyl and the like.
    The term "aryl" refers to OH, O (alkyl), SH, S (alkyl), amine, halogen, acid, ester, amide, alkyl ketone, aldehyde, nitrile, fluoroalkyl, amidine, nitro, sulfone, sulfoxide or (C 1-6) alkyl, thioamide, O-alkyl aryl, benzylamino, C (NH) (NHNH 2 ), N- hydroxy-amidine, N- methyl-amidine with an optionally substituted carbocyclic having 6 to 16 Represents click ring (s). Typical rings include phenyl, naphthyl, phenanthryl and anthracenyl. Preferred aryl rings are phenyl, substituted phenyl and naphthyl.
    The term "arylalkyl" refers to aromatic radicals in which "aryl" and "alkyl" are bonded to an alkyl radical as defined above and include, for example, benzyl and naphthylmethyl.
    The term “heterocycle” means a saturated and unsaturated mono or polycyclic (ie bicyclic) ring incorporating one or more (ie 1 to 4) heteroatoms selected from N, O and S. The heterocycle is optionally OH, O (alkyl), SH, S (alkyl), amine, halogen, acid, ester, amide, amidine alkyl ketone, aldehyde, nitrile, fluoroalkyl, nitro, sulfone, sulfoxide or C 1 It is understood that it is substituted with -6 alkyl. Examples of suitable monocyclic heterocycles include, but are not limited to, substituted or unsubstituted thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl isoxazolyl, triazolyl, Tetrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, piperidinyl, pyrrolidinyl, piperazinyl, azetidinyl, aziridinyl, morpholinyl, thietanyl, oethanyl. Preferred monoidheterocycles include, but are not limited to, 2- or 3-thienyl, 2- or 3-furanyl, 1-, 2-, or 3-pyrrolyl, 1-, 2-, 4-, or 5 Imidazolyl, 1-, 3-, 4-, or 5-pyrazolyl, 2-, 4-, or 5-thiazolyl, 3-, 4-, or 5-isothiazolyl, 2-, 4- Or 5-oxazolyl, 3-, 4-, or 5-isooxazolyl, 1,3-, or 5-triazolyl, 1-, 2-, or 3-tetrazolyl, 2,3-, or 4 -Pyridinyl, 2-pyrazinyl, 2-, 4-, or 5-pyrimidinyl, 1-, 2-, 3-, or 4-piperidinyl, 1-, 2-, or 3-pyrrolidinyl , 1- or 2-piperazinyl, 1-, 2-, or 3-azetidinyl, 1- or 2-aziridinyl, 2-, 3-, or 4-morpholinyl, 2- or 3- Thiethanol, 2- or 3-oxetanyl. Suitable bicyclic heterocycles include, but are not limited to, indolylzinyl, isoindoleyl, benzothienyl, benzooxazolyl, benzimidazolyl, quinolinyl, isoquinolinyl and preferably 1-, 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 1-, 2-, 3-, 5-, 6-, 7-, or 8-indolinyl, 1-, 2-, 3 -, 4-, 5-, 6-, or 7-isoindoleyl, 2-, 3-, 4-, 5-, 6-, or 7-benzothienyl, 2-, 4-, 5-, 6 Or 7-benzoxazolyl, 1-, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, 2-, 3-, 4-, 5-, 6-, 7-, Or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolinyl.
    As used herein, the term “heteroatom” refers to oxygen, nitrogen or sulfur (O, N or S) as well as sulfoxyl or sulfonyl (SO or SO 2 ) unless otherwise indicated. It is understood that alkyl chains interrupted by one or more heteroatoms mean that the carbon atoms of the chain are replaced with heteroatoms having the appropriate valences. Preferably, the alkyl chain is interrupted by 1 to 4 heteroatoms and not two adjacent carbon atoms are exchanged. Examples of such groups are methoxymethyl, 3-thiomethylpropyl, and 2-thiomethoxyethoxymethyl.
    The term "amine" refers to NH 2 , NHalkyl, NH (cycloalkyl), NH (cycloalkylalkyl), NH (aryl), NH (arylalkyl), NH (heteroaryl), NH (heteroarylalkyl), N ( Alkyl) (alkyl), N (alkyl) (cycloalkyl), N (alkyl) (cycloalkyl), N (alkyl) (aryl), N (alkyl) (arylalkyl), N (alkyl) (heteroaryl), N (alkyl) (heteroarylalkyl), N (cycloalkyl) (cycloalkyl), N (cycloalkyl) (cycloalkylalkyl), N (cycloalkyl) (aryl), N (cycloalkyl) (arylalkyl), N (cycloalkyl) (heteroaryl), N (cycloalkyl) (heteroarylalkyl), N (cycloalkylalkyl) (cycloalkylalkyl), N (cycloalkylalkyl) (aryl), N (cycloalkylalkyl) ( Arylalkyl), N (cycloalkylalkyl) (heteroaryl), N (cycloalkylalkyl) (heteroarylalkyl), N (aryl) (cycloalkylalkyl), N (aryl) (aryl), N (aryl) ( Arylalkyl), N (aryl) (heteroaryl), N (aryl) (heteroarylalkyl), N (arylalkyl) (arylalkyl), N (arylalkyl) (heteroaryl), N (arylalkyl) Group such as (heteroarylalkyl), N (heteroaryl) (heteroaryl), N (heteroaryl) (heteroarylalkyl), N (heteroarylalkyl) (heteroarylalkyl).
    The term “acid” means C (═O) OH.
    The term "ketone" refers to C (= 0) alkyl, C (= 0) cycloalkyl, C (= 0) cycloalkylalkyl, C (= 0) aryl, C (= 0) arylalkyl, C (= 0) hetero Aryl, C (═O) heteroarylalkyl.
    The term "ester" refers to C (= 0) Oalkyl, C (= 0) Ocycloalkyl, C (= 0) Ocycloalkylalkyl, C (= 0) Oaryl, C (= 0) Oarylalkyl, C A group such as (= O) O heteroaryl or C (= O) O heteroarylalkyl.
    The term "amide" refers to C (= 0) NH 2 , C (= 0) NHalkyl, C (= 0) NH (cycloalkyl), C (= 0) NH (cycloalkylalkyl), C (= 0) NH (Aryl), C (= 0) NH (arylalkyl), C (= 0) NH (heteroaryl), C (= 0) NH (heteroarylalkyl), C (= 0) NH (alkyl) (alkyl) , C (= 0) NH (alkyl) (cycloalkyl), C (= 0) NH (alkyl) (cycloalkylalkyl), C (= 0) N (alkyl) (aryl), C (= 0) N ( Alkyl) (arylalkyl), C (= 0) N (alkyl) (heteroaryl), C (= 0) N (alkyl) (heteroarylalkyl), C (= 0) N (cycloalkyl) (cycloalkyl) , C (= 0) N (cycloalkyl) (cycloalkylalkyl), C (= 0) N (cycloalkyl) (aryl), C (= 0) N (cycloalkyl) (arylalkyl), C (= 0 ) N (cycloalkyl) (heteroaryl), C (= 0) N (cycloalkyl) (heteroarylalkyl), C (= 0) N (cycloalkylalkyl) (cycloalkylalkyl), C (= 0) N (Cycloalkylalkyl) (aryl), C (= 0) N (cycloalkylalkyl) (arylalkyl), C (= 0) N (cycloalkylalkyl) (heteroaryl), C (= 0) N (cycloalkyl) Alkyl) (heteroarylalkyl), C (= 0) N (arylalkyl) (arylalkyl), C (= 0) N (arylalkyl) (heteroaryl), C (= O) N (arylalkyl) (heteroarylalkyl), C (= 0) N (heteroaryl) (heteroaryl), C (= 0) N (heteroaryl) (heteroarylalkyl), C (= 0) N Group such as (heteroarylalkyl) (heteroarylalkyl).
    The term "element" refers to NHC (= 0) N (alkyl) (alkyl), NHC (= 0) N (alkyl) (cycloalkyl), NHC (= 0) N (alkyl) (cycloalkylalkyl), NHC (= O) N (alkyl) (aryl), NHC (= 0) N (alkyl) (arylalkyl), NHC (= 0) N (alkyl) (heteroaryl), NHC (= 0) N (alkyl) (heteroaryl Alkyl), NHC (= 0) N (cycloalkyl) (cycloalkyl), NHC (= 0) N (cycloalkyl) (cycloalkylalkyl), NHC (= 0) N (cycloalkyl) (aryl), NHC ( ═O) N (cycloalkyl) (arylalkyl), NHC (═O) N (cycloalkyl) (heteroaryl), NHC (═O) N (cycloalkyl) (heteroarylalkyl), NHC (= 0) N (Cycloalkylalkyl) (cycloalkylalkyl), NHC (= 0) N (cycloalkylalkyl) (aryl), NHC (= 0) N (cycloalkylalkyl) (arylalkyl), NHC (= 0) N (cyclo Alkylalkyl) (heteroaryl), NHC (= 0) N (cycloalkylalkyl) (heteroarylalkyl), NHC (= 0) N (aryl) (cycloalkylalkyl), NHC (= 0) N (aryl) ( Aryl), NHC (= 0) N (aryl) (arylalkyl), NHC (= 0) N (aryl) (heteroaryl), NHC (= 0) N (aryl) (heteroarylalkyl), NHC (= 0 ) N (arylalkyl) (arylalkyl), NHC (= O) N (arylal Ke) (heteroaryl), NHC (= 0) N (arylalkyl) (heteroarylalkyl), NHC (= 0) N (heteroaryl) (heteroaryl), NHC (= 0) N (heteroaryl) (hetero) Arylalkyl), NHC (= 0) N (heteroarylalkyl) (heteroarylalkyl).
    The term "halogen" means chlorine, fluorine, bromine and iodine.
    or (wedge or hash) is just an expression of stereochemical techniques. All stereoisomers, including enantiomers and diastereomers, are included in Formulas 1-8 and provided by the present invention. If particular isomers are shown, these are the preferred isomers.
    In some cases, compounds may exist as tautomers. All tautomers are included in Formulas 1-8 and provided by the present invention.
    When administering a compound, some metabolism can occur. All metabolites are included in Formulas 1-8 and provided by the present invention.
    When the bond to a substituent is shown as intersecting a bond connected to two atoms in the ring, such substituent may be attached to any atom of the ring if the atom can accept a substituent without disturbing its valency. If several atoms of a substituent appear that can be attached to a ring atom, this is the first atom of the substituent listed as being attached to the ring.
    When a bond is represented by a line such as "-", it is expressed that there is no bond, or only present if the compound obtained is stable and of sufficient valence.
    The compounds of the present invention are not only salts derived from organic acids such as aliphatic mono and dicarboxylic acids or aliphatic and aromatic sulfonic acids, but also acid addition salts with inorganic acids such as hydrochloric acid, sulfuric acid and the like (eg, Berge SM , et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 1977: 1-10). Acid addition salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt. The free base form can be regenerated by contacting the salt form with a base. Free bases differ in salt form from physical properties such as solubility, but for the purposes of the present invention, salts are equivalent to their respective free bases.
    Some compounds of the present invention may exist in unsolvated forms as well as solvated forms, including hydrate forms. In general, solvated forms, including hydrated forms, are equivalent to unsolvated forms, which will be included within the scope of the present invention.
    "Prodrug" will include any covalently bonded carrier that releases the active mother drug according to Formulas 1-8 in vivo. Examples of prodrugs include acetate, formate, benzoate derivatives of alcohols and amines present in compounds of Formulas 1-8. They also include derivatives of amidine or guanine functionality, wherein C (= NR 3 ) NH 2 , wherein R 3 is OH, NH 2 , C 1-4 alkoxy group, C 6-10 aryloxy, C 1-10 Alkoxycarbonyl, C 6-10 aryloxycarbonyl). Preferred derivatives include examples in which R 3 is OH, NH 2 , methoxy and ethoxycarbonyl.
    The table below provides abbreviations and their definitions used in the present invention.
    Abbreviation Explanation AMC Aminomethylcoumarin aPTT Activation partial thromboplastin time BOC Tert-butyloxycarbonyl BOP-Reagent Benzotriazone-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate Bz Benzoate CDCl 3 Deuterochloroform DMF Dimethyl formamide DMSO Dimethyl sulfoxide1 H-NMR Quantum nuclear magnetic resonance HCl Hydrogen chloride HF Hydrogen fluoride HMPA Hexamethylphosphoramide HPLC High pressure liquid chromatography MOT Mean occlusion time MS (APCI) Mass spectrometry (atmospheric pressure CI) MS (CI) Mass spectrometry (chemical ionization reaction) MS (ES) Mass spectrometry (electrospray) NaOH Sodium hydroxide nBuLi n-butyl lithium NH 4 Cl Ammonium chloride Pd / C Palladium on carbon PtO 2 Platinum oxide r.t. Or RT Room temperature TFA Trifluoroacetic acid THF Tetrahydrofuran TT Thrombin time VAZO-52 2,2'-azobis-2-methylvaleronitrile
    The present invention also provides a method of preventing and treating acute, subacute and chronic thrombotic disorders in a mammal by administering to the mammal an effective amount of a compound of Formulas 1-8. The compounds are useful as anticoagulants for the treatment and prevention of disorders such as venous and arterial thrombosis, pulmonary embolism and ischemic events such as myocardial infarction or cerebral infarction. The compounds are also therapeutically useful for the prevention and treatment of coagulation associated with endothelial vascular access ports and arteriovenous shortcomings and with cardiopulmonary circuits or other extracorporeal systems. Such compounds are useful for the prevention or treatment of unstable anesthesia, refractory anesthesia, intermittent claudication, disseminated intravascular coagulation and the accumulation of fibrin in the eye. Since thrombin and serine proteases have also been described as activating numerous different cell types, the compounds are useful for the treatment and prevention of pulmonary pulmonary shock and other inflammatory reactions, such as acute or chronic atherosclerosis. The compounds are also useful for treating tumor / metastasis and neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. In a preferred method, the thrombotic disorder is selected from venous thrombosis, arterial thrombosis, pulmonary embolism, myocardial infarction, cerebral infarction, angina, cancer, diabetes. Another embodiment of the invention is a pharmaceutical formulation comprising a compound of formula 1-8 administered with a diluent, excipient or carrier.
    <Preparation of the compound of the present invention>
    Compounds of Formulas 1-8 may be prepared by any of a variety of methods known to those skilled in the organic chemistry art. The following schemes represent the preferred routes for providing the compounds herein. The reaction is typically carried out in a solvent suitable for the reagents and substrates used. It will be appreciated that the functional groups present in the molecule should be suitable for the proposed reagents and reaction conditions. All of the compounds of the formulas 1 to 8 belonging to a given group may not be suitable for some of the described reaction conditions. Such limitations will be apparent to those skilled in the art of organic synthesis, so other methods must be used.
    Step a:
    Aldehydes are described in Tanaka J., Org. Chem., 1989: 444] to trichloromethyl carbinol by treatment with carbon tetrachloride and aluminum / lead bromide DMF at room temperature. Other methods include trimethylsilyl trichloromethane and tetrabutylammonium fluoride or more typically Galun, Org. Synth. Coll., 1973; V: 130, including the addition of chloroform and potassium hydroxide. See also Weissman, Org. Proced. Int., 1995; 27 (5): 590-592, it should be noted that trimethylsilyl trichloroacetate in the presence of potassium fluoride is an effective method for the preparation of trichloromethylcarbinol.
    Step b:
    Gukasyan et al., Arm. Khim. Zh., 1988; 41 (9): 572-575, to provide benzoxazinone by addition of o-aminophenol and base. This typically involves treating trichloromethylcarbinol with suitably substituted ortho-amino phenol in a solvent such as DMF or DMSO in the presence of potassium hydroxide or sodium hydride at room temperature to 100 ° C. Using chiral trichloromethyl carbinol it is clear that the benzoxazinone obtained will be in chiral form.
    Step c:
    The alkylation reaction is typically accomplished by treatment with a suitable electrophile in a bipolar aprotic solvent and addition of base. Typical conditions include, for example, the use of bis-electrophilic substrates such as 1,5-dibromopentane in a bipolar aprotic solvent such as DMF or DMSO, and the addition of a base such as sodium hydride. Alternatively, the alkylation reaction can be accomplished by adding a phase transfer reagent such as an alkylammonium salt, for example benzyltriethylammonium chloride, and using a base such as sodium ethoxide. Since the reaction rate is typically improved by the application of heat, the reaction is carried out at about 0 ° C to 70 ° C.
    Step d:
    Treatment with an amine such as cis-2,6-dimethylpiperidine at an elevated temperature of about 50 ° C. gives the expected N-alkylated piperidine. The amines can be used as solvents or alternatively added in stoichiometric ratios, and the reaction mixture can be refluxed in a solvent such as ethanol, acetonitrile or toluene. The product, which is a suitable acid addition salt, is then neutralized by addition of a base such as aqueous potassium hydroxide. If the amine is volatile, then the reaction mixture is heated to typically 50 ° C. to 150 ° C. in a sealed tube.
    Step e:
    The conversion of the nitrile to hydroxyamidine is accomplished by reacting the nitrile with hydroxylamine in methanol at room temperature. Typically, the reaction is initiated by adding hydroxyamine hydrochloride to the nitrile containing substrate at room temperature and adding a base such as potassium carbonate or diisopropylethylamine. The reaction is generally monitored by HPLC to determine the absence of the starting material nitrile, which is typically completed within a 24 hour period.
    Step f:
    By adding acetic anhydride of trifluoroacetic anhydride intermediate in a solvent such as acetic acid or trifluoroacetic acid, the amidoxime was activated to obtain an O-acylated intermediate, which can be isolated or otherwise used directly in the next reduction step. Can be. This step and the next reduction reaction can be combined, i.e. reduction with Pd / C in acetic anhydride / acetic acid or trifluoroacetic anhydride / trifluoroacetic acid.
    Step g:
    The substrate is dissolved in methanol or acetic acid or trifluoroacetic acid, treated with a transition metal catalyst such as palladium dispersed on carbon and then briefly, typically, hydrogenated for 1 to 12 hours. The product is then typically crystallized or isolated via chromatography, such as reversed phase HPLC.
    Another method of mother benzoxazinone synthesis includes, for example, Scheme 2 below.
    Step a:
    Methyl alpha-bromo phenylacetate is treated with ortho-nitrophenol and base to easily provide phenolic acid ethers. Of course, it is understood that activation of carbon benzyl acid, such as chloride or mesylate, is also sufficient to proceed with the initial etherification. Typically, the potassium or sodium salt of ortho-nitrophenol is added to the electrophiles in a solvent such as DMF and the mixture is typically warmed to 50 ° C. until determined to be complete by TLC. Chiral alpha-functionalized aryl acetates can be used to provide chiral adducts.
    Step b:
    The reduction reaction of the nitro group to the corresponding aniline can be easily accomplished by treatment with transition metals such as palladium on carbon or Raney nickel and hydrogen, or alternatively with tin in aqueous hydrochloric acid. These anilines are readily cyclized to the corresponding benzoxazinones during the reduction reaction or upon heating in a solvent such as methanol.
    Step c:
    Otherwise, Bull. Soc. Chim. Belg., 1987: 473-480, the benzoxazin-2-ones are directly isolated by the addition of ortho-amenophenols according to the method of.
    Another alternative to the preparation of essential benzoxazinones is described in Krapcho, Tawada et al., Chem. Pharm. In a similar manner to that described in Bull., 1990: 1238-1245, it is necessary to treat substituted amino phenols with acid chlorides as shown in Scheme 3 below.
    Step a:
    Treatment of ortho amino phenol with acid chloride in a solvent such as dichloromethane in the presence of a base such as diisopropylethylamine gives the N-acylated product.
    Step b:
    Subsequent treatment with a base, such as potassium carbonate, in a solvent such as DMF, adds phenoxide intramolecularly nucleophilic to the secondary bromide to provide the mother benzoxazinone.
    Another alternative is outlined in Scheme 4 below, which is initiated by esterification of ortho-halo phenol with alpha-bromo phenylacetamide. The following intramolecular nucleophilic substitution reactions provide N-alkylated benzoxazinones (Coutts and Southcott J., Chem. Soc., Perkin Trans. 1, 1990: 767-771).
    Step a:
    After treating the sodium salt of phenol with an electrophile in a solvent such as methylene chloride or dioxane, the reaction mixture is warmed to 100 ° C. for 4 hours.
    Step b:
    Sodium hydride is added in a solvent such as DMPU and warmed to 100 ° C. to give the desired benzoxazinone.
    Scheme 5 below illustrates another alternative that can be used.
    Step a:
    2-hydroxy-2H-1,4-benzoxazine- by the method of Sahu A., Indian Journal of Chemistry, 1990; 603-605 or Matlin SA, JCS Perkin Trans I, 1979; 2481-2487. After preparing 3 (4H) -one, 2-bromo-2H was treated with HBr for 24 to 48 hours in acetic acid / acetic anhydride at room temperature according to the method of Tietze LF, Synthesis, 1991; 1118-1120. -1,4-benzoxazine-3 (4H) -one. The product is precipitated from the reaction mixture, which is used directly in the next reaction step because of its hydrolysis instability. Alternatively, the acetate can be prepared by treating the alcohol with acetic anhydride in the presence of pyridine and catalytic DMAP. The addition of HBr to acetate in acetic acid also provides the corresponding bromide.
    Step b:
    Phenolic acid ethers such as phenol or 4-bromo anisole and Lewis acids such as tin (IV) or aluminum (III) chloride were added and refluxed for several hours to give the corresponding 2-aryl substituted benzoxazinones. do.
    Step c-f:
    It is carried out in a similar manner to the above scheme.
    The substituted alpha-bromo phenylacetates used in this reaction are prepared by a number of standard methods, as shown in Scheme 6 below.
    An acetic acid derivative is prepared by, for example, converting substituted benzoic acid to the corresponding acid chloride using oxalyl chloride and catalytic DMF and then treated with etheric diazomethane. Rearrangement with silver oxide in an alcoholic solvent such as methanol gives an approved methyl acetate. The functionalization of the alpha position is then achieved by refluxing the solution of the ester in carbon tetrachloride with N-bromosuccinimide in the presence of a radical initiator such as AIBN. It is, of course, obvious that the acetic acid derivatives will be treated with bromine to obtain alpha-bromo phenyl acetate in the presence of phosphorus tribromide in a similar manner to the reaction termed the Hell-Volhard-Zelinskii reaction. .
    Alternatively, intermediate alpha bromo esters are described in Robert A., Jaguelin S., Guinamant JL " Synthesis of esters of α-halo acids from gem dicyano epoxides. Tetrahedron. 1986; 42 (8): 2275-2281. Can be prepared as shown in Scheme 7 below.
    As a representative example in this case, an aldehyde such as 3-bromobenzaldehyde is reacted with malonitrile in a solvent such as dioxane in the presence of catalytic piperidine to give 2-[(3-bromophenyl) -methylene] malonitrile. do. The epoxide formation reaction proceeds easily with commercially available bleaches at pH 5-6. Treatment with hydrobromic acid in methanol gives the desired methyl 2-bromo-2- (3-bromophenyl) acetate. Similarly methyl 2-bromo-2- (3-cyanophenyl) acetate was prepared.
    Another method for converting nitrile to amidine is also provided as shown in Scheme 8 below. Further, for example, palladium catalyzed cross-coupling reactions with Zn (CN) 2 or aryl bromide with copper cyanide (I) at elevated temperatures can provide nitriles. The nitrile is treated with hydrogen chloride in alcohol solvent to give the corresponding iminoether hydrochloride. This intermediate is then treated with an ammonia source, for example ammonia in methanol or ammonium chloride or ammonium acetate and the mixture is stirred and, if necessary, warmed to give amidine.
    Benzothiazinone of Formula 1 may also be prepared according to Scheme 9 below.
    The reaction sequence is similar to that described in Scheme 1, except that 2-aminophenyl thiol replaces 2-aminophenol in the initial reaction sequence.
    It is often desirable to prepare optically pure materials because some of the compounds of formula 1 exist as mixtures of enantiomers. In this case it is isolated by preparing an addition salt with chiral acid and crystallizing the mixture. The parent compound is then isolated by treatment with a base such as potassium hydroxide. Enantiomers can also be separated by chiral HPLC. Suitable columns for separating enantiomers of intermediates such as 3- (3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl) benzenecarbonitrile are 50% water and acetonitrile Beta-cyclodextrins (keystone chiral β-PM) using the mixture. Alternatively, asymmetric synthesis can be used to synthesize certain enantiomers. In particular, suitably substituted phenoxides (for benzoxazinone) or thiophenoxides (for benzothiazinone) are described by Koh, J. Org. Chem., 1994; 59: 4683-4686 and can be added to the pentolactone derivatives as outlined in Scheme 10 below.
    (R) Pantolactone esters are used to provide the (S) diastereomers. In the above scheme, Y is a substituent that can be prepared to provide aniline, and the aniline provides the desired chiral benzoxazinone through an intramolecular cyclization reaction. Examples of such substituents may include nitro functional groups or N-acetyl groups.
    Another alternative to the production of chiral benzoxazinone intermediates is the lactamide derived ester of racemic alpha-halo carboxylic acid (Devine, Tetrahedron Letts., 1996: 2683-2686) as outlined in Scheme 11 below. Provided by application.
    The diastereomeric selectivity of this reaction is good and the product has a (R) stereochemistry, thus providing a complementary approach to the product of Scheme 10 above.
    It should be noted that chiral alpha-trichloromethyl carbinone treated with phenoxide provides another optically active alpha-aryloxy acid while providing another alternative to producing chiral benzoxazinone or benzothiazinone. Corey, Tetrahedron Lett., 1992: 3431].
    An alternative method for preparing chiral benzoxazinone is outlined in Scheme 12 below.
    Step a:
    For example, potassium carbonate or sodium hydroxide and benzyl bromide in a solvent such as DMF or ethanol form a suitable protecting group, benzyl ether in the scheme, to protect the aldehyde.
    Step b:
    Cyanide is added to aldehydes to easily form intermediate cyano hydrins in a solvent such as methanol. It will be appreciated that this method can also be carried out using one of the following general methods in an asymmetric way; Danda, H et al., Chem Lett 1991, 731. Poly (quinidine-co-acrylonitrile) Effenberger, F et al., Tetrahedron Lett 1990, 31 (9), 1249. (Oxynitrilase) Mori, A. et al ., Chem Lett 1989 (12), 2119. Cyclo- (Leu-His) or Tanaka, K. et al., J Org Chem 1990, 55, 181. cyclo ((S) -Phe- (S) -His). Minamikawa, H. et al., Bull Chem Soc Jpn 1988, 61 (12), 4379. 1,1,4,4-Tetraphenylbutanetetraol- (2R, 3R) -O, O-phenylethylidene Ti (i-PrO) 2 Cl 2 Harrington, K. J et al., Aust J Chem 1986, 39, 1135. 1) beta-Cyclodextrin].
    Step c:
    Conversion of cyano functional groups to methyl esters is readily accomplished by treating nitrile with HCl in an alcohol solvent such as methanol. Water is then added to convert the intermediate imino ethers into esters.
    Step d:
    The oxidation of alcohols to keto-esters is readily accomplished by oxidizing agents such as oxalyl chloride and dimethyl sulfoxide or by heating with manganese dioxide in a solvent such as toluene or methylene chloride.
    Step e:
    The chiral reduction reaction of the keto-ester is best achieved by a reducing agent such as R-alpha borane. This reduction reaction is typically slow and takes several days to complete.
    Step f:
    Mitsunobo coupling reaction followed by nitrophenol (also possibly amino phenol), diisopropylazodicarboxylate (or other alkylazodicarboxyl) in a solvent such as ethyl acetate at a low temperature such as -40 ° C. And triphenylphosphine) in chiral alcohol.
    Step g:
    The reduction reaction of the nitro group is best achieved under a neutral Raney nickel and hydrogen atmosphere in a solvent such as methanol. It is important that the solution not be basic because enantiomeric excess reduction reactions can be observed.
    Compounds of the invention are also characterized by the ability to inhibit catalytic activity of factor Xa, which is demonstrated in the following assay. Compounds of the present invention can be prepared by dissolving them in buffer for analysis to obtain solutions in a concentration range of 1-100 μM. In the assay to determine the inhibitory dissociation constant K i for a given compound, a pigmented or fluorogenic substrate of factor Xa is added to a solution containing the test compound and factor Xa, and the catalytic activity of the obtained enzyme is determined spectrophotometrically. do. Such assays are well known to those skilled in the art and are commonly used to determine antithrombotic activity.
    The compounds of the present invention can be used as anticoagulants in vitro or ex vivo, such as where contact activation with heterologous thrombus generating surfaces is found in the tubes used for in vitro shorts. Compounds of the invention can also be used to coat the surface of such thrombogenic conduits. For this purpose, the compounds of the present invention can be prepared as lyophilized powders and redissolved in isotonic saline or similar diluents and added in an amount sufficient to maintain blood in an anticoagulant state.
    The therapeutic agents of the invention may be administered alone or in combination with a pharmaceutically acceptable carrier. The proportion of each carrier is determined by the solubility and chemical nature of the compound, route of administration and standard pharmaceutical practice. For example, the compound can be injected parenterally, ie intramuscularly, intravenously, or subcutaneously. For parenteral administration, the compounds may be used in the form of sterile solutions containing sufficient saline or glucose to make other solutes, for example, the solution isotonic. The compounds may be administered orally in the form of tablets, capsules or granules containing suitable excipients such as starch, lactose, sugar and the like. The compounds can also be administered sublingually in the form of tablets or lozenges, with each active ingredient combined with sugar or corn syrup, sweeteners and dyes, and dehydrated sufficiently to produce a mixture suitable for pressing into solid form. The compound may be administered orally in the form of a solution which may contain coloring and / or sweetening agents. Typical formulations will contain from about 5% to 95% by weight of the compound of the present invention.
    The amount of a compound of the present invention used to prevent and treat thrombotic disorders is an amount effective to prevent or treat a condition without causing unacceptable side effects. Such an effective amount will be about 0.01 mg / Kg to about 500 mg / Kg, preferably about 1 mg / Kg to about 100 mg / Kg. Doctors will determine the correct dosage of the best treatment for this treatment. The dosage may vary depending on the mode of administration and the particular compound selected. In addition, the dosage may vary depending on the particular patient being treated.
    When the composition is administered orally, a higher amount of active agent will be needed to produce the same effect, since typically less is provided parenterally.
    To further understand the present invention, the following non-limiting examples of factor Xa inhibitory compounds are provided. The following examples are of course not intended to specifically limit the invention, and variations that are presently known or later developed will be contemplated as being within the scope of the skilled person and within the scope of the invention as described herein. While preferred compounds of the present invention are synthesized through conventional manufacturing steps and recovery methods known to those skilled in the art of organic and bio-organic synthesis, the present invention provides novel and unique combinations for the overall synthesis of each compound. Preferred synthetic routes of intermediates are included in the synthesis as well as the antithrombogenic compounds of the invention obtained.
    In general, evaporation of the reaction mixture was carried out by rotary evaporation at room temperature of 18 ° C. to 25 ° C. or vacuum at elevated temperatures of up to 50 ° C. Chromatography, preferably by medium pressure liquid chromatography, is generally carried out on Merck Kieselgel. Reverse phase purification, in particular by high pressure liquid chromatography (HPLC) for polar compounds, was carried out on C-18 reverse phase silica gel using a gradient elution of acetonitrile containing water and 0.1% trifluoroacetic acid. The final products were expressed in nuclear magnetic resonance (NMR) spectra and mass spectra consistent with their designated structures. Intermediates are typically not fully specified, but their purity is typically analyzed by HPLC or thin layer chromatography.
    <Example 1>
    4-5-[(2R, 6S) -2,6-dimethylhexahydro-1-pyridinyl] pentyl-2- (4-methoxyphenyl) -3,4-dihydro-2H-1,4-benz Oxazine-3-one
    Step (a): Preparation of Methyl 2-bromo-2- (4-methoxyphenyl) acetate
    To methyl 4-methoxyphenylacetate (1) (5.0 g, 27.7 mmol) in carbon tetrachloride were added N-bromosuccinimide (5.92 g, 33.3 mmol) and VAZO52 (152 mg, 0.612 mmol). The reaction mixture was stirred and heated at reflux for 3 hours. 1 H NMR showed that the starting material was completely brominated. The mixture was cooled in an ice bath. The precipitate was filtered off and washed with carbon tetrachloride. The filtrate was evaporated in vacuo to give (2) in quantitative yield as a brown oil, which was pure enough for use in the next reaction.
    Step (b): Preparation of Methyl 2- (4-methoxyphenyl) -2- (2-nitrophenoxy) acetate
    To (3) (7.18 g, 27.7 mmol) in DMSO (20 ml) was added o-nitrophenol sodium salt (7.32 g, 45.5 mmol). The reaction mixture was stirred at 70 ° C for 24 h. The reaction mixture was cooled, diluted with water and extracted with ethyl acetate (3 x 300 ml). The combined organic extracts were washed with brine (200 ml) and dried over magnesium sulfate, filtered and evaporated in vacuo. The residue was purified on a silica gel column eluting with 20% ethyl acetate in hexanes. Product (4) was isolated as 2.90 g (33%) as an orange oily solid.
    Step (c): Preparation of 2- (4-methoxyphenyl) -3,4-dihydro-2H-1,4-benzoxazin-3-one
    Phenolic acid ether (4) (2.88 g, 9.08 mmol) was hydrogenated with Raney nickel (1 g) in THF (50 ml) and methanol (50 ml) at room temperature for 23 hours. The mixture was filtered and the filter pad was washed with methanol and THF. The combined filtrates and washes were evaporated in vacuo to give benzoxazinone (5) in quantitative yield as an orange solid.
    Step (d): Preparation of 4- (5-bromopentyl) -2- (4-methoxyphenyl) -3,4-dihydro-2H-1,4-benzoxazin-3-one
    To benzoxazinone (5) (2.42 g, 9.48 mmol) in DMF (9 ml) was added sodium hydride (0.433 g, 10.82 mmol) and the solution was stirred at 70 ° C. for 15 minutes until no foaming occurred. To this solution was added 1,5-dibromopentane (8.66 g, 37.7 mmol) and the solution was further stirred at 70 ° C. for 5 hours. The solution was cooled and diluted with water and extracted with ethyl acetate (5 x 200 ml). The combined organic extracts were washed with brine (2 x 100 ml) and dried over magnesium sulfate, filtered and evaporated in vacuo. The residue was purified on a silica gel column eluting with 20% ethyl acetate in hexanes. Product (6) was isolated as 1.85 g (48%) as yellow oil.
    Step (e): 4-5-[(2R, 6S) -2,6-dimethylhexahydro-1-pyridinyl] pentyl-2- (4-methoxyphenyl) -3,4-dihydro-2H- Preparation of 1,4-benzoxazine-3-one
    (6) To (0.50 g, 1.23 mmol) cis-2,6-dimethylpiperidine (2 ml, 14.8 mmol) was added and the solution was stirred at 50 ° C for 16 h. The solution was cooled and diluted with water and extracted with ethyl acetate (3 x 100 ml). The combined organic extracts were washed with saturated sodium bicarbonate (2 x 100 ml), brine (2 x 100 ml), dried over magnesium sulfate, filtered and evaporated in vacuo. The residue was eluted with a mixture of purified HPLC (Vydac 218TP1022 C-18, (i) 0.1% trifluoroacetic acid in water, and (ii) 0.1% trifluoroacetic acid in acetonitrile, gradient profile Purification via 95: 5 (i) :( ii) to 60:40 (i) :( ii), flow rate 20 ml / min, λ = 214 nM) over 90 minutes and freeze-dried to yield product (7) Obtained 27 mg (12%) as a fluff white solid.
    HPLC: RT = 17.28 min (Beckman 235328 C-18 5 μm 4.6 mm × 25 cm, consisting of (i) 0.1% trifluoroacetic acid in water, and (ii) 0.1% trifluoroacetic acid in acetonitrile) Elution with mixture of solvents, gradient profile from 80:20 (i) :( ii) to 10:90 (i) :( ii), flow rate 1.5 ml / min, λ = 214 nM over 23 minutes)
    <Example 2>
    3- (4-5-[(2R, 6S-2,6-dimethylhexahydro-1-pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2 -Yl) -1-benzenecarboximidamide
    Step (a): Preparation of 3- (2,2,2, -trichloro-1-hydroxyethyl) benzonitrile
    To a mixture of lead (II) bromide (1.69 g, 4.60 mmol) and finely divided aluminum foil (1.25 g, 45.8 mmol) in DMF (226 ml) 3-cyanobenzaldehyde (6.01 g, 45.8 mmol) and carbon tetrachloride (8.84 ml) , 91.7 mmol), and the mixture was stirred at ambient temperature for 3 hours. The reaction was quenched with aqueous 1 N hydrochloric acid (100 ml) and the mixture was extracted with ethyl acetate (3 × 300 ml). The combined organic extracts were washed with brine (200 ml), dried over magnesium sulfate, filtered, evaporated in vacuo and dried in high vacuum to give trichloromethyl carbinol (9) in quantitative yield as a brown oil.
    Step (b): Preparation of 2- (3-cyanophenyl) -3,4-dihydro-2H-1,4-benzoxazin-3-one
    To the o-aminophenol hydrochloride (3.29 g, 13.1 mmol) in DMSO (15 ml) was added sodium hydroxide (2.63 g, 65.8 mmol). After bubbling and heat release ceased, a solution of (10) (3.29 g, 13.1 mmol) in DMSO (10 ml) was added dropwise over 15 minutes. After heat generation ceased, the mixture was stirred at 70 ° C for 4 h. The reaction was cooled and diluted with water and extracted with ethyl acetate (5 x 500 ml). The combined organic extracts were washed with brine (200 ml) and dried over magnesium sulfate, filtered and evaporated in vacuo. The residue was purified on a silica gel column eluting with 25% ethyl acetate in dichloromethane. Product (11) was isolated 0.55 g (17%) as an orange solid.
    Step (c): Preparation of 4- (5-bromopentyl) -2- (3-cyanophenyl) -3,4-dihydro-2H-1,4-benzoxazin-3-one
    To benzoxazinone (11) (0.72 g, 2.87 mmol) in DMF (5 ml) was added sodium hydroxide (0.126 g, 3.15 mmol) and the solution was stirred at 70 ° C. for 15 minutes until no foaming occurred. To this solution 1,5-dibromopentane (1.57 ml, 11.5 mmol) was added and the solution was further stirred at 70 ° C. for 3 hours. The solution was cooled and diluted with water and extracted with ethyl acetate (5 x 200 ml). The combined organic extracts were washed with brine (2 x 100 ml) and dried over magnesium sulfate, filtered and evaporated in vacuo. The residue was purified on a silica gel column eluting with 20% to 40% ethyl acetate in hexanes. Product (12) was isolated as 0.64 g (56%) as yellow oil.
    Step (d): 4-5-[(2R, 6S) -2,6-dimethylhexahydro-1-pyridinyl] pentyl-2- (3-cyanophenyl) -3,4-dihydro-2H- Preparation of 1,4-benzoxazine-3-one
    (12) To (1.08 g, 2.70 mmol) cis-2,6-dimethylpiperidine (8 ml, 60 mmol) was added. The solution was stirred at 70 ° C for 16 h. The solution was cooled and diluted with water and extracted with ethyl acetate (3 x 200 ml). The combined organic extracts were washed with saturated sodium bicarbonate (2 x 100 ml), brine (2 x 100 ml), dried over magnesium sulfate, filtered and evaporated in vacuo, co-evaporated with toluene and dried in high vacuum ( 13) was obtained as a yellow oil 1.09 g (49%).
    HPLC: RT = 13.88 min (Beckman 235328 C-18 5 μm 4.6 mm × 25 cm, mixture of solvent consisting of (i) 0.1% trifluoroacetic acid in water, and (ii) 0.1% trifluoroacetic acid in acetonitrile) Elution, gradient profile from 80:20 (i) :( ii) to 10:90 (i) :( ii), flow rate 1.5 ml / min, λ = 214 nM over 23 minutes)
    Step (e): 3- (4-5-[(2R, 6S) -2,6-dimethylhexahydro-1-pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4 Preparation of -benzoxazine-2-yl) -1-N-hydroxybenzenecarboximidamide
    To (13) (1.09 g, 2.53 mmol) in methanol (30 ml) was added hydroxylamine hydrochloride (0.438 g, 6.30 mmol) and diisopropylethylamine (0.44 ml, 2.53 mmol). The solution was stirred at rt for 16 h. The solvent was evaporated in vacuo and the oil dried in high vacuum to give (14) in quantitative yield.
    HPLC: RT = 8.39 min (Beckman 235328 C-18 5 μm 4.6 mm × 25 cm, mixture of solvent consisting of (i) 0.1% trifluoroacetic acid in water, and (ii) 0.1% trifluoroacetic acid in acetonitrile) Elution, gradient profile from 80:20 (i) :( ii) to 10:90 (i) :( ii), flow rate 1.5 ml / min, λ = 214 nM over 23 minutes)
    Step (f): 3- (4-5-[(2R, 6S) -2,6-dimethylhexahydro-1-pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4 Preparation of -benzoxazine-2-yl) -1-N-hydroxytrifluoroacetatebenzenecarboximidamide
    Trifluoroacetic anhydride (7 ml) was added to (14) (0.53 g, 1.14 mmol) and the solution was stirred at room temperature for 2 hours. The solvent was removed in vacuo to give (15) in quantitative yield as a yellow oil.
    HPLC: RT = 17.44 min (Beckman 235328 C-18 5 μm 4.6 mm × 25 cm, mixture of solvent consisting of (i) 0.1% trifluoroacetic acid in water, and (ii) 0.1% trifluoroacetic acid in acetonitrile) Elution, gradient profile from 80:20 (i) :( ii) to 10:90 (i) :( ii), flow rate 1.5 ml / min, λ = 214 nM over 23 minutes)
    Step (g): 3- (4-5-[(2R, 6S) -2,6-dimethylhexahydro-1-pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4 Preparation of -benzoxazine-2-yl) -1-benzenecarboximidamide
    To 15 (0.57 g, 1.13 mmol) in trifluoroacetic acid (16 ml) was added 20% palladium on carbon (0.1 g) and the mixture was hydrogenated at 23 ° C. for 48 hours. The mixture was filtered and the filter pad was washed with trifluoroacetic acid. The combined filtrates and washes were evaporated in vacuo and the residue was purified by HPLC (Bidda 218TP1022 C-18, (i) 0.1% trifluoroacetic acid in water, and (ii) 0.1% trifluoroacetic acid in acetonitrile). Elution to mixture, gradient profile from 95: 5 (i) :( ii) to 60:40 (i) :( ii), flow rate 20 ml / min, λ = 214 nM) over 90 minutes, lyophilization 251 mg (50%) of bis TFA salt (16) were obtained. To (16) in acetonitrile (2 ml) and water (2 ml) was added Amberlite (R) (Amberlite) IRA-400 (CI) ion exchange resin (3.36 g). The mixture was filtered and the filtrate was lyophilized to give 155 mg (26%) of bis hydrochloride salt (16).
    CI MS M + 1 = 449
    HPLC: RT = 8.26 min (Beckman 235328 C-18 5 μm 4.6 mm × 25 cm, mixture of solvent consisting of (i) 0.1% trifluoroacetic acid in water, and (ii) 0.1% trifluoroacetic acid in acetonitrile) Elution, gradient profile from 80:20 (i) :( ii) to 10:90 (i) :( ii), flow rate 1.5 ml / min, λ = 214 nM over 23 minutes)
    <Example 3>
    3- (4,5-[(2R, 6S) -2,6-dimethylhexahydro-1-pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazine- Preparation of 2-yl) -1-benzenecarboximidamide
    Step (a): Preparation of 2- (3-cyanophenyl) -3,4-dihydro-2H-1,4-benzothiazin-3-one
    To o-aminothiophenol (2.39 ml, 22.3 mmol) in DMF (60 ml) was added sodium hydride (3.61 g, 90.3 mmol). After foaming and heat release were stopped, a solution of (10) (5.67 g, 22.6 mmol) in DMSO (40 ml) was added dropwise over 15 minutes. After heat generation ceased, the mixture was stirred at 50 ° C. for 6 hours and at room temperature for 16 hours. The reaction mixture was cooled and diluted with water and extracted with ethyl acetate (5 x 500 ml). The combined organic extracts were washed with brine (200 ml) and dried over magnesium sulfate, filtered and evaporated in vacuo. The residue was taken up in silica gel and purified on a silica gel column eluting with 1% to 4% methanol in dichloromethane. The residue was crystallized from ethyl acetate and hexanes to give 1.71 g (29%) of product (17) as a tan solid.
    Step (b): Preparation of 4- (5-bromopentyl) -2- (3-cyanophenyl) -3,4-dihydro-2H-1,4-benzothiazin-3-one
    To benzothiazinone (17) (0.75 g, 2.82 mmol) in DMF (5 ml) was added sodium hydroxide (0.124 g, 3.09 mmol) and the solution was stirred at 70 ° C. for 15 minutes until no foaming occurred. To this solution was added 1,5-dibromopentane (1.54 ml, 11.2 mmol) and the solution was further stirred at 70 ° C. for 16 h. The solution was cooled and diluted with water and extracted with ethyl acetate (3 x 300 ml). The combined organic extracts were washed with brine (2 x 100 ml) and dried over magnesium sulfate, filtered and evaporated in vacuo. The residue was purified on a silica gel column eluting with 20% to 30% ethyl acetate in hexanes. Product (18) was isolated as 0.66 g (52%) as yellow oil.
    Step (c): 4-5-[(2R, 6S) -2,6-dimethylhexahydro-1-pyridinyl] pentyl-2- (3-cyanophenyl) -3,4-dihydro-2H- Preparation of 1,4-benzothiazin-3-one
    To (18) (0.66 g, 1.59 mmol) cis-2,6-dimethylpiperidine (6.0 ml, 44 mmol) was added. The solution was stirred at 70 ° C for 48 h. The solution was cooled and diluted with water and extracted with ethyl acetate (3 x 200 ml). The combined organic extracts were washed with saturated sodium bicarbonate (2 x 100 ml), washed with brine (2 x 100 ml), dried over magnesium sulfate, filtered and evaporated in vacuo, co-evaporated with toluene and dried in high vacuum to yellow color. 0.69 g (97%) of (19) was obtained as an oil.
    HPLC: RT = 14.16 min (Beckman 235328 C-18 5 μm 4.6 mm × 25 cm, mixture of solvent consisting of (i) 0.1% trifluoroacetic acid in water, and (ii) 0.1% trifluoroacetic acid in acetonitrile) Elution, gradient profile from 80:20 (i) :( ii) to 10:90 (i) :( ii), flow rate 1.5 ml / min, λ = 214 nM over 23 minutes)
    Step (d): 3- (4-5-[(2R, 6S) -2,6-dimethylhexahydro-1-pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4 Preparation of -benzothiazin-2-yl) -1-N-hydroxybenzenecarboximidamide
    To (19) (0.30 g, 0.67 mmol) in methanol (10 ml) was added hydroxylamine hydrochloride (0.116 g, 1.67 mmol) and diisopropylethylamine (0.12 ml, 0.67 mmol). The solution was stirred at rt for 24 h. The solvent was evaporated in vacuo and the oil dried in high vacuum to give (20) in quantitative yield.
    HPLC: RT = 8.83 min (Beckman 235328 C-18 5 μm 4.6 mm × 25 cm, mixture of solvent consisting of (i) 0.1% trifluoroacetic acid in water, and (ii) 0.1% trifluoroacetic acid in acetonitrile) Elution, gradient profile from 80:20 (i) :( ii) to 10:90 (i) :( ii), flow rate 1.5 ml / min, λ = 214 nM over 23 minutes)
    Step (e): 3- (4-5-[(2R, 6S) -2,6-dimethylhexahydro-1-pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4 Preparation of -benzothiazin-2-yl) -1-N-hydroxyacetatebenzenecarboximidamide
    (20) To (0.32 g, 0.66 mmol) was added acetic anhydride (2 ml) and the solution was stirred at room temperature for 2 hours. The solution was diluted with acetic acid and the solvent removed in vacuo to give (21) in quantitative yield as a yellow oil.
    HPLC: RT = 12.08 min (Beckman 235328 C-18 5 μm 4.6 mm × 25 cm, mixture of solvent consisting of (i) 0.1% trifluoroacetic acid in water, and (ii) 0.1% trifluoroacetic acid in acetonitrile) Elution, gradient profile from 80:20 (i) :( ii) to 10:90 (i) :( ii), flow rate 1.5 ml / min, λ = 214 nM over 23 minutes)
    Step (f): 3- (4-5-[(2R, 6S) -2,6-dimethylhexahydro-1-pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4 Preparation of -benzothiazin-2-yl) -1-benzenecarboximidamide
    To 21 (0.34 g, 0.65 mmol) in acetic acid (2 ml) was added 20% palladium on carbon (45 mg) and the mixture was hydrogenated at 23 ° C. for 2 hours. The mixture was filtered through Celite and the filtration pad was washed with acetic acid. The combined filtrates and washes were evaporated in vacuo and the residue was purified by HPLC (Bidda 218TP1022 C-18, (i) 0.1% trifluoroacetic acid in water, and (ii) 0.1% trifluoroacetic acid in acetonitrile). Elution to mixture, gradient profile from 95: 5 (i) :( ii) to 60:40 (i) :( ii), flow rate 20 ml / min, λ = 214 nM) over 90 minutes, lyophilization To give 50 mg (16%) of the product (22) as a lint-free, off-white solid.
    HPLC: RT = 8.92 min (86%) and 8.19 min (13%) (Beckman 235328 C-18 5 μm 4.6 mm × 25 cm, (i) 0.1% trifluoroacetic acid in water, and (ii) in acetonitrile Elution with a mixture of solvents consisting of 0.1% trifluoroacetic acid, 80:20 (i) :( ii) to 10:90 (i) :( ii), flow rate 1.5 ml / min, λ = over a 23 minute gradient profile 214 nM)
    <Example 4>
    3- (4-5-[(2R, 6S) -2,6-dimethylhexahydro-1-pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazine- 2-yl) -1-benzenecarbothioamide
    Intermediate 13 (0.49 g, 1.14 mmol) was dissolved in pyridine (50 ml) in a three-neck flask. Nitrogen was bubbled through the solution for 30 minutes. Hydrogen sulfide was bubbled through the yellow solution for 20 minutes. The solution turned green and the flask was sealed and stirred at room temperature for 24 hours. HPLC showed completion of reaction. Nitrogen was bubbled through the solution for 30 minutes. The solution was evaporated in vacuo to co-evaporate with toluene and a mixture of solvents consisting of purified HPLC (Bidda 218TP1022 C-18, (i) 0.1% trifluoroacetic acid in water, and (ii) 0.1% trifluoroacetic acid in acetonitrile). Elution, gradient profile from 95: 5 (i) :( ii) to 60:40 (i) :( ii), flow rate 20 ml / min, λ = 214 nM) over 90 minutes, and lyophilized Product (23) was obtained 28 mg (6%) as a yellow solid.
    CI MS M + 1 = 466
    HPLC: RT = 12.48 min (Beckman 235328 C-18 5 μm 4.6 mm × 25 cm, mixture of solvent consisting of (i) 0.1% trifluoroacetic acid in water, and (ii) 0.1% trifluoroacetic acid in acetonitrile) Elution, gradient profile from 80:20 (i) :( ii) to 10:90 (i) :( ii), flow rate 1.5 ml / min, λ = 214 nM over 23 minutes)
    <Example 5>
    3- (4-5-[(2R, 6S-2,6-dimethyltetrahydro-1- (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benz Oxazine-2-yl) -4-hydroxybenzenecarboximidamide
    Step (a): Preparation of 2- (benzyloxy) -5-bromobenzenecarbaldehyde
    To 5-bromosalicylatealdehyde 24 (10.01 g, 49.8 mmol) in DMF (50 ml) was added benzyl bromide (6.5 ml, 54.6 mmol) and potassium carbonate (13.76 g, 99.6 mmol). The reaction mixture was stirred at rt for 72 h. The solution was diluted with water and extracted with ethyl acetate (3 x 200 ml). The combined organic extracts were washed with brine (2 × 100 ml) and dried over magnesium sulfate, filtered, evaporated in vacuo and dried in high vacuum. Crystallization from ethyl acetate in hexanes gave 10.96 g (76%) of product (25) as a white solid.
    Step (b): Preparation of 1- [2- (benzyloxy) -5-bromophenyl] -2,2,2-trichloro-1-ethanol
    To a mixture of lead (II) bromide (1.38 g, 3.76 mmol) and finely divided aluminum foil (1.02 g, 37.8 mmol) in DMF (188 ml) (25) (10.96 g, 37.6 mmol) and carbon tetrachloride (7.6 ml, 78.8) mmol) was added and the mixture was stirred at ambient temperature for 3 hours. The reaction was quenched with aqueous 1 N hydrochloric acid (100 ml) and the mixture was extracted with ethyl acetate (3 × 300 ml). The combined organic extracts were washed with brine (200 ml), dried over magnesium sulfate, filtered, evaporated in vacuo and dried in high vacuum to give trichloromethyl carbinol (26) in quantitative yield as a brown oil.
    Step (c): Preparation of 2- [2- (benzyloxy) -5-bromophenyl] -2H-1,4-benzoxazin-3 (4H) -one
    To o-aminophenol hydrochloride (0.88 g, 6.04 mmol) in DMSO (15 ml) was added sodium hydride (1.21 g, 30.2 mmol). After foaming and heat release were stopped, a solution of (26) (2.50 g, 6.09 mmol) in DMSO (10 ml) was added dropwise at room temperature over 30 minutes. After heat generation ceased, the mixture was stirred at 70 ° C for 4 h. The reaction mixture was cooled and diluted with water and extracted with ethyl acetate (5 x 500 ml). The combined organic extracts were washed with brine (200 ml) and dried over magnesium sulfate, filtered and evaporated in vacuo. The residue was purified on a silica gel column eluting with 20% ethyl acetate in hexanes. Product (27) was isolated as 0.67 g (27%) as a solid.
    Step (d): Preparation of 4- (benzyloxy) -3- (3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl) benzenecarbonitrile
    A mixture of benzoxazinone (27) (0.17 g, 0.477 mmol) and copper cyanide (I) (0.09 g, 1.00 mmol) in DMF (3 ml) was stirred for 16 h at 160 ° C. in a sealed tube. The solution was cooled and diluted with water (50 ml) and ammonium hydroxide (50 ml) and extracted with ethyl acetate (3 x 100 ml). The combined organic extracts were washed with brine (2 × 100 ml), dried over magnesium sulfate, filtered, evaporated in vacuo and dried in high vacuum to give 0.16 g (94%) of the product (28) as a solid.
    Step (e): 4- (benzyloxy) -3- [4- (5-bromopentyl) -3-oxo-3,4-dihydro-2H-1, 4-benzoxazin-2-yl] Preparation of Benzenecarbonitrile
    To benzoxazinone (28) (1.63 g, 4.57 mmol) in DMF (5 ml) was added sodium hydride (0.20 g, 5.00 mmol) and the solution was stirred at 0 ° C. for 10 minutes until bubbling ceased. . To this solution 1,5-dibromopentane (2.5 ml, 18.3 mmol) was added and the solution was further stirred at 0 ° C. for 2 hours. The solution was cooled and diluted with water and extracted with ethyl acetate (5 x 200 ml). The combined organic extracts were washed with brine (2 x 100 ml) and dried over magnesium sulfate, filtered and evaporated in vacuo. The residue was purified on a silica gel column eluting with 20% ethyl acetate in hexanes. Product (29) was isolated 1.14 g (61%) as foam.
    Step (f): 4- (benzyloxy) -3- (4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3, Preparation of 4-dihydro-2H-1,4-benzoxazin-2-yl) benzenecarbonitrile
    To (29) (1.14 g, 2.26 mmol) cis-2,6-dimethylpiperidine (10 ml, 74 mmol) was added. The solution was stirred at 70 ° C for 16 h. The solution was cooled and diluted with water and extracted with ethyl acetate (3 x 200 ml). The combined organic extracts were washed with saturated sodium bicarbonate (2 x 100 ml), brine (2 x 100 ml), dried over magnesium sulfate, filtered and evaporated in vacuo, co-evaporated with toluene and dried at high pressure ( 30) was obtained in quantitative yield as a yellow oil.
    HPLC: RT = 16.26 min (Beckman 235328 C-18 5 μm 4.6 mm × 25 cm, mixture of solvent consisting of (i) 0.1% trifluoroacetic acid in water, and (ii) 0.1% trifluoroacetic acid in acetonitrile) Elution, gradient profile from 80:20 (i) :( ii) to 10:90 (i) :( ii), flow rate 1.5 ml / min, λ = 214 nM over 23 minutes)
    Step (g): 4- (benzyloxy) -3- (4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3, Preparation of 4-dihydro-2H-1,4-benzoxazin-2-yl) -N-hydroxybenzenecarboximidamide
    To (30) (1.21 g, 2.25 mmol) in methanol (25 ml) was added hydroxylamine hydrochloride (0.39 g, 5.61 mmol) and diisopropylethylamine (0.39 ml, 2.24 mmol). The solution was stirred at rt for 16 h. The solvent was evaporated in vacuo and the oil dried in high vacuum to give (31) in quantitative yield.
    HPLC: RT = 13.46 min (Beckman 235328 C-18 5 μm 4.6 mm × 25 cm, mixture of solvent consisting of (i) 0.1% trifluoroacetic acid in water, and (ii) 0.1% trifluoroacetic acid in acetonitrile) Elution, gradient profile from 80:20 (i) :( ii) to 10:90 (i) :( ii), flow rate 1.5 ml / min, λ = 214 nM over 23 minutes)
    Step (h): 4- (benzyloxy) -3- (4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3, Preparation of 4-dihydro-2H-1,4-benzoxazin-2-yl) -N-[(2,2,2-trifluoroacetyl) oxy] benzenecarboximidamide
    (31) (1.28 g, 2.24 mmol) was added trifluoroacetic anhydride (10 ml) and the solution was stirred at room temperature for 2 hours. The solvent was evaporated in vacuo to give (32) in quantitative yield as a yellow oil.
    HPLC: RT = 21.62 min (Beckman 235328 C-18 5 μm 4.6 mm × 25 cm, mixture of solvent consisting of (i) 0.1% trifluoroacetic acid in water, and (ii) 0.1% trifluoroacetic acid in acetonitrile) Elution, gradient profile from 80:20 (i) :( ii) to 10:90 (i) :( ii), flow rate 1.5 ml / min, λ = 214 nM over 23 minutes)
    Step (i): 3- (4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H- Preparation of 1,4-benzoxazin-2-yl) -4-hydroxybenzenecarboxyimidamide
    To 32 (1.49 g, 2.24 mmol) in trifluoroacetic acid (32 ml) was added 20% palladium on carbon (0.2 g) and the mixture was hydrogenated at 23 ° C. for 48 hours. The mixture was filtered and the filter pad was washed with trifluoroacetic acid. The combined filtrates and washes were evaporated in vacuo and the residue was purified by HPLC (Bidda 218TP1022 C-18, (i) 0.1% trifluoroacetic acid in water, and (ii) 0.1% trifluoroacetic acid in acetonitrile). Elution to mixture, gradient profile from 95: 5 (i) :( ii) to 60:40 (i) :( ii), flow rate 20 ml / min, λ = 214 nM) over 90 minutes, lyophilization To give a white powder. Amberlite (R) IRA-400 (CI) ion exchange resin was added to the white powder in acetonitrile (2 ml) and water (200 ml). The mixture was filtered and the filtrate was lyophilized to afford (53) 553 mg (45%) as a white solid.
    CI MS M + 1 = 465
    HPLC: RT = 8.22 min (Beckman 235328 C-18 5 μm 4.6 mm × 25 cm, mixture of solvent consisting of (i) 0.1% trifluoroacetic acid in water, and (ii) 0.1% trifluoroacetic acid in acetonitrile) Elution, gradient profile from 80:20 (i) :( ii) to 10:90 (i) :( ii), flow rate 1.5 ml / min, λ = 214 nM over 23 minutes)
    <Example 6>
    3-((2S) -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1 , 4-benzoxazin-2-yl) -4-hydroxybenzenecarboxymimidamide
    Step (a): Preparation of 2- (benzyloxy) -5-bromobenzenecarbaldehyde
    5-Bromosalicylaldehyde (34) (50.0 g, 0.249 mol) was suspended in 150 ml of EtOH with stirring. KOH (13.97 g, 0.249 mol) was dissolved in 40 ml of water and added to the aldehyde suspension. After 30 minutes benzyl bromide (51.05 g, 35.5 ml, 0.298 mol) was added slowly. The mixture was refluxed overnight. After cooling to room temperature water (50 ml) was added and after 5 minutes an off-white solid was collected by filtration. It was dried in vacuo overnight to give 61.71 g of the desired product (35) in 84.6% yield.
    1 H NMR (CDCl 3 ) δ 10.46 (1H, s), 7.94 (1H, d), 7.60 (1H, dd), 7.41 (5H, m), 6.95 (1H, d), 5.18 (2H, s).
    APCI MS: No M + 1, M-91 (201). HPLC: 20.91 min, @ 1.5 ml / min on C-18 column. 90% of the> H 2 0 (.1% TFA ) CH 3 CN (.1% TFA) (0 - - H 2 0 (.1% TFA) in 20% CH 3 CN (.1% TFA)> 22 minutes)
    Step (b): Preparation of 2- [2- (benzyloxy) -5-bromophenyl] -2-hydroxyacetonitrile
    To a suspension of (35) (50 g, 0.172 mol) in MeOH (400 ml) was added KCN (50.31 g, 0.773 mol) to give a yellow color. Acetic acid (15.72 ml, 0.275 mol) was added dropwise over 10 minutes and the reaction stirred at room temperature for 2.5 hours. The mixture was filtered and concentrated to 75%. Ethyl acetate (250 ml) was added and washed with water (2 × 150 ml) and saturated NaCl (1 × 150 ml), then the organic phase was dried over MgSO 4 and finally concentrated to brown oil. 35.4 g of the desired product (36) was obtained in 64.8% yield on flash silica using 10%-> 20% ethyl acetate in hexanes.
    Step (c): Preparation of Methyl 2- [2- (benzyloxy) -5-bromophenyl] -2-hydroxyacetate
    Diethyl ether (45 ml), dioxane (45 ml), MeOH (12 ml) were mixed at room temperature and then HCl gas was bubbled into the solution for 3-4 minutes at a good rate (to prepare a saturated HCl solution). It was. HCl solution was added to (36) (35.2 g, 0.111 mol) which caused the formation of thick white ppt after 15 minutes. After further stirring for 45 minutes, the white solid was filtered off and washed with diethyl ether (3 × 100 ml). This solid was then stirred with 200 ml of 1: 1 dioxane: water and for about 1 hour to stir until the mixture became homogeneous. Water (100 ml) was added and the solution extracted with ethyl acetate (2 x 200 ml). The organic layer was dried over MgSO 4 and evaporated to give a clear oil, which after drying under high vacuum overnight provided (37) as a waxy white solid (31.3 g, 80.4%).
    Step (d): Preparation of Methyl 2- [2- (benzyloxy) -5-bromophenyl] -2-oxoacetate
    Methylene chloride (30 ml) was cooled to -70 ° C through a dry ice / acetone bath with stirring under N 2 followed by the addition of oxalyl chloride (3.07 ml, 0.035 mol). Then DMSO (4.97 ml, 0.70 mole) was added slowly along the side of the flask while the temperature did not exceed −60 ° C. After stirring for 15 minutes, alcohol (37) (10.26 g, 0.026 mol) was added dropwise into a solution in CH 2 Cl 2 while again preventing the temperature from rising above -60 ° C. The mixture was stirred at −65 ° C. for 30 minutes and then Et 3 N (20.40 ml, 0.145 mol) was added dropwise while the temperature did not reach −60 ° C. Upon warming to room temperature, water (150 ml) was added and the product extracted with ethyl acetate. The organic phase was dried over MgSO 4 and then rotary evaporated to give 10.03 g of a pale yellow solid (38) in 98% yield.
    Step (e): Preparation of Methyl (2R) -2- [2- (benzyloxy) -5-bromophenyl] -2-hydroxyethanoate
    Ketoester (38) (12.9 g, 0.037 mol) is slurried in CH 2 Cl 2 (6 ml), then R-Alpine Borane (14.07 ml, 0.052 mol) is added dropwise and the slurry is cooled to room temperature. It was allowed to stir at. After 5 days an additional amount of R-alpha borane (10.1 ml, 0.037 mol) was added and the mixture was further stirred for 24 h. Acetaldehyde (6.0 ml) was added together with CH 2 Cl 2 (100 ml) and ethanolamine (4.0 ml) and then the mixture was stirred for 1 hour. The mixture was evaporated to ˜50% and then directly columned on flash silica using 15%-> 20% ethyl acetate in hexane to give 12.2 g of the desired product in 94% yield.
    Step (f): Preparation of Methyl (2S) -2- [2- (benzyloxy) -5-bromophenyl] -2- (2-nitrophenoxy) ethanoate
    Chiral alcohol (39) (5.0 g, 0.014 mole) was dissolved in ethyl acetate (75 ml) and then triphenyl phosphine (4.85 g, 0.018 mole) and o-nitro phenol (2.37 g, 0.017 mole) were added with stirring. . The reaction was placed under N 2 and cooled to −40 ° C. through a dry ice / acetone bath and DIAD (3.63 ml, 0.018 mol) was added dropwise. The reaction was stirred at -40 ° C for 2 hours. The volume was reduced to ˜50% and the reaction was chromatographed directly on flash silica with 15%-> 20% ethyl acetate in hexanes to give the desired product 40 (5.6 g, 83.3%).
    Step (g): Preparation of (2S) -2- [2- (benzyloxy) -5-bromophenyl] -2H-1,4-benzoxazin-3 (4H) -one
    Chiral ether 40 (9.3 g, 0.020 mol) was dissolved in 400 ml of MeOH and then 10 g of neutral RaNi was added (washed with 10 × of water followed by MeOH 3 ×). The mixture was placed under 53.8 psi of H 2 . After 15 hours, the pressure was observed to drop to 48.0 psi. The reaction was chromatographed on flash silica with 20% ethyl acetate in hexanes, then filtered and evaporated to afford the desired product (41) (5.17 g, 64% and 93.8% ee via chiral HPLC). Recrystallization from EtOAc yielded variable results in an effort to improve enantiomeric excess. The filtrate typically contained a rich enantiomeric excess. Thus, the material was finally obtained at 95.5% ee.
    Step (h): Preparation of 4- (benzyloxy) -3-[(2S) -3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl] benzenecarbonitrile
    To (41) (4.15 g, 0.010 mol) in DMF (6 ml) was added CuCN (1.57 g, 0.18 mol) and the mixture was heated to 160 ° C. overnight with stirring under N 2 . The reaction mixture was cooled to RT and then ethyl acetate (100 ml) was added. Washed with saturated brine / NH 4 OH (9: 1) (2 × 130 ml), dried over MgSO 4 and dried to give a brown solid. Crystallization from ethyl acetate gave a portion (0.76 g), and the remainder was purified by chromatography using 25%-> 50% ethyl acetate in hexane to give 1.53 g (2.29 g, 63.6%).
    Step (i): 4- (benzyloxy) -3-[(2S) -4- (5-bromopentyl) -3-oxo-3,4-dihydro-2H-1,4-benzoxazine- 2-yl] benzenecarbonitrile
    To (42) (2.2 g, 0.0062 mol) in anhydrous DMF (15 ml) was added dibromopentane (3.76 ml, 0.025 mol) with stirring under N 2 and then the mixture was cooled to 0 ° C. KN (TMS) 2 (11.11 ml 0.5 M solution., 0.0055 mol) was added dropwise over ˜15 minutes and the mixture was heated at 0 ° C. for 1 hour and then at room temperature for 2 hours. Ethyl acetate (75 ml) was added and the mixture was extracted with water (2 × 50 ml) and the organic layer was dried over MgSO 4 to evaporate the solvent. Chromatography on flash silica afforded the desired product (43) (1.51 g, 48%).
    Step (j): 4- (benzyloxy-3-[(2S) -4- (5-iodopentyl) -3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2 -Yl] preparation of benzenecarbonitrile
    NaI (2.21 g, 0.015 mol) was added to (43) (1.49 g, 0.0029 mol) in acetone (20 ml), and then the mixture was refluxed for 1 hour and filtered to rotary evaporate the acetone and slurried in 30 ml of ethyl acetate. And 30 ml of H 2 O followed by 30 ml of saturated NaCl, and the organic phase was dried over MgSO 4 and rotary evaporated to give 1.48 g (crude) of yellow oil (44).
    Step (k): 4- (benzyloxy) -3-((2S) -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3- Preparation of oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl) benzenecarbonitrile
    Cis-2,6 dimethylpiperidine (2 ml) was added to (44) in anhydrous DMF (2 ml) and the mixture was stirred overnight at room temperature. 30 ml ethyl acetate was added and washed with H 2 O (2 × 30 ml) and the organic layer was dried over MgSO 4 and evaporated to yield 1.27 g in 80.4% yield as light yellow oil over two steps. It was used in the next reaction without purification.
    Step (l): 4- (benzyloxy) -3-((2S) -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] -pentyl-3 Preparation of -oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl) -N-hydroxybenzenecarboxyimidamide
    To 45 (0.54 g, 0.001 mol) in 5 ml of MeOH was added hydroxylamine HCl (0.208 g, 0.003 mol), followed by the dropwise addition of diisopropylethylamine (0.348 ml, 0.002 mol) and the reaction overnight at room temperature. Stirred. MeOH was evaporated, 50 ml of CH 2 Cl 2 was added, washed with saturated NaHCO 3 and the organic layer was dried over MgSO 4 and evaporated to give 560 mg (crude) of a white waxy solid (46). It was used in the next reaction without purification.
    Step (m): 3-((2S) -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-di Preparation of Hydro-2H-1,4-Benzoxazin-2-yl) -4-hydroxybenzenecarboxyimidamide
    Of TFA (2 ml) of the 46 mixture and the addition of TFAA (4 ml) in (0.50 g, 0.00087 mol) under N 2 was stirred at room temperature overnight. The solvent was rotovap to give a gray oil. And after the addition of TFA (5 ml) was added 20% Pd / C 0.060 g and the flask was repeatedly evacuated (via balloon flask) filled with H 2 was allowed to stir overnight under a H 2 atmosphere. The reaction was filtered through celite and washed with CH 2 Cl 2 followed by rotovap. Chromatography on purified HPLC. The clean fractions were converted to HCl salt by flowing through an IRA 400 (Cl) resin as an aqueous solution. It was lyophilized to obtain 0.060 g of the desired product (47).
    <Intermediate>
    2- (3-cyanophenyl) -3,4-dihydro-2H-1,4-benzoxazin-3-one
    Step (a): Preparation of 2-[(3-cyanophenyl) methylene] malononitrile
    Piperidine (1.5 ml) was added slowly to a mixture of 3-cyanobenaldehyde (I1) (24.8 g, 0.189 mol) and malononitrile (11.9 ml, 0.189 mol) in dioxane (120 ml). The solution was stirred at rt for 1 h. The precipitate was filtered off, washed with water and dried in a high vacuum oven to afford 7.11 g (21%) of product (I2) as a yellow solid. Ethanol and water were added to the filtrate to further crystallize 10.29 g (30%) as a yellow solid.
    Step (b): Preparation of 3- (3-cyanophenyl) -2,2-oxiradicarbonitrile
    Intermediate (I2) (17.38 g, 97.0 mmol) was dissolved in acetonitrile (90 ml) and THF (113 ml) with vigorous stirring in a 3-neck flask at room temperature. Sodium hypochlorite (183 ml) was added dropwise while the pH of the solution was maintained at 4.5-6 by adding 2N sulfuric acid (20 ml) during the addition. Once the addition was complete, stirring was continued for 20 minutes. Ethyl acetate was added and the layers separated. The aqueous layer was extracted with ethyl acetate (3 x 300 ml). The combined organic extracts were washed with brine (2 x 100 ml) and dried over magnesium sulfate, filtered and evaporated in vacuo. The residue was passed through a pad of silica gel eluting with 50% ethyl acetate in hexanes. Product (I3) was isolated to 11.18 g (58%) as a tan solid.
    Step (c): Preparation of 2-bromo-2- (3-cyanophenyl) acetic acid
    To epoxide (I3) (5.12 g, 26.2 mmol) in THF (30 ml) was added 48% HBr (4.4 ml) and the solution was refluxed for 3 hours. THF was removed in vacuo and the residue was dissolved in ether (200 ml). The acid was extracted from ether with 1 N NaOH (100 ml). The aqueous solution was then acidified with HCl and the acid was extracted with ether (2 × 200 ml). The combined organic extracts were dried over magnesium sulfate, filtered, evaporated in vacuo and dried under high vacuum to give 4.32 g (69%) of product (I4) as a brown oil.
    Step (d): Preparation of 2-bromo-2- (3-cyanophenyl) acetyl chloride
    To acid (I4) (1.01 g, 4.21 mmol) in dichloromethane (12 ml) was added oxalyl chloride (1 equiv) and catalytic amount of DMF (0.1 ml). Bubbling occurred and the resulting solution was stirred for 1 hour. The solvent was removed in vacuo to give (I5) in quantitative yield as a brown oil.
    1 H NMR (CDCl 3 , 300 MHz): δ 7.80-7.72 (3H, m), 7.592 (1H, m), 5.64 (1H, s).
    Step (e): Preparation of N1- (2-hydroxyphenyl) -2-bromo-2- (3-cyanophenyl) acetamide
    To (I5) (1.08 g, 4.17 mmol) in dichloromethane (10 ml) was added o-aminophenol hydrochloride (0.62 g, 4.26 mmol) and diisopropylethylamine (0.72 ml, 4.11 mmol). The solution was stirred at rt for 4 h. The solution was diluted with water and extracted with ethyl acetate (5 x 100 ml). The combined organic extracts were washed with brine (200 ml), dried over magnesium sulfate, filtered and evaporated in vacuo to give (I6) in quantitative yield as a brown oil.
    Step (f): Preparation of 2- (3-cyanophenyl) -3,4-dihydro-2H-1,4-benzoxazin-3-one
    To benzoxazinone (I6) (1.38 g, 4.17 mmol) in DMF (5 ml) was added potassium carbonate (1.40 g, 10.1 mmol) and the solution was stirred at rt for 1 h. The solution was diluted with water and extracted with ethyl acetate (3 x 150 ml). The combined organic extracts were washed with brine (2 x 100 ml) and dried over magnesium sulfate, filtered and evaporated in vacuo. The residue was purified on a silica gel column eluting with 25% ethyl acetate in dichloromethane. 0.48 g (46%) of product (I1) was isolated as a pale orange solid.
    1 H NMR (CDCl 3 , 300 MHz): δ 7.99 (1H, s), 7.75 (2H, m), 7.64 (1H, m), 7.49 (1H, m), 7.11-6.97 (3H, m), 6.80 (1 H, m), 5.69 (1 H, s).
    Alternatives to prepare 2- (3-cyanophenyl) -3,4-dihydro-2H-1,4-benzoxazin-3-one
    The steps (a) to (f) described above starting from 3-brobobenzaldehyde, 2- (3-bromophenyl) -3,4-dihydro-2H-1,4-benzoxazin-3-one; It can be prepared by a similar method.
    Cyanation in a solution of 2- (3-bromophenyl) -3,4-dihydro-2H-1,4-benzoxazin-3-one (I7) (3.00 g. 9.87 mmol) in DMF (20 ml) Zinc (0.68 g, 5.79 mmol) was added followed by tetrakistripetylphosphine palladium (0) (0.96 g, 8 mol%). The degassing solution was heated to 100 ° C. for 5 hours, cooled to room temperature and then treated with water (50 ml). The product was extracted with ethyl acetate (2 × 100 ml), washed with brine (50 ml), dried over MgSO 4 and purified by silica gel chromatography eluting with 50% ethyl acetate in hexane. This method gave the title compound (1.866 g, 76%) recrystallized from ethanol / water.
    (APCI MS) 251
    Elemental Analysis of C 15 H 10 N 2 O 2 :
    Theoretical values: C, 71.99; H, 4.03; N, 11.19.
    Found: C, 71.59; H, 4. 22; N, 10.96
    Process for the preparation of methyl 2-bromo-2- (3-bromophenyl) acetate:
    PBr 3 (11.2 ml, 118 mmol) was added to 3-bromophenylacetic acid (10 g, 47 mmol) under argon and the suspension was stirred at rt for 45 min. Bromine (11.1 ml, 216 mmol) was added dropwise over 5 minutes. The mixture was stirred at 100 ° C. for 3 hours and then cooled. Anhydrous methanol (35 ml) was added dropwise over 30 minutes, then the reaction mixture was diluted with ether (400 ml), washed with 5% NaHCO 3 (800 ml) and brine (200 ml) and dried over MgSO 4 . The mixture was filtered and concentrated in vacuo to provide a material of sufficient purity for direct use.
    Other preparation methods of 2- (5-bromo-2-methoxyphenyl) -2H-1,4-benzoxazin-2 (4H) -one
    2-bromo-2H-1,4-benzoxazin-3 (4H) -one (I10) (1.40 g, 6.14 mmol) in methylene chloride (20 ml) followed by 4-bromoanisole followed by tin chloride ( IV) was added. Tin chloride (IV) was added to form a brown solution. The solution was refluxed for 5 hours, diluted with methylene chloride (100 ml) and washed with water (2 x 50 ml). The mixture was dried over magnesium sulfate and concentrated until product (I11) (0.58 g) precipitated. The mother liquor was concentrated and chromatographed on silica gel to give additional amount of product (I11) (0.55 g).
    (APCI MS) 334
    Preparation of 4-methoxy-3- (3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl) benzenecarbonitrile
    To a solution of 2- (5-bromo-2-methoxyphenyl) -2H-1,4-benzoxazin-3 (4H) -one (I11) (0.90 g, 2.70 mmol) in DMF (10 ml) Copper cyanide (I) (1.3 g, 5 equiv) was added and the mixture was heated at 160 ° C. for 12 h. The mixture was cooled and methylene chloride (100 ml) and aqueous ammonium hydroxide (10 ml) were added. The methylene chloride layer was separated, dried over MgSO 4 and evaporated in vacuo to afford the desired product (I12) (0.67 g, 89%).
    (APCI MS) 281
    Factor Xa, thrombin and Factor VIIa inhibitory activities for the compounds of the invention have been demonstrated by standard assays generally used by those skilled in the art.
    Determination of Factor Xa IC 50 and K i Constants
    Of a test substance that inhibits the ability of the human factor Xa to degrade 50% of the chromogenic substrate S2765 (N-CBz-D-Arg-L-Gly-L-Arg-p-nitroanilide. 2HCl, DiaPharma). The ability of the compound to act as an inhibitor of human factor Xa catalytic activity was assessed by determining the concentration (IC 50 ). Typically, 145 μl of human factor Xa (final 1 nM, Enzyme Research Laboratories) in HEPES 10 mM, NaCl 150 mM, 0.1% BSA, pH 7.4 (HBSA buffer), and DMSO (final 2%) ) Was incubated for 60 minutes at room temperature. After preheating for 5 minutes at 37 ° C., 100 μl of S2765 (final 400 μM) in HBSA buffer was added to this mixture. By teomo Max (R) (ThermoMax) measuring the initial rate of change of optical density to OD 405 nM for 5 min using a kinetic microplate reader (Kinetic Microplate Reader) every 10 seconds was determined S2765 rate of hydrolysis at 37 ℃ .
    In order to determine K i , the analysis conditions were essentially the same as above except for the following. The concentration of Factor Xa was 50 pM, and the concentration of substrate was in the range of 10-500 μM for this fluorogenic S2765 (ie AMC labeled S2765 instead of pNA of California Peptide Research). Test compounds and substrates in HBSA buffer were incubated as above and the reaction was initiated with enzyme-buffer. Competitive inhibition data (commutation-state rates at various concentrations of substrate and inhibitor) were analyzed using the method described by Segal (Enzyme Kinetics, Wiley Intetscience Publications, 1993). Dynamic parameters (K m , V max and K i ) using Michaelis-Menten and Inverse Dixon plot fits in Kaleidograph and / or Microsoft Excel, nonlinear regression programs ) Was used to evaluate.
    Determination of Thrombin IC 50 and K i Constants
    Concentration of test substance (IC 50 ) that inhibits the ability of human thrombin to degrade the chromogenic substrate Chromozym TH (Tosyl-Gly-Pro-Atg-pNA * Ac, Boehringer Manheim) ) Was evaluated for the ability of the compound to act as an inhibitor of human thrombin catalytic activity. Typically, 5 μl of test substance in HPB buffer (HEPES 10 mM, NaCl 100 mM, 0.05% BSA, 0.1% PEG-8000, pH 7.4) and DMSO (final 2%) were incubated at room temperature for 60 minutes. After preheating at 37 ° C. for 5 minutes, 100 μl of chromozyme TH (final 24 μM) in HBSA buffer was added to this mixture. The chromozyme TH hydrolysis rate was determined at 37 ° C. by measuring the initial rate of change of optical density at OD 405 nM for 5 minutes every 10 seconds using a Thermomax (R) kinetic microplate reader.
    In order to determine K i , the analysis conditions were essentially the same as above except for the following. The concentration of thrombin used was 50 pM and the concentration of fluorogenic chromozyme TH (ie chromozyme TH labeled with AMC instead of pNA labeling from Novabiochem) ranged from 1 to 40 μM. Test compounds and substrates in HBSA buffer were incubated as above and the reaction was initiated with enzyme-buffer and continued at 24 ° C. Kinetic analysis was performed as in the determination of factors Xa, K i .
    Determination of Tyrosine IC 50 and K i Constants
    Test substance that inhibits the ability of human tropsin to degrade 50% of the chromogenic substrate S2222 (N-Bz-L-Ile-L-Glu-L-Gly-L-Arg-p-nitroanilide.HCl, diaphama) The ability of the compound to act as an inhibitor of human trypsin catalytic activity was determined by determining the concentration of (IC 50 ). Typically, 145 μL human trypsin (final 0.5 nM) and 5 μL test substance in DMSO (final 2%) in HEPES 10 mM, 150 mM NaCl, 0.1% BSA were incubated at room temperature for 60 minutes. On the 37 ℃ preheating for 5 minutes, HBSA buffer to the mixture (final 100 μM) was added to S2222 100 ㎕ in and teomo Max (R) for 5 min using a kinetic microplate reader every 10 seconds OD 405 nM The S2222 hydrolysis rate was determined at 37 ° C. by measuring the rate of initial change of optical density with a furnace.
    To determine K i , the assay conditions were essentially the same as above except for starting the enzyme-buffer and continuing at 24 ° C. using a substrate range of 10-500 μM. Kinetic analysis was performed as in the determination of factors Xa, K i .
    Determination of Tissue Factor / Factor VIIa IC 50
    Concentration of test substance that inhibits the ability of human tropsin to degrade the chromogenic substrate Spectrozyme VIIa (CH 3 SO 2 -D-CHA-Arg-pNA * AcOH, American Diagnostica) The ability of the compound to act as an inhibitor of human tissue factor / factor VIIa complex catalytic activity was determined by determining (IC 50 ). Typically, 50 μl human factor VIIa (Enzyme Research Laboratories) 95 μl (American diognostica) of recombinant human tissue factor in modified HBSA buffer (Hepes 10 mM, CaCl 2 5 mM, 0.1% BSA, pH 8.0) ) Was incubated for 10 min with a 1: 1 mixture (final 5 nM each). Then 5 μl of test substance in DMSO (final 2%) was added and incubated for 60 minutes at room temperature. On the 37 ℃ preheating for 5 minutes, adding a spectrometer load VIIa 100 ㎕ in HBSA-modified to the mixture, and teomo Max (R) optically to OD 405 nM for 5 min using a kinetic microplate reader every 10 seconds The spectrozyme VIIa hydrolysis rate was determined at 37 ° C. by measuring the rate of initial change in density.
    In vitro analysis of human prothrombinase
    This assay demonstrates the ability of the test compounds of the present invention to inhibit human prothrombinase (PTase) complexes (typically including human factor Va, human factor Xa, Ca 2+ and phospholipid residues) to subsequently degrade prothrombin to obtain thrombin. Prove that. In order to determine the IC 50 (PTase) of the compounds of the present invention, PTase activity was shown by thrombin activity.
    The PTase reaction was modified in 30:70 ratio PTase (20 μM) PCPS (Avanti polar lipids following the method modified from the method of Barenholz et al., Biochemistry, 1977; 16: 2806-2810), modified Human Factor Va 2.5 nM (Enzyme Research Laboratories), Human Prothrombin 3 μM (Enzyme Research) in HEPES buffer (Hepes 10 mM, NaCl 150 mM, 0.1% PEG-8000, 0.05% BSA, CaCl 2 2.5 mM, pH 7.4) Laboratories) and various concentrations of test compound (1 nM to 100 nM in DMSO, final 2%) containing 100 μl. The reaction was initiated by co-culturing PTase with the test compound for 60 minutes at room temperature and then adding prothrombin for 6 minutes at room temperature. Next, the reaction was quenched by adding 100 μl of 20 mM EDTA. Then OD 405 for 5 minutes every 10 seconds using a Thermomax (R) kinetic microplate reader in the presence of 50 μl C2238 (final 250 μM, HD-Phe-Pip-Arg-pNA * Ac, Diapama) as substrate. The activity of thrombin (product) was determined by measuring the change at 37 ° C. with nM.
    The IC 50 of the compound of Example 5 in this assay was 0.00017 μM.
    Determination of Prothrombin Time (PT)
    Rat, rabbit, dog and human blood (typically 1.8 ml) were collected and diluted 1:10 by addition of sodium citrate (3.8%). After centrifugation (2000 g for 10 minutes), the plasma was stored at -70 ° C to 0 ° C. Conventional prothrombin time (PT) tests were performed in the presence of various concentrations of test compound and the concentration of test compound needed to double the coagulation time was determined. Typically, test compounds (volume 50 μl of various concentrations from 0.1 μM to 1000 μM) and plasma (100 μl of volume) are incubated at 37 ° C. for 10 minutes and then treated with tissue thromboplastin, typically American bioproducts (with calcium). Neoplastin from American Bioproducts was added. Fibrin formation and coagulation formation time were measured twice using an automated ST4 coagulation detection system.
    In the ex vivo variant of this assay the drug was administered intravenously or orally to a group of rats or rabbits. Blood samples were collected at various times and PT coagulation assays were performed as described above.
    Arterial-vein Shunt Congestive Antithrombotic Model
    See Vogel et al., Thromb. Res., 1989; 54: 399-410, the antithrombotic activity was measured in vivo. Briefly, the vena cava was removed and the lateral vein was ligated to loosely suture the suture near the lower vena cava. The sutures were tightened after drug administration within the ligation of the vena cava causing congestion. After an appropriate time, the thrombus was isolated and weighed. The effect of diversification on thrombi mass with varying drug concentrations administered intravenously or orally reflected antithrombotic activity.
    Alternatively, Smith et al., Br. J. Pharmacol., 1982; 77: 29-38], the left jugular vein and the right carotid artery were taken out and the cannula inserted. Subsequently, a paragraph containing a silk thread or a pre-weighed cotton thread was inserted to connect the two cannula inserted blood vessels. Once the drug was administered, the short circuit was closed and the thrombus formed on the heterologous surface in the short circuit was removed after a period of time. Accordingly, the weight of coagulum reflected antithrombotic activity.
    Arterial thrombosis model
    FeCl 3 -induced Carotid Artery Injury Model
    FeCl 3 -induced damage to the carotid arteries of rats is described by Kurz KD, Main RW, Sandusky GE, Thrombosis Research, 1990; 60: 269-280 and Schumacher WA et al., J. Pharmacology and Experimental Therapeutics, 1993; 267: 1237 -1242].
    Male Sprague-Dawly rats (375 g-410 g) were anesthetized with urethane (1500 mg / kg ip). Animals were placed on a 37 ° C. heating pad. The carotid artery was removed by dissection of the central line. Careful blunt dissection was used to isolate blood vessels from carotid artery debris. Using forceps, the artery was lifted to provide sufficient clearance and a small piece of two polyethylene tubes (PE-205) was inserted below it. A temperature probe (Physitemp MT23 / 3) was placed between one piece of duct and the artery. Damage was induced by topical application of a small disc (What 3 mm) of Whatman No. 1 filter paper previously immersed in a 35% FeCl 3 solution onto the carotid artery on a temperature probe. The incision area was covered with aluminum foil to prevent FeCl 3 from being decomposed by light. Vascular temperature was monitored for 60 minutes after application of FeCl 3 as an indication of blood flow. Vascular temperature changes were recorded on thermistors (Cole-Palmer model 08533-41).
    The time between the application of FeCl 3 and the time when the vessel temperature decreases rapidly (> 2.4 ° C.) was recorded as the vessel occlusion time. Thus, the change in fold in mean occlusion time (MOT) is the occlusion time of drug treated animals divided by the control occlusion time. Inhibitory compounds were IV injected (50 μg / kg / min from femoral vein) immediately after intravenous (IV) administration as a bolus (0.75 mg / kg).
    rescuedesignationThrombin IC 50 μMTrypsin IC 50 μMXa IC 50 μMVIIa inhibition% @ 100 μM 3- (4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] -pentyl-3-oxo-3,4-dihydro-2H-1,4- Benzothiazin-2-yl) -benzenecarboximidamide (Example 3)1.780.7820.10831 3- (4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] -pentyl-3-oxo-3,4-dihydro-2H-1,4- Benzoxazine-2-yl) -benzenecarboximidamide (Example 2)2.0200.4740.00730 3- (4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] -pentyl-3-oxo-3,4-dihydro-2H-1,4- Benzoxazine-2-yl) -4-hydroxybenzenecarboximidamide (Example 5)1.030.38<0.00129 3-((2S) -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] -pentyl-3-oxo-3,4-dihydro-2H- 1,4-benzoxazin-2-yl) -4-hydroxybenzenecarboximidamide (Example 6)0.390.750.003 (Ki 0.076 nM)37
    Biological Data of Examples 2 and 5 Compounds
    In vitro analysis of diluted prothrombin time (dPT)
    The effects of Examples 2 and 5 compounds on dPT were evaluated using pooled plasma from rabbit, dog, and human volunteers. Both compounds prolong concentration-dependently and showed similar efficacy in rabbit and dog plasma. However, in human plasma the Example 5 compound was about one order more potent than the Example 2 compound. The concentrations of compounds 2 and 5 extending dTP 5 times were 1.1 μM and 0.97 μM in rabbit plasma, 1.8 μM and 1.2 μM in dog plasma and 0.53 μM and 0.063 μM in human plasma, respectively.
    In vitro analysis of diluted prothrombin time (dPT)
    2X5X10X rabbit DX-9065a (μM)1.421.896.8 Example 2 (μM)0.331.12.4 Example 5 (μM)0.440.971.86 dog DX-9065a (μM)2.551.1118.6 Example 2 (μM)0.571.84.9 Example 5 (μM)0.841.21.81 Person DX-9065a (μM)0.060.531.3 Example 2 (μM)0.170.530.2 Example 5 (μM)0.00690.0630.157 Data are concentrations extending 2-, 5-, and 10-fold dPT reference values. DX-9065a is a reference factor Xa inhibitor.
    The effect of Example 2 on thrombosis and hemostasis was studied in the rabbit venous-vein shunt model of thrombosis. In this model, cotton-containing plastic shorts were inserted into the abdominal vena cava to develop thrombi inside the paragraphs under controlled conditions. End points of the test are occlusion time (TTO) and thrombus weight. Example 2 Compounds were administered to rabbits via the jugular vein as a single bolus, followed by constant infusion for 140 minutes. This dose was tested in a total of 15 rabbits (5 rabbits in each group): 30 μg / kg / min + 1 μg / kg / min, 60 μg / kg / min + 2 μg / kg / min, And 90 μg / kg / min + 3 μg / kg / min. Example 2 Compounds prolonged occlusion time dose-dependently and reduced net thrombus weight. In the highest dose group, 4 out of 5 increased TTO from 16.8 ± 5.4 minutes to 98.2 ± 21.8 minutes under controlled conditions without occlusion thrombus formation during the 120 minute test period. Net thrombus weight decreased from 56.4 ± 4.3 mg to 21.3 ± 7.8 mg in this group. At the highest dose, Example 2 compounds extended aPTT, TT, PT and bleeding time by 5.4, 1.5, 1.8 and 2.5 times, respectively. In contrast, in all three groups only ACT increased slightly.
    Using the above biological tests, the compounds of the present invention may be used for thrombotic disorders such as venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary and cerebral arterial thrombosis, cerebral embolism, renal embolism, pulmonary embolism, first or It has been found to be useful in preventing and treating recurrent myocardial infarction, unstable angina and cerebral infarction, stroke and atherosclerosis.
    The compounds of the present invention can be administered alone or in combination with one or more therapeutic agents. Therapeutic agents include, for example, other anticoagulants, antiplatelet agents or platelet inhibitors, which include nonsteroidal anti-inflammatory agents, such as aspirin, ibuprofen, naproxen sodium, indomethacin, pyricampam and ticlopidine, argatroban, epegatran, Thrombin inhibitors such as inogatran, factor VIIa inhibitors, tissue plasminogen activators, thrombolytic or fibrinolytic agents such as urokinase or streptokinase and GP IIIb-IIa antagonists.
    Thus, the compounds are suitable for formulations which are conveniently administered to mammals for the prevention and treatment of such disorders. The following examples illustrate typical formulations provided by the present invention.
    <The first time>
    ingredientamount Compounds of formulas 1-8200 mg Sodium benzoate5 mg Isotonic saline1000 ml
    The ingredients are mixed and dissolved in saline and administered IV for example to a person suffering from arterial thrombosis.
    <Optimum 2>
    ingredientamount Compounds of formulas 1-8100 mg Cellulose, microcrystalline400 mg Stearic acid5 mg Silicon dioxide10 mg Confectionery, sugar50 mg
    The ingredients are uniformly blended and compressed into tablets, which is suitable for oral administration to humans, for example to prevent cerebral infarction.
    <The third>
    ingredientamount Compounds of formulas 1-8200 mg Dry starch250 mg Magnesium stearate10 mg
    The ingredients are combined and milled to provide a material suitable for filling hard gelatin capsules, for example administered to a person suffering from venous thrombosis.
    〈Title 4〉
    ingredientVolume (% weight / weight) Compounds of formulas 1-8One Polyethylene Glycol 100074.5 Polyethylene Glycol 400024.5
    The ingredients are combined by melting and then poured into a mold containing a total weight of 2.5 g.
    <Opposition 5>
    ingredientVolume (% weight / weight) Compounds of formulas 1-80.1% Propellant 11/1298.9% Oleic acidOne %
    The components are dispersed in oleic acid with propellant. The mixture is added to an aerosol container equipped with a meter.
    权利要求:
    Claims (36)
    [1" claim-type="Currently amended] A compound of Formula 1 or a stereoisomer or pharmaceutically acceptable salt form or prodrug thereof.
    <Formula 1>

    Where
    A is O, S, S (= O), S (= O) (= O), OCH 2 , CH 2 O, SCH 2 , S (= O) CH 2 , S (= O) (= O) CH 2 , CH 2 S, CH 2 S (= 0), CH 2 S (= 0) (= 0),
    B is selected from cycloalkyl, heteroalkyl, cycloalkylalkyl, heteroalkylalkyl, aryl, arylalkyl, heterocycle, heterocycloalkyl, which may be substituted with R 1 and R 2 , respectively,
    D is selected from H, alkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heteroalkylalkyl, aryl, arylalkyl, heterocycle, heterocycloalkyl, which may be substituted with R 1 and R 2 , respectively,
    E is absent or selected from O, S, NH,
    F is selected from N, NCH 2 , CH 2 N,
    G is absent or selected from alkyl, alkyl in which one or more heteroatoms are present, cycloalkyl, cycloalkyl through one or more heteroatoms,
    J is selected from aryl or heterocycle which may be absent or substituted with R 1 and R 2 , respectively,
    K is absent or selected from alkyl, which may be substituted with R 1 and R 2 , respectively, alkyl via one or more heteroatoms, cycloalkyl via one or more heteroatoms, cycloalkylalkyl via one or more heteroatoms,
    L is H, chlorine, fluorine, bromine, iodine, OH, O (alkyl), amine, alkyl, fluoroalkyl, amide, NO 2 , SH, S (O) n (alkyl), SO 3 H, SO 3 alkyl , Aldehyde, ketone, acid, ester, urea, O alkylamide, O alkyl ester, O alkyl acid, N alkyl acid, alkylamine, alkyl amide, alkyl ketone, alkyl acid, alkyl ester, alkyl urea, N alkyl amide, N Selected from alkyl esters, NC (= 0) alkyl, NC (= 0) aryl, NC (= 0) cycloalkyl, NC (= 0) cycloalkylalkyl, NC (= 0) alkylaryl, R 1 R 2 , nitrile Become,
    R 1 is H, amine, alkylamine, amide, C (= NH) NHNH 2 , alkyl C (= NH) NHNH 2 , C (= NH) NHOH, alkyl C (= NH) NHOH, NHC (= NH) NH 2 , alkyl NHC (= NH) NH 2 , C (= S) NH 2 , alkyl C (= S) NH 2 , C (= NH) alkyl, alkylC (= NH) alkyl, C (= NR 3 ) N (R 4 ) (R 5 ), alkyl C (═NR 3 ) N (R 4 ) (R 5 ),
    R 2 is H, chlorine, fluorine, bromine, iodine, OH, Oalkyl, amine, alkylaldehyde, alkylamide, alkylester, alkylketone, alkyl acid, Oalkylamide, Oalkyl acid, Oalkyl ester, nonalkyl acid , Aminealkylamides, aminealkyl esters, NC (= 0) alkyl, NC (= 0) aryl, NC (= 0) cycloalkyl, NC (= 0) alkylaryl, alkylamines, amides, aldehydes, esters, ketones, NO 2 , SH, S (O) n (C 1-10 alkyl), SO 3 H, SO 3 alkyl, CHO, acid, alkyl, C (= NH) alkyl, C (= NH) NHNH 2 , alkyl C ( = NH) NHNH 2 , C (= NH) NHOH, alkyl C (= NH) NHOH, NHC (= NH) NH 2 , alkylNHC (-NH) NH 2 , C (= S) NH 2 , alkyl C (= S) NH 2 , alkylC (= NH) alkyl, C (= NR 3 ) N (R 4 ) (R 5 ), alkylC (= NR 3 ) N (R 4 ) (R 5 ),
    R 3 , R 4 and R 5 are hydrogen atoms, alkyl groups having 1 to 4 carbon atoms which may be interrupted by one heteroatom, or R 4 and R 5 are bonded to-(CH 2 ) p -W- (CH 2 ) q- (where p and q are integers of 2 or 3), and a constant position of the methylene chain is unsubstituted or substituted by an alkyl group having 1 to 4 carbon atoms, W is a direct bond, -CH 2- , -O-, -N (R 6 )-or -S (O) r- (wherein R 6 is H or alkyl and r is 0 or 1 or 2),
    n is selected from 0, 1, 2,
    X 1 is C or N,
    X 2 is C or N,
    X 3 is C or N,
    X 4 is C or N.
    [2" claim-type="Currently amended] The compound of claim 1 or a stereoisomer or pharmaceutically acceptable salt, ester, amide or prodrug thereof.
    <Formula 2>

    Where
    A, B, E, G, J, K and L are as defined above.
    [3" claim-type="Currently amended] The compound of claim 1 or a stereoisomer or pharmaceutically acceptable salt, ester, amide or prodrug thereof.
    <Formula 3>

    Where
    B, G, J, K and L are as defined above.
    [4" claim-type="Currently amended] The compound of claim 1 or a stereoisomer or pharmaceutically acceptable salt, ester, amide or prodrug thereof.
    <Formula 4>

    Where
    B, G, J, K and L are as defined above.
    [5" claim-type="Currently amended] The compound of formula 5 or a stereoisomer or pharmaceutically acceptable salt, ester, amide or prodrug thereof.
    <Formula 5>

    Where
    R 1 , R 2 , G, J, K and L are as defined above.
    [6" claim-type="Currently amended] The compound according to claim 1, wherein the compound of formula 6 or a stereoisomer or pharmaceutically acceptable salt, ester, amide or prodrug thereof.
    <Formula 6>

    Where
    R 1 , R 2 , G, J, K and L are as defined above.
    [7" claim-type="Currently amended] A compound of formulas 7 and 8 or a stereoisomer or a pharmaceutically acceptable salt or prodrug thereof.
    <Formula 7>

    <Formula 8>

    Where
    R 7 is (3-amidino) phenyl, (3-hydroxy) phenyl, [3-hydroxyamino (imino) methyl] -phenyl, [3-hydrazino (imino) methyl] -phenyl, (3 -Aminomethyl) phenyl, (3-amino) phenyl, (3-methylamino) phenyl, (3-dimethylamino) phenyl, (5-amidino-2-hydroxy) phenyl, (5-amidino-2- Methoxy) phenyl, (1-amidino) piperid-3-yl, (1-amidino) pyrrolid-3-yl, (5-amidino) thien-2-yl, (5-amidino) furan 2-yl, (5-amidino) -1,3-oxazol-2-yl, (2-amidino) -1,3-oxazol-5-yl, 1H-pyrazol-5-yl, Tetrahydro-1H-pyrazol-3-yl, (1-amidino) tetrahydro-1H-pyrazol-3-yl, (2-amidino) -1H-imidazol-4-yl, (2-amino ) -1H-imidazol-4-yl, (5-amidino) -1H-imidazol-2-yl, (5-amino) -1H-imidazol-2-yl, pyridin-3-yl, (4 -Amino) pyridin-3-yl, (4-dimethylamino) pyridin-3-yl, (6-amino) pyridin-2-yl, (6-amidino) pyridin-2-yl, (2-amino) pyridine -4-yl, (2-amidi Pyridin-4-yl, (2-amidino) pyrimid-4-yl, (2-amino) pyrimidin-4-yl, (4-amidino) pyrimid-2-yl, (4-amino) Pyrimidin-2-yl, (6-amidino) pyrazin-2-yl, (6-amino) pyrazin-2-yl, (4-amidino) -1,3,5-triazin-2-yl, (4-amino) -1,3,5-triazin-2-yl, (3-amidino) -1,2,4-triazin-5-yl, (3-amino) -1,2,4 -Triazin-5-yl, (3-amidino) benzyl, (3-amino) benzyl, (3-aminomethyl) benzyl, (1-amidino) piperid-3-ylmethyl, (1-amidino) ) Pyrrolid-3-ylmethyl, (5-amidino) thien-2-ylmethyl, (5-amidino) furan-2-ylmethyl, (5-amidino) oxazol-2-ylmethyl, ( 2-amidino) imidazol-5-ylmethyl, (5-amidino) imidazol-2-ylmethyl, (6-amidino) pyridin-2-ylmethyl, (6-amino) pyridin-2-yl Methyl, (2-amidino) pyrimidin-4-ylmethyl, (2-amino) pyrimidin-4-ylmethyl, (4-amidino) pyrimidin-2-ylmethyl, (4-amino) pyrimidine 2-ylmethyl, (6-amidino) pyrazine- 2-ylmethyl, (6-amino) pyrazin-2-ylmethyl, 3-aminocyclohexyl, 3-amidinocyclohexyl, 3-aminocyclohexylmethyl, 3-amidinocyclohexylmethyl, 3-aminocyclopentyl , 3-amidinocyclopentyl, 3-aminocyclopentylmethyl and 3-amidinocyclopentylmethyl,
    R 8 is Br, I, C 2 H 5 , H, Cl, F, SH, SMe, CF 3 , CH 3 , CO 2 H, CO 2 Me, CN, C (= NH) NH 2 , C (= NH ) NHOH, C (= NH) NHNH 2 , C (= O) NH 2 , CH 2 OH, CH 2 NH 2 , NO 2 , OH, OMe, OCH 2 Ph, OCH 2 CO 2 H, O (CH 2 ) 2 CO 2 H, O (CH 2 ) 3 CO 2 H, NHCH 2 CO 2 H, NH (CH 2 ) 2 CO 2 H, NH (CH 2 ) 3 CO 2 H, OCH 2 CH 2 OH, OCH 2 ( 1H-tetrazol-5-yl), NH 2 , NHbutyl, NMe 2 , NHPh, NHCH 2 Ph, NHC (= 0) Me, NHC (= 0) c-hexyl, NHC (= 0) CH 2 c- Hexyl, NHC (= 0) Ph, NHC (= 0) CH 2 Ph, NHS (= 0) 2 Me, NHS (= 0) 2 c-hexyl, NHS (= 0) 2 CH 2 c-hexyl, NHS ( = O) 2 Ph and NHS (= O) 2 CH 2 Ph,
    R 9 is (CH 2 ) 5 , (CH 2 ) 4 , (CH 2 ) 6 , CH 2 C (= 0) NHCH 2 CH 2 , CH 2 CH 2 NHC (= 0) CH 2 , (CH 2 ) 2 NH (CH 2 ) 2 , (CH 2 ) 2 O (CH 2 ) 2 , C 6 H 4 , CH 2 C 6 H 4 , C 6 H 4 CH 2 , C 6 H 10 , CH 2 C 6 H 10 , C 6 H 10 CH 2 , C 5 H 8 , CH 2 C 5 H 8 , C 5 H 8 CH 2 and CH 2 CH = CHCH 2 CH 2 ,
    R 10 is 2,6-dimethylpiperidinyl, 2,2,6,6-tetramethyl-piperidinyl-4-one, piperidinyl, 2,2,6,6-tetramethylpiperidinyl, ( 2-carboxy) piperidinyl, (3-carboxy) piperidinyl, (4-carboxy) piperidinyl, 3,5-dimethylpiperidinyl, (4-hydroxy) piperidinyl, (2-imino ) Piperidinyl, piperidin-4-one-yl, (2-dimethylaminomethyl) -piperidinyl, (4-dimethylamino) -piperidinyl, (4-sulfonyloxy) -piperidinyl, (2-phenyl) piperidinyl, 2,5-dimethylpyrrolidinyl, pyrrolidinyl, (2-carboxy) pyrrolidinyl, (3-N-acetyl-N-methyl) pyrrolidinyl, (3-amino Pyrrolidinyl, (2,5-bis-methoxymethyl) -pyrrolidinyl, 2-hydroxymethyl-pyrrolidinyl, 2-hydroxymethyl-5-methyl-pyrrolidinyl, diisopropylamino, Diethylamino, methylamino, 1-methyl-4,5-dihydro-1H-imidazol-2-yl, 2,5-dimethyl-1H-imidazolyl, morpholinyl, 2,6-dimethylmorpholi Neil, piperage A 2,6-dimethyl piperazinyl, 1H- pyrazolyl, tetrahydro -1H- pyrazolyl and 2,5-dimethyl-tetrahydro -1H-1- pyrazolyl.
    [8" claim-type="Currently amended] 8. Compounds according to claim 7, wherein R 7 is (2-hydroxy-5-amidino) phenyl.
    [9" claim-type="Currently amended] 8. The compound of claim 7, wherein R 8 is H.
    [10" claim-type="Currently amended] 8. Compounds according to claim 7, wherein R 9 is (CH 2 ) 5 .
    [11" claim-type="Currently amended] 8. A compound according to claim 7, wherein R 10 is 2,6-dimethylpiperidinyl.
    [12" claim-type="Currently amended] 8. The compound of claim 7, wherein R 8 is H, R 9 is (CH 2 ) 5 and R 10 is 2,6-dimethylpiperidinyl.
    [13" claim-type="Currently amended] 8. The compound of claim 7, wherein R 8 is H, R 9 is (CH 2 ) 5 and R 10 is 2,5-dimethylpyrrolidinyl.
    [14" claim-type="Currently amended] 3- (4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benzo Thiazin-2-yl) -4-methoxybenzenecarboximidamide,
    3- (4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benzo Thiazin-2-yl) -benzenecarboximidamide,
    4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2- (3-hydroxyphenyl) -2H-1,4-benzothiazine-3 (4H) -on,
    3- (4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benzo Thiazin-2-yl) -N-hydroxybenzenecarboximidamide,
    3- (4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benzo Thiazin-2-yl) -N-hydroxybenzenecarboximidamide,
    3- (4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benzo Thiazin-2-yl) benzenecarboximidohydrazide,
    2- [3- (aminomethyl) phenyl] -4,5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2H-1,4-benzothiazine -3 (4H) -on,
    2- (3- (aminophenyl) -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2H-1,4-benzothiazine-3 (4H) -on,
    4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2- [3- (methylamino) phenyl] -2H-1,4-benzothiazine -3 (4H) -on,
    2- [3- (dimethylamino) phenyl] -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2H-1,4-benzothiazine -3 (4H) -on,
    3- (4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benzo Thiazin-2-yl) -4-hydroxybenzenecarboximidamide,
    3- (4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benzo Thiazin-2-yl) tetrahydro-1 (2H) -pyridinecarboximidamide,
    3- (4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benzo Thiazin-2-yl) -1-pyrrolidinecarboximidamide,
    5- (4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benzo Thiazin-2-yl) -2-thiophenecarboximidamide,
    5- (4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benzo Thiazin-2-yl) -2-furancarboximidamide,
    2- (4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benzo Thiazin-2-yl) -1,3-oxazole-5-carboximidamide,
    5- (4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benzo Thiazin-2-yl) -1,3-oxazole-2-carboximidamide,
    4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2- (1H-pyrazol-5-yl) -2H-1,4-benzothia Jin-3 (4H) -one,
    5- (4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benzo Thiazin-2-yl) -1-pyrazolidinecarboximidamide,
    4- (4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benzo Thiazin-2-yl) -1H-imidazole-2-carboximidamide,
    2- (2-amino-1H-imidazol-4-yl) -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2H-1, 4-benzothiazine-3 (4H) -one,
    2- (4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benzo Thiazin-2-yl) -1H-imidazole-5-carboximidamide,
    2- (5-amino-1H-imidazol-2-yl) -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2H-1, 4-benzothiazine-3 (4H) -one,
    4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2- (3-pyridinyl) -2H-1,4-benzothiazine-3 ( 4H) -on,
    2- (4-amino-3-pyridinyl) -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2H-1,4-benzothia Jin-3 (4H) -one,
    2- [4- (dimethylamino) -3-pyridinyl] -4,5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2H-1,4 Benzothiazine-3 (4H) -one,
    2- (6-amino-2-pyridinyl) -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2H-1,4-benzothia Jin-3 (4H) -one,
    6- (4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benzo Thiazin-2-yl) -2-pyridinecarboximidamide,
    2- (2-amino-4-pyridinyl) -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2H-1,4-benzothia Jin-3 (4H) -one,
    4- (4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benzo Thiazin-2-yl) -2-pyridinecarboximidamide,
    4- (4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benzo Thiazin-2-yl) -2-pyrimidinecarboximidamide,
    2- (2-amino-4-pyrimidinyl) -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2H-1,4-benzo Thiazine-3 (4H) -one,
    2- (4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benzo Thiazin-2-yl) -4-pyrimidinecarboximidamide,
    2- (4-amino-2-pyrimidinyl) -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2H-1,4-benzo Thiazine-3 (4H) -one,
    6- (4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benzo Thiazin-2-yl) -2-pyrazinecarboximidamide,
    2- (6-amino-2-pyrazinyl) -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2H-1,4-benzothia Jin-3 (4H) -one,
    4- (4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benzo Thiazin-2-yl) -1,3,5-triazine-2-carboximidamide,
    2- (4-Amino-1,3,5-triazin-2-yl) -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl- 2H-1,4-benzothiazine-3 (4H) -one,
    5- (4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benzo Thiazin-2-yl) -1,2,4-triazine-3-carboximidamide,
    2- (3-amino-1, 2,4-triazin-5-yl) -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl- 2H-1,4-benzothiazine-3 (4H) -one,
    3-[(4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4- Benzothiazin-2-yl) methyl] benzenecarboximidamide,
    2- (3-aminobenzyl) -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2H-1,4-benzothiazine-3 ( 4H) -on,
    2-[(3-aminomethyl) benzyl) -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2H-1,4-benzothiazine -3 (4H) -on,
    3-([4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4- Benzothiazin-2-yl) methyl] tetrahydro-1 (2H) -pyridinecarboximidamide,
    3-([4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4- Benzothiazin-2-yl) methyl] -1-pyrrolidinecarboximidamide,
    5-([4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4- Benzothiazin-2-yl) methyl] -2-thiophenecarboximidamide,
    5-([4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4- Benzothiazin-2-yl) methyl] -2-furancarboximidamide,
    2-[(4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4- Benzothiazin-2-yl) methyl] -1,3-oxazole-5-carboximidamide,
    5-[(4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4- Benzothiazin-2-yl) methyl] -1 H-imidazole-2-carboximidamide,
    2-[(4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4- Benzothiazin-2-yl) methyl] -1 H-imidazole-5-carboximidamide,
    6-[(4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4- Benzothiazin-2-yl) methyl] -2-pyridinecarboximidamide,
    2-[(6-amino-2-pyridinyl) methyl] -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2H-1,4 Benzothiazine-3 (4H) -one,
    4-[(4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4- Benzothiazin-2-yl) methyl] -2-pyrimidinecarboximidamide,
    2-[(2-amino-4-pyrimidinyl) methyl] -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2H-1, 4-benzothiazine-3 (4H) -one,
    2-[(4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4- Benzothiazin-2-yl) methyl] -4-pyrimidinecarboximidamide,
    2-[(4-amino-2-pyrimidinyl) methyl] -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2H-1, 4-benzothiazine-3 (4H) -one,
    6-[(4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4- Benzothiazin-2-yl) methyl] -2-pyrazinecarboximidamide,
    2-[(6-amino-2-pyrazinyl) methyl] -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2H-1,4 Benzothiazine-3 (4H) -one,
    2- (3-aminocyclohexyl) -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2H-1,4-benzothiazine-3 (4H) -on,
    3- (4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benzo Thiazin-2-yl) cyclohexanecarboximidamide,
    2-[(3-aminocyclohexyl) methyl] -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2H-1,4-benzothia Jin-3 (4H) -one,
    3-[(4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4- Benzothiazin-2-yl) methyl] cyclohexanecarboximidamide,
    2- (3-aminocyclopentyl) -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2H-1,4-benzothiazine-3 (4H) -on,
    3- (4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benzo Thiazin-2-yl) cyclopentanecarboximidamide,
    2-[(3-aminocyclopentyl) methyl] -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2H-1,4-benzothia Jin-3 (4H) -one,
    3-[(4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4- Benzothiazin-2-yl) methyl] cyclopentanecarboximidamide,
    3- (4-4-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] butyl-3-oxo-3,4-dihydro-2H-1,4-benzo Thiazin-2-yl) benzenecarboximidamide,
    3- (4-6-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] hexyl-3-oxo-3,4-dihydro-2H-1,4-benzo Thiazin-2-yl) benzenecarboximidamide,
    2- (2-3- [amino (imino) methyl] phenyl-3-oxo-2,3-dihydro-4H-1,4-benzothiazin-4-yl) -N-2-[(2R , 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] ethylacetamide,
    3- (2-3- [amino (imino) methyl] phenyl-3-oxo-2,3-dihydro-4H-1,4-benzothiazin-4-yl) -N-2-[(2R , 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] methylpropanamide,
    3-4- [2- (2-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] ethylamino) ethyl-3-oxo-3,4-dihydro-2H -1,4-benzothiazin-2-ylbenzenecarboximidamide,
    3-4- [2-2-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] ethoxyethyl) -3-oxo-3,4-dihydro-2H- 1,4-benzothiazin-2-yl] benzenecarboximidamide,
    3- (4-4-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] phenyl-3-oxo-3,4-dihydro-2H-1,4-benzo Thiazin-2-yl) benzenecarboximidamide,
    3- (4-4-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] benzyl-3-oxo-3,4-dihydro-2H-1,4-benzo Thiazin-2-yl) benzenecarboximidamide,
    3- [4- (4-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] methylphenyl-3-oxo-3,4-dihydro-2H-1,4- Benzothiazin-2-yl] benzenecarboximidamide,
    3- (4-4-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] cyclohexyl-3-oxo-3,4-dihydro-2H-1,4- Benzothiazin-2-yl) benzenecarboximidamide,
    3- [4- (4-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] cyclohexylmethyl-3-oxo-3,4-dihydro-2H-1, 4-benzothiazin-2-yl] benzenecarboximidamide,
    3- [4- (4-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] methylcyclohexyl-3-oxo-3,4-dihydro-2H-1, 4-benzothiazin-2-yl] benzenecarboximidamide,
    3- (4-3-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] cyclopentyl-3-oxo-3,4-dihydro-2H-1,4- Benzothiazin-2-yl) benzenecarboximidamide,
    3- [4- (3-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] cyclopentylmethyl) -3-oxo-3,4-dihydro-2H-1 , 4-benzothiazin-2-yl] benzenecarboximidamide,
    3- [4- (3-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] methylcyclopentyl) -3-oxo-3,4-dihydro-2H-1 , 4-benzothiazin-2-yl] benzenecarboximidamide,
    3- (4- (E) -5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] -2-pentenyl-3-oxo-3,4-dihydro -2H-1,4-benzothiazin-2-yl) benzenecarboximidamide,
    3- [3-oxo-4- (5-piperidinopentyl) -3,4-dihydro-2H-1,4-benzothiazin-2-yl] benzenecarboximidamide,
    3-3-oxo-4- [5- (2,2,6,6-tetramethylpiperidino) pentyl] -3,4-dihydro-2H-1,4-benzothiazin-2-ylbenzene Carboximidamide,
    1- [5- (2-3- [amino (imino) methyl] phenyl-3-oxo-2,3-dihydro-4H-1,4-benzothiazin-4-yl) pentyl] -2- Piperidinecarboxylic acid,
    1- [5- (2-3- [amino (imino) methyl] phenyl-3-oxo-2,3-dihydro-4H-1,4-benzothiazin-4-yl) pentyl] -3- Ferridinecarboxylic acid,
    1- [5- (2-3- [amino (imino) methyl] phenyl-3-oxo-2,3-dihydro-4H-1,4-benzothiazin-4-yl) pentyl] -4- Piperidinecarboxylic acid,
    3-4- [5- (3,5-dimethylpiperidino) pentyl] -3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-ylbenzenecarboximidamide ,
    3-4- [5- (4-hydroxypiperidino) pentyl] -3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-ylbenzenecarboximidamide,
    3-4- [5- (2-iminopiperidino) pentyl] -3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-ylbenzenecarboximidamide,
    3-3-oxo-4- [5- (4-oxopiperidino) pentyl] -3,4-dihydro-2H-1,4-benzothiazin-2-ylbenzenecarboximidamide,
    3- [4- (5-2-[(dimethylamino) methyl] piperidinopentyl) -3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl] benzenecarbox Voximidamide,
    3- (4- (5- [4- (dimethylamino) piperidino] pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl) benzenecarboximime Damide,
    1- [5- (2,3- [amino (imino) methyl] phenyl-3-oxo-3,4-dihydro-4H-1,4-benzothiazin-4-yl) pentyl] -4- Piperidine Sulfonic Acid,
    3-3-oxo-4- [5- (2-phenylpiperidino) pentyl] -3,4-dihydro-2H-1,4-benzothiazin-2-ylbenzenecarboximidamide,
    3-4- [5- (2,5-dimethyl-1-pyrrolidinyl) pentyl] -3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-ylbenzenecarbox Imidamide,
    3-3-oxo-4- [5- (1-pyrrolidinyl) pentyl] -3,4-dihydro-2H-1,4-benzothiazin-2-ylbenzenecarboximidamide,
    1- [5- (2,3- [amino (imino) methyl] phenyl-3-oxo-3,4-dihydro-4H-1,4-benzothiazin-4-yl) pentyl] -4- Pyrrolidinecarboxylic acid,
    N-1- [5- (2,3- [amino (imino) methyl] phenyl-3-oxo-3,4-dihydro-4H-1,4-benzothiazin-4-yl) pentyl] tetra Hydro-1H-pyrrole-3-yl-N-methylacetamide,
    3-4- [5- (3-amino-1-pyrrolidinyl) pentyl] -3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-ylbenzenecarboximida mid,
    3- (4-5- [2,5-bis (methoxymethyl) -1-pyrrolidinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazine-2- (1) benzene carboximidamide,
    3- (4-5- [2- (hydroxymethyl) -1-pyrrolidinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl) benzene Carboximidamide,
    3- (4-5- [2- (hydroxymethyl) -5-methyl-1-pyrrolidinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazine-2 -Yl) benzenecarboximidamide,
    3-4- [5- (diisopropylamino) pentyl] -3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-ylbenzenecarboximidamide,
    3-4- [5- (diethylamino) pentyl] -3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-ylbenzenecarboximidamide,
    3-4- [5- (methylamino) pentyl] -3-oxo-3,4-dihydro-2H-1, 4-benzothiazin-2-ylbenzenecarboximidamide,
    3-4- [5- (1-methyl-1H-imidazol-2-yl) pentyl] -3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-ylbenzenecarba Voximidamide,
    3-4- [5- (2,5-dimethyl-1H-imidazol-1-yl) pentyl] -3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl Benzenecarboximidamide,
    3- [4- (5-morpholinopentyl) -3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl] benzenecarboximidamide,
    3-4- [5- (3,5-dimethylmorpholino) pentyl] -3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-ylbenzenecarboximidamide ,
    3- [3-oxo-4- (5-piperazinopentyl) -3,4-dihydro-2H-1,4-benzothiazin-2-yl] benzenecarboximidamide,
    3-4- [5- (2,6-dimethylpiperazino) pentyl] -3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-ylbenzenecarboximidamide ,
    3-3-oxo-4- [5- (1H-pyrazol-1-yl) pentyl] -3,4-dihydro-2H-1,4-benzothiazin-2-ylbenzenecarboximidamide ,
    3- [3-oxo-4- (5-tetrahydro-1H-pyrazol-1-ylpentyl) -3,4-dihydro-2H-1,4-benzothiazin-2-yl] benzenecarbox Imidamide,
    3-4- [5- (2,5-dimethyltetrahydro-1H-pyrazol-1-yl) pentyl] -3-oxo-3,4-dihydro-2H-1,4-benzothiazine-2 Monobenzenecarboximidamide,
    3- (6-chloro-4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1 , 4-benzothiazin-2-yl) benzenecarboximidamide,
    3- (4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-6-fluoro-3-oxo-3,4-dihydro-2H- 1,4-benzothiazin-2-yl) benzenecarboximidamide,
    3- (4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-6-sulfanyl-3,4-dihydro-2H- 1,4-benzothiazin-2-yl) benzenecarboximidamide,
    3- [4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-6- (methylsulfanyl) -3-oxo-3,4-dihydro -2H-1,4-benzothiazin-2-yl] benzenecarboximidamide,
    3- [4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-6- (trifluoromethyl) -3,4-di Hydro-2H-1,4-benzothiazin-2-yl] benzenecarboximidamide,
    3- (4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-6-methyl-3-oxo-3,4-dihydro-2H-1 , 4-benzothiazin-2-yl) benzenecarboximidamide,
    2-3- [amino (imino) methyl] phenyl-4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4 -Dihydro-2H-1,4-benzothiazine-6-carboxylic acid,
    Methyl 2-3- [amino (imino) methyl] phenyl-4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3, 4-dihydro-2H-1,4-benzothiazine-6-carboxylate,
    3- (6-cyano-4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H- 1,4-benzothiazin-2-yl) benzenecarboximidamide,
    2-3- [amino (imino) methyl] phenyl-4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4 -Dihydro-2H-1,4-benzothiazine-6-carboximidamide,
    2-3- [amino (imino) methyl] phenyl-4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-N-hydroxy-3- Oxo-3,4-dihydro-2H-1,4-benzothiazine-6-carboximidamide,
    3-4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-6- [hydrazino (imino) methyl] -3-oxo-3,4 -Dihydro-2H-1,4-benzothiazin-2-ylbenzenecarboximidamide,
    2-3- [amino (imino) methyl] phenyl-4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4 -Dihydro-2H-1,4-benzothiazine-6-carboxyamide,
    3- [4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-6- (hydroxymethyl) -3-oxo-3,4-dihydro -2H-1,4-benzothiazin-2-yl] benzenecarboximidamide,
    3- (6- (aminomethyl) -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro- 2H-1,4-benzothiazin-2-yl) benzenecarboximidamide,
    3- [4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-6-nitro-3-oxo-3,4-dihydro-2H-1 , 4-benzothiazin-2-yl) benzenecarboximidamide,
    3- (4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-6-hydroxy-3-oxo-3,4-dihydro-2H- 1,4-benzothiazin-2-yl) benzenecarboximidamide,
    3- (4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-6-methoxy-3-oxo-3,4-dihydro-2H- 1,4-benzothiazin-2-yl) benzenecarboximidamide,
    3- (6- (benzyloxy) -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro- 2H-1,4-benzothiazin-2-yl) benzenecarboximidamide,
    2-[(2-3- [amino (imino) methyl] phenyl-4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo -3,4-dihydro-2H-1,4-benzothiazin-6-yl) oxy] acetic acid,
    3-[(2-3- [amino (imino) methyl] phenyl-4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo -3,4-dihydro-2H-1,4-benzothiazin-6-yl) oxy] propanoic acid,
    4-[(2-3- [amino (imino) methyl] phenyl-4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo -3,4-dihydro-2H-1,4-benzothiazin-6-yl) oxy] butanoic acid,
    2-[(2-3- [amino (imino) methyl] phenyl-4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo -3,4-dihydro-2H-1,4-benzothiazin-6-yl) amino] acetic acid,
    3-[(2-3- [amino (imino) methyl] phenyl-4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo -3,4-dihydro-2H-1,4-benzothiazin-6-yl) amino] propanoic acid,
    4-[(2-3- [amino (imino) methyl] phenyl-4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo -3,4-dihydro-2H-1,4-benzothiazin-6-yl) amino] butanoic acid,
    3- [4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-6- (2-hydroxyethoxy) -3-oxo-3,4 -Dihydro-2H-1,4-benzothiazin-2-yl] benzenecarboximidamide,
    3- [4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-6- (2H-1,2,3,4-tetra Azole) -5-ylmethoxy) -3,4-dihydro-2H-1,4-benzothiazin-2-yl] benzenecarboximidamide,
    3- (6-amino-4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1 , 4-benzothiazin-2-yl) benzenecarboximidamide,
    3- (6- (butylamino) -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro- 2H-1,4-benzothiazin-2-yl) benzenecarboximidamide,
    3- (6- (dimethylamino) -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro- 2H-1,4-benzothiazin-2-yl) benzenecarboximidamide,
    3- (6-anilino-4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H- 1,4-benzothiazin-2-yl) benzenecarboximidamide,
    3- (6- (benzylamino) -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro- 2H-1,4-benzothiazin-2-yl) benzenecarboximidamide,
    N- (2,3- [amino (imino) methyl] phenyl-4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo- 3,4-dihydro-2H-1,4-benzothiazin-6-yl) acetamide,
    N- (2,3- [amino (imino) methyl] phenyl-4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo- 3,4-dihydro-2H-1,4-benzothiazin-6-yl) cyclohexanecarboxamide,
    N- (2,3- [amino (imino) methyl] phenyl-4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo- 3,4-dihydro-2H-1,4-benzothiazin-6-yl) -2-cyclohexylacetamide,
    N- (2,3- [amino (imino) methyl] phenyl-4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo- 3,4-dihydro-2H-1,4-benzothiazin-6-yl) benzenecarboxamide,
    N- (2,3- [amino (imino) methyl] phenyl-4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo- 3,4-dihydro-2H-1,4-benzothiazin-6-yl) -2-phenylacetamide,
    3-4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-6-[(methylsulfonyl) amino] -3-oxo-3,4- Dihydro-2H-1,4-benzothiazin-2-ylbenzenecarboximidamide,
    3- (6-[(cyclohexylsulfonyl) amino] -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3, 4-dihydro-2H-1,4-benzothiazin-2-yl) benzenecarboximidamide,
    3- (6-[(cyclohexylmethyl) sulfonyl] amino-4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3 , 4-dihydro-2H-1,4-benzothiazin-2-yl) benzenecarboximidamide,
    3-4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-6-[(phenylsulfonyl) amino] -3,4- Dihydro-2H-1,4-benzothiazin-2-ylbenzenecarboximidamide, or
    3- (6- (benzylsulfonyl) amino] -4,5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4- Dihydro-2H-1,4-benzothiazin-2-yl) benzenecarboximidamide
    Phosphorus compounds.
    [15" claim-type="Currently amended] 3- (4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benz Oxazine-2-yl) -4-methoxybenzenecarboximidamide,
    3- (4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benz Oxazine-2-yl) -benzenecarboximidamide,
    4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2- (3-hydroxyphenyl) -2H-1,4-benzoxazine-3 (4H) -on,
    3- (4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benz Oxazin-2-yl) -N-hydroxybenzenecarboximidamide,
    3- (4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benz Oxazine-2-yl) benzenecarboximidohydrazide,
    2- [3- (aminomethyl) phenyl] -4,5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2H-1,4-benzoxazine -3 (4H) -on,
    2- (3-aminophenyl) -4,5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2H-1,4-benzoxazine-3 ( 4H) -on,
    4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2- [3- (methylamino) phenyl] -2H-1,4-benzoxazine -3 (4H) -on,
    2- [3- (dimethylamino) phenyl] -4,5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2H-1,4-benzoxazine -3 (4H) -on,
    3- (4,5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benz Oxazine-2-yl) -4-hydroxybenzenecarboximidamide,
    3- (4,5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benz Oxazin-2-yl) tetrahydro-1 (2H) -pyridinecarboximidamide,
    3- (4,5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benz Oxazine-2-yl) -1-pyrrolidinecarboximidamide,
    5- (4,5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benz Oxazine-2-yl) -2-thiophene carboximidamide,
    5- (4,5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benz Oxazine-2-yl) -2-furancarboximidamide,
    2- (4,5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benz Oxazin-2-yl) -1,3-oxazole-5-carboximidamide,
    5- (4,5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benz Oxazin-2-yl) -1,3-oxazole-2-carboximidamide,
    4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2- (1H-pyrazol-5-yl) -2H-1,4-benzox Photo-3 (4H) -On,
    4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2-tetrahydro-1H-pyrazol-3-yl-2H-1,4-benz Oxazine-3 (4H) -one,
    5- (4,5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benz Oxazine-2-yl) -1-pyrazolidinecarboximidamide,
    4- (4,5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benz Oxazine-2-yl) -1H-imidazole-2-carboximidamide,
    2- (2-amino-1H-imidazol-4-yl) -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2H-1, 4-benzoxazine-3 (4H) -one,
    2- (4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benz Oxazin-2-yl) -1H-imidazole-5-carboximidamide,
    2- (5-amino-1H-imidazol-2-yl) -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2H-1, 4-benzoxazine-3 (4H) -one,
    4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2- (3-pyridinyl) -2H-1,4-benzoxazin-3 ( 4H) -on,
    2- (4-amino-3-pyridinyl) -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2H-1,4-benzox Photo-3 (4H) -On,
    2- [4- (dimethylamino) -3-pyridinyl] -4,5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2H-1,4 Benzoxazine-3 (4H) -one,
    2- (6-amino-2-pyridinyl) -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2H-1,4-benzox Photo-3 (4H) -On,
    6- (4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benz Oxazine-2-yl) -2-pyridinecarboximidamide,
    2- (2-amino-4-pyridinyl) -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2H-1,4-benzox Photo-3 (4H) -On,
    4- (4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benz Oxazine-2-yl) -2-pyridinecarboximidamide,
    4- (4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benz Oxazine-2-yl) -2-pyrimidinecarboximidamide,
    2- (2-amino-4-pyrimidinyl) -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2H-1,4-benz Oxazine-2-yl) -3 (4H) -one,
    2- (4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benz Oxazine-2-yl) -2-pyrimidinecarboximidamide,
    2- (4-amino-2-pyrimidinyl) -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2H-1,4-benz Oxazine-3 (4H) -one,
    6- (4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benz Oxazine-2-yl) -2-pyrazinecarboximidamide,
    2- (6-amino-2-pyrazinyl) -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2H-1,4-benzox Photo-3 (4H) -On,
    4- (4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benz Oxazine-2-yl) -1,3,5-triazine-2-carboximidamide,
    2- (4-Amino-1,3,5-triazin-2-yl) -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl- 2H-1,4-benzoxazin-3 (4H) -one,
    5- (4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benz Oxazine-2-yl) -1,2,4-triazine-3-carboximidamide,
    2- (3-amino-1, 2,4-triazin-5-yl) -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl- 2H-1,4-benzoxazin-3 (4H) -one,
    3-[(4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4- Benzoxazine-2-yl) methyl] benzenecarboximidamide,
    2- (3-aminobenzyl) -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2H-1,4-benzoxazine-3 ( 4H) -on,
    2-[(3-aminomethyl) benzyl) -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2H-1,4-benzoxazine -3 (4H) -on,
    3-([4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4- Benzoxazine-2-yl) methyl] tetrahydro-1 (2H) -pyridinecarboximidamide,
    3-([4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4- Benzoxazine-2-yl) methyl] -1-pyrrolidinecarboximidamide,
    5-([4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4- Benzoxazine-2-yl) methyl] -2-thiophenecarboximidamide,
    5-([4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4- Benzoxazine-2-yl) methyl] -2-furancarboximidamide,
    2-[(4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4- Benzoxazine-2-yl) methyl] -1,3-oxazole-5-carboximidamide,
    5-[(4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4- Benzoxazine-2-yl) methyl] -1 H-imidazole-2-carboximidamide,
    2-[(4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4- Benzoxazine-2-yl) methyl] -1 H-imidazole-5-carboximidamide,
    6-[(4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4- Benzoxazine-2-yl) methyl] -2-pyridinecarboximidamide,
    2-[(6-amino-2-pyridinyl) methyl] -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2H-1,4 Benzoxazine-3 (4H) -one,
    4-[(4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4- Benzoxazine-2-yl) methyl] -2-pyrimidinecarboximidamide,
    2-[(2-amino-4-pyrimidinyl) methyl] -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2H-1, 4-benzoxazine-3 (4H) -one,
    2-[(4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4- Benzoxazine-2-yl) methyl] -4-pyrimidinecarboximidamide,
    2-[(4-amino-2-pyrimidinyl) methyl] -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2H-1, 4-benzoxazine-3 (4H) -one,
    6-[(4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4- Benzoxazine-2-yl) methyl] -2-pyrazinecarboximidamide,
    2-[(6-amino-2-pyrazinyl) methyl] -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2H-1,4 Benzoxazine-3 (4H) -one,
    2- (3-aminocyclohexyl) -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2H-1,4-benzoxazin-3 (4H) -on,
    3- (4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benz Oxazine-2-yl) cyclohexanecarboximidamide,
    2-[(3-aminocyclohexyl) methyl] -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2H-1,4-benzox Photo-3 (4H) -On,
    3-[(4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4- Benzoxazine-2-yl) methyl] cyclohexanecarboximidamide,
    2- (3-aminocyclopentyl) -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2H-1,4-benzoxazin-3 (4H) -on,
    3- (4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benz Oxazine-2-yl) cyclopentanecarboximidamide,
    2-[(3-aminocyclopentyl) methyl] -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-2H-1,4-benzox Photo-3 (4H) -On,
    3-[(4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4- Benzoxazine-2-yl) methyl] cyclopentanecarboximidamide,
    3- (4-4-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] butyl-3-oxo-3,4-dihydro-2H-1,4-benz Oxazine-2-yl) benzenecarboximidamide,
    3- (4-6-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] hexyl-3-oxo-3,4-dihydro-2H-1,4-benz Oxazine-2-yl) benzenecarboximidamide,
    2- (2-3- [amino (imino) methyl] phenyl-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl) -N-2-[(2R , 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] ethylacetamide,
    3- (2-3- [amino (imino) methyl] phenyl-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl) -N-[(2R, 6S ) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] methylpropanamide,
    3-4- [2- (2-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] ethylamino) ethyl-3-oxo-3,4-dihydro-2H -1,4-benzoxazin-2-ylbenzenecarboximidamide,
    3-4- [2-2-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] ethoxyethyl) -3-oxo-3,4-dihydro-2H- 1,4-benzoxazin-2-yl] benzenecarboximidamide,
    3- (4-4-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] phenyl-3-oxo-3,4-dihydro-2H-1,4-benz Oxazine-2-yl) benzenecarboximidamide,
    3- (4-4-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] benzyl-3-oxo-3,4-dihydro-2H-1,4-benz Oxazine-2-yl) benzenecarboximidamide,
    3- [4- (4-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] methylphenyl-3-oxo-3,4-dihydro-2H-1,4- Benzoxazine-2-yl] benzenecarboximidamide,
    3- (4-4-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] cyclohexyl-3-oxo-3,4-dihydro-2H-1,4- Benzoxazine-2-yl) benzenecarboximidamide,
    3- [4- (4-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] cyclohexylmethyl-3-oxo-3,4-dihydro-2H-1, 4-benzoxazine-2-yl] benzenecarboximidamide,
    3- [4- (4-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] methylcyclohexyl-3-oxo-3,4-dihydro-2H-1, 4-benzoxazine-2-yl] benzenecarboximidamide,
    3- (4-3-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] cyclopentyl-3-oxo-3,4-dihydro-2H-1,4- Benzoxazine-2-yl) benzenecarboximidamide,
    3- [4- (3-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] cyclopentylmethyl) -3-oxo-3,4-dihydro-2H-1 , 4-benzoxazine-2-yl] benzenecarboximidamide,
    3- [4- (3-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] methylcyclopentyl) -3-oxo-3,4-dihydro-2H-1 , 4-benzoxazine-2-yl] benzenecarboximidamide,
    3- (4- (E) -5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] -2-pentenyl-3-oxo-3,4-dihydro -2H-1,4-benzoxazin-2-yl) benzenecarboximidamide,
    3- [3-oxo-4- (5-piperidinopentyl) -3,4-dihydro-2H-1,4-benzoxazin-2-yl] benzenecarboximidamide,
    3-3-oxo-4- [5- (2,2,6,6-tetramethylpiperidino) pentyl] -3,4-dihydro-2H-1,4-benzoxazin-2-ylbenzene Carboximidamide,
    1- [5- (2-3- [amino (imino) methyl] phenyl-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl) pentyl] -2- Piperidinecarboxylic acid,
    1- [5- (2-3- [amino (imino) methyl] phenyl-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl) pentyl] -3- Ferridinecarboxylic acid,
    1- [5- (2-3- [amino (imino) methyl] phenyl-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl) pentyl] -4- Piperidinecarboxylic acid,
    3-4- [5- (3,5-dimethylpiperidino) pentyl] -3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-ylbenzenecarboximidamide ,
    3-4- [5- (4-hydroxypiperidino) pentyl] -3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-ylbenzenecarboximidamide,
    3-4- [5- (2-iminopiperidino) pentyl] -3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-ylbenzenecarboximidamide,
    3-3-oxo-4- [5- (4-oxopiperidino) pentyl] -3,4-dihydro-2H-1,4-benzoxazin-2-ylbenzenecarboximidamide,
    3- [4- (5-2-[(dimethylamino) methyl] piperidinopentyl) -3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl] benzenecarbox Voximidamide,
    3- (4-5- [4- (dimethylamino) piperidino] pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl) benzenecarboximida mid,
    1- [5- (2-3- [amino (imino) methyl] phenyl-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl) pentyl] -4- Piperidine Sulfonic Acid,
    3-3-oxo-4- [5- (2-phenylpiperidino) pentyl] -3,4-dihydro-2H-1,4-benzoxazin-2-ylbenzenecarboximidamide,
    3-4- [5- (2,5-dimethyl-1-pyrrolidinyl) pentyl] -3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-ylbenzenecarbox Imidamide,
    3-3-oxo-4- [5- (1-pyrrolidinyl) pentyl] -3,4-dihydro-2H-1,4-benzoxazin-2-ylbenzenecarboximidamide,
    1- [5- (2,3- [amino (imino) methyl] phenyl-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl) pentyl] -2- Pyrrolidinecarboxylic acid,
    N-1- [5- (2-3- [amino (imino) methyl] phenyl-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl) pentyl] tetra Hydro-1H-pyrrole-3-yl-N-methylacetamide,
    3-4- [5- (3-amino-1-pyrrolidinyl) pentyl] -3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-ylbenzenecarboximida mid,
    3- (4-5- [2,5-bis (methoxymethyl) -1-pyrrolidinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2- (1) benzene carboximidamide,
    3- (4-5- [2- (hydroxymethyl) -1-pyrrolidinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl) benzene Carboximidamide,
    3- (4-5- [2- (hydroxymethyl) -5-methyl-1-pyrrolidinyl] pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2 -Yl) benzenecarboximidamide,
    3-4- [5- (diisopropylamino) pentyl] -3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-ylbenzenecarboximidamide,
    3-4- [5- (diethylamino) pentyl] -3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-ylbenzenecarboximidamide,
    3-4- [5- (methylamino) pentyl] -3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-ylbenzenecarboximidamide,
    3-4- [5- (1-methyl-1H-imidazol-2-yl) pentyl] -3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-ylbenzenecarba Voximidamide,
    3-4- [5- (2,5-dimethyl-1H-imidazol-1-yl) pentyl] -3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl Benzenecarboximidamide,
    3- [4- (5-morpholinopentyl) -3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl] benzenecarboximidamide,
    3-4- [5- (3,5-dimethylmorpholino) pentyl] -3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-ylbenzenecarboximidamide ,
    3- [3-oxo-4- (5-piperazinopentyl) -3,4-dihydro-2H-1,4-benzoxazin-2-yl] benzenecarboximidamide,
    3-4- [5- (2,6-dimethylpiperidino) pentyl] -3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-ylbenzenecarboximidamide ,
    3-3-oxo-4- [5- (1H-pyrazol-1-yl) pentyl] -3,4-dihydro-2H-1,4-benzoxazin-2-ylbenzenecarboximidamide ,
    3- [3-oxo-4- (5-tetrahydro-1H-pyrazol-1-ylpentyl) -3,4-dihydro-2H-1,4-benzoxazin-2-yl] benzenecarbox Imidamide,
    3-4- [5- (2,5-dimethyltetrahydro-1H-pyrazol-1-yl) pentyl] -3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2 Monobenzenecarboximidamide,
    3- (6-chloro-4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1 , 4-benzoxazin-2-yl) benzenecarboximidamide,
    3- (4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-6-fluoro-3-oxo-3,4-dihydro-2H- 1,4-benzoxazin-2-yl) benzenecarboximidamide,
    3- (4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-6-sulfanyl-3,4-dihydro-2H- 1,4-benzoxazin-2-yl) benzenecarboximidamide,
    3- [4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-6- (methylsulfanyl) -3-oxo-3,4-dihydro -2H-1,4-benzoxazin-2-yl] benzenecarboximidamide,
    3- [4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-6- (trifluoromethyl) -3,4-di Hydro-2H-1,4-benzoxazin-2-yl] benzenecarboximidamide,
    3- (4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-6-methyl-3-oxo-3,4-dihydro-2H-1 , 4-benzoxazin-2-yl) benzenecarboximidamide,
    2-3- [amino (imino) methyl] phenyl-4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4 -Dihydro-2H-1,4-benzoxazine-6-carboxylic acid,
    Methyl 2-3- [amino (imino) methyl] phenyl-4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3, 4-dihydro-2H-1,4-benzoxazin-6-carboxylate,
    3- (6-cyano-4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H- 1,4-benzoxazin-2-yl) benzenecarboximidamide,
    2-3- [amino (imino) methyl] phenyl-4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4 -Dihydro-2H-1,4-benzoxazine-6-carboximidamide,
    2-3- [amino (imino) methyl] phenyl-4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-N-hydroxy-3- Oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboximidamide,
    3-4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-6- [hydrazino (imino) methyl] -3-oxo-3,4 -Dihydro-2H-1,4-benzoxazin-2-ylbenzenecarboximidamide,
    2-3- [amino (imino) methyl] phenyl-4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4 -Dihydro-2H-1,4-benzoxazin-6-carboxyamide,
    3- [4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-6- (hydroxymethyl) -3-oxo-3,4-dihydro -2H-1,4-benzoxazin-2-yl] benzenecarboximidamide,
    3- (6- (aminomethyl) -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro- 2H-1,4-benzoxazin-2-yl) benzenecarboximidamide,
    3- [4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-6-nitro-3-oxo-3,4-dihydro-2H-1 , 4-benzoxazin-2-yl) benzenecarboximidamide,
    3- (4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-6-hydroxy-3-oxo-3,4-dihydro-2H- 1,4-benzoxazin-2-yl) benzenecarboximidamide,
    3- (4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-6-methoxy-3-oxo-3,4-dihydro-2H- 1,4-benzoxazin-2-yl) benzenecarboximidamide,
    3- (6- (benzyloxy) -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro- 2H-1,4-benzoxazin-2-yl) benzenecarboximidamide,
    2-[(2-3- [amino (imino) methyl] phenyl-4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo -3,4-dihydro-2H-1,4-benzoxazin-6-yl) oxy] acetic acid,
    3-[(2-3- [amino (imino) methyl] phenyl-4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo -3,4-dihydro-2H-1,4-benzoxazin-6-yl) oxy] propanoic acid,
    4-[(2-3- [amino (imino) methyl] phenyl-4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo -3,4-dihydro-2H-1,4-benzoxazin-6-yl) oxy] butanoic acid,
    2-[(2-3- [amino (imino) methyl] phenyl-4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo -3,4-dihydro-2H-1,4-benzoxazin-6-yl) amino] acetic acid,
    3-[(2-3- [amino (imino) methyl] phenyl-4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo -3,4-dihydro-2H-1,4-benzoxazin-6-yl) amino] propanoic acid,
    4-[(2-3- [amino (imino) methyl] phenyl-4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo -3,4-dihydro-2H-1,4-benzoxazin-6-yl) amino] butanoic acid,
    3- [4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-6- (2-hydroxyethoxy) -3-oxo-3,4 -Dihydro-2H-1,4-benzoxazin-2-yl] benzenecarboximidamide,
    3- [4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-6- (2H-1,2,3,4-tetra Azole) -5-ylmethoxy) -3,4-dihydro-2H-1,4-benzoxazin-2-yl] benzenecarboximidamide,
    3- (6-amino-4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1 , 4-benzoxazin-2-yl) benzenecarboximidamide,
    3- (6- (butylamino) -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro- 2H-1,4-benzoxazin-2-yl) benzenecarboximidamide,
    3- (6- (dimethylamino) -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro- 2H-1,4-benzoxazin-2-yl) benzenecarboximidamide,
    3- (6-anilino-4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H- 1,4-benzoxazin-2-yl) benzenecarboximidamide,
    3- (6- (benzylamino) -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro- 2H-1,4-benzoxazin-2-yl) benzenecarboximidamide,
    N- (2,3- [amino (imino) methyl] phenyl-4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo- 3,4-dihydro-2H-1,4-benzoxazin-6-yl) acetamide,
    N- (2,3- [amino (imino) methyl] phenyl-4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo- 3,4-dihydro-2H-1,4-benzoxazin-6-yl) cyclohexacarboxamide,
    N- (2,3- [amino (imino) methyl] phenyl-4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo- 3,4-dihydro-2H-1,4-benzoxazin-6-yl) -2-cyclohexylacetamide,
    N- (2,3- [amino (imino) methyl] phenyl-4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo- 3,4-dihydro-2H-1,4-benzoxazin-6-yl) benzenecarboxamide,
    N- (2,3- [amino (imino) methyl] phenyl-4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo- 3,4-dihydro-2H-1,4-benzoxazin-6-yl) -2-phenylacetamide,
    3-4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-6-[(methylsulfonyl) amino] -3-oxo-3,4- Dihydro-2H-1,4-benzoxazin-2-ylbenzenecarboximidamide,
    3- (6-[(cyclohexylsulfonyl) amino] -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3, 4-dihydro-2H-1,4-benzoxazin-2-yl) benzenecarboximidamide,
    3- (6-[(cyclohexylmethyl) sulfonyl] amino-4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3 , 4-dihydro-2H-1,4-benzoxazin-2-yl) benzenecarboximidamide,
    3-4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-6-[(phenylsulfonyl) amino] -3,4- Dihydro-2H-1,4-benzoxazin-2-ylbenzenecarboximidamide, or
    3- (6- (benzylsulfonyl) amino] -4,5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4- Dihydro-2H-1,4-benzoxazin-2-yl) benzenecarboximidamide
    Phosphorus compounds.
    [16" claim-type="Currently amended] 3-((2R) -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1 , 4-benzoxazin-2-yl) -4-methoxybenzenecarboximidamide,
    3-((2S) -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1 , 4-benzoxazin-2-yl) -4-methoxybenzenecarboximidamide,
    3-((2R) -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1 , 4-benzoxazin-2-yl) -4-hydroxybenzenecarboximidamide,
    3-((2S) -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1 , 4-benzoxazin-2-yl) -4-hydroxybenzenecarboximidamide,
    3-((2R) -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1 , 4-benzoxazin-2-yl) benzenecarboximidamide, or
    3-((2S) -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1 , 4-benzoxazin-2-yl) benzenecarboximidamide
    Phosphorus compounds.
    [17" claim-type="Currently amended] 3-((2S) -4-5-[(2R, 6S) -2,6-dimethyltetrahydro-1 (2H) -pyridinyl] pentyl-3-oxo-3,4-dihydro-2H-1 , 4-benzoxazin-2-yl) -4-hydroxybenzenecarboximidamide.
    [18" claim-type="Currently amended] 2H-1,4-Benzoxazine-3 (4H) -one, 4- [3- (2,6-dimethyl-1-piperidinyl) propyl] -2-phenyl-,
    4- [5- (2,5-dimethyl-pyrrolidin-1-yl) -pentyl] -2-phenyl-4H-benzo [1,4] oxazin-3-one,
    2H-1,4-Benzoxazine-3 (4H) -one, 4- [5-bis (1-methylethyl) amino] pentyl] -2-phenyl-,
    2H-1,4-Benzoxazine-3 (4H) -one, 4- [3- (2,5-dimethyl-1-pyrrolidinyl) propyl] -2-phenyl-,
    2H-1,4-Benzoxazine-3 (4H) -one, 4- [3-bis (1-methylethyl) amino) propyl] -2-phenyl-,
    4- [5- (2,6-dimethyl-piperidin-1-yl) -pentyl] -2-phenyl-4H-benzo [1,4] oxazin-3-one,
    4- (5-diethylamino-pentyl) -2-phenyl-4H-benzo [1,4] oxazin-3-one,
    2-phenyl-4- (5-pyrrolidin-1-yl-pentyl) -4H-benzo [1,4] oxazin-3-one,
    2- [5- (3-oxo-2-phenyl-2,3-dihydro-benzo [1,4] oxazin-4-yl) -pentyl] -isoindole-1,3-dione,
    4- (5-imidazol-1-yl-pentyl) -2-phenyl-4H-benzo [1,4] oxazin-3-one,
    2- (4-chloro-phenyl) -4- [5- (2,6-dimethyl-piperidin-1-yl) -pentyl] -4H-benzo [1,4] oxazin-3-one,
    2- (2-chloro-phenyl) -4- [5- (2,5-dimethyl-pyrrolidin-1-yl) -pentyl] -4H-benzo [1,4] oxazin-3-one,
    2- (2-chloro-phenyl) -4- [5- (2,6-dimethyl-piperidin-1-yl) -pentyl] -4H-benzo [1,4] oxazin-3-one,
    5- (3-oxo-2-phenyl-2,3-dihydro-benzo [1,4] oxazin-4-yl) -pentaneamidine,
    2-phenyl-4- (5-piperidin-1-yl-pentyl) -4H-benzo [1,4] oxazin-3-one,
    2- (4-chloro-phenyl) -4- [5- (2,5-dimethyl-pyrrolidin-1-yl) -pentyl] -4H-benzo [1,4] oxazin-3-one,
    2-phenyl-4- (5-pyrrolidin-1-yl-pentyl) -4H-benzo [1,4] oxazin-3-one,
    Compound with trifluoro-acetic acid,
    3- (3-oxo-2-phenyl-2,3-dihydro-benzo [1,4] oxazin-4-ylmethyl) -benzonitrile,
    4- [6- (2,5-dimethyl-pyrrolidin-1-yl) -hexyl] -2-phenyl-4H-benzo [1,4] oxazin-3-one,
    3- (3-oxo-2-phenyl-2,3-dihydro-benzo [1,4] oxazin-4-ylmethyl) -benzamidine,
    2-naphthalen-2-yl-4- (5-piperidin-1-yl-pentyl) -4H-benzo [1,4] oxazin-3-one,
    4- (5-amino-pentyl) -2-phenyl-4H-benzo [1,4] -oxazin-3-one,
    4- [5- (2,6-dimethyl-piperidin-1-yl) -pentyl] -2-phenyl-4H-benzo [1,4] oxazin-3-one,
    6-methyl-2-phenyl-4- (5-piperidin-1-yl-pentyl) -4H-benzo [1,4] oxazin-3-one,
    7-methoxy-2-phenyl-4- (5-piperidin-1-yl-pentyl) -4H-benzo [1,4] oxazin-3-one,
    8-chloro-2-phenyl-4- (5-piperidin-1-yl-pentyl) -4H-benzo [1,4] oxazin-3-one,
    3-oxo-2-phenyl-4- (5-piperidin-1-yl-pentyl) -3,4-dihydro-2H-benzo [l, 4] oxazine-6-carbonitrile,
    4- (3-oxo-2-phenyl-2,3-dihydro-benzo [1,4] oxazin-4-ylmethyl) -benzamidine,
    1- [5- (3-oxo-2-phenyl-2,3-dihydro-benzo [1,4] oxazin-4-yl) -pentyl] -piperidine-2,6-dione,
    3- (3-oxo-2-phenyl-2,3-dihydro-benzo [1,4] oxazin-4-yl) -propionitrile,
    4- (3-oxo-2-phenyl-2,3-dihydro-benzo [1,4] oxazin-4-yl) -butyronitrile,
    5- (3-oxo-2-phenyl-2,3-dihydro-benzo [1,4] oxazin-4-yl) -pentanenitrile,
    N- [3- (3-oxo-2-phenyl-2,3-dihydro-benzo [1,4] oxazin-4-yl) -propyl] -guanidine,
    N- [5- (3-oxo-2-phenyl-2,3-dihydro-benzo [1,4] oxazin-4-yl) -pentyl] -guanidine,
    4- (3-oxo-2-phenyl-2,3-dihydro-benzo [1,4] oxazin-4-ylmethyl) -benzamidine,
    2- (4-methoxy-phenyl) -4- (5-piperidin-1-yl-pentyl) -4H-benzo [1,4] oxazin-3-one,
    7-methyl-2-phenyl-4- (5-piperidin-1-yl-pentyl) -4H-benzo [1,4] oxazin-3-one,
    5-methyl-2-phenyl-4- (5-piperidin-1-yl-pentyl) -4H-benzo [1,4] oxazin-3-one,
    6-methoxy-2-phenyl-4- (5-piperidin-1-yl-pentyl) -4H-benzo [1,4] oxazin-3-one,
    N-hydroxy-4- (3-oxo-2-phenyl-2,3-dihydro-benzo [1,4] oxazin-4-ylmethyl) -benzamidine,
    6-chloro-2-phenyl-4- (5-piperidin-1-yl-pentyl) -4H-benzo [1,4] oxazin-3-one,
    2- (4-methoxy-phenyl) -4- (5-piperazin-1-yl-pentyl) -4H-benzo [1,4] oxazin-3-one,
    2- (4-hydroxy-phenyl) -4- (5-piperidin-1-yl-pentyl) -4H-benzo [1,4] oxazin-3-one,
    4- [5- (2,6-dimethyl-piperidin-1-yl) -pentyl] -2- (4-hydroxy-phenyl) -4H-benzo [1,4] oxazin-3-one,
    2- (4-methoxy-phenyl) -4- [5- (4-methyl-piperazin-1-yl) -pentyl] -4H-benzo [1,4] oxazin-3-one,
    4- {4- [5- (2,6-Dimethyl-piperidin-1-yl) -pentyl] -3-oxo-3,4-dihydro-2H-benzo [1,4] oxazine-2 -Yl} -benzonitrile,
    4- {4- [5- (2,6-Dimethyl-piperidin-1-yl) -pentyl] -3-oxo-3,4-dihydro-2H-benzo [1,4] oxazine-2 -Yl} -benzoamidine,
    4- {4- [5- (2,6-Dimethyl-piperidin-1-yl) -pentyl] -3-oxo-3,4-dihydro-2H-benzo [1,4] oxazine-2 -Yl} -thiobenzamide,
    [2- (4-methoxy-phenyl) -3-oxo-2,3-dihydro-benzo [1,4] oxazin-4-yl} -acetic acid,
    4- {4- [5- (2,6-Dimethyl-piperidin-1-yl) -pentyl] -3-oxo-3,4-dihydro-2H-benzo [1,4] oxazine-2 -Yl} -N-hydroxy-benzamidine,
    Benzenecarboxyimide acid, 4- [3,4-dihydro-4- [5- (2,6-dimethyl-1-piperidinyl) pentyl] -3-oxo-2H-1,4-benzoxazine- 2-yl]-, hydrazide,
    6-amino-2-phenyl-4- (5-piperidin-1-yl-pentyl) -4H-benzo [1,4] oxazin-3-one,
    4- (5-bromo-pentyl) -2- (3,4-dimethoxy-phenyl) -4H-benzo [1,4] oxazin-3-one,
    4- (5-bromo-pentyl) -2- (3,4,5-trimethoxy-phenyl) -4H-benzo [1,4] oxazin-3-one,
    4- (5-bromo-pentyl) -2- (4-methoxy-phenyl) -4H-benzo [1,4] oxazin-3-one,
    N- [2- (2,6-Dimethyl-piperidin-1-yl) -ethyl] -2- [2- (4-methoxy-phenyl) -3-oxo-2,3-dihydro-benzo [1,4] oxazin-4-yl] -acetamide,
    4- [5- (2,6-dimethyl-piperidin-1-yl) -pentyl] -2- (3,4,5-trimethoxy-phenyl) -4H-benzo [1,4] oxazine -3-one,
    2- (3,4-Dimethoxy-phenyl) -4- [5- (2,6-dimethyl-piperidin-1-yl) -pentyl] -4H-benzo [1,4] oxazine-3- On,
    2- (4-bromo-phenyl) -4- [5- (2,6-dimethyl-piperidin-1-yl) -pentyl] -4H-benzo [1,4] oxazin-3-one,
    8-methyl-2-phenyl-4- (5-piperidin-1-yl-pentyl) -4H-benzo [1,4] oxazin-3-one,
    2- (4-benzylamino-phenyl) -4- [5- (2,6-dimethyl-piperidin-1-yl) -pentyl] -4H-benzo [1,4] oxazin-3-one,
    2- (4-methoxy-phenyl) -4- [5- (2,2,6,6-tetramethyl-piperidin-1-yl) -pentyl] -4H-benzo [1,4] oxazine -3-one,
    4- (2-bromo-ethyl) -2- (4-methoxy-phenyl) -4H-benzo [1,4] oxazin-3-one,
    4- (5-bromo-pentyl) -2- (3,4-dichloro-phenyl) -4H-benzo [1,4] oxazin-3-one,
    4- (2-hydroxy-ethyl) -2- (4-methoxy-phenyl) -4H-benzo [1,4] oxazin-3-one,
    2- (3,4-Dichloro-phenyl) -4- [5- (2,6-dimethyl-piperidin-1-yl) -pentyl] -4H-benzo [1,4] oxazin-3-one ,
    4- [3- (2,6-Dimethyl-piperidin-1-ylmethyl) -benzyl] -2- (4-methoxy-phenyl) -4H-benzo [1,4] oxazin-3-one ,
    4- (2-amino-ethyl) -2- (4-methoxy-phenyl) -4H-benzo [1,4] oxazin-3-one,
    2- (2,6-dimethyl-piperidin-1-yl) -N- {2- [2 (4-methoxy-phenyl) -3-oxo-2,3-dihydro-benzo [1,4 ] Oxazin-4-yl] -ethyl} acetamide,
    4- [5- (2,6-Dimethyl-piperidin-1-yl) -5-oxo-pentyl] -2- (4-methoxy-phenyl) -4H-benzo [1,4] oxazine- 3-on,
    3- {4- [4- (2,6-Dimethyl-piperidin-1-yl) -butyl] -3-oxo-3,4-dihydro-2H-benzo [1,4] oxazine-2 Benzamidine,
    3- {4- [6- (2,6-Dimethyl-piperidin-1-yl) -hexyl] -3-oxo-3,4-dihydro-2H-benzo [1,4] oxazine-2 Benzamidine,
    2- (5-aminomethyl-2-hydroxy-phenyl) -4- [5- (2,6-dimethyl-piperidin-1-yl) -pentyl] -4H-benzo [1,4] oxazine -3-one,
    2- (3-aminomethyl-phenyl) -4- [5- (2,6-dimethyl-piperidin-1-yl) -pentyl] -4H-benzo [1,4] oxazin-3-one,
    3- {4- [5- (2,6-Dimethyl-piperidin-1-yl) -pentyl] -7-methyl-3-oxo-3,4-dihydro-2H-benzo [1,4] Oxazine-2-yl} -benzamidine,
    3- {4- [5- (2,6-Dimethyl-piperidin-1-yl) -pentyl] -3-oxo-3,4-dihydro-2H-benzo [1,4] oxazine-2 -Yl} -4-methoxy-benzamidine,
    2- (5-aminomethyl-2-methoxy-phenyl) -4- [5- (2,6-dimethyl-piperidin-1-yl) -pentyl] -4H-benzo [1,4] oxazine -3-one,
    3- {4- [5- (2,6-Dimethyl-piperidin-1-yl) -pentyl] -3-oxo-3,4-dihydro-2H-benzo [1,4] oxazine-2 -Yl} -N-hydroxy-4-methoxy-benzamidine,
    3- {4- [5- (2,6-Dimethyl-piperidin-1-yl) -pentyl] -3-oxo-3,4-dihydro-2H-benzo [1,4] oxazine-2 -Yl} -N-hydroxy-benzamidine,
    3- {7-chloro-4- [5- (2,6-dimethyl-piperidin-1-yl) -pentyl] -3-oxo-3,4-dihydro-2H-benzo [1,4] Oxazine-2-yl} -benzamidine,
    4- (5-bromo-pentyl) -2-phenyl-4H-benzo [1,4] oxazin-3-one,
    3- [3-oxo-4- (5-piperidin-1-yl-pentyl) -3,4-dihydro-2H-benzo [1,4] oxazin-2-yl] -benzamidine,
    N- {2- (3-Carbamimidoyl-phenyl) -4- [5- (2,6-dimethyl-piperidin-1-yl) -pentyl] -3-oxo-3,4-dihydro -2H-benzo [1,4] oxazin-6-yl} -acetamide,
    3- {4- [5- (2,6-dimethyl-piperidin-1-yl) -pentyl] -2-methyl-3-oxo-3,4-dihydro-2H-benzo [1,4] Oxazin-2-yl} -N-hydroxy-benzamidine,
    3- [4- (5-Diisopropylamino-pentyl) -3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-2-yl] -benzamidine,
    3- (4- {4-[(Diisopropylamino) -methyl] -benzyl} -3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-2-yl) -benz Amidine,
    3- {4- [4- (2,6-Dimethyl-piperidin-1-ylmethyl) -benzyl] -3-oxo-3,4-dihydro-2H-benzo [1,4] oxazine- 2-yl} -benzamidine,
    3- {4- [5- (2,6-Dimethyl-piperidin-1-yl) -pentyl] -3-oxo-3,4-dihydro-2H-benzo [1,4] oxazine-2 -Yl} -4-hydroxy-benzamidine,
    3- {4- [5- (2,6-Dimethyl-piperidin-1-yl) -pentyl] -3-oxo-3,4-dihydro-2H-benzo [1,4] oxazine-2 -Yl} -N-methyl-benzamidine,
    {2- (3-Carbamimidoyl-phenyl) -4- [5- (2,6-dimethyl-piperidin-1-yl) -pentyl] -3-oxo-3,4-dihydro-2H -Benzo [1,4] oxazin-6-yl} -acetic acid,
    3- (4- {3-[(Diisopropylamino) -methyl] -benzyl} -3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-2-yl) -benz Amidine,
    3- {4- [3- (2,6-Dimethyl-piperidin-1-ylmethyl) -benzyl] -3-oxo-3,4-dihydro-2H-benzo [1,4] oxazine- 2-yl} -benzamidine,
    2- (3-Carbamimidoyl-phenyl) -4- [5- (2,6-dimethyl-piperidin-1-yl) -pentyl] -3-oxo-3,4-dihydro-2H- Benzo [1,4] oxazine-7-carboxylic acid,
    3- {3-oxo-4- [4- (pyridin-2-ylamino) -butyl] -3,4-dihydro-2H-benzo [1,4] oxazin-2-yl} -benzamidine ,
    2- (3-Carbamimidoyl-phenyl) -4- [5- (2,6-dimethyl-piperidin-1-yl) -pentyl] -3-oxo-3,4-dihydro-2H- Benzo [1,4] oxazine-7-carboxylic acid methyl ester,
    3- [4- (5-dihexylamino-pentyl) -3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-2-yl] -benzamidine,
    3- {4- [4- (Methyl-pyridin-2-yl-amino) -butyl] -3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-2-yl}- Benzamidine,
    4- [5- (2,6-Dimethyl-piperidin-1-yl) -pentyl] -2- [3- (imino-morpholin-4-yl-methyl) -phenyl] -4H-benzo [ 1,4] oxazine-3-one,
    3- {3-oxo-4- [4- (pyrimidin-2-ylamino) -butyl] -3,4-dihydro-2H-benzo [1,4] oxazin-2-yl} -benzami Dean,
    3- [4- (4-cyclohexylamino-butyl) -3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-2-yl] -benzamidine,
    3- {4- [5- (2,5-Dimethyl-pyrrolidin-1-yl) -pentyl] -3-oxo-3,4-dihydro-2H-benzo [1,4] oxazine-2 -Day] -benzamidine,
    3- [4- (5-morpholin-4-yl-pentyl) -3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-2-yl] -benzamidine,
    3- {4- [5- (2,6-Dimethyl-piperidin-1-yl) -2,3-dihydroxy-pentyl] -3-oxo-3,4-dihydro-2H-benzo [ 1,4] oxazine-2-yl} -benzamidine,
    4- [2- (3-Carbamimidoyl-phenyl) -3-oxo-2,3-dihydro-benzo [1,4] oxazin-4-ylmethyl] -N, N-dimethyl-benzamide ,
    2- (3-Carbamimidoyl-phenyl) -4- [5- (2,6-dimethyl-piperidin-1-yl) -pentyl] -3-oxo-3,4-dihydro-2H- Benzo [1,4] oxazine-6-carboxylic acid,
    3- [2- (3-Carbamimidoyl-phenyl) -3-oxo-2,3-dihydro-benzo [1,4] oxazin-4-ylmethyl] -N, N-dimethyl-benzamide ,
    3- {4- [5- (2,6-Dimethyl-piperidin-1-yl) -pent-2-enyl] -3-oxo-3,4-dihydro-2H-benzo [1,4] Oxazine-2-yl} -benzamidine,
    3- [4- (5-amino-pentyl) -3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-2-yl] -benzamidine,
    2- (3-Carbamimidoyl-phenyl) -4- [5- (2,6-dimethyl-piperidin-1-yl) -pentyl] -3-oxo-3,4-dihydro-2H- Benzo [1,4] oxazine-6-carboxylic acid methyl ester,
    4-methoxy-3- [4- (4-methoxy-benzyl) -3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-2-yl] -benzonitrile,
    3- {4- [5- (2,6-Dimethyl-piperidin-1-yl) -pent-3-enyl] -3-oxo-3,4-dihydro-2H-benzo [1,4] Oxazine-2-yl} -benzamidine,
    4- [2- (3-cyano-phenyl) -3-oxo-2,3-dihydro-benzo [1,4] oxazin-4-ylmethyl] -N, N-dimethyl-benzamide,
    3- [2- (3-carbamimidoyl-phenyl) -3-oxo-2,3-dihydro-benzo [1,4] oxazin-4-ylmethyl] -5- (2,6-dimethyl Piperidin-1-ylmethyl) -benzoic acid,
    3- {4- [5- (2,6-Dimethyl-piperidin-1-yl) -pentyl] -3-oxo-3,4-dihydro-2H-benzo [1,4] oxazine-2 -Yl} -4-hydroxy-benzamidine,
    3-acetyl-2- (2-methoxy-phenyl) -thiazolidine-4-carboxylic acid 4-cyano-2- {4- [5- (2,6-dimethyl-piperidine-1- Yl) -pentyl] -3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-2-yl} -phenyl ester,
    3- [2- (3-carbamimidoyl-phenyl) -3-oxo-2,3-dihydro-benzo [1,4] oxazin-4-ylmethyl] -5- (2,6-dimethyl -Piperidin-1-ylmethyl) -N-hydroxy-benzamide,
    4- (2-dimethylamino-ethyl) -7-nitro-2-phenyl-4H-benzo [1,4] -thiazin-3-one,
    4- (2-diethylamino-ethyl) -7-nitro-2-phenyl-4H-benzo [1,4] -thiazin-3-one,
    2H-1,4-benzothiazine-3 (4H) -one, 4- [2- (dimethylamino) ethyl] -7-nitro-2-phenyl-, monohydrochloride,
    2H-1,4-benzothiazine-3 (4H) -one, 4- [2- (diethylamino) ethyl] -7-nitro-2-phenyl-, monohydrochloride,
    4- [5- (2,6-dimethyl-piperidin-1-yl) -pentyl] -2- (4-methoxy-phenyl) -4H-benzo [1,4] thiazin-3-one,
    4- {4- [5- (2,6-Dimethyl-piperidin-1-yl) -pentyl] -3-oxo-3,4-dihydro-2H-benzo [1,4] thiazine-2 -Yl} -benzonitrile,
    4- {4- [5- (2,6-Dimethyl-piperidin-1-yl) -pentyl] -3-oxo-3,4-dihydro-2H-benzo [1,4] thiazine-2 -Yl} -thiobenzamide,
    4- [5- (2,6-dimethyl-piperidin-1-yl) -pentyl] -2- (4-methoxy-phenyl) -4H-benzo [1,4] thiazin-3-one,
    Compound with trifluoro-acetic acid,
    3- {4- [5- (2,6-Dimethyl-piperidin-1-yl) -pentyl] -3-oxo-3,4-dihydro-2H-benzo [1,4] thiazine-2 -Yl} -benzonitrile,
    3- {4- [5- (2,6-Dimethyl-piperidin-1-yl) -pentyl] -3-oxo-3,4-dihydro-2H-benzo [1,4] thiazine-2 -Yl} -benzamide,
    4- [5- (2,6-dimethyl-piperidin-1-yl) -pentyl] -2- (3-methoxy-phenyl) -2- (4-methoxy-phenyl) -4H-benzo [ 1,4] thiazin-3-one,
    4- [5- (2,6-Dimethyl-piperidin-1-yl) -pentyl] -2- (4-methoxy-phenyl) -1,1-dioxo-1,4-dihydro-2H -Benzo [1,4] thiazin-3-one,
    2- (4-benzyloxy-phenyl) -4- [5- (2,6-dimethyl-piperidin-1-yl) -pentyl] -4H-benzo [1,4-thiazin-3-one,
    2- (4-butoxy-phenyl) -4- [5- (2,6-dimethyl-piperidin-1-yl) -pentyl] -4H-benzo [1,4-thiazin-3-one,
    3- {4- [5- (2,6-Dimethyl-piperidin-1-yl) -pentyl] -3-oxo-3,4-dihydro-2H-benzo [1,4] thiazine-2 -Yl} -thiobenzamide,
    4- {4- [5- (2,6-Dimethyl-piperidin-1-yl) -pentyl] -3-oxo-3,4-dihydro-2H-benzo [1,4] thiazine-2 Benzamidine,
    3- {4- [5- (2,6-Dimethyl-piperidin-1-yl) -pentyl] -3-oxo-3,4-dihydro-2H-benzo [1,4] thiazine-2 -Yl} -N-hydroxy-benzamide,
    3- {4- [5- (2,6-Dimethyl-piperidin-1-yl) -pentyl] -3-oxo-3,4-dihydro-2H-benzo [1,4] thiazine-2 -Yl} -benzamide,
    3- {4- [5- (2-hydroxymethyl-pyrrolidin-1-yl) -pentyl] -3-oxo-3,4-dihydro-2H-benzo [1,4] thiazine-2 Benzamidine,
    4-allyl-2,2-diphenyl-4H-benzo [1,4] thiazin-3-one,
    4- (2-diethylamino-ethyl) -7-nitro-2-phenyl-4H-benzo [1,4] thiazin-3-one,
    2- (3-diethylamino-propylamino) -4-methyl-2-phenyl-4H-benzo [1,4] thiazin-3-one,
    4- (2-diethylamino-ethyl) -2,2-diphenyl-4H-benzo [1,4] thiazin-3-one,
    2-benzyl-4- (5-piperidin-1-yl-pentyl) -4H-benzo [1,4] oxazin-3-one,
    2-cyclohexyl-4- [5- (2,6-dimethyl-piperidin-1-yl) -pentyl] -4H-benzo [1,4] thiazin-3-one,
    2H-1,4-benzothiazine-3 (4H) -one, 4-methyl-2,2-diphenyl-,
    4-ethyl-2-phenyl-2-piperidin-1-yl-4H-benzo [1,4] thiazin-3-one,
    4-methyl-2-phenyl-2-piperidin-1-yl-4H-benzo [1,4] thiazin-3-one,
    3- {4- [5- (2-Dimethyl-piperidin-1-yl) -pentyl] -3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-2-yl } -Piperidine-1-carboxamidine,
    4- [5- (2,6-dimethyl-piperidin-1-yl) -pentyl] -2-piperidin-3-yl-4H-benzo [1,4] oxazin-3-one,
    3-oxo-2-phenyl-2,4-bis- (5-piperidin-1-yl-pentyl) -3,4-dihydro-2H-benzo [1,4] oxazine-6-carbonitrile ,
    4- [5- (2,6-dimethyl-piperidin-1-yl) -pentyl] -2-pyridin-2-yl-4H-benzo [1,4] oxazin-3-one,
    N-hydroxy-3-oxo-2-phenyl-4- (5-piperidin-1-yl-pentyl) -3,4-dihydro-2H-benzo [1,4] oxazine-6-carr Voxamidine,
    3-oxo-2-phenyl-4- (5-piperidin-1-yl-pentyl) -3,4-dihydro-2H-benzo [1,4] oxazine-6-carboxamidine,
    3- {4- [5- (2,6-Dimethyl-piperidin-1-yl) -pentyl] -3-oxo-3,4-dihydro-2H-benzo [1,4] oxazine-2 -Yl} -thiobenzamide,
    3- {4- [5- (Adamantan-1-ylamino) -pentyl] -3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-2-yl} -benz amides,
    2- (3-diethylamino-propylamino) -4-methyl-2-phenyl-4H-benzo [1,4] oxazin-3-one,
    4- [3- (2,6-dimethyl-1-piperidinyl) propyl] -2-phenyl-2H-1,4-benzoxazin-3 (4H) -one, or
    4-Methyl-2-phenyl-2H-1,4-benzoxazin-3 (4H) -one
    Phosphorus compounds.
    [19" claim-type="Currently amended] A method of treating or preventing a thrombotic disorder in a mammal, comprising administering to the mammal an effective amount of the compound of claim 1.
    [20" claim-type="Currently amended] The method of claim 19, wherein the disorder is venous thrombosis.
    [21" claim-type="Currently amended] The method of claim 19, wherein said disorder is arterial thrombosis.
    [22" claim-type="Currently amended] The method of claim 19, wherein said disorder is pulmonary embolism.
    [23" claim-type="Currently amended] The method of claim 19, wherein the disorder is myocardial infarction.
    [24" claim-type="Currently amended] The method of claim 19, wherein the disorder is cerebral infarction.
    [25" claim-type="Currently amended] The method of claim 19, wherein said disorder is restenosis.
    [26" claim-type="Currently amended] The method of claim 19, wherein said disorder is cancer.
    [27" claim-type="Currently amended] The method of claim 19, wherein the disorder is Angena.
    [28" claim-type="Currently amended] The method of claim 19, wherein said disorder is diabetes.
    [29" claim-type="Currently amended] The method of claim 19, wherein the disorder is atrial fibrillation.
    [30" claim-type="Currently amended] The method of claim 19, wherein the disorder is heart failure.
    [31" claim-type="Currently amended] A pharmaceutical formulation comprising the compound of claim 1 in admixture with a carrier, diluent or excipient.
    [32" claim-type="Currently amended] A pharmaceutical formulation comprising a compound according to claim 2 together with a carrier, diluent or excipient.
    [33" claim-type="Currently amended] A pharmaceutical formulation comprising a compound according to claim 14 together with a carrier, diluent or excipient.
    [34" claim-type="Currently amended] A pharmaceutical formulation comprising a compound according to claim 15 together with a carrier, diluent or excipient.
    [35" claim-type="Currently amended] A method for inhibiting serine protease, comprising administering to a mammal an effective amount of the serine protease inhibitor of claim 1.
    [36" claim-type="Currently amended] 36. The method of claim 35, wherein said serine protease is Factor Xa.
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    同族专利:
    公开号 | 公开日
    AU765223B2|2003-09-11|
    WO1999050257A1|1999-10-07|
    NZ506985A|2003-10-31|
    HU0101699A3|2002-05-28|
    HU0101699A2|2002-04-29|
    PL343317A1|2001-08-13|
    IL137656D0|2001-10-31|
    JP2002509925A|2002-04-02|
    US6509335B1|2003-01-21|
    NO20004698L|2000-09-20|
    AU765223C|2004-03-18|
    AU1918399A|1999-10-18|
    EP1068191A1|2001-01-17|
    CA2319551A1|1999-10-07|
    ZA9902445B|1999-10-01|
    BR9815784A|2000-11-21|
    IS5590A|2000-08-18|
    NO20004698D0|2000-09-20|
    US20030187256A1|2003-10-02|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    1998-03-31|Priority to US8014298P
    1998-03-31|Priority to US60/080,142
    1998-12-15|Application filed by 로즈 암스트롱, 크리스틴 에이. 트러트웨인, 워너-램버트 캄파니
    1998-12-15|Priority to PCT/US1998/026708
    2001-05-25|Publication of KR20010042296A
    优先权:
    申请号 | 申请日 | 专利标题
    US8014298P| true| 1998-03-31|1998-03-31|
    US60/080,142|1998-03-31|
    PCT/US1998/026708|WO1999050257A1|1998-03-31|1998-12-15|Benzoxazinones/benzothiazinones as serine protease inhibitors|
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