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WO2000076970A2 - Composes - Google Patents

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Publication number
WO2000076970A2
WO2000076970A2 PCT/GB2000/002296 GB0002296W WO0076970A2 WO 2000076970 A2 WO2000076970 A2 WO 2000076970A2 GB 0002296 W GB0002296 W GB 0002296W WO 0076970 A2 WO0076970 A2 WO 0076970A2
Authority
WO
WIPO (PCT)
Prior art keywords
amino
methyl
phenylglycinyl
group
optionally substituted
Prior art date
Application number
PCT/GB2000/002296
Other languages
English (en)
Other versions
WO2000076970A3 (fr
Inventor
John Walter Liebeschuetz
Amanda Jane Lyons
Christopher William Murray
Andrew David Rimmer
Stephen Clinton Young
Nicholas Paul Camp
Stuart Donald Jones
Phillip John Morgan
Simon James Richards
William Alexander Wylie
Sarah Elizabeth Lively
Martin James Harrison
Bohdan Waszkowycz
John Joseph Masters
Michael Robert Wiley
Original Assignee
Eli Lilly And Company
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GBGB9913823.2A external-priority patent/GB9913823D0/en
Priority claimed from GBGB9918741.1A external-priority patent/GB9918741D0/en
Priority claimed from GBGB9929552.9A external-priority patent/GB9929552D0/en
Priority claimed from GBGB9929553.7A external-priority patent/GB9929553D0/en
Application filed by Eli Lilly And Company filed Critical Eli Lilly And Company
Priority to CA002383008A priority Critical patent/CA2383008A1/fr
Priority to AU54136/00A priority patent/AU5413600A/en
Priority to EP00938912A priority patent/EP1192135A2/fr
Publication of WO2000076970A2 publication Critical patent/WO2000076970A2/fr
Publication of WO2000076970A3 publication Critical patent/WO2000076970A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
    • C07C237/36—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/58—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
    • C07C255/60—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton at least one of the singly-bound nitrogen atoms being acylated
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    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
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    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
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    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/32—Oxygen atoms
    • C07D209/34—Oxygen atoms in position 2
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    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
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    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
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    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/34—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
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    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
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    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D217/04—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
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    • C07D217/06—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with the ring nitrogen atom acylated by carboxylic or carbonic acids, or with sulfur or nitrogen analogues thereof, e.g. carbamates
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    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
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    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
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    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
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    • C07C2602/42—Systems containing two condensed rings the rings having more than two atoms in common the bicyclo ring system containing seven carbon atoms

Definitions

  • This invention relates to compounds that are inhibitors of serine proteases. More particularly, it relates to their use as serine protease inhibitors in the treatment of the human or animal body.
  • the serine proteases are a group of proteolytic enzymes which have a common catalytic mechanism characterized by a particularly reactive Ser residue.
  • serine proteases include trypsin, tryptase, chymotrypsin, elastase, thrombin, plasmin, kallikrein, Complement Cl, acrosomal protease, lysosomal protease, cocoonase, ⁇ -lytic protease, protease A, protease B, serine carboxypeptidase II, subtilisin, urokinase, Factor Vila, Factor IXa, and Factor Xa.
  • Serine protease inhibitors play a central role in the regulation of a wide variety of physiological processes including coagulation, fibrinolysis, fertilization, development, malignancy, neuromuscular patterning and inflammation. It is well known that these compounds inhibit a variety of circulating proteases as well as proteases that are activated or released in tissue.
  • serine protease inhibitors inhibit critical cellular processes, such as adhesion, migration, free radical production and apoptosis.
  • animal experiments indicate that intravenously administered serine protease inhibitors, variants or cells expressing serine protease inhibitors, provide a protective effect against tissue damage.
  • Serine protease inhibitors have also been predicted to have potential beneficial uses in the treatment of disease in a wide variety of clinical areas such as oncology, neurology, haematology, pulmonary medicine, immunology, inflammation and infectious disease.
  • serine protease inhibitors may be beneficial in the treatment of thrombotic diseases, asthma, emphysema, cirrhosis, arthritis, carcinoma, melanoma, restenosis, atheroma, trauma, shock and reperfusion injury.
  • an inhibitor of Factor Xa has value as a therapeutic agent as an anticoagulant, e.g. in the treatment and prevention of thrombotic disorders.
  • the use of a Factor Xa inhibitor as an anticoagulant is desirable in view of the selectivity of its effect.
  • Many clinically approved anticoagulants have been associated with adverse events owing to the non-specific nature of their effects on the coagulation cascade.
  • Tryptase is the major secretory protease of human mast cells and is proposed to be involved in neuropeptide processing and tissue inflammation.
  • Mature human tryptase is a glycosylated, heparin- associated tetramer of catalytically active subunits. Its amino-acid structure appears to have no close counterpart among the other serine proteases which have been characterised. Tryptase is stored in mast cell secretory granules and after mast cell activation, human tryptase can be measured readily in a variety of biological fluids. For example, after anaphylaxis, tryptase appears in the blood stream where it is readily detectable for several hours. Tryptase also appears in samples of nasal and lung lavage fluid from atopic subjects challenged with specific antigen.
  • Tryptase has been implicated in a variety of biological processes where activation and degranulation of mast cells occur. Accordingly, mast cell tryptase inhibition may be of great value in the prophylaxis and treatment of a variety of mast cell mediated conditions.
  • Mast cells can degranulate by both IgE-dependent and independent mechanisms thereby implicating tryptase in both atopic and non-atopic inflammatory conditions.
  • Tryptase can activate proteases such as pro-urokinase and pro-MMP3 (pro-matrix metalloprotease 3, pro-stromelysin) , thereby indicating a pathological role in tissue inflammation and remodelling.
  • tryptase can activate certain G-protein coupled receptors (eg PAR2) and induce neurogenic inflammation points to a broader physiological role, for example in modulating pain mechanisms.
  • G-protein coupled receptors eg PAR2
  • tryptase inhibitors may be beneficial in a broad range of diseases.
  • asthma chronic obstructive pulmonary disease
  • COPD chronic obstructive pulmonary disease
  • pulmonary fibrotic diseases rhinitis; psoriasis; urticaria; dermatitis; arthritis; Crohn's disease; colitis; angiogenesis; atherosclerosis; multiple sclerosis; interstitial cystitis; migraine headache; neurogenic inflammation and pain mechanisms; wound healing; cirrhosis of the liver; Kimura's disease; pre- eclampsia; bleeding problems associated with menstruation and the menopause; cancer (particularly melanoma and tumour metastasis) ; pancreatitis; and certain viral infections (Yong, Exp.
  • the Factor Xa inhibitors of this invention are potentially useful for the prophylaxis or treatment of thrombotic disorders such as amongst others venous thrombosis, pulmonary embolism, arterial thrombosis, myocardial ischaemia, myocardial infarction, and cerebral thrombosis. They potentially have benefit in the treatment of acute vessel closure associated with thrombolytic therapy and restenosis, e.g. after transluminal coronary angioplasty or bypass grafting of the coronary or peripheral arteries and in the maintenance of vascular access patency in long term hemodialysis patients.
  • Factor Xa inhibitors of this invention may, with benefit, form part of a combination therapy with an anticoagulant with a different mode of action or with a thrombolytic agent.
  • the invention also provides the use of certain compounds which have been found to be inhibitors of both Factor Xa and thrombin. These compounds have excellent potential therapeutic value and may synergistically boost Fxa antithrombotic effect.
  • the compounds that are tryptase inhibitors will be useful not only in the treatment and prophylaxis of asthma but also of other allergic and inflammatory conditions mediated by tryptase such as allergic rhinitis, skin conditions such as eczema, psoriasis, atopic dermatitis and urticaria, rheumatoid arthritis, conjunctivitis, inflammatory bowel disease, neurogenic inflammation, atherosclerosis and cancer. It has been reported in W099/11658 and W099/11657 that certain benzamidine and aminoisoquinoline derivatives carrying a bulky lipophilic side chain are excellent inhibitors of serine proteases. Unfortunately, it has since been found that benzamidine compounds of WO 99/11658 in general demonstrate poor oral bioavailability.
  • the invention provides a method of treatment of the human or non-human animal body (e.g. a mammalian, avian or reptilian body) to combat a condition responsive to a serine protease inhibitor, said method comprising administering to said body an effective amount of a serine protease inhibitor compound of formula
  • R2 represents a 5 or 6 membered aromatic carbon ring optionally interrupted by a nitrogen, oxygen or sulphur ring atom, optionally being substituted in the 3 and/or 4 position (in relation to the point of attachment of X-X) by halo, nitro, thiol, haloalkoxy, hydrazido, alkylhydrazido, amino, cyano, haloalkyl, alkylthio, alkenyl, alkynyl, acylamino, tri or difluoromethoxy, carboxy, acyloxy, MeS ⁇ 2 ⁇ or Rj_, or the substituents at the 3 and 4 positions taken together form a fused ring which is a 5 or 6 membered carbocyclic or heterocyclic ring optionally substituted by halo, haloalkoxy, haloalkyl, cyano, nitro, amino, hydrazido, alkylthio, alkenyl, al
  • each X independently is a C, N, 0 or S atom or a CO, CR ⁇ a , C(R ⁇ a )2 or NR ⁇ a group, at least one X being C, CO, CR la or C(R la ) 2 ; each R ⁇ a independently represents hydrogen or hydroxyl, alkoxy, alkyl, aminoalkyl, hydroxyalkyl alkoxyalkyl, alkoxycarbonyl, alkylaminocarbonyl , alkoxycarbonylamino, acyloxymethoxycarbonyl or alkylamino optionally substituted by hydroxy, alkylamino, alkoxy, oxo,
  • L is an organic linker group containing 1 to 5 backbone atoms selected from C, N, O and S, or a branched alkyl or cyclic group;
  • Y (the ⁇ -atom) is a nitrogen atom or a CR k group
  • Cy is a saturated or unsaturated, mono or poly cyclic, homo or heterocyclic group, preferably containing 5 to 10 ring atoms and optionally substituted by groups R 3a or phenyl optionally substituted by R 3a ; each R 3a independently is R ⁇ c , amino, halo, cyano, nitro, thiol, alkylthio, alkylsulphonyl, alkylsulphenyl , triazolyl, imidazolyl, tetrazolyl, hydrazido, alkyl imidazolyl, thiazolyl, alkyl thiazolyl, alkyl oxazolyl, oxazolyl, alkylsulphonamido, alkylaminosulphonyl , aminosulphonyl , haloalkoxy and haloalkyl ;
  • Lp is a lipophilic organic group
  • D is a hydrogen bond donor group; and n is 0, 1 or 2; and Ri, Rib, R ⁇ c and Ri j are as defined for R ⁇ a , or a physiologically tolerable salt thereof, e.g. a halide, phosphate or sulphate salt or a salt with ammonium or an organic amine such as ethylamine or meglumine.
  • a physiologically tolerable salt thereof e.g. a halide, phosphate or sulphate salt or a salt with ammonium or an organic amine such as ethylamine or meglumine.
  • treatment includes prophylaxis, amelioration or elimination of a condition for which a human or non-human animal body is being treated.
  • the "effective amount" or dosage of the inhibitor compound of formula (I) will depend upon the nature and severity of the condition being treated, the administration route and the size and species of the patient. However in general, quantities of from 0.01 to 100 ⁇ mol/kg bodyweight will be administered.
  • the invention provides the use of a serine protease inhibitor compound of formula I as defined hereinabove, or physiologically tolerable salt thereof, for the manufacture of a medicament for use in a method of treatment of the human or non-human animal body (e.g. a mammalian, avian or reptilian body) to combat (i.e. treat or prevent) a condition responsive to said inhibitor.
  • the serine protease is preferably a serine protease with a negatively charged PI specificity pocket (i.e. trypsin-like) .
  • the present invention provides a method of treatment of the human or non-human animal body (e.g. a mammalian, avian or reptilian body) to combat a condition responsive to a Factor Xa inhibitor (e.g.
  • a condition such as a thrombotic disorder, including venous thrombosis, pulmonary embolism, arterial thrombosis, myocardial ischaemia, myocardial infarction and cerebral thrombosis, acute vessel closure associated with thrombolytic therapy and restenosis, including after transluminal coronary angioplasty or bypass grafting of the coronary or peripheral arteries and in the maintenance of vascular access patency in long term hemodialysis patients) , said method comprising administering to said body an effective amount of a serine protease inhibitor compound of formula (I) as defined hereinabove, provided that Ri is not an unsubstituted aminoalkyl group, or a physiologically tolerable salt thereof.
  • a serine protease inhibitor compound of formula (I) as defined hereinabove provided that Ri is not an unsubstituted aminoalkyl group, or a physiologically tolerable salt thereof.
  • the present invention provides a method of treatment of the human or non-human animal body (e.g. a mammalian, avian or reptilian body) to combat a condition responsive to a tryptase inhibitor (e.g.
  • a condition such as asthma, allergic rhinitis, eczema, psoriasis, atopic dermatitis, urticaria, rheumatoid arthritis, conjunctivitis, inflammatory bowel disease, neurogenic inflammation, atherosclerosis or cancer
  • said method comprising administering to said body an effective amount of a serine protease inhibitor compound of formula (I) as defined hereinabove which is substituted in the 3 and/or 4 position by R and in which Ri is an unsubstituted aminoalkyl group, or a physiologically tolerable salt thereof.
  • the present invention further provides the use of a serine protease inhibitor compound of formula (I) as defined hereinabove, provided that Ri is not an unsubstituted aminoalkyl group, or a physiologically tolerable salt thereof for the manufacture of a medicament for use as a Factor Xa inhibitor.
  • the present invention further provides the use of a serine protease inhibitor compound of formula (I) as defined hereinabove, which is substituted in the 3 and/or 4 position by Ri and in which Ri is an unsubstituted aminoalkyl group, or a physiologically tolerable salt thereof for the manufacture of a medicament for use as a tryptase inhibitor.
  • a serine protease inhibitor compound of formula (I) as defined hereinabove, which is substituted in the 3 and/or 4 position by Ri and in which Ri is an unsubstituted aminoalkyl group, or a physiologically tolerable salt thereof for the manufacture of a medicament for use as a tryptase inhibitor.
  • the alpha atom is carbon it preferably has the conformation that would result from construction from a D- ⁇ -aminoacid NH 2 -CRik(Cy) -COOH where the NH 2 represents part of X-X.
  • aryl groups preferably contain 5 to 10 ring atoms optionally including 1, 2 or 3 heteroatoms selected from 0, N and S ; alkyl , alkenyl or alkynyl groups or alkylene moieties preferably contain up to 6 carbons, e.g. C ⁇ _g or c l - 3 '' cyclic groups preferably have ring sizes of 3 to 8 atoms; and fused multicyclic groups preferably contain 8 to 16 ring atoms.
  • R ⁇ a examples of particular values for R ⁇ a are: hydrogen, methyl or ethyl.
  • R a is preferably a hydrogen atom.
  • the X moiety nearest to the alpha atom is an NH or 0 atom, most preferably a NH group.
  • the X moiety alpha to the aromatic ring is preferably a carbon based group such as CH 2 or CO, preferably CO.
  • a particularly preferred linker X-X is -CONH-.
  • the linker is preferably a -OCH 2 - grou .
  • Ru- examples are: hydrogen, (1-4C) alkyl, such as methyl or hydroxy (1-4C) alkyl, such as hydroxymethyl.
  • Rib is preferably a hydrogen atom.
  • the alpha atom (Y) is preferably a CH or C(CH3) group, especially CH.
  • the linker group from the alpha atom to the lipophilic group is preferably CO, CH 2 NH, CONR 1 3 (CH 2 ) m , (CH 2 ) m N(R ⁇ d )CO(CH 2 ) m , (CH 2 ) m+2 , C0(CH 2 ) m , (CH 2 ) m CO,
  • R ⁇ d examples of particular values for R ⁇ d are: hydrogen; for alkyl optionally substituted by hydroxy, alkylamino, alkoxy, oxo, aryl or cycloalkyl: (1-6C) alkyl, such as methyl or ethyl, or aryl (1-6C) alkyl, such as benzyl or phenylethyl; for aminoalkyl optionally substituted by hydroxy, alkylamino, alkoxy, oxo, aryl or cycloalkyl: (2-
  • carboxamido such as carboxamidomethyl ; for hydroxyalkyl optionally substituted by hydroxy, alkylamino, alkoxy, oxo, aryl or cycloalkyl: (1-
  • carboxyalkyl such as carboxymethyl, carboxyethyl or carboxypropyl ; for alkoxyalkyl optionally substituted by hydroxy, alkylamino, alkoxy, oxo, aryl or cycloalkyl: (1-
  • R ⁇ d is preferably a hydrogen atom.
  • the linker may be optionally branched, for example, to incorporate a polar functionality.
  • L examples of particular values for L are CO, CONH,
  • representative lipophilic groups include methylcyclohexyl, methylcyclohexylmethyl, methylphenylmethyl , phenylethyl , benzylpiperidinyl , benzoylpiperidinyl, bispiperidinyl and phenylpiperazinyl .
  • Phenylethyl is an example of a combination of an alkyl group and a carbocyclic group linked through a single bond.
  • Benzylpiperidinyl is an example of a combination of an alkyl group, a carbocyclic group and a heterocyclic group linked by single bonds.
  • Methylcyclohexylmethyl is an example of a combination of an alkyl group (methyl) and a carbocyclic group (cyclohexyl) linked by a single bond and having a substituent R 3 (methyl) on cyclohexyl. It will be appreciated that this group could alternatively have been regarded as a combination of two alkyl groups and a carbocyclic group. However, in order to provide clarity, in this specification any terminal alkyl group in Lp will be treated as a substituent R3.
  • the lipophilic group comprises an alkyl group
  • this may be, for example, a (1-3C) alkyl group, such as methyl, ethyl or propyl.
  • an alkyl group is unsubstituted.
  • the lipophilic group comprises a carbocyclic group
  • this may be, for example, a non-aromatic or aromatic, mono or polycyclic hydrocarbon group containing up to 25, more preferably up to 10 carbon atoms.
  • the carbocyclic group may thus be, for example, a cycloalkyl, polycycloalkyl, phenyl or naphthyl group, or a cycloalkyl group fused with a phenyl group .
  • cycloalkyl group examples include (3-6C) cycloalkyl groups, such as cyclopentyl and cyclohexyl.
  • a cycloalkyl group is preferably unsubstituted or substituted by one group R 3 , preferably amino or an alkyl group, such as methyl.
  • polycycloalkyl group examples include (6-10C) polycycloalkyl groups, such as bicycloalkyl, for example decalinyl, norbornyl or adamantyl .
  • a polycycloalkyl group is preferably unsubstituted or substituted by one, two or three R 3 groups, for example alkyl such as methyl .
  • An example of a polycycloalkyl group substituted by alkyl is isopinocamphenyl .
  • a phenyl group is preferably unsubstituted or substituted by one or two R 3 groups. More preferably it is substituted by one or two R 3 groups.
  • a naphthyl group is preferably unsubstituted or substituted by one R 3 group.
  • Examples of a cycloalkyl or cycloalkenyl group fused with a phenyl group are indanyl and tetrahydronaphthyl .
  • This group is preferably unsubstituted or substituted by oxo or one or two R 3 groups.
  • Examples of groups substituted by oxo are l-oxoindan-5-yl, l-oxo-5, 6, 7, 8-tetrahydronaphth-5-yl and l-oxo-5, 6,7, 8-tetrahydronaphth-6-yl .
  • the lipophilic group comprises a heterocyclic group
  • this may be, for example, a non-aromatic or aromatic, mono or polycyclic group containing one or two oxygen, nitrogen or sulfur atoms in the ring system, and in total up to 25, more preferably up to 10 ring system atoms.
  • heterocyclic group when it is a non- aromatic monocyclic group are azacycloalkyl groups, such as pyrrolidinyl and piperidinyl; azacycloalkenyl groups, such as pyrrolinyl; diazacycloalkyl groups, such as piperazinyl; oxacycloalkyl groups, such as tetrahydropyranyl ; and thiacycloalkyl groups, such as tetrahydrothiopyranyl .
  • azacycloalkyl groups such as pyrrolidinyl and piperidinyl
  • azacycloalkenyl groups such as pyrrolinyl
  • diazacycloalkyl groups such as piperazinyl
  • oxacycloalkyl groups such as tetrahydropyranyl
  • thiacycloalkyl groups such as tetrahydrothiopyranyl .
  • a non- aromatic monocyclic group preferably contains 5, 6 or 7 ring atoms and is preferably unsubstituted or substituted by one group R 3 , preferably alkyl, such as methyl or ethyl, or hydroxyalkyl , such as hydroxymethyl .
  • heterocyclic group when it is a non- aromatic polycyclic group are bicyclic groups, such as azacycloalkyl fused with phenyl, for example dihydroindolyl , dihydroisoindolyl, tetrahydroquinolinyl and tetrahydroisoquinolinyl; azacycloalkyl fused with cycloalkyl, such as decahydroisoquinolyl , and tricyclic groups, such as azacycloalkyl fused with indolyl, for example tetrahydropyrido [3 , 4-b] indole .
  • This group is preferably unsubstituted.
  • heterocyclic group when it is an aromatic monocyclic group are furyl, pyrrolyl, thienyl, imidazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, oxazolyl, oxadiazolyl (such as 1, 3 , 4-oxadiazolyl) , thiadiazolyl (such as 1, 3 ,4-thiadiazolyl) , triazinyl and thiazolyl.
  • This group is preferably unsubstituted or substituted by one or two R 3 groups .
  • heterocyclic group when it is an aromatic polycyclic group is bicyclic groups such as benzofuryl, quinolinyl, isoquinolinyl, benzothienyl , indolyl and benzothiazolyl . This group is preferably unsubstituted or substituted by one R 3 .
  • Lp comprises a combination of at least two groups, it preferably comprises a combination of two or three such groups.
  • R ⁇ e examples of particular values for R ⁇ e are hydrogen and (1-6C) alkyl, such as methyl or ethyl.
  • the lipophilic group Lp may be selected, for example, from:
  • R 3 is as hereinbefore defined; m represents 0 or 1;
  • R 4 represents hydrogen, (CH 2 ) w COOH or (CH 2 ) w CONH 2 ; w represents an integer from 0 to 4; and
  • X represents CH or N.
  • X atoms are present in a ring, preferably at least one is CH.
  • L represents CO when the Lp group is linked to L through N, or CONH when the Lp group is linked to L through C.
  • R 3 examples of particular values for R 3 are:- for alkylaminocarbonyl : N-methyl-N-ethylaminocarbonyl , methylaminocarbonyl or dimethylaminocarbonyl ; for N-alkylaminoalkanoyl : N-methylacetyl ; for N-alkanoylaminoalkanoyl : 2-N-acetylaminoacetyl or 2-N- acetylaminopropanoyl ; for C-hydroxyaminoalkanoyl : 2-amino-3-hydroxypropanoyl or 2- amino-3 -hydroxybutanoyl ; hydrogen; hydroxyl ; for alkoxy optionally substituted by hydroxy, alkylamino, alkoxy, oxo, aryl or cycloalkyl: alkoxy such as methoxy or ethoxy; for alkyl optionally substituted by hydroxy, alkylamino, alkoxy, o
  • alkyl such as aminomethyl, aminocarbonyl , aminocarbonyl-
  • alkylamino optionally substituted by hydroxy, alkylamino, alkoxy, oxo, aryl or cycloalkyl: (1-
  • alkylamino such as methylamino, dimethylamino or ethylamino, or (1-6C) alkanoylamino, such as formylamino or acetylamino; amino; for halo: fluoro or chloro; cyano; nitro; thiol; for alkylthio: methylthio; for alkylsulphonyl : methylsulphonyl, ethylsulphonyl or isopropylsulphonyl ; for alkylsulphenyl : methylsulphenyl ; for triazolyl: 1, 2 , 4-triazol-2-yl , 1, 2 , 4-triazol-4-yl or
  • 1,2, 3-triazol-4-yl for imidazolyl: 1, 3-imidazol-l-yl or 1, 3-imidazol-4-yl ; for tetrazolyl: tetrazol-1-yl or tetrazol-5-yl; hydrazido; for alkylsulphonamido: methylsulphonamido, ethylsulphonamido or propylsulphonamido; for alkylaminosulphonyl : methylaminosulphonyl , ethylaminosulphonyl or propylaminosulphonyl ; aminosulphonyl ; for haloalkoxy: trifluoromethoxy; and for haloalkyl: trifluoromethyl or trichloromethyl .
  • R 3 When R 3 is present as a substituent on an aromatic ring, it may be selected, for example, from hydrogen, alkylsulphonyl, aminosulphonyl, alkylaminosulphonyl, alkylaminocarbonyl , amino, amido, alkoxycarbonyl, acetylamino, chloro, fluoro, cyano, methoxy, ethoxy, nitro, hydroxy, alkylsulphonylamino, triazolyl and tetrazolyl.
  • R 3 When R 3 is present as a substituent on a saturated ring, it may be selected, for example, from hydrogen, hydroxy, amino, (1-3C) alkoxy, (1-3C) hydroxyalkyl , (1- 3C) alkyl, carboxy, methoxycarbonyl and ethoxycarbonyl . It has been found that certain groups L and, especially, Lp are associated with selectivity for Factor Xa, whereas others are associated with selectivity for tryptase .
  • Preferred compounds comprising this group are those in which Lp is a group of formula:
  • r is 1 or 2; one of X a and X]-, is N and the other is CH or N provided that when r is 1, X a and Xfc are not both N; s , t and u are each 0 or 1 ;
  • G is (l-6C)alkanediyl
  • R ⁇ o is (1-6C) alkyl ; (3 -6C) cycloalkyl which is unsubstituted or substituted by (1-6C) alkyl ; indanyl; pyridyl; tetrahydropyranyl ; tetrahydrothiopyranyl ; phenyl which is unsubstituted or substituted by one or two R 3 groups; pyrrolinyl; or a group of formula
  • provisos exclude compounds having two heteroatoms bonded directly together or separated by an alkyl group having only one carbon atom in the chain.
  • L is preferably CO or CH 2 CO.
  • L is preferably CONH, CONHCH 2 or CH 2 NHCO.
  • Examples of values for G are CH2 , (CH2)2 an ⁇ 3 (0 ⁇ ) 3 .
  • Examples of values for R ⁇ are hydrogen, methyl, ethyl or 2-propyl, or when X d is CH, hydroxymethyl.
  • Examples of values for R]_Q are: for (1-6C) alkyl: methyl, ethyl, 2-propyl and 3-pentyl; for (3-6C) cycloalkyl which is unsubstituted or substituted by (1-6C) alkyl: cyclopentyl, 3 -methylcyclopentyl , cyclohexyl and 4-methylcyclohexyl; for indanyl : 2-indanyl; for pyridyl: pyrid-2-yl, pyrid-3-yl and pyrid-4-yl; for tetrahydropyranyl : tetrahydropyran-4-yl ; for tetrahydrothiopyranyl
  • piperidin-l-yl 4-methyl-piperidin-l-yl, piperidin-4-yl, 1- methylpiperidin-4-yl, 1- (2-propyl) piperidin-4-yl , pyrrolidin-1-yl, 3 -methylpyrrolidin-1-yl , pyrrolidin-3-yl , l-methyl-pyrrolidin-3-yl, 1- (2-propyl) pyrrolidin-3-yl , 1- methyl-piperazin-4-yl, l-ethylpiperazin-4-yl , 1- (2- propyl)piperazin-4-yl, hexahydro-1, 4-diazapin-l-yl and 4- methyl-hexahydro-1, 4-diazapin-l-yl .
  • Factor Xa inhibitors Another group of compounds of particular interest as Factor Xa inhibitors are compounds of formula (I) in which -L-Lp(D) n is
  • q 1 or 2;
  • Q is a direct bond; and Rg is piperidin-4-yl which may bear a C]__ 3 alkyl substituent at the 1-position; or Rg is R a Rk in which each of R a and R]-, independently is hydrogen or C ⁇ _3alkyl; or one of R a and R]-, is hydrogen or methyl and the other of R a and RJ- J is -CH2-R C or-CH2-R(j in which R c is pyridyl or phenyl (which phenyl may bear a fluoro, chloro, methyl, CONH 2 , S0 2 NH 2 , methylaminosulphonyl , dimethylammosulphonyl, methylsulphonylamino, methoxy or methylsulphonyl substituent) and in which R ⁇ is isopropyl or cyclopentyl, or NR a Rfc, is pyrrolidino, piperidino, morpholino,
  • Q is methylene; and Rg is NR a Rk which is defined as above .
  • q is preferably 2.
  • Factor Xa inhibitors Another group of compounds of particular interest as Factor Xa inhibitors are compounds of formula (I) in which -L-Lp(D) n is
  • R r is -(CH2) C -R c -CHR e Rf, -CH -CHR e Rf, or Rg in which c is 1 or 2 and R c is defined as above; each of R e and Rf independently is hydrogen or C ⁇ _ 3 alkyl; or CHR e Rf is cyclopentyl (which may bear a methyl, ethyl or hydroxymethyl substituent at the 3- or 4-position) , cyclohexyl (which may bear a methyl, ethyl or hydroxymethyl substituent at the 3- or 4-position) , tetrahydropyran-4-yl, tetrahydrothiopyran-4- yl, pyrrolidin-3-yl (which may bear a 1-methyl substituent) , piperidin-4-yl (which may bear a 1-methyl substituent) , or indan-2-yl; and Rg is 2-methylsulphonylphenyl which may bear a
  • R c is pyrid-2-yl, pyrid-3-yl or pyrid-4-yl.
  • Factor Xa inhibitors Another group of compounds of particular interest as Factor Xa inhibitors are compounds of formula (I) in which -L-Lp(D) n is
  • R s is -(CH2) C -R C . -CHR e Rf, or -CH 2 -CHR e Rf each of which is defined as above.
  • s is 1.
  • Factor Xa inhibitors Another group of compounds of particular interest as Factor Xa inhibitors are compounds of formula (I) in which -L-Lp(D) n is
  • Rj- is piperidin-4-yl , piperidin-3-yl or pyrrolidin- 3-yl (especially piperidin-4-yl) , any of which may bear a C__ 3 alkyl substituent at the 1-position (preferably methyl, ethyl or, more preferably, 2-propyl) ; or R ⁇ is phenyl (which phenyl may bear a fluoro, chloro, C 1 -. 4 alkyl, methoxy or methylsulphonyl substituent) .
  • Factor Xa inhibitors are compounds of formula (I) in which -L-Lp(D) n is in which Het is a divalent 5 membered heteroaromatic group containing 1, 2 or 3 heteroatoms selected from 0, N and S and having the two ring atoms at which it is connected separated by one ring atom; h is 0 or 1; and
  • R ⁇ is phenyl which may bear one or more R 3 substituents, for example independently selected from, for an ortho or a para substituent: C 1 -. 5 alkyl, fluoro, chloro, difluoromethyl, trifluoromethyl , methoxy, dimethylamino, methylsulphonyl, and C ⁇ _2 acyl, and for a meta substituent: fluoro, chloro and methyl.
  • a particularly preferred group of compounds is that in which -L-Lp(D) n is
  • R ⁇ is phenyl which may bear one or two R 3 substituents, for example an ortho and/or a para substituent independently selected from, for an ortho: methyl, fluoro, chloro, methylsulphonyl and acetyl, and for a para substituent: methyl, fluoro, chloro, methoxy and dimethylamino; , ⁇ is S, Z 2 is CH, h is 0; or
  • Z]_ is NH, Z2 is N, h is 1.
  • Lp lipophilic groups Lp that has been found to be associated with Factor Xa inhibitor activity is that of formula in which L x represents 0 or NH.
  • Rg is as defined for R 3 (preferably as defined for a substituent on an aromatic ring) , especially where Rg represents H, OMe, S ⁇ 2 e, F, cyano, amido, amino, NO 2 , Cl or
  • R is hydrogen or (1-6C) alkyl (such as methyl, ethyl or 2-propyl) .
  • X 2 is hydrogen or fluoro.
  • Compounds in which the lipophilic group is based on the formula (K) or (J) have been found to perform relatively well in the prothrombin time assay, when compared with corresponding aminoisoquinolines of W099/11657.
  • R 3 preferably represents hydrogen, hydroxyl or alkylaminocarbonyl .
  • Lp in this sub-group examples are pyrrolidin-1-yl, piperidin-1-yl, 3-N-methyl, N- ethylaminocarbonylpiperidin-1-yl , decahydroisoquinolin-2-yl and 2, 3-dihydroindol-l-yl .
  • R 3 is preferably hydrogen, amino, hydroxy, alkyl or aminoalkyl.
  • L represents CONH and Lp represents in which R 3 is alkylammocarbonyl, N-alkylaminoalkanoyl , N- alkanoylaminoalkanonyl , C-hydroxyaminoalkanoyl , hydrogen, alkoxy, alkyl, aminoalkyl, aminocarbonyl , hydroxyalkyl, alkoxyalkyl , alkoxycarbonyl , acyloxymethoxycarbonyl , alkylamino, amino, halo, cyano, nitro, thiol, alkylthio, alkylsulphonyl, alkylsulphenyl , triazolyl, imidazolyl, tetrazolyl, hydrazido, alkyl imidazolyl, thiazolyl, alkyl thiazolyl, alkyl oxazolyl, oxazolyl, oxazolyl
  • the phenyl group is unsubstituted or substituted by one or two R 3 groups.
  • Examples of particular values are phenyl, 3-cyano-4- methylphenyl , 3-aminocarbonylphenyl, 4-aminocarbonyl-phenyl, 4-chloro-3 -aminocarbonyl-phenyl, 4-chlorophenyl, 3,5- dichlorophenyl , 3-aminomethylphenyl, 4-methyl-3- acetylaminophenyl , 4- (1-hydroxethyl) phenyl and 4- isopropylphenyl .
  • R 3x represents R 3 or a group of formula
  • R j represents a carbocyclic or heterocyclic group, optionally substituted by R 3 .
  • Lp represents a group as described above, it corresponds to a group in which Lp is a combination of a heterocyclic group (2 , 3 -dihydroindolyl) , a carbocyclic or heterocyclic group (R j ) and optionally an alkyl group (G x ) , which groups are linked by a single bond or a carbonyl group.
  • R j examples of particular values for R j are the examples given above for a carbocyclic or heterocyclic group forming part of Lp.
  • pyyrolidinyl such as pyrrolidin-1- yl, phenyl, thiazolyl, such as thiazol-4-yl , imidazolyl, such as imidazol-4-yl, and pyridyl, such as pyrid-2-yl, pyrid-3-yl and pyrid-4-yl.
  • Examples of values for G are -CH 2 -, and CH 2 CH 2 .
  • the 2, 3 -dihydroindolyl group in the above formula is preferably a 2 , 3-dihydroindol-5-yl or -6-yl group, especially a 2, 3-dihydroindol-6-yl group.
  • Examples of structures of compounds comprising a 2,3- dihydroindolyl group as described above are :
  • R 3 is a substituent on the 1-position of a 2,3- dihydroindolyl group, it preferably represents alkylammocarbonyl ; N-alkylaminoalkanoyl ; N- alkanoylaminoalkanonyl ; C-hydroxyaminoalkanoyl ; hydrogen; alkyl ; alkanoyl ; alkoxycarbonyl ; acyloxymethoxycarbonyl ; aminoalkyl ; aminoalkanoyl ; hydroxyalkyl ; hydroxyalkanoyl ; alkoxyalkyl; or alkanoylamino.
  • N-methylaminoacetyl N-acetylaminoacetyl, N- acetylalaninoyl, serinoyl, threoninoyl, hydrogen, methyl, acetyl, propanoyl, 2-methylpropanoyl, 3-methylbutyryl, 2- hydroxypropanoyl , hydroxyacetyl , aminoacetyl and alaninoyl .
  • examples of particular values for Lp are: 1- (N-methylaminoacetyl) -2, 3-dihydroindol-6-yl; 1- (N- acetylaminoacetyl) -2 , 3-dihydroindol-6-yl; 1- (N- acetylalaninoyl) -2, 3-dihydroindol-6-yl ; 1- (serinoyl) -2,3- dihydroindol-6-yl ; 1- (threoninoyl) -2 , 3-dihydroindol-6-yl ; 2, 3-dihydroindol-5-yl; l-methyl-2 , 3-dihydroindol-6-yl ; 1- acetyl-2 , 3-dihydroindol-6-yl; l-propanoyl-2 , 3-dihydroindol- 6-yl; 1- (2-methylpropan
  • R 3 is a substituent on a phenyl, thiazolyl, imidazolyl or pyridyl group, it is preferably hydrogen, amino, alkyl or aminoalkyl. Examples of particular values are hydrogen, amino, alkyl or aminomethyl .
  • Lp further examples of particular values for Lp are: 2 , 3 -dihydroindol-5-yl, l-prolinoyl-2 , 3 -dihydroindol- 6-yl, 1-phenylacetyl-2, 3-dihydroindol-6-yl, 1- (2- hydroxy) phenylacetyl-2 , 3-dihydroindol-6-yl, 1- (3 - hydroxy) phenylacetyl-2 , 3 -dihydroindol-6-yl , 1- (4- hydroxy) phenylacetyl-2, 3-dihydroindol-6-yl, 1- (4- pyridyl) acetyl-2, 3 -dihydroindol-6-yl, 1- (3 -pyridyl) acetyl- 2, 3-dihydroindol-6-yl, l-imidazol-4-ylacetyl-2
  • the hydrogen bond donor group which may be attached to the lipophilic group preferably has a nitrogen or oxygen atom as the hydrogen bearing donor atom and conveniently is a hydroxyl group, a primary, secondary or tertiary amine, or a primary or secondary imine group (as part of an amidine or guanidine) or a saturated or unsaturated heterocyclic group containing a ring nitrogen, preferably a group containing 5 to 7 ring atoms.
  • the donor atom is a ring nitrogen
  • the remote portion of the heterocyclic ring may be part of the lipophilic group.
  • the cyclic group attached to the alpha carbon is preferably an optionally R 3a substituted phenyl, pyridyl (such as pyrid-2-yl, pyrid-3-yl or pyrid-4-yl), thienyl
  • thien-2-yl or thien-3-yl such as thien-2-yl or thien-3-yl
  • thiazolyl such as thiazol-2-yl, thiazol-4-yl or thiazol-5-yl
  • naphthyl such as naphth-1-yl
  • piperidinyl such as piperidin-4-yl
  • cycloalkyl such as a cyclohexyl group.
  • R 3a examples of particular values for R 3a are : - hydrogen; hydroxyl ; for alkoxy: methoxy or ethoxy; for alkyl optionally substituted by hydroxy, alkylamino, alkoxy, oxo, aryl or cycloalkyl: alkyl, such as methyl or ethyl, or alkylaminoalkyl , such as methylaminomethyl or dimethylaminomethyl ; for hydroxyalkyl optionally substituted by hydroxy, alkylamino, alkoxy, oxo, aryl or cycloalkyl: hydroxymethyl or carboxy; for alkoxyalkyl : methoxymethyl ; for alkoxycarbonyl : methoxycarbonyl or ethoxycarbonyl ; for alkylammocarbonyl : methylaminocarbonyl or dimethylaminocarbonyl ; for aminoalkyl optionally substituted by hydroxy, alkylamino,
  • alkylamino optionally substituted by hydroxy, alkylamino, alkoxy, oxo, aryl or cycloalkyl: (1- 6C) alkanoylamino, such as formylamino or acetylamino; for alkoxycarbonylamino: methoxycarbonylamino, ethoxycarbonylamino or t-butoxycarbonylamino; amino ; for halo: fluoro or chloro; cyano; nitro; thiol ; for alkylthio: methylthio; for alkylsulphonyl : methylsulphonyl or ethylsulphonyl ; for alkylsulphenyl : methylsulphenyl ; for imidazolyl: imidazol-4-yl ; hydrazido; for alkylimidazolyl : 2-methylimi
  • R ] _ c examples of particular values for R ] _ c are: hydrogen; hydroxyl ; for alkoxy: methoxy or ethoxy; for alkyl optionally substituted by hydroxy, alkylamino, alkoxy, oxo, aryl or cycloalkyl: alkyl, such as methyl or ethyl, or alkylammoalkyl, such as methylaminomethyl or dimethylaminomethyl ; for hydroxyalkyl : hydroxymethyl ; for alkoxyalkyl : methoxymethyl ; for alkoxycarbonyl : methoxycarbonyl or ethoxycarbonyl ; for alkylammocarbonyl : methylaminocarbonyl or dimethylaminocarbonyl ; for alkoxycarbonylamino: methoxycarbonylamino, ethoxycarbonylamino or t-butoxycarbonylamino; for alkylamino optionally substitute
  • Cy is preferably unsubstituted or substituted by one or two R 3a groups.
  • R 3a is hydrogen, hydroxyl, methoxy, methyl, amino, aminomethyl, hydroxymethyl, formylamino, acetylamino, aminoacetyl, fluoro, chloro, ethylsulphonylamino, amido or methylaminocarbonyl .
  • Cy examples of particular values for Cy are phenyl, 4- aminophenyl, 4-amidophenyl, 4- (N-methyl) amidophenyl , 4-(N,N- dimethyl) amidophenyl, 2-chlorophenyl, 2-methylphenyl , 2- fluorophenyl, 3 -fluorophenyl , 4 -fluorophenyl, 4- hydroxyphenyl , 2-methoxyphenyl, 4-methoxyphenyl, 3- aminomethylphenyl , 4-aminomethylphenyl, 2- hydroxymethylphenyl , 3-hydroxymethylphenyl, 4- hydroxymethylphenyl, 4-carboxyphenyl , 3- ethylsulphonylaminophenyl, thien-2-yl, thien-3-yl, thiazol- 4-yl, thiazol-5-yl, 2-methylthiazol-4-yl , 2-aminothiazol-4- yl, 2-formylamino
  • examples of a 5 or 6 membered aromatic carbon ring optionally interrupted by a nitrogen, oxygen or sulphur ring atom are phenyl; pyrrolyl, such as 2 -pyrrolyl; pyridyl, such as 3 -pyridyl; pyrazinyl, such as 2-pyrazinyl; furyl , such as 2-furyl; and thienyl, such as 2-thienyl or 3-thienyl.
  • the ring is interrupted (i.e. a carbon atom is replaced) by at most one heteroatom. More preferably the ring is phenyl, 2-thienyl or 2-pyrrolyl. Most preferably, the ring is phenyl.
  • the group R 2 may be a group of formula
  • R 5 is amino, hydroxy, aminomethyl, hydroxymethyl or hydrogen
  • Rg and R 7 which may be the same or different represent halo, nitro, thiol, cyano, haloalkyl, haloalkoxy, amido, hydrazido, amino, alkylthio, alkenyl, alkynyl or R ⁇ _ or taken together form a 5 or 6 membered fused carbocyclic ring or 5 membered heterocyclic ring, which may itself be substituted by Rij , amino, halo, cyano, nitro, thiol, alkylthio, haloalkyl, haloalkoxy.
  • examples of the resultant bicyclic ring are naphthyl, such as 2-naphthyl; benzimidazolyl, such as benzimidazol-5-yl or benzimidazol-6- yl ; isoquinolinyl , such as isoquinolin-7-yl; indolyl , such as indol-2-yl, indol-5-yl or indol-6-yl; indazolyl, such as indazol-5-yl; indazol-6-yl ; 3 , 4-methylenedioxyphenyl ; dihydroindolyl, such as 2 , 3 -dihydroindol-6-yl ; benzothiazolyl, such as benzothiazol-2-yl or benzothiazol
  • R 2 preferably represents:
  • phenyl optionally being substituted in the 3 and/or 4 position by halo, nitro, thiol, haloalkoxy, hydrazido, alkylhydrazido, amino, cyano, haloalkyl, alkylthio, alkenyl, alkynyl, acylamino, tri or difluoromethoxy, carboxy, acyloxy, eS ⁇ 2 ⁇ or R ⁇ , and optionally substituted at the 6 position by amino, hydroxy, halo, alkyl, carboxy, alkoxycarbonyl, cyano, amido, aminoalkyl, alkoxy or alkylthio;
  • thien-2-yl or thien-3-yl optionally substituted at the 4 or 5 position by halo, haloalkoxy, haloalkyl, cyano, nitro, amino, hydrazido, alkylthio, alkenyl, alkynyl or R ⁇ ;
  • 3 4-methylenedioxyphenyl, 2 , 3 -dihydroindol-6-yl , 3 , 3-dichloro-2-oxo-indol-6-yl or l-methyl-3-aminoindazol-5- yi ;
  • pyrazol-2-yl optionally substituted at the 5 position by halo, haloalkoxy, haloalkyl, cyano, nitro, amino, hydrazido, alkylthio, alkenyl, alkynyl or R]_;
  • pyrid-2-yl optionally substituted at the 5 position by halo, haloalkoxy, haloalkyl, cyano, nitro, amino, hydrazido, alkylthio, alkenyl, alkynyl or R ⁇ ;
  • pyrid-3-yl optionally substituted at the 6 position by halo, haloalkoxy, haloalkyl, cyano, nitro, amino, hydrazido, alkylthio, alkenyl, alkynyl or R ⁇ ;
  • benzofur-2-yl optionally substituted at the 3 position by amino, hydroxy, halo, al
  • substituents that may be present on R 2 are : for halo: fluoro, chloro, bromo or iodo; nitro; thiol; for haloalkoxy: difluoromethoxy or trifluoromethoxy; hydrazido; for alkylhydrazido: methylhydrazido; amino; cyano; for haloalkyl: trifluoromethyl ; for alkylthio: methylthio; for alkenyl: vinyl; for alkynyl : ethynyl ; for acylamino: acetylamino; carboxy; for acyloxy: acetoxy; hydroxy; for alkyl : methyl or ethyl ; amido (CONH 2 ) ; for aminoalkyl : aminomethyl ; and for alkoxy: methoxy or ethoxy.
  • Ri examples of particular values for Ri are: hydrogen; hydroxy; for alkoxy: methoxy or ethoxy; for alkyl optionally substituted by hydroxy, alkylamino, alkoxy, oxo, aryl or cycloalkyl: alkyl, such as methyl or ethyl, alkylammoalkyl , such as dimethylaminomethyl, or alkanoyl, such as acetyl ; for hydroxyalkyl : hydroxymethyl ; for alkoxyalkyl : methoxymethyl ; for alkoxycarbonyl : methoxycarbonyl ; for alkylammocarbonyl : methylaminocarbonyl; for alkylamino: methylamino, ethylamino or dimethylamino; for hydroxyalkyl substituted by hydroxy, alkylamino, alkoxy, oxo, aryl or cycloalkyl: carboxyl or carboxymethyl
  • Rij examples of particular values for Rij are: hydrogen; hydroxy; for alkoxy: methoxy or ethoxy; for alkyl optionally substituted by hydroxy, alkylamino, alkoxy, oxo, aryl or cycloalkyl: alkyl, such as methyl or ethyl, or alkanoyl, such as acetyl; for hydroxyalkyl : hydroxymethyl ; for alkoxyalkyl : methoxymethyl ; for alkoxycarbonyl : methoxycarbonyl ; for alkylamino: methylamino, ethylamino or dimethylamino; for hydroxyalkyl substituted by hydroxy, alkylamino, alkoxy, oxo, aryl or cycloalkyl: carboxyl or carboxymethyl; and for aminoalkyl substituted by hydroxy, alkylamino, alkoxy, oxo, aryl or cycloalkyl:
  • phenyl optionally being substituted in the 3 and/or 4 position by fluoro, chloro, bromo, iodo, nitro, difluoromethoxy, trifluoromethoxy, amino, cyano, trifluoromethyl, methylthio, vinyl, carboxy, acetoxy, MeS ⁇ 2 -, hydroxy, methoxy, ethoxy, methyl, aminomethyl, methoxycarbonyl, methylamino, ethylamino or amido, and optionally substituted at the 6 position by amino, hydroxy, fluoro, methoxycarbonyl, cyano or aminomethyl (preferably phenyl substituted in the 4 position by chloro, amino, vinyl, methylamino, methyl or methoxy, optionally at the 3 position with amino or hydroxy, and optionally at the 6 position with amino or hydroxy) ;
  • R 2 examples of particular values for R 2 are: (i) phenyl, 2-aminophenyl, 3-aminophenyl , 2-amino-3- fluorophenyl, 2 -amino-4-fluorophenyl , 2-amino-4- chlorophenyl, 2-amino-3-bromophenyl, 2-amino-3-nitrophenyl, 2 -amino-4 -nitrophenyl, 3 , 4-dimethoxy-5-aminophenyl , 2-amino- 4-methylphenyl, 2-amino-3-methylphenyl, 2-amino-3- methoxyphenyl , 3 , 4-diaminophenyl , 3 , 5-diaminophenyl, 3- amino-4-fluorophenyl, 3 -amino-4-chlorophenyl , 3-amino-4- bromophenyl, 3 -amino-4-hydroxyphenyl, 3 -amin
  • R 5 is amino, hydroxy, aminomethyl, hydroxymethyl or hydrogen
  • R 6a is hydrogen or methyl
  • R 2 is 3- aminomethylphenyl or 3 -aminomethyl- 6 -aminophenyl . Most preferably it is 3-aminomethylphenyl .
  • aromatic R2 group is an optionally substituted phenyl, naphthyl, indolyl or isoindolyl group and accordingly, preferred compounds of formula (I) are of formula (II)
  • R5 is amino, hydroxy or hydrogen
  • Rg and R which may be the same or different represent halo, nitro, thiol, cyano, haloalkyl, haloalkoxy, amido, hydrazido, amino, alkylthio, alkenyl, alkynyl or Ri or taken together form a 5 or 6 membered fused carbocyclic ring or 5 membered heterocyclic ring, which may itself be substituted by Rij, amino, halo, cyano, nitro, thiol, alkylthio, haloalkyl, haloalkoxy;
  • Ar is an unsubstituted or substituted aryl group, preferably phenyl
  • X-X is -CONH-, -CH 2 CH 2 -, CH 2 0-, -COO-, -CH 2 NH-, -OCH 2 - or -NHCH2-, especially -CONH-;
  • Li is a valence bond or an organic linker group containing 1 to 4 backbone atoms selected from C, N, 0 and S;
  • D is a hydrogen bond donor group; and n is 0, 1 or 2.
  • Suitable R 2 groups may be
  • R 5 is hydrogen, amino or hydroxy and R 3 (in relation to R 2 ) is halo, haloalkoxy, haloalkyl, cyano, nitro, amino, hydrazido, alkylthio, alkenyl, alkynyl or Rij.
  • R 2 group is an indole as marked by a * above in which R 5 is hydrogen and
  • R 3 is a hydrogen or halogen present at the 3 position.
  • Rg and R 7 be other than hydrogen and that Rg, if present, is preferably a substituent containing one or more polar hydrogens such as hydroxy, amino, alkylamino, aminoalkyl, alkylammoalkyl , aminocarbonyl, alkylammocarbonyl , hydrazo and aIky1hydrazo; alternatively Rg and R 7 are joined together in the formation of a naphthyl or indolyl or azaindolyl or diazaindolyl group .
  • Rg be amino and R 7 be chloro, bromo, methyl, methoxy or vinyl; or that Rg and R 7 taken together form an indolyl ring with the NH at the 6- position or taken together form a naphthyl ring.
  • L2 is a valence bond or an organic linker group containing 1 to 3 backbone atoms selected from C, N, O and S and Rg a an( Rg a are hydrogen or taken together with the carbon atom to which they are attached form a carbonyl group) .
  • the phenyl derivative forming part of the R 2 functionality may instead be a nitrogen heterocyclic group, e.g. pyridine.
  • L2 comprises the backbone of an alpha amino acid, the lipophilic group being the side chain of the amino acid.
  • L 2 represents a valence bond and the lipophilic group is bound directly to a carbonyl alpha to the alpha atom via a nitrogen atom which forms part of the lipophilic group.
  • Suitable lipophilic groups in this case therefore include piperidinyl, pyrrolidinyl and piperazinyl .
  • the piperidine or piperazinyl group is further substituted by a phenyl, benzyl, phenoxy, piperidine, pyridine or benzoyl group, optionally substituted on the phenyl ring by one or more R 3 groups.
  • a piperazine is substituted with a phenyl group substituted at the 2- position with an electron withdrawing group such as fluoro, nitro, triazolyl, cyano, alkoxycarbonyl, aminocarbonyl, aminosulphonyl, alkylaminosulphonyl and, especially preferred, alkylsulphonyl; and, at the 4-position, with hydrogen, fluoro, alkoxy or hydroxy.
  • a piperidine is substituted at the 4- position with 4-piperidine which itself may be substituted on nitrogen by alkyl or aminocarbonylalkyl or alkylammocarbonyl alkyl .
  • the lipophilic group has attached a group of the formula -COORig or -CON-aminoacid or ester derivative thereof (where Rig is as defined for R ⁇ a ) .
  • Particularly preferred compounds are those of formula (G)
  • Rg and R7 are as hereinbefore defined, and R5 represents hydrogen or amino
  • Rg is amino and R7 a halogen, especially chlorine.
  • phenyl derivative forming part of the R2 functionality in formulae (G) and (H) may instead be a nitrogen heterocyclic group, e.g. pyridine, indole.
  • the group binding the alpha carbon atom to the lipophilic group comprises a heterocyclic group. Accordingly, preferred compounds of formula (I) also include those of formula (III)
  • R5, Rg, R7, Ar, X-X, Lp , D n are as hereinbefore defined; m is 0, 1 or 2 ; Het is a 5 or 6-membered heterocyclic group interrupted by 1, 2 or 3 heteroatoms selected from 0, N and S optionally substituted by a group R 3 b where R 3 b is as defined for R 3 ) .
  • the phenyl derivative forming part of the R 2 functionality may instead be a nitrogen heterocyclic group, e.g. pyridine.
  • Het is a five membered ring
  • the two ring atoms at which it is connected are preferably separated by one ring atom.
  • the two ring atoms at which it is connected are preferably separated by one or two ring atoms.
  • Representative heterocyclic groups include thiazole, oxazole, oxadiazole, triazole, thiadiazole or imidazole.
  • R 3 k this is preferably a COOH or COORig connected to the heterocycle via a valence bond or alkylene chain (where Rih is as defined for R ⁇ a ) .
  • the lipophilic group has attached a group of the formula -COORig or -CON-aminoacid or ester derivative thereof.
  • the main aromatic R 2 ring in the compounds of the invention is a five membered aromatic ring leading to compounds of formula (IV) or (IVa)
  • R5 , Rg , R7 , X-X, Ar, Li, Lpi, D and n are as hereinbefore described for formula (II) and Z represents N, 0 or S
  • Rg and R7 be other than hydrogen, or that Rg and R7 taken together enable the formation of an indolyl, or azaindolyl group or diazaindolyl group.
  • Preferences for other substituents are as for formula (A) above. Examples of possible fused systems are given below.
  • Lpi is connected to the carbonyl via a nitrogen atom
  • Rg, R 7 , Ar, Z, Lpi, D n are as hereinbefore defined and R5 is hydrogen or amino) preferences for Ar, Lpi, D n are as for formula (A) above.
  • Particularly preferred compounds of formula (I) for use as Factor Xa inhibitors are the compounds of Examples 35, 63, 66, 73, 100, 318 and 320, and physiologically tolerable salts thereof.
  • X 3 represents hydrogen or a polar group such as amino or CONH 2 , especially CONH ;
  • R" represents a cyclic group bound to the carbonyl by a nitrogen atom or an optionally substituted group of formula
  • a group of compounds of particular interest for use as tryptase inhibitors is that of formula
  • L-Lp(D) n CO-L x ;
  • R 5 represents amino, hydroxy, aminomethyl, hydroxymethyl or hydrogen
  • R 6a represents hydrogen or methyl
  • Cy is a saturated or unsaturated, mono or poly cyclic, • homo or heterocyclic group, preferably containing 5 to 10 ring atoms and optionally substituted by groups R 3a or phenyl optionally substituted by R 3a ; each R 3a independently is R lc , amino, halo, cyano, nitro, thiol, alkylthio, alkylsulphonyl , alkylsulphenyl, hydrazido, alkylsulphonamido, alkylamino-sulphonyl, aminosulphonyl, haloalkoxy, and haloalkyl;
  • each R lc independently represents hydrogen or hydroxyl, alkoxy, alkyl, aminoalkyl, hydroxyalkyl alkoxyalkyl, alkoxycarbonyl , acyloxymethoxycarbonyl or alkylamino optionally substituted by hydroxy, alkylamino, alkoxy, oxo, aryl or cycloalkyl;
  • L x is a mono or bicyclic group bound to the carbonyl via a pendent nitrogen atom or nitrogen atom which forms part of the mono or bicyclic ring; or a physiologically tolerable salt thereof, e.g. a halide, phosphate or sulphate salt or a salt with ammonium or an organic amine such as ethylamine or meglumine .
  • the group CO-L x corresponds with the group L-Lp(D) n in which L is CONH and Lp is a mono or bicyclic group.
  • the group CO-Lx corresponds with the group L-Lp(D) n in which L is CO and Lp is a mono or bicyclic group containing a nitrogen atom in the ring and bound to L via this nitrogen. It is believed that an aminomethyl group positioned on the 3 position of the phenyl ring will give rise to excellent binding within the SI binding pocket of tryptase. Without wishing to be limited by theory it is believed that the presence of a hydrogen bond donating group attached to the phenyl group will be essential for successful inhibition of tryptase.
  • R 5 and R 6 are both preferably hydrogen. Most preferably the Lx group comprises
  • a and B are independently chosen from NH, N, 0, S, CH, CH 2 ;
  • R lx and R 2x are independently chosen from hydrogen, alkoxy, alkyl, aminoalkyl, hydroxyalkyl, alkoxyalkyl, alkoxycarbonyl, amino, halo, cyano, nitro, thiol, alkylthio, alkylsulphonyl, alkylsulphenyl, oxo, heterocyclo optionally substituted by R 3x , cycloalkyl optionally substituted by R 3x or aryl optionally substituted by R 3x ; and R 3x is hydrogen, alkoxy, alkyl, amino, hydroxy, alkoxy, alkoxycarbonyl, halo, cyano, nitro, thiol, sulphonyl, or sulphenyl .
  • heterocyclic R lx and R 2x groups are piperidine, piperazine and pyrrolidine.
  • the cyclic group attached to the alpha atom is preferably an optionally R 3a substituted phenyl.
  • Lx is as hereinbefore defined. It is envisaged that especially preferred Lx groups will be those in which a cyclic or bicyclic ring is substituted by hydrogen bond donating and/or acceptor groups.
  • the compounds of formula (I) may be prepared by conventional chemical synthetic routes or by routes as illustrated by the following examples, e.g. by amide bond formation to couple the aromatic function to the alpha atom and to couple the lipophilic function to the alpha atom.
  • the alpha atom is a carbon
  • the cyclic group-alpha atom combination may conveniently derive from an alpha amino acid with the aromatic deriving from for example an acid derivative of a compound based on R2 , e.g. o-amino-benzoic acid or aminomethylbenzoic acid.
  • the lipophilic group (and optionally simultaneously the hydrogen bond donor) may then conveniently be introduced by reaction of a compound of formula (V) (or another analogous carboxylic acid) optionally after transformation into an activated form, e.g. an acid chloride or active ester, with a lipophilic group carrying an amine, hydroxylamine, hydrazine or hydroxyl group, e.g.
  • Cyclisation can be base induced via nucleophilic attack of the alpha atom on a leaving group on the active side chain. If necessary the amide linkage can be reduced using an appropriate reducing agent employing the necessary protection depending on whether concurrent reduction of the carboxylic acid moiety is also desired.
  • a compound of formula V or another analogous carboxylic acid may be transformed into an alcohol by reaction with isobutylchloroformate and reduction with sodium borohydride .
  • R 2 - CONH - CH(Cy)CH 2 OH (VI) can be reacted to introduce the lipophilic group by reactions such as: alkylation with an alkyl halide in the presence of a base ; under Mitsunobu conditions, such as reaction with diethyl azodicarboxylate/triphenylphosphine and a hydroxylated aryl compound; by reaction with an activated carboxylic acid (e.g.
  • an acid chloride or with a carboxylic acid and diethylazodicarboxylate/triphenylphosphine; by reaction with an isocyanate; and by treatment with methanesulphonyl chloride or trifluoromethanesulphonic anhydride and reaction with an amine, or with a thiol optionally followed by oxidation, e.g. with potassium metaperiodate or hydrogen peroxide.
  • the reactions described above may be performed on a corresponding compound of formula (VI) in which R 2 is replaced with a protecting group, such as t- butoxycarbonyl (Boc) , followed by deprotection and introduction of the group R 2 .
  • a protecting group such as t- butoxycarbonyl (Boc)
  • reaction with manganese dioxide or DMSO/oxalyl chloride or DMSO/SO 3 or Dess-Martin reagent which may be reacted to introduce the lipophilic group by reactions such as: reaction with Wittig reagents or Horner-Emmons reagents, optionally followed by reduction of the resulting carbon: carbon double bond using H 2 /Pd-carbon; reaction with an organometallic, eg a Grignard reagent, optionally followed by reaction on the resulting hydroxyl group, such as oxidation (eg with Mn ⁇ 2 , DMSO/oxalyl chloride or Dess-Martin reagent) , alkylation (eg with an alkyl halide in the presence of a base in a solvent such as DMF) , arylation (eg with diethylazo dicarboxylate/triphenyl phosphine and a hydroxyaryl compound) , ester formation (eg with an acid chloride or with
  • R 2 -CONH-CH(Cy) -CH 2 -NR ⁇ d H Such an amine reagent may be reacted to introduce the lipophilic group, e.g. by acylation with an acid halide or activated ester, by reaction with isocyanate, by reaction with an isothiocyanate, or by reaction with a sulphonyl chloride.
  • acylation with an acid halide or activated ester by reaction with isocyanate, by reaction with an isothiocyanate, or by reaction with a sulphonyl chloride.
  • compounds with linkages of -CH 2 NR ⁇ d - CO-, -CH 2 -NR ⁇ d -CO-NR ⁇ -, -CH 2 NR ⁇ d -CS-NR ld - and -CH 2 NR ⁇ d -S0 2 - between the alpha carbon and the lipophilic groups may be produced.
  • the transformation of acid to amide referred to above may be used
  • Such amides may be reacted to introduce lipophilic groups, e.g. by reaction with a haloketone (e.g. phenacyl bromide) . This provides a linkage
  • the amide may be transformed to a thioamide by reaction with Lawesson's reagent and then reacted with a haloketone to form a linkage
  • the amide reagent may likewise be transformed to a nitrile reagent by dehydration, e.g. with trifluoroacetic anhydride.
  • the nitrile reagent may be reacted with hydrazine then with acyl halide and then cyclized, (e.g. with trifluoroacetic anhydride) to produce a linkage
  • the hydrazide produced by reaction of a carboxylic acid reagent with hydrazine discussed above may likewise be used as a reagent for lipophilic group introduction, e.g. as a compound of formula
  • the hydrazide may be transformed by reaction with Lawesson's reagent and then reacted with an acyl halide and cyclized (e.g. with trifluoroacetic anhydride) to produce the linkage
  • PG Protecting group The protecting group may then be removed before coupling of the for example o-amino benzoic acid (optionally protected) .
  • carboxy protecting groups include C x - C 6 alkyl groups such as methyl, ethyl, t-butyl and t-amyl; aryl (C 1 -C 4 ) alkyl groups such as benzyl, 4-nitrobenzyl, 4- methoxybenzyl , 3 , 4-dimethoxybenzyl, 2 , 4-dimethoxybenzyl , 2 , 4, 6-trimethoxybenzyl, 2 , 4 , 6-trimethylbenzyl , benzhydryl and trityl; silyl groups such as trimethylsilyl and t- butyldimethylsilyl; and allyl groups such as allyl and 1- (trimethylsilylmethyl)prop-l-en-3-yl .
  • aryl (C 1 -C 4 ) alkyl groups such as benzyl, 4-nitrobenzyl, 4- methoxybenzyl , 3 , 4-dimethoxybenzyl, 2 ,
  • amine protecting groups include acyl groups, such as groups of formula RCO in which R represents C- L - s alkyl, C 3 - 10 cycloalkyl, phenyl C _ 6 alkyl, phenyl, C ⁇ alkoxy, phenyl alkoxy, or a C 3 - 10 cycloalkoxy, wherein a phenyl group may be optionally substituted, for example by one or two of halogen, C ⁇ d alkyl and C- . -C,, alkoxy.
  • Preferred amino protecting groups include benzyloxycarbonyl (CBz) , t-butoxycarbonyl (Boc) and benzyl.
  • ⁇ -Amino acids of formula (VII) which are not commercially available can be synthesized by methods known in the art, for example as described in "Synthesis of Optically Active ⁇ -Amino Acids” by Robert M. Williams (Pergamon Press, 1989) and “Asymmetric Synthesis of ArylGlycines” , Chem. Rev. 1992, 889-917.
  • a starting reagent for lipophilic group introduction where the alpha atom is nitrogen may be produced for example by reaction of a beta protected hydrazine (such protection to be chosen as to be compatible with the subsequent reagents to be employed) with phosgene, diphosgene, triphosgene or N,N' carbonyl diimidazole to give a reactive compound of the type :
  • PG Protecting group This intermediate may be used as has been described above for the carboxylic starting reagents where the alpha atom is carbon .
  • the compounds of formula (I) may be prepared by a process which comprises coupling a lipophilic group to a compound of formula (VIII)
  • the compounds of formula I may alternatively be prepared by a process in which the group R 2 is introduced in the final process step.
  • the compounds of formula (I) may also be prepared by a process which comprises coupling a lipophilic group to a compound of formula (IX)
  • Z 3 is COOH or a reactive derivative thereof, such as a acyl halide or an anhydride, for example as described in the Examples herein.
  • lipophilic group Lp comprises more than one group
  • it may generally be formed by coupling these groups together at an appropriate stage in the preparation of the compound of formula I using conventional methods or as descibed in the Examples.
  • alkylation may be carried out using any conventional method; however, generally preferred is a reductive alkylation using the appropriate aldehyde or ketone, for example as described in the Alkylation Methods in the Examples .
  • a particular starting material for the alkylation is one of formula
  • RI Q is a group of formula
  • X d is N and Rn is (1-6C) alkyl
  • Rn is (1-6C) alkyl
  • a reductive alkylation using the appropriate aldehyde or ketone, for example as described in the Alkylation Methods in the Examples.
  • methyl l-acetyl-3-formylindole-6- carboxylic acid may be converted to the 3 -formate by the method of Merour et al (Synthesis, 1994, 411) and then reacted with trimethyl orthoformate to give methyl 1-acetyl- 3-methoxyindole-6-carboxylate which is then hydrolysed to methyl 1-acetyl-3 -methoxyindole-6-carboxylate .
  • 5-Fluoroindole-6-carboxylic acid may be prepared from 4-fluoro-3-methoxyaniline by the following method. 4-Fluoro- 3-methoxyaniline is treated with glyoxal-1, 1-dimethyl acetal and then hydrogenated over Pd/C. The product is N-protected with methanesulphonyl chloride and then cyclised using titanium tetrachloride in toluene.
  • the compounds of formula (I) may be administered by any convenient route, e.g. into the gastrointestinal tract (e.g. rectally or orally) , the nose, lungs, musculature or vasculature or transdermally.
  • the compounds may be administered in any convenient administrative form, e.g. tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches etc.
  • Such compositions may contain components conventional in pharmaceutical preparations, e.g. diluents, carriers, pH modifiers, sweeteners, bulking agents, and further active agents.
  • the compositions will be sterile and in a solution or suspension form suitable for injection or infusion. Such compositions form a further aspect of the invention.
  • Hard gelatin capsules are prepared using the following ingredients :
  • the above ingredients are mixed and filled into hard gelatin capsules in 460 mg quantities.
  • Tablets each containing 60 mg of active ingredient are made as follows:
  • the active ingredient, starch, and cellulose are passed through a No. 45 mesh U.S. sieve and mixed thoroughly.
  • the solution of polyvmylpyrrolidone is mixed with the resultant powders which are then passed through a No. 14 mesh U.S. sieve.
  • the granules so produced are dried at 50°C and passed through a No. 18 mesh U.S. sieve.
  • the sodium carboxymethyl starch, magnesium stearate, and talc previously passed through a No. 60 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 150 mg.
  • the compounds of the invention will have excellent oral bioavailability.
  • the compounds of formula (I) and their physiologically tolerable salts will generally be adminstered to a patient in pharmaceutical composition which comprises a serine protease inhibitor of formula (I) together with at least one pharmaceutically acceptable carrier or excipient.
  • the pharmaceutical composition may also optionally comprise at least one further antithrombotic and/or thrombolytic agent.
  • the dosage of the inhibitor compound of formula (I) will depend upon the nature and severity of the condition being treated, the administration route and the size and species of the patient. However in general, quantities of from 0.01 to 100 ⁇ mol/kg bodyweight will be administered.
  • Amino acid derivatives, resins and coupling reagents were obtained, for example, from Novabiochem (Nottingham, UK) and other solvents and reagents from Rathburn (Walkerburn, UK) or Aldrich (Gillingham, UK) and were used without further purification. All solution concentrations are expressed as %Vol./%Vol. unless otherwise stated.
  • Purification was by gradient reverse phase Hplc on a Waters Deltaprep 4000 at a flow rate of 50 ml/ min. using a Deltapak C18 radial compression column (40 mm x 210 mm, 10-15 mm particle size) .
  • Eluant A consisted of aqTFA (0.1%) and eluant B 90% MeCN in aq TFA(0.1%) with gradient elution (Gradient 1, 0 min. 20%B then 20% to 100% over 36 min., Gradient 2, 0 min. 5%B for 1 min. then 5%B to 20%B over 4 min., then 20% to 60% over 32 min. or Gradient 3, 0 min. 20%B then 20% to 100% over 15 min.) . Fractions were analysed by analytical Hplc and MALDI-TOF before pooling those with >95% purity for lyophilisation.
  • Trityl chloride resin was typically treated with greater than 2 fold excess of the di-amine in dry DCM . The resin was further modified by the attachment of acids. Activation of Fmoc protected amino acid (2-5eq) was by TBTU/ DIPEA, all couplings ( minimum 120 min.) were carried out in DMF. Deprotection of the Fmoc group was achieved with 20% piperidine in DMF.
  • HOBt or HOAt esters were added as the HOBt or HOAt esters either by activation with HBTU/HATU or HATU/EDCI with or without Boc protection of amino groups.
  • Cleavage of the products from the resin was by treatment (30 min., ambient) with 10% triethylsilane in TFA, filtration, evaporation and trituration with diethylether.
  • the Symphony Multiple Peptide Synthesiser is charged with DMF, DCM, TBTU in DMF(450 mM) , DIPEA in DMF (900 mM) , 20% piperidine in DMF. Resins are held in plastic reaction vessels that allow the introduction of reagents and solvents and nitrogen for agitation or air drying.
  • the reaction vessel containing the resin (0.1 mmol) is charged with the Fmoc protected amino acid (0.5 mmol) and then this is dissolved in DMF (2.5ml), treated with TBTU (0.56 mmol, 1.25ml) and DIPEA (1.1 mmol, 1.25ml) and agitated with nitrogen for 2 hours (agitation times may vary) .
  • DMF 6x 5ml
  • DIPEA 1.1 mmol, 1.25ml
  • 4,4-Bipiperidine.dihydrochloride (4mmol,lg) was dissolved in water (5ml) and 2M sodium hydroxide solution (lOmmol, 5ml) added. The solution was extracted with ethylacetate (2x 50ml) the combined extracts were washed with water, dried over anhydrous sodium carbonate, filtered and evaporated to give the 4,4 bipiperidine (0.35g) as a white solid.
  • the 4,4 bipiperidine was dissolved in dry DMF (2ml) and added to Peg-tritylchloride resin (0.95 mmol/g, 1.5g) pre swollen in dry DCM (10ml) . After 2h the resin was washed with DCM (6x5ml) , DMF (6x5ml) and DCM (6x5ml) . The resin was then air dried to allow aliquots to be taken.
  • the 4,4 bipiperidine trityl resin (0.1 mmol) was treated with Fmoc-D-Phenylglycine (0.5 mmol, 187mg) , DMF (2.5ml), TBTU in DMF (1.25ml of a 450mM solution) and DIPEA in DMF (1.25ml of a 900 mM solution) . The mixture was agitated with nitrogen for 2 hours. Deprotection and washing as above.
  • Example 3 1- (2-_?_mino-4-methylbenzoyl-D-phenylglycinyl) -4,4 ' - bispiperidine iH nmr (CD 3 CN) 7.30 (6H,m); 6.50 (lH,s); 6.45 (lH,d); 5.80 (IH, S) ; 4.40 (lH,m); 3.75 (IH, m) ; 2.30-2.95 (6H, m) ; 2.05 (3H,S); 1.60 (4H, m) ; 1.10 (6H, m) MS TOF 436 (M+1 + ) . Hplc (Magellan C8 , Gradient 3, water/acetonitrile/TFA) rt 9.22 min.
  • Example 8 1- (3-Amino-2-naphthoyl-D-phenylglycinyl) -4,4 ' -bispiperidine 1 H nmr (CD 3 CN) 7.90 (lH,d); 7.60 (lH,d); 7.40 (lH,m); 7.30 (6H,m); 7.05 (lH,m); 6.90 (lH,s); 5.85 (IH, s) ; 4.40 (lH,m); 3.75 (IH, m) ; 2.30-2.95 (6H, m) ; 1.60 (4H, m) ; 1.10 (6H, m) MS TOF 471 (M+1+) . Hplc (Magellan C8, Gradient 3, water/acetonitrile/TFA) rt 9.87 min.
  • Method 2 By solution phase strategy: Typically an activated amino acid was treated with an amine (primary or secondary) or alcohol (leq.). Activation of the protected amino acid (Boc or Cbz protection) was by HATU/DIPEA (1:2) by TBTU/DIPEA (1:2), by HOBt or HOAt and a carbodiimide (EDCI or DCC) , or by diethyl cyanophosphonate and triethylamine or DIPEA, all couplings (minimum 120min.) were carried out in
  • Boc D-phenylglycine (251 mg, 1 mmol.) was dissolved in DMF(3ml) with HATU (380 mg., 1 mmol.) and DIPEA(350 ⁇ l ., 2 mmol.) . To this mixture was added 4- methylbenzylamine(121mg. , 1 mmol.) and DIPEA (170 ⁇ l., 1 mmol.) . The mixture was stirred overnight. The mixture was then taken up into ethylacetate and washed with water, sodium carbonate solution, water, 10% hydrochloric acid solution and water. The ethylacetate was evaporated without drying and treated immediately with TFA for 30 min.
  • Example 20 1- (2-Amino-4-chlorobenzoyl-D-phenylglycinyl) -4- (4-fluoro-2- methylsulphonylphenyl) piperazine
  • Example 29 1- (Benzoyl-D-phenylglycinyl) -4- (4-fluoro-2 -methyl- sulphonylphenyl) piperazine iH nmr (CD3CN) 7.75 (2H, m) ; 7.70 (IH, m) ; 7.40 (10H, m) ; 6.05 (IH, s) ; 3.15 (3H,s); 3.00-2.00 (8H,m).
  • MS TOF 496 (M+1 + ) .
  • Hplc Magneticellan C8, Gradient 3, water/acetonitrile/TFA) rt 12.84 min.
  • Example 35 1- (3-Amino-4-chlorobenzoyl-D-phenylglycinyl) -4- (4-fluoro-2- methy1sulphonylpheny1) iperazine
  • Example 39 1- (4-Methoxybenzoyl-D-phenylglycinyl) -4- (4-fluoro-2- methy1sulphonylpheny1) iperazine iH nmr (CD 3 CN) 7.85 (2H, d) ; 7.65 (IH, m) ; 7.50 (2H, m) ; 7.40 (5H, m) ; 6.80 (2H, d) ; 6.00 (IH, s) ; 3.80 (3H, s) ; 3.20 (3H,s); 3.00-2.00 (8H,m).
  • MS TOF 526 M+1+).
  • Hplc Magneticellan C8, Gradient 3, water/acetonitrile/TFA
  • Example 42 1- (Naphth-2-oyl-D-phenylglycinyl) -4- (4-fluoro-2 -methyl- sulphonylphenyl) piperazine iH nmr (CDCI3) 8.35 (IH, s) ; 8.00 (IH, d) ; 7.85 (5H, m) ; 7.45 (4H, m) ; 7.25 (4H, m) ; 6.10 (IH, s) ; 3.20 (3H,s); 3.00- 2.50 (8H,m) .
  • MS TOF 546 (M+1 + ) .
  • Hplc Magnellan C8, Gradient 3, water/acetonitrile/TFA) rt 16.66 min.
  • Example 44 1- (Thiophene-3-carbonyl-D-phenylglycinyl) -4- (4-fluoro-2- methylsulphonylphenyl) iperazine iH nmr (CDCI3) 8.15 (IH, s) ; 7.95 (IH, m) ; 7.85 (IH, m) ; 7.60 (8H, m) ; 6.30 (IH, s); 3.45 (3H,s); 2.00-2.50 (8H,m).
  • MS TOF 502 (M+1+) .
  • Hplc Magneticellan C8 , Gradient 3, water/acetonitrile/TFA) rt 14.28 min.
  • Example 49 1- (Indol-6-carbonyl-D-phenylglycinyl) -4- (4-fluoro-2- methy1sulphonylpheny1) piperazine iH nmr (CD3CN) 7.95 (2H, m) ; 7.60 (2H, m) ; 7.50 (3H, m) ; 7.35 (5H, m) ; 6.45 (IH, s) ; 6.05 (IH, s) ; 3.25 (3H,s); 3.00- 2.50 (8H,m) .
  • MS TOF 535 M+1 + ) .
  • Hplc Magneticellan C8 , Gradient 3, water/acetonitrile/TFA
  • Example 55 1- (4-Methylthiobenzoyl-D-phenylglycinyl) -4- (4-fluoro-2 - methylsulphonylphenyl) piperazine iH nmr (CD 3 CN) 7.85 (2H, d) ; 7.80 (IH, m) ; 7.60 (2H, m) ; 7.50 (5H, m) ; 7.40 (2H, d) ; 6.15 (IH, s) ; 3.40 (3H, s) ; 3.10-2.70 (8H, m) ; 2.60 (3H, s) .
  • MS TOF 542 (M+1 + ).
  • Hplc Magnellan C8 , Gradient 3, water/acetonitrile/TFA
  • Example 58 1- (3-Methyl-4-bromobenzoyl-D-phenylglycinyl) -4- (4-fluoro-2- methylsulphonylphenyl) piperazine iH nmr (CD 3 CN) 7.65 (3H, m) ; 7.45 (3H, m) ; 7.30 (5H, m) ; 6.00 (IH, s) ; 3.25 (3H, s) ; 3.00-2.50 (8H, m) ; 2.40 (3H, s) .
  • MS TOF 589 M+1+
  • Hplc Magneticellan C8, Gradient 3, water/acetonitrile/TFA
  • Example 61 1- (Benzimidazo-5-carbonyl-D-phenylglycinyl) -4- (4-fluoro-2- methylsulphonylphenyl) piperazine iH nmr (CD 3 CN) 8.75 (IH, s) ; 8.25 (IH, s) ; 7.75 (2H, m) ; 7.60 (IH, m) ; 7.50 (2H, m) ; 7.35 (5H, m) ; 6.60 (2H, d) ; 6.05 (IH, s) ; 3.30 (3H, s) ; 3.00-2.50 (8H, m) .
  • MS TOF 536 (M+1+) .
  • Hplc Magnellan C8, Gradient 3, water/acetonitrile/TFA) rt 10.08 min.
  • Example 70 1- (4- (Methylamino)benzoyl-D-phenylglycinyl) -1 ' -methyl-4, 4 ' - bispiperidine iH nmr (CD3CN) a mixture of conformers only one recorded here 7.70 (3H, m) ; 7.35 (5H, m) ; 6.60 (2H, d) ; 5.90 (IH, S) ; 4.45 (IH, m) ; 3.85.1H, m) ; 3.40 (2H, m) ; 2.9-2.4 (8H, m) ; 2.70 (3H, s) ; 1.60 (2H, m) ; 1.30 (2H, m) ; 1.00 (2H, m) .
  • MS TOF 465 M+1+
  • Example 71 1- (4-Ethylaminobenzoyl-D-phenylglycinyl) -4- (4-fluoro-2- methy1sulphonylphenyl) piperazine
  • Example 87 1- (4-Methylcarboxybenzoyl-D-phenylglycinyl) -4- (4-fluoro-2- methylsulphonylphenyl) piperazine
  • Example 94 1- (3,3-Dichloro-2-oxo- (IH) indol-6-carbonyl-D-phenylglycinyl) 4- (4-fluoro-2 -methylsulphonylphenyl) -piperazine
  • IH nmr (CD3CN) a mixture of conformers only one recorded here 7.95 (IH, m) ; 7.85 (2H,m); 7.65 (lH,m); 7.45 (2H, m) ;
  • IH nmr (CD3CN) a mixture of conformers only one recorded here 7.85 (2H, m) ; 7.30 (7H, m) ; 5.85 (IH, s) ; 4.45 (IH, m) ; 3.85 (IH, m) ; 3.30 (2H, m) ; 2.90-2.40 (8H, m) ; 2.65 (3H, s) ; 1.60 (2H, m) ; 1.30 (2H, m) ; 1.00 (2H, m) .
  • MS TOF 493 (M+1+) .
  • IH nmr (CD3CN) a mixture of conformers only one recorded here 7.85 (2H, m) ; 7.30 (7H, m) ; 5.85 (IH, s) ; 4.45 (IH, m) ;
  • IH nmr (CD3CN) a mixture of conformers only one recorded here 7.85 (IH, m) ; 7.70 (2H,m); 7.40 (6H, m) ; 6.75 (lH,m); 6.00 (IH, s) ; 5.85 (lH,d); 5.50 (lH,d); 4.55 (IH, m) ; 3.95 (IH, m) ; 3.30 (2H, m) ; 2.90-2.40 (8H, m) ; 2.65 (3H, s) ; 1.60 (2H, m) ; 1.30 (2H, m) ; 1.00 (2H, m) .
  • MS TOF 446 (M+1+) .
  • Hplc Magneticellan C8, Gradient 3, water/acetonitrile/TFA) rt 11.21min.
  • Example 107 1- (3-Amino-4-chlorobenzoyl-D-phenylglycinyl) -4- (4-nitro-2- methylsulphonylphenyl) piperazine
  • Example 110 1- (3 -Amino-4 -chlorobenzoyl-D-4- (methylcarboxamido) phenyl- glycinyl) -4- (4-fluoro-2 -methylsulphonylphenyl) piperazine IH nmr (CD3CN) 7.70 (2H, d) ; 7.55 (IH, d) ; 7.45 (2H, d) ; 7.25 (2H,m) ; 7.20 (2H,d); 6.90 (IH, d) ; 6.10 (IH, s) ; 3.20 (3H, s) ; 2.70 (3H,s); 3.00-2.50 (8H, m) .
  • MS TOF 602 M+1+) .
  • Hplc Magnellan C8 , Gradient 3, water/acetonitrile/TFA
  • Example 114 3-Amino-4-chlorobenzoyl-D-4-carboxamidophenylglycine (S) -N - benzyl-alpha-methylbenzylamide MS TOF 541 (M+1+) . Hplc (Magellan C8 , Gradient 3, water/acetonitrile/TFA) rt 15.34 min.
  • Example 128 1- (4-Methoxybenzoyl-D-phenylglycinyl) -3- (R,S) - (3- methoxyphenoxy) pyrrolidine From 4-methoxybenzoyl-D-phenylglycinyl-R, S-3- hydroxypyrrolidine and 3-methoxyphenol :
  • Hplc (Luna C18, Gradient3, water/acetonitrile/TFA), rt , 15.8min.
  • the reaction was warmed to room temperature and monitored by tic (Si ⁇ 2 - ethyl acetate) .
  • the reaction mixture was poured into water (5ml) and extracted with dichloromethane (100ml) .
  • the organic solution was washed with sat .
  • Benzyloxycarbonyl-D-phenylglycinyl-4 -hydroxypiperidine By a similar method using benzyloxycarbonyl -D-phenylglycine and 4 -hydroxypiperidine, benzyloxycarbonyl-D-phenylglycinyl- 4 -hydroxypiperidine was prepared. Hplc (Luna C18, Gradient3, water/acetonitrile/TFA), rt, 11.9min LCMS M+l 369 Nmr. D-Phenylglycinyl-R, S-3-hydroxypyrrolidine
  • Benzyloxycarbonyl-D-phenylglycinyl-4- (3-pyridoxy) piperidine (l.l ⁇ g 2.64mmol) was dissolved in ethanol (120ml) containing Pd/C 10% (lOOmg) and acetic acid (0.3ml) and hydrogenated at atmospheric pressure for 8h - (incomplete by tic) .
  • the catalyst was removed by filtration and the solution evaporated to an oil.
  • the oil was re-hydrogenated as before.
  • the catalyst was removed by filtration and the solvent evaporated in vacuo to an oil which was taken up in dilute hydrochloric acid.
  • the aqueous solution was washed with dichloromethane and then basified with solid sodium bicarbonate.
  • D-phenylglycinyl-R, S-3- (3- pyridoxy) pyrrolidine was prepared from benzyloxycarbonyl -D- phenylglycinyl-R, S-3- (3-pyridoxy) pyrrolidine by hydrogenation over Pd/C in ethanol. Nmr.
  • Example 141 1- (3-Chloroindole-6-carbonyl-D-phenylglycinyl) -3- (R,S) - (3- pyridoxy) pyrrolidine
  • Examples 144 to 147 were prepared by coupling to the appropriate carboxylic acid to D- phenylglycinyl-4,4 ' - (1 ' -methylbispiperidine) using EDC and HOAt as described previously.
  • Example 148 1- (Indole-6-carbonyl-D-phenylglycinyl) -1' -isopropyl-4, 4 ' - bispiperidine
  • Examples 149 to 154 were prepared by coupling Boc-D-4-carboxamidophenylglycine to the appropriate amine with EDCI/HOAt, deprotection with TFA/DCM and coupling to 3 -amino-4 -chlorobenzoic acid with EDCI/HOAt as previously described.
  • Methyl l-acetyl-2 , 3 -dihydroindol-3 -one-6-carboxylate (233mg, 1 mmol) , trimethyl orthoformate (10ml) and p-toluene sulphonic acid (20 mg) were heated under reflux for 3 h. in methanol (10ml) .
  • the reaction mixture was concentrated under reduced pressure, poured into water and extracted with chloroform.
  • Example 157 1- (3-Amino-4-chlorobenzoyl-D,L-l-napthylglycinyl) -4- (4- fluoro-2 -methylsulfonylphenyl) -piperazine
  • Hplc (Luna C18, Gradient3, water/acetonitrile/TFA) rt 15.69min.
  • Boc-R-4-Hydroxyphenylglycine methyl ester hydrochloride To a stirred mixture of R-4-hydroxyphenylglycine methyl ester hydrochloride 14g and sodium bicarbonate 11.7g in tetrahydrofuran (THF) 150ml and water 50ml, was added in one portion, di- t-butyl dicarbonate 15.9g. The mixture was stirred rapidly to allow thorough mixing for 4h. Hexane (75ml) was added and the organic layer separated and washed with sat. sodium bicarbonate solution, then brine and then dried with magnesium sulphate. The drying agents was filtered off and washed with a little THF and evaporated to dryness, finishing with a high vacuum pump to remove the last traces of di- t-butyl dicarbonate. Yield 19.7g 96%.
  • THF tetrahydrofuran
  • Boc-R-4- (trifluoro ethanesulphonyloxy) phenylglycine methyl ester hydrochloride To a stirred solution of Boc-R-4-hydroxyphenylglycine methyl ester 19g in dichloromethane 400ml was added 2,6-lutidine 9.44ml and 4-dimethylaminopyridine 1.65g and the mixture cooled in an ice bath. Trifluoromethanane-sulphonic anhydride 13.74ml was added over a period of 5min and then the reaction left to warm to room temperature over 4h. The organic solution was washed with water, 2 x 150ml, IN HCl 2 x 150ml and the saturated sodium bicarbonate 150ml.
  • Boc-R-4- (carboxymethyl) phenylglycine methyl ester Boc-R-4- (carboxymethyl) phenylglycine methyl ester.
  • Boc-R-4-trifluoromethanesulphonyloxyphenylglycine methyl ester (15g) , methanol (32.6ml), bis-1,3- diphenylphosphinylpropane (448mg) , palladium (II) acetate (255mg) , triethylamine (10.2ml) and dimethylformamide (72ml) were placed in the glass liner of the Parr reactor and the reactor assembled. The vessel was pressurised to ⁇ 10psi with nitrogen and the gas released (repeated five times to remove all oxygen from the system) .
  • Carbon monoxide gas was then carefully introduced (use extreme care -the gas cylinder is pressurised to far beyond the bursting disc pressure of the Parr, ideally use a pressure regulator to reduce the pressure to -lOOpsi) to ⁇ 20psi and released three times (into the back of a fume hood) . Carbon monoxide was then added to -lOOpsi and the stirrer started. The vessel was slowly heated to 65°C internal temperature and then stirred at 65°C overnight. (At the early stages more carbon monoxide was added to maintain -lOOpsi) A sample was removed after 18h and examined by tic. When complete, the reaction was cooled to ⁇ 30°C, the gas released and the vessel flushed five times with nitrogen as before.
  • Boc-R-4- (carboxymethyl) phenylglycine Boc-R-4- (carboxymethyl) phenylglycine.
  • Boc-R- 4-trifluoromethanesulphonyloxyphenylglycine methyl ester and benzyl alcohol By the same method as described above, using 27.6g of Boc-R- 4-trifluoromethanesulphonyloxyphenylglycine methyl ester and benzyl alcohol to give the Boc-D-4-
  • Boc-R-4- (carboxybenzyl) henylglycine methyl ester (500mg) was dissolved in THF containing Pd/C 10% (lOOmg) and hydrogenated at latm for 2h. Removal of the catalyst by filtration and evaporation of solvent gave Boc-R-4- (carboxy) phenylglycine methyl ester (330mg, 87%) .
  • Boc-R-4-hydroxyphenylglycine methyl ester was converted to Boc-R-4-methoxyphenylglycine using the alkylation method described by Basak et al . (Tetrahedron Lett. 1998, 39 (27), 4883-4886) followed by hydrolysis of the methyl ester with lithium hydroxide in aqueous THF. Nmr

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Abstract

L'invention porte sur l'utilisation de composés de la formule (I) dans laquelle R2, chaque X, L, Y, Cy, Lp, D et n sont tels que définis dans la demande, tels que des inhibiteurs de la sérine protéase.
PCT/GB2000/002296 1999-06-14 2000-06-13 Composes WO2000076970A2 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
CA002383008A CA2383008A1 (fr) 1999-06-14 2000-06-13 Composes
AU54136/00A AU5413600A (en) 1999-06-14 2000-06-13 Compounds
EP00938912A EP1192135A2 (fr) 1999-06-14 2000-06-13 Composes

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GBGB9913823.2A GB9913823D0 (en) 1999-06-14 1999-06-14 Compounds
GB9913823.2 1999-06-14
US14206499P 1999-07-02 1999-07-02
US60/142,064 1999-07-02
GBGB9918741.1A GB9918741D0 (en) 1999-08-09 1999-08-09 Compounds
GB9918741.1 1999-08-09
GB9929552.9 1999-12-14
GBGB9929552.9A GB9929552D0 (en) 1999-12-14 1999-12-14 Compounds
GB9929553.7 1999-12-14
GBGB9929553.7A GB9929553D0 (en) 1999-12-14 1999-12-14 Compounds

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Publication number Priority date Publication date Assignee Title
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US8293917B2 (en) 2008-05-06 2012-10-23 Boehringer Ingelheim International Gmbh Pyrazole compounds as CCR1 antagonists
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US8394826B2 (en) 2009-05-01 2013-03-12 Aerie Pharmaceuticals, Inc. Dual mechanism inhibitors for the treatment of disease
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US8426420B2 (en) 2007-12-26 2013-04-23 Sanofi Heterocyclic pyrazole-carboxamidesas P2Y12 antagonists
US8455514B2 (en) 2008-01-17 2013-06-04 Aerie Pharmaceuticals, Inc. 6-and 7-amino isoquinoline compounds and methods for making and using the same
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US8546442B2 (en) 2010-12-23 2013-10-01 Boehringer Ingelheim International Gmbh Pyrazolopiperidine compounds as CCR1 receptor antagonists
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US8927550B2 (en) 2009-10-27 2015-01-06 Boehringer Ingelheim International Gmbh Heterocyclic compounds as CCR1 receptor antagonists
US9056858B2 (en) 2009-10-21 2015-06-16 Boehringer Ingelheim International Gmbh Indazole and pyrazolopyridine compounds as CCR1 receptor antagonists
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US9643927B1 (en) 2015-11-17 2017-05-09 Aerie Pharmaceuticals, Inc. Process for the preparation of kinase inhibitors and intermediates thereof
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US9849122B2 (en) 2013-03-15 2017-12-26 Aerie Pharmaceuticals, Inc. Combination therapy
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US10858339B2 (en) 2017-03-31 2020-12-08 Aerie Pharmaceuticals, Inc. Aryl cyclopropyl-amino-isoquinolinyl amide compounds
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US11389441B2 (en) 2016-08-31 2022-07-19 Aerie Pharmaceuticals, Inc. Ophthalmic compositions
US11427563B2 (en) 2018-09-14 2022-08-30 Aerie Pharmaceuticals, Inc. Aryl cyclopropyl-amino-isoquinolinyl amide compounds

Families Citing this family (1)

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Publication number Priority date Publication date Assignee Title
BR112022023983A2 (pt) * 2020-05-27 2022-12-20 Sanofi Sa Compostos terapêuticos

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2062943B1 (es) * 1993-03-23 1995-11-16 Uriach & Cia Sa J Nuevos derivados de la (2-metil-3-piridil) cianometilpiperazinas.
IL123986A (en) * 1997-04-24 2011-10-31 Organon Nv Medicinal compounds
US6262069B1 (en) * 1997-08-29 2001-07-17 Protherics Molecular Design Limited 1-amino-7-isoquinoline derivatives as serine protease inhibitors

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US8329718B2 (en) 2005-06-27 2012-12-11 Bristol-Myers Squibb Company N-linked heterocyclic antagonists of P2Y1 receptor useful in the treatment of thrombotic conditions
US7714002B2 (en) 2005-06-27 2010-05-11 Bristol-Myers Squibb Company Carbocycle and heterocycle antagonists of P2Y1 receptor useful in the treatment of thrombotic conditions
WO2007002635A2 (fr) 2005-06-27 2007-01-04 Bristol-Myers Squibb Company Antagonistes cycliques a liaison c du recepteur p2y1, utiles pour traiter des etats pathologiques thrombotiques
US7700620B2 (en) 2005-06-27 2010-04-20 Bristol-Myers Squibb Company C-linked cyclic antagonists of P2Y1 receptor useful in the treatment of thrombotic conditions
US7829724B2 (en) 2005-08-15 2010-11-09 Zentaris Gmbh Triazole derivatives as ghrelin analogue ligands of growth hormone secretagogue receptors
US8710089B2 (en) 2005-08-15 2014-04-29 Zentaris Gmbh Triazole derivatives as ghrelin analogue ligands of growth hormone secretagogue receptors
EP1757290A1 (fr) 2005-08-16 2007-02-28 Zentaris GmbH Derivés de triazole comme ligands du recepteur de l'hormone de croissance
EP2308874A1 (fr) 2005-12-07 2011-04-13 Basilea Pharmaceutica AG Combinaisons utiles de monobactames antibiotiques et inhibiteurs de bèta-lactamase
US8901293B2 (en) 2005-12-07 2014-12-02 Basilea Pharmaceutica Ag Useful combinations of monobactam antibiotics with beta-lactamase inhibitors
US10624882B2 (en) 2006-09-20 2020-04-21 Aerie Pharmaceuticals, Inc. Rho kinase inhibitors
US8809326B2 (en) 2006-09-20 2014-08-19 Aerie Pharmaceuticals, Inc. Isoquinolinone Rho kinase inhibitors
US7960569B2 (en) 2006-10-17 2011-06-14 Bristol-Myers Squibb Company Indole antagonists of P2Y1 receptor useful in the treatment of thrombotic conditions
US7964732B2 (en) 2006-11-17 2011-06-21 Pfizer Inc. Substituted bicyclocarboxyamide compounds
WO2008076805A2 (fr) 2006-12-15 2008-06-26 Bristol-Myers Squibb Company Analogues d'arylpropionamide, d'arylacrylamide, d'arylpropynamide ou d'arylméthylurée en tant qu'inhibiteurs du facteur xia
WO2008079836A2 (fr) 2006-12-20 2008-07-03 Bristol-Myers Squibb Company Inhibiteurs macrocycliques du facteur viia utiles en tant qu'anticoagulants
US8921392B2 (en) 2007-01-10 2014-12-30 Aerie Pharmaceuticals, Inc. 6-aminoisoquinoline compounds
US9365518B2 (en) 2007-01-10 2016-06-14 Aerie Pharmaceuticals, Inc. 6-aminoisoquinoline compounds
US9890123B2 (en) 2007-01-10 2018-02-13 Aerie Pharmaceuticals, Inc. 6-aminoisoquinoline compounds
US10472327B2 (en) 2007-01-10 2019-11-12 Aerie Pharmaceuticals, Inc. 6-aminoisoquinoline compounds
US10899714B2 (en) 2007-01-10 2021-01-26 Aerie Pharmaceuticals, Inc. 6-aminoisoquinoline compounds
US8455513B2 (en) 2007-01-10 2013-06-04 Aerie Pharmaceuticals, Inc. 6-aminoisoquinoline compounds
US8669266B2 (en) 2007-04-23 2014-03-11 Sanofi Quinoline-carboxamide derivatives as P2Y12 antagonists
US8426420B2 (en) 2007-12-26 2013-04-23 Sanofi Heterocyclic pyrazole-carboxamidesas P2Y12 antagonists
US8455514B2 (en) 2008-01-17 2013-06-04 Aerie Pharmaceuticals, Inc. 6-and 7-amino isoquinoline compounds and methods for making and using the same
US8871757B2 (en) 2008-01-17 2014-10-28 Aerie Pharmaceuticals, Inc. 6-and 7-amino isoquinoline compounds and methods for making and using the same
US8008327B2 (en) 2008-04-29 2011-08-30 Boehringer Ingelheim International Gmbh Indazole compounds as CCR1 receptor antagonists
US8263597B2 (en) 2008-04-29 2012-09-11 Boehringer Ingelheim International Gmbh Indazole compounds as CCR1 receptor antagonists
US8293917B2 (en) 2008-05-06 2012-10-23 Boehringer Ingelheim International Gmbh Pyrazole compounds as CCR1 antagonists
US10882840B2 (en) 2008-07-25 2021-01-05 Aerie Pharmaceuticals, Inc. Beta- and gamma-amino-isoquinoline amide compounds and substituted benzamide compounds
US8450344B2 (en) 2008-07-25 2013-05-28 Aerie Pharmaceuticals, Inc. Beta- and gamma-amino-isoquinoline amide compounds and substituted benzamide compounds
AU2009273932B2 (en) * 2008-07-25 2014-11-20 Alcon Inc. Beta-and gamma-amino-isoquinoline amide compounds and substituted benzamide compounds
US10112920B2 (en) 2008-07-25 2018-10-30 Aerie Pharmaceuticals, Inc. Beta- and gamma-amino-isoquinoline amide compounds and substituted benzamide compounds
US9512101B2 (en) 2008-07-25 2016-12-06 Aerie Pharmaceuticals, Inc. Beta- and gamma-amino-isoquinoline amide compounds and substituted benzamide compounds
US10532993B2 (en) 2008-07-25 2020-01-14 Aerie Pharmaceuticals, Inc. Beta- and gamma-amino-isoquinoline amide compounds and substituted benzamide compounds
US11021456B2 (en) 2008-07-25 2021-06-01 Aerie Pharmaceuticals, Inc. Beta- and gamma-amino-isoquinoline amide compounds and substituted benzamide compounds
AU2009273932C1 (en) * 2008-07-25 2015-06-11 Alcon Inc. Beta-and gamma-amino-isoquinoline amide compounds and substituted benzamide compounds
US9884840B2 (en) 2008-07-25 2018-02-06 Aerie Pharmaceuticals, Inc. Beta- and gamma-amino-isoquinoline amide compounds and substituted benzamide compounds
US8759388B2 (en) * 2008-07-25 2014-06-24 Aerie Pharmaceuticals, Inc. Beta- and gamma-amino-isoquinoline amide compounds and substituted benzamide compounds
US9096569B2 (en) 2008-07-25 2015-08-04 Aerie Pharmaceuticals, Inc. Beta- and gamma-amino-isoquinoline amide compounds and substituted benzamide compounds
US20120196916A1 (en) * 2008-07-25 2012-08-02 Delong Mitchell A Beta- and gamma-amino-isoquinoline amide compounds and substituted benzamide compounds
US8163918B2 (en) 2008-09-26 2012-04-24 Boehringer Ingelheim International Gmbh Azaindazole compounds as CCR1 receptor antagonists
US8338610B2 (en) 2008-09-26 2012-12-25 Boehringer Ingelheim International Gmbh Pyridinyl compounds useful as intermediates
US8063065B2 (en) 2008-09-26 2011-11-22 Boehringer Ingelheim International Gmbh Azaindazole compounds as CCR1 receptor antagonists
US7879873B2 (en) 2008-09-26 2011-02-01 Boehringer Ingelheim International Gmbh Azaindazole compounds as CCR1 receptor antagonists
US11028081B2 (en) 2009-05-01 2021-06-08 Aerie Pharmaceuticals, Inc. Dual mechanism inhibitors for the treatment of disease
US10174017B2 (en) 2009-05-01 2019-01-08 Aerie Pharmaceuticals, Inc. Dual mechanism inhibitors for the treatment of disease
US9951059B2 (en) 2009-05-01 2018-04-24 Aerie Pharmaceuticals, Inc. Dual mechanism inhibitors for the treatment of disease
US10316029B2 (en) 2009-05-01 2019-06-11 Aerie Pharmaceuticals, Inc. Dual mechanism inhibitors for the treatment of disease
US11618748B2 (en) 2009-05-01 2023-04-04 Aerie Pharmaceuticals, Inc. Dual mechanism inhibitors for the treatment of disease
US8394826B2 (en) 2009-05-01 2013-03-12 Aerie Pharmaceuticals, Inc. Dual mechanism inhibitors for the treatment of disease
US8716310B2 (en) 2009-05-01 2014-05-06 Aerie Pharmaceuticals, Inc. Dual mechanism inhibitors for the treatment of disease
US10654844B2 (en) 2009-05-01 2020-05-19 Aerie Pharmaceuticals, Inc. Dual mechanism inhibitors for the treatment of disease
US9056858B2 (en) 2009-10-21 2015-06-16 Boehringer Ingelheim International Gmbh Indazole and pyrazolopyridine compounds as CCR1 receptor antagonists
US8927550B2 (en) 2009-10-27 2015-01-06 Boehringer Ingelheim International Gmbh Heterocyclic compounds as CCR1 receptor antagonists
WO2011100402A1 (fr) 2010-02-11 2011-08-18 Bristol-Myers Squibb Company Macrocycles en tant qu'inhibiteurs du facteur xia
EP3786165A1 (fr) 2010-02-11 2021-03-03 Bristol-Myers Squibb Company Intermédiaires de synthèse utiles à la préparation de macrocycles utilisés en tant qu'inhibiteurs du facteur xia
WO2011100401A1 (fr) 2010-02-11 2011-08-18 Bristol-Myers Squibb Company Macrocycles utilisés en tant qu'inhibiteurs du facteur xia
US8871786B2 (en) 2010-04-30 2014-10-28 Boehringer Ingelheim International Gmbh Azaindazole amide compounds as CCR1 receptor antagonists
EP2431035A1 (fr) 2010-09-16 2012-03-21 Æterna Zentaris GmbH Nouveaux dérivés de triazole avec activité de récepteur améliorée et propriétés de biodisponibilité en tant qu'antagonistes de ghréline de récepteurs de secrétagogue d'hormone de croissance
WO2012035124A1 (fr) 2010-09-16 2012-03-22 Æterna Zentaris Gmbh Nouveaux dérivés de triazole ayant une activité de récepteur améliorée et de meilleures propriétés de biodisponibilité en tant qu'antagonistes de la ghréline des récepteurs sécrétagogues de l'hormone de croissance
US8546442B2 (en) 2010-12-23 2013-10-01 Boehringer Ingelheim International Gmbh Pyrazolopiperidine compounds as CCR1 receptor antagonists
EP3070087A1 (fr) 2011-08-05 2016-09-21 Bristol-Myers Squibb Company Intermediaires pour la synthèse de lieurs p1 cycliques en tant qu'inhibiteurs du facteur xia
WO2013022818A1 (fr) 2011-08-05 2013-02-14 Bristol-Myers Squibb Company Nouveaux macrocycles en tant qu'inhibiteurs du facteur xia
WO2013022814A1 (fr) 2011-08-05 2013-02-14 Bristol-Myers Squibb Company Lieurs p1 cycliques en tant qu'inhibiteurs du facteur xia
WO2013056034A1 (fr) 2011-10-14 2013-04-18 Bristol-Myers Squibb Company Composés de tétrahydroisoquinoléine substitués en tant qu'inhibiteurs du facteur xia
WO2013055984A1 (fr) 2011-10-14 2013-04-18 Bristol-Myers Squibb Company Composés tétrahydroisoquinolines substitués en tant qu'inhibiteurs du facteur xia
EP2899183A1 (fr) 2011-10-14 2015-07-29 Bristol-Myers Squibb Company Composés de tétrahydroisiquinoline substitués en tant qu'inhibiteurs du facteur xia
EP3309148A1 (fr) 2011-10-14 2018-04-18 Bristol-Myers Squibb Company Composés de tétrahydroisiquinoline substitués en tant qu'inhibiteurs du facteur xia
WO2013056060A1 (fr) 2011-10-14 2013-04-18 Bristol-Myers Squibb Company Composés de tétrahydroisoquinoléine substitués comme inhibiteurs du facteur xia
WO2014022767A1 (fr) 2012-08-03 2014-02-06 Bristol-Myers Squibb Company Récepteurs p1 de la dihydropyridone en tant qu'inhibiteurs du facteur xia
WO2014022766A1 (fr) 2012-08-03 2014-02-06 Bristol-Myers Squibb Company Récepteurs p1 de la dihydropyridone en tant qu'inhibiteurs du facteur xia
US11185538B2 (en) 2013-03-15 2021-11-30 Aerie Pharmaceuticals, Inc. Compositions for treating glaucoma or reducing intraocular pressure
US11020385B2 (en) 2013-03-15 2021-06-01 Aerie Pharmaceuticals, Inc. Combination therapy
US9993470B2 (en) 2013-03-15 2018-06-12 Aerie Pharmaceuticals, Inc. Combination therapy
US11197853B2 (en) 2013-03-15 2021-12-14 Aerie Pharmaceuticals, Inc. Combination therapy
US9849122B2 (en) 2013-03-15 2017-12-26 Aerie Pharmaceuticals, Inc. Combination therapy
US9931336B2 (en) 2013-03-15 2018-04-03 Aerie Pharmaceuticals, Inc. Combination therapy
US10588901B2 (en) 2013-03-15 2020-03-17 Aerie Pharmaceuticals, Inc. Combination therapy
US10568878B2 (en) 2013-03-15 2020-02-25 Aerie Pharmaceuticals, Inc. Combination therapy
WO2014160668A1 (fr) 2013-03-25 2014-10-02 Bristol-Myers Squibb Company Tétrahydroisoquinolines comprenant des azoles substitués en tant qu'inhibiteurs du facteur xia
WO2014208751A1 (fr) * 2013-06-27 2014-12-31 味の素株式会社 Nouvel agent conférant un goût d'umami
WO2015116886A1 (fr) 2014-01-31 2015-08-06 Bristol-Myers Squibb Company Macrocycles à groupes hétérocycliques p2' servant d'inhibiteurs du facteur xia
EP3392249A1 (fr) 2014-01-31 2018-10-24 Bristol-Myers Squibb Company Macrocycles a groupes heterocycliques p2' servant d'inhibiteurs du facteur xia
EP3988549A1 (fr) 2014-01-31 2022-04-27 Bristol-Myers Squibb Company Macrocycles avec des groupes p2' hétérocycliques en tant qu'inhibiteurs du facteur xia
WO2015116882A1 (fr) 2014-01-31 2015-08-06 Bristol-Myers Squibb Company Inhibiteurs macrocycliques du facteur xia condensés à l'aide d'hétérocycles
WO2015116885A1 (fr) 2014-01-31 2015-08-06 Bristol-Myers Squibb Company Macrocycles à groupes hétérocycliques p2' servant d'inhibiteurs du facteur xia
EP3828186A2 (fr) 2014-10-01 2021-06-02 Bristol-Myers Squibb Company Pyrimidinones en tant qu'inhibiteurs du facteur xia
WO2016053455A1 (fr) 2014-10-01 2016-04-07 Bristol-Myers Squibb Company Pyrimidines utilisées en tant qu'inhibiteurs du facteur xia
EP4286372A2 (fr) 2014-10-01 2023-12-06 Bristol-Myers Squibb Company Pyrimidinones en tant qu'inhibiteurs du facteur xia
WO2016205482A1 (fr) 2015-06-19 2016-12-22 Bristol-Myers Squibb Company Macrocycles diamides utilisés en tant qu'inhibiteurs du facteur xia
EP3868753A1 (fr) 2015-07-29 2021-08-25 Bristol-Myers Squibb Company Nouveau macrocycle de facteur xia portant un groupe p2' non aromatique
WO2017023992A1 (fr) 2015-08-05 2017-02-09 Bristol-Myers Squibb Company Nouveaux inhibiteurs de fxia dérivés de glycine substitués
US10550087B2 (en) 2015-11-17 2020-02-04 Aerie Pharmaceuticals, Inc. Process for the preparation of kinase inhibitors and intermediates thereof
US9643927B1 (en) 2015-11-17 2017-05-09 Aerie Pharmaceuticals, Inc. Process for the preparation of kinase inhibitors and intermediates thereof
WO2017151746A1 (fr) 2016-03-02 2017-09-08 Bristol-Myers Squibb Company Macrocycles diamide présentant une activité inhibitrice du facteur xia
US11389441B2 (en) 2016-08-31 2022-07-19 Aerie Pharmaceuticals, Inc. Ophthalmic compositions
US11707460B2 (en) 2016-08-31 2023-07-25 Aerie Pharmaceuticals, Inc. Ophthalmic compositions
US11312700B2 (en) 2017-03-31 2022-04-26 Aerie Pharmaceuticals, Inc. Aryl cyclopropyl-amino-isoquinolinyl amide compounds
US10858339B2 (en) 2017-03-31 2020-12-08 Aerie Pharmaceuticals, Inc. Aryl cyclopropyl-amino-isoquinolinyl amide compounds
US12018012B2 (en) 2017-03-31 2024-06-25 Aerie Pharmaceuticals, Inc. Aryl cyclopropyl-amino-isoquinolinyl amide compounds
US11427563B2 (en) 2018-09-14 2022-08-30 Aerie Pharmaceuticals, Inc. Aryl cyclopropyl-amino-isoquinolinyl amide compounds
US11891376B2 (en) 2018-09-14 2024-02-06 Aerie Pharmaceuticals, Inc. Aryl cyclopropyl-amino-isoquinolinyl amide compounds

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