Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
  • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
  • C07K5/06—Dipeptides
  • C07K5/06008—Dipeptides with the first amino acid being neutral
  • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
  • C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
  • C07K5/06043—Leu-amino acid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
  • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
  • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
  • A61K47/545—Heterocyclic compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/04—Antineoplastic agents specific for metastasis
• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides

Definitions

• the present invention relates to novel disubstituted dipeptide pharmaceutical compounds, and salts thereof, particularly physiologically acceptable salts formed with organic or inorganic acids. Specifically, the present invention relates to a process for the preparation of such compounds, to the uses thereof for the prevention and treatment of thromboembolic diseases, and to pharmaceutical compositions containing them.
• the novel compounds of the present invention are useful as competitive inhibitors of tryptase- like serine proteases, particularly thrombin.
• Thrombosis is caused by a series of complex reactions that cause blood clotting.
• the normal coagulation cascade of living organisms can quickly and securely seal the damaged vessel wall, thus avoiding bleeding.
• Uncontrolled activation of coagulation system or lack of inhibition mechanisms during activation processes may result in a variety of related diseases or complications, for example: Deep Venous Thrombosis (DVT), Pulmonary Embolism (PE), Myocardial Infarction or Cerebral Infarction, Atrial Fibrillation, and the like.
• DVT Deep Venous Thrombosis
• PE Pulmonary Embolism
• Myocardial Infarction or Cerebral Infarction Atrial Fibrillation, and the like.
• thrombin inhibitors There are two main types of oral anticoagulant drugs currently on the market: direct thrombin inhibitors and direct factor Xa inhibitors.
• Blood coagulation is the result of a complex series of enzymes, a key step in which endogenous and exogenous chain reactions lead to the activation of prothrombin to thrombin by multiple amplification steps.
• Thrombin is a tryptase-like serine protease that acts to hydrolyze fibrinogen to form insoluble fibrous aggregates, triggering coagulation and platelet aggregation, and plays a key role in the blood coagulation cascade. Therefore, inhibition of thrombin activity can block the formation of thrombus.
• Dabigatran etexilate marketed in 2008, is currently the only orally effective direct thrombin inhibitor.
• dabigatran etexilate can be used as an alternative to warfarin, and as one of the first choices for preventing stroke and systemic embolism in patients with nonvalvular atrial fibrillation (NVAF) and preventing postoperative deep vein thrombosis.
• NVAF nonvalvular atrial fibrillation
• dabigatran etexilate has a low oral bioavailability and is mainly excreted by the kidneys, so it still has its defects.
• convenient treatment of thrombosis, effective selectivity, and oral bioavailable thrombin inhibitors have represented an attractive option.
• the present invention provides a novel orally administrable series of compounds which have significant antithrombotic effects and which have good stability, solubility, pharmacokinetic properties, low toxicity or long-acting effects.
• methods of preparation, methods of use, for example, for inhibiting thrombin and/or for treating or preventing a thrombin-mediated and/or thrombin-related diseases are also provided.
• the present invention provides the following exemplary embodiments, Embodiments 1-32:
• Embodiment 1 A compound of Formula I, or a pharmaceutically acceptable salt thereof,
• R 1 is hydrogen, an optionally substituted alkyl, an optionally substituted alkenyl, or an optionally substituted alkynyl, and
• R 2 is hydrogen
• p is an integer ranging from 1-6, and
• R 3 is an optionally substituted alkyl (e.g., an optionally substituted aralkyl or optionally substituted heteroaralkyl), an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted aryl, or an optionally substituted heteroaryl; and
• R 6 is hydrogen, an optionally substituted alkyl (e.g., an optionally substituted aralkyl or optionally substituted heteroaralkyl), an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted aryl, or an optionally substituted heteroaryl;
• an optionally substituted alkyl e.g., an optionally substituted aralkyl or optionally substituted heteroaralkyl
• an optionally substituted alkenyl e.g., an optionally substituted alkynyl
• cycloalkyl e.g., an optionally substituted heterocyclyl
• R 6 is hydrogen, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted aryl, or an optionally substituted hetero
• R 1 and R 2 are not both hydrogen.
• Embodiment 2 The compound of embodiment 1, or a pharmaceutically acceptable salt thereof, wherein R 1 is an optionally substituted Ci -6 alkyl.
• Embodiment 3 The compound of embodiment 1, or a pharmaceutically acceptable salt thereof, wherein R 1 is an unsubstituted Ci -6 alkyl.
• Embodiment 4 The compound of embodiment 1, or a pharmaceutically acceptable salt thereof, wherein R 1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, or tert-butyl.
• R 2 is , and R 3 is an optionally substituted C1-12 alkyl, e.g., unsubstituted or substituted with 1, 2, or 3 substituents each independently selected from hydroxyl, carboxyl, halogen (e.g., F), alkyl (e.g., Ci -6 alkyl), heteroalkyl (e.g., Ci -6 heteroalkyl), alkoxy (e.g., Ci -6 alkoyl), aryl (e.g., phenyl), heteroaryl (e.g, 5 or 6 membered heteroaryl), acyl, sulfonyl, sulfhydryl, alkyl sulphanyl, cycloalkyl, heterocyclyl, amino, alkyl amino, dialkyl amino, cyano, ester group, and trifluoromethyl.
• substituents each independently selected from hydroxyl, carboxyl, halogen (e.g., F), alkyl (e.g
• Embodiment 6 The compound of embodiment 5, or a pharmaceutically acceptable salt thereof, wherein R 3 is a CI alkyl (e.g., methyl) optionally substituted with an optionally
• Embodiment 7 The compound of embodiment 5, or a pharmaceutically acceptable salt thereof, wherein R 3 is an unsubstituted linear or branched C1-12 alkyl (e.g., n-hexyl).
• Embodiment 8 The compound of embodiment 7, or a pharmaceutically acceptable salt thereof, wherein R 3 is an unsubstituted linear or branched Ci -6 alkyl, e.g., ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, or n-hexyl.
• R 3 is an unsubstituted linear or branched Ci -6 alkyl, e.g., ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, or n-hexyl.
• Embodiment 9 The compound of embodiment 5, or a pharmaceutically acceptable salt thereof, wherein R 2 is
• n is an integer ranging from 1-6;
• R 4 is hydrogen, an optionally substituted alkyl (e.g., an optionally substituted aralkyl or heteroaralkyl), an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted aryl, or an optionally substituted heteroaryl.
• Embodiment 10 The compound of embodiment 9, or a pharmaceutically acceptable salt thereof, wherein n is 1, 2, or 3.
• Embodiment 11 The compound of embodiment 9 or 10, or a pharmaceutically acceptable salt thereof, wherein R 4 is hydrogen, a C1-12 alkyl (e.g., a Ci- 6 alkyl e.g., ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, or n-hexyl), phenyl, or benzyl.
• R 4 is hydrogen, a C1-12 alkyl (e.g., a Ci- 6 alkyl e.g., ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, or n-hexyl), phenyl, or benzyl.
• a C1-12 alkyl e.g., a Ci- 6 alkyl e.g., ethyl, n-propyl, isopropyl, n-butyl
• Embodiment 12 The compound of embodiment 5, or a pharmaceutically acceptable salt thereof, wherein R 2 is
• R 5 is hydrogen, an optionally substituted alkyl (e.g., an optionally substituted aralkyl or heteroaralkyl), an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted aryl, or an optionally substituted heteroaryl.
• Embodiment 13 The compound of embodiment 12, or a pharmaceutically acceptable salt thereof, wherein R 5 is hydrogen, a C1-12 alkyl (e.g., a Ci- 6 alkyl), phenyl, or benzyl.
• R 5 is hydrogen, a C1-12 alkyl (e.g., a Ci- 6 alkyl), phenyl, or benzyl.
• Embodiment 14 The compound of any one of embodiments 1-4, or a pharmaceutically
• Embodiment 15 The compound of embodiment 14, or a pharmaceutically acceptable salt thereof, wherein R 6 is hydrogen, or a C1-12 alkyl (e.g., a Ci -6 alkyl).
• Rmbodiment 16 The compound of any one of embodiments 1-4, or a pharmaceutically acceptable salt thereof, wherein R 2 is
• Embodiment 17 The compound of any one of embodiments 1-4, or a pharmaceutically acceptable salt thereof, wherein R 2 is
• Embodiment 18 A compound selected from Compound Nos. 1-19, or a pharmaceutically acceptable salt thereof.
• Embodiment 19 A pharmaceutical composition comprising one or more compounds of any of embodiments 1-18 or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier.
• Embodiment 20 The pharmaceutical composition of embodiment 19, formulated for oral administration, such as tablet, capsule, pulvis, granule, liquid (e.g., oral solution, suspension, emulsion etc.) or syrup.
• Embodiment 21 A method of treating a venous and/or arterial thrombotic disease, comprising administering to a subject in need thereof a therapeutically effective amount of one or more compounds of any of embodiments 1-18 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of embodiment 19 or 20.
• Embodiment 22 The method of embodiment 21, wherein the thrombotic disease is selected from deep leg vein thrombosis, reocclusion after a bypass operation or angioplasty (PT(C)A), occlusion in peripheral arterial disease, pulmonary embolism, disseminated intravascular coagulation, coronary thrombosis, stroke, and the occlusion of a shunt or stent.
• the thrombotic disease is selected from deep leg vein thrombosis, reocclusion after a bypass operation or angioplasty (PT(C)A), occlusion in peripheral arterial disease, pulmonary embolism, disseminated intravascular coagulation, coronary thrombosis, stroke, and the occlusion of a shunt or stent.
• Embodiment 23 A method of reducing the risk of stroke and systemic embolism in a subject with non- valvular atrial fibrillation comprising administering to the subject a
• Embodiment 24 A method of treating deep venous thrombosis and/or pulmonary embolism in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of one or more compounds of any of embodiments 1-18 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of embodiment 19 or 20.
• Embodiment 25 A method of reducing the risk of recurrence of deep venous thrombosis and/or pulmonary embolism in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of one or more compounds of any of embodiments 1-18 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of embodiment 19 or 20.
• Embodiment 26 A method of prophylactic treatment of deep venous thrombosis and/or pulmonary embolism in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of one or more compounds of any of embodiments 1-18 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of embodiment 19 or 20.
• Embodiment 27 The method of embodiment 26, wherein the subject has undergone hip replacement surgery.
• Embodiment 28 A method of treating atherosclerosis, coronary artery disease, cerebral arteriopathy, and/or peripheral arteriopathy in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of one or more compounds of any of embodiments 1-18 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of embodiment 19 or 20.
• Embodiment 29 A method of providing antithrombotic support in thrombolytic treatment, e.g., with rt-PA or streptokinase, in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of one or more compounds of any of embodiments 1- 18 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of embodiment 19 or 20.
• Embodiment 30 A method of preventing long-term restenosis after PT(C)A in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of one or more compounds of any of embodiments 1-18 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of embodiment 19 or 20.
• Embodiment 31 A method of preventing metastasis, the growth of clot-dependent tumours and/or fibrin-dependent inflammatory processes in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of one or more compounds of any of embodiments 1-18 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of embodiment 19 or 20.
• Embodiment 32 The method of any one of embodiments 21-31, wherein the administering is via oral administration.
• One objective of the present invention is to provide a novel orally administrable series of compounds which have significant antithrombotic effects and which have good stability, solubility, pharmacokinetic properties, low toxicity or long-acting effects.
• the present invention provides a novel compound of Formula
• R 1 is hydrogen, an optionally substituted alkyl, an optionally substituted alkenyl, or an optionally substituted alkynyl, and
• R 2 is hydrogen
• p is an integer ranging from 1-6, and
• R 3 is an optionally substituted alkyl (e.g., an optionally substituted aralkyl or optionally substituted heteroaralkyl), an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted aryl, or an optionally substituted heteroaryl; and
• R 6 is hydrogen, an optionally substituted alkyl (e.g., an optionally substituted aralkyl or optionally substituted heteroaralkyl), an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted aryl, or an optionally substituted heteroaryl;
• an optionally substituted alkyl e.g., an optionally substituted aralkyl or optionally substituted heteroaralkyl
• an optionally substituted alkenyl e.g., an optionally substituted alkynyl
• cycloalkyl e.g., an optionally substituted heterocyclyl
• R 6 is hydrogen, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted aryl, or an optionally substituted hetero
• R 1 and R 2 are not both hydrogen.
• R 1 is an optionally substituted Ci-b alkyl, for example, R 1 is an unsubstituted Ci- 6 alkyl, preferably, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec -butyl, or tert-butyl.
• R 2 can be ' 3 ⁇ 4 ⁇ o'
• R 3 is an optionally substituted Ci-i2 alkyl, e.g., unsubstituted or substituted with 1, 2, or 3 substituents each
• hydroxyl independently selected from hydroxyl, carboxyl, halogen (e.g., F), alkyl (e.g., Ci -6 alkyl), heteroalkyl (e.g., Ci -6 heteroalkyl), alkoxy (e.g., Ci-e alkoyl), aryl (e.g., phenyl), heteroaryl (e.g, 5 or 6 membered heteroaryl), acyl, sulfonyl, sulfhydryl, alkyl sulphanyl, cycloalkyl, heterocyclyl, amino, alkyl amino, dialkyl amino, cyano, ester group, and trifluoromethyl.
• halogen e.g., F
• alkyl e.g., Ci -6 alkyl
• heteroalkyl e.g., Ci -6 heteroalkyl
• alkoxy e.g., Ci-e alkoyl
• aryl e.g.
• R 3 can be a C I alkyl optionally substituted with an
• R 3 can be an unsubstituted linear or branched C1-12 alkyl (e.g., n-hexyl).
• R 3 can be an unsubstituted linear or branched Ci -6 alkyl, e.g., ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, or n-hexyl.
• R 2 is
• n is an integer ranging from 1-6;
• R 4 is hydrogen, an optionally substituted alkyl (e.g., an optionally substituted aralkyl or heteroaralkyl), an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted aryl, or an optionally substituted heteroaryl.
• n can be 1, 2, or 3.
• R 4 can be hydrogen, a C1-12 alkyl (e.g., a Ci -6 alkyl e.g., ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, or n-hexyl), phenyl, or benzyl.
• a Ci -6 alkyl e.g., ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, or n-hexyl
• phenyl or benzyl.
• R 2 can be any organic compound
• R 5 is hydrogen, an optionally substituted alkyl (e.g., an optionally substituted aralkyl or heteroaralkyl), an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted aryl, or an optionally substituted heteroaryl.
• R 5 can be hydrogen, a C1-12 alkyl (e.g., a Ci-b alkyl as described herein), phenyl, or benzyl.
• R 2 can be any organic compound
• R 6 can be hydrogen, or a C1-12 alkyl (e.g., a Ci- 6 alkyl).
• R 2 in Formula (I) contains a substituent, such as 1, 2 or 3 substituents
• the "substituent” can be preferably independently selected from C1-4 alkyl (e.g., methyl, ethyl etc.), halogen (especially fluorine), or trifluoromethyl.
• R 2 can be any organic compound
• R 2 can be any organic compound
• R 1 in Formula (I) can be hydrogen. In some embodiments,
• R 2 in Formula (I) can be hydrogen.
• alkyl refers to a straight or branched saturated
• hydrocarbon chain such as a straight or branched saturated hydrocarbon chain containing from 1 to 20 carbon atoms.
• Cx-y alkyl refers to a straight or branched saturated hydrocarbon containing from x to y carbon atoms.
• Ci- 6 alkyl means a straight or branched saturated hydrocarbon having 1 to 6 carbon atoms.
• alkyl groups include, but are not limited to, methyl, ethyl, n- propyl, isopropyl, n-butyl, sec -butyl, isobutyl, tert-butyl, n-pentyl, isopentyl , neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n- decyl and n-decyl.
• alkenyl refers to a straight or branched hydrocarbon chain containing at least one carbon-carbon double bond, such as a straight or branched hydrocarbon chain containing from 2 to 20 carbons and containing at least one carbon- carbon double bond.
• Cx-y alkenyl refers to a straight or branched hydrocarbon chain containing from x to y carbon atoms containing at least one carbon- carbon double bond.
• C3-6 alkenyl refers to an alkenyl group containing from 3 to 6 carbon atoms.
• alkenyl include, but are not limited to, butane-2, 3-dienyl, vinyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4- pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl- l-heptenyl and 3-decenyl.
• alkynyl refers to a straight or branched alkyne group containing at least one carbon-carbon triple bond, such as a straight or branched chain containing from 2 to 20 carbon atoms and containing at least one carbon-carbon triple bond.
• Cx-y alkynyl refers to a straight or branched hydrocarbon group containing from x to y carbon atoms.
• C3-6 alkynyl refers to a straight or branched chain hydrocarbon radical containing from 3 to 6 carbon atoms and containing at least one carbon-carbon triple bond.
• alkynyl include, but are not limited to, ethynyl, l-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and l-butynyl.
• heteroalkyl refers to a group in which one or more ChF or CH in an alkyl group is replaced by independently selected O, S, S(O), SO2, N or NH.
• aralkyl refers to an alkyl group substituted with one or more independently selected aryl groups.
• heteroarylkyl refers to an alkyl group substituted with one or more independently selected heteroaryl groups.
• alkoxy refers to "0-R a ", wherein R a is alkyl.
• cycloalkoxy refers to "0-R a " wherein R a is cycloalkyl or heterocycloalkyl.
• cycloalkyl refers to a monocyclic or bridged
• Monocyclic cycloalkyl groups are carbocyclic systems containing from 3 to 10 carbon atoms, zero heteroatoms, saturated or unsaturated (non aromatic rings).
• saturated monocyclic systems include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
• a saturated monocyclic ring may contain one or two alkylene bridges, each comprising one, two or three carbon atoms, each bridge connecting two non-adjacent carbon atoms of the ring system.
• bridged cycloalkyl ring systems include, but are not limited to, bicyclo [3.1.1] heptane, bicyclo [2.2.1] heptane, bicyclo [2.2.2] octane, Bicyclo[3.2.2]decane, bicyclo[3.3.l]decane, bicyclo[4.2.l]nonane, tricyclo[3.3.l.O 3,7]decane (octahydro-2,5-methylenecyclopentadiene or noradamantane) and
• Some unsaturated monocyclic rings may contain an olefinic bond having four to ten carbon atoms and zero heteroatoms.
• a four-membered ring system can have one double bond
• a five- or six- membered ring system can have one or two double bonds
• a seven- or eight-membered ring system can have one, two or three double bonds
• a nine- or ten-membered ring can have one or two, three or four double bonds.
• unsaturated monocyclic cycloalkyl include, but are not limited to, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.
• the unsaturated monocyclic ring may also contain one or two alkylene bridges, each comprising one, two or three carbon atoms, each bridging two non-adjacent carbon atoms of the ring system.
• unsaturated bridged rings containing olefinic bonds include, but are not limited to, 4,5,6,7-tetrahydro-3aH-indane, octahydronaphthyl, and l,6-dihydro- cyclopentadiene.
• Monocyclic and bridged cycloalkyl groups can be attached to the parent molecular moiety through any substitutable atom contained within the ring system
• heterocycle or “heterocycloalkyl” or “heterocycloalkylene” as used herein, refers to a monocyclic or bridged three, four, five, six, seven or eight membered ring system containing at least one heteroatom, saturated or unsaturated (non- aromatic), the heteroatoms being independently selected from the group consisting of O, N and S.
• the nitrogen and sulfur heteroatoms in the heterocycle can be optionally oxidized, and the nitrogen atom can optionally be quatemized.
• saturated heterocycloalkyl groups include, but are not limited to, morpholinyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, dioxolanyl, tetrahydrofuranyl, thiomorpholinyl, 1 ,4-dioxanyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, oxetane, piperazinyl, imidazolidinyl, azetidine, azepanyl, aziridinyl, diazepanyl, dithiatyl, dithianyl, isoxazolidinyl, isothiazolidinyl, oxadiazolidinyl, oxazolidinyl, pyrazolidinyl, tetrahydrothiophenyl, thiadiazolidinyl, thiazolidinyl, thiomorpholinyl, trithia
• unsaturated heterocycles such as heterocycles containing olefinic bonds include, but are not limited to, l,4,5,6-tetrahydropyridazinyl, 1, 2,3,6- tetrahydropyridyl, dihydropyranyl, imidazolinyl, isothiazolinyl, oxadiazolyl, isoxazolinyl, oxazolinyl, pyranyl, pyrazolinyl, pyrrolinyl, thiadiazolyl, thiazolyl and thiopyranyl.
• Unsaturated heterocycles also include the following:
• the monocyclic and bridged heterocycles can be attached to the parent molecular moiety through any substitutable carbon atom or any substitutable nitrogen atom contained within the ring.
• aryl refers to a monocyclic or polycyclic aromatic ring that does not contain a heteroatom, such as phenyl or naphthyl.
• heteroaryl ring or “heteroaryl” or “heteroarylene” as used herein, refers to 5 or 6 membered aromatic ring having at least one carbon atom and one or more independently selected nitrogen, oxygen or sulfur atom.
• the heteroaryl ring of the present invention can be attached through any adjacent atom in the ring, provided that the normal valence is maintained.
• heteroaryl include, but are not limited to, furanyl (including but not limited to: furan-2-yl), imidazolyl (including but not limited to: IH-imidazol-l-yl), isoxazolyl, isothiazolyl, oxadiazolyl, l,3-oxazolyl, pyridyl (e.g., pyridin-4-yl, pyridin-2-yl and pyridin-3-yl), pyridazinyl, pyrimidinyl , pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, l,3-thiazolyl, thienyl (including but not limited to: thiophen-2-yl and thiophen-3-yl), triazolyl and triazinyl.
• heteroaryl include the structural unit represented by formula (II):
• modified can be unsubstituted or substituted, for example, substituted with 1, 2 or 3 substituents.
• substituent such as 1, 2 or 3 substituents
• the "substituent” can be independently selected from the group consisting of hydroxyl, carboxyl, halogen, alkyl, alkoxy, aryl, heteroaryl, acyl, sulfonyl, - SH, alkylthio, cycloalkyl, heterocycloalkyl, amino, alkylamino, dialkylamino, cyano, ester or trifluoromethyl, each of the foregoing (e.g., alkyl, etc.) can be further optionally substituted with, for example, 1, 2 or 3 independently selected substituents.
• the "substituent” can be preferably independently selected from Ci- 4 alkyl (e.g., methyl, ethyl etc.), halogen (especially fluorine), or trifluoromethyl.
• optionally substituted alkyl includes unsubstituted alkyl, and also includes alkyl substituted with 1, 2 or 3 substituents independently selected from hydroxy, carboxy, halo (e.g., F), alkyl (e.g., Ci- 6 alkyl), heteroalkyl (e.g., Ci - 6 heteroalkyl), alkoxy (e.g., Ci- 6 alkoxy), aryl (e.g., phenyl), heteroaryl (e.g., 5 or 6 membered heteroaryl), acyl, sulfonyl, - SH, alkylthio, cycloalkyl, heterocycloalkyl, amino, alkylamino, dialkylamino, cyano, ester and trifluoromethyl.
• substituents independently selected from hydroxy, carboxy, halo (e.g., F), alkyl (e.g., Ci- 6 alkyl), heteroalkyl (e.g., Ci
• Compounds of the present invention may also exist in the form of hydrates or solvates. Exemplary embodiments of compounds of the present invention include those described in Embodiments 1-18. Those skilled in the art would understand that Compounds of the present invention may also exist in a tautomeric mixture.
• Compounds of the present invention contain an asymmetric carbon atom in R or S configuration.
• the two chiral centers of formula (I) of the present invention are present predominantly in the configuration shown, for example, greater than 80% ee for each chiral center.
• the configuration shown in Formula (I) is about 85% to 90% more than the other configuration, more preferably about 95% to 99%, more preferably about 99%, or the other configuration cannot be detected.
• Compounds of the present invention may exist in isotopically labeled or enriched forms comprising one or more atoms having an atomic mass or mass number different from the atomic mass or mass number of the largest amount found in nature.
• An isotope can be a radioactive or non-radioactive isotope.
• Isotopes of atoms such as hydrogen, carbon, phosphorus, sulfur, fluorine, chlorine and iodine include, but are not limited to:
• Certain preferred specific compounds of the present invention include but are not limited to the following:
• the present disclosure also includes pharmaceutically acceptable salts of the compounds herein.
• the compounds of formula (I) of the present invention are useful for mediating the activity of tryptase-like serine proteases. More specifically, compounds of the present invention are useful as anticoagulants and agents for modulating or inhibiting the activity of tryptase-like serine proteases, thereby treating thromboembolic diseases and other related cardiovascular diseases.
• suitable acids include, but are not limited to, sulfuric acid, sulfurous acid, hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, metaphosphoric acid,
• pyrophosphoric acid maleic acid, fumaric acid, succinic acid, citric acid, malic acid, perchloric acid, Tartaric acid, formic acid, acetic acid, propionic acid, heptanoic acid, oxalic acid, benzoic acid, salicylic acid, cinnamic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, lactic acid, nicotinic acid, and mandelic acid.
• a second object of the present invention is to provide a process for the preparation of a compound of formula (I), which comprises preparing a final product starting from an N-protected amino acid.
• the process can be carried out with similar conventional reactions known in the art (compounds of the invention can be prepared according to the following general procedures). Starting materials, reagents, techniques and methods used in the synthetic routes are also known and understood by those skilled in the art.
• a protected amino acid such as N-tert-butoxycarbonyl-D-leucine can be coupled with a desired amine using a coupling agent such as EDCI/HOBt.
• the product can then be converted into an amidine through hydrogenation.
• a R 2 group can then be attached to the amidine.
• the deprotected product can then be converted into the final compound with a nucleophilic substitution reaction.
• Protected amino acid to which the modifying group has been attached, can be coupled with a desired amine using a coupling agent such as EDCI/HOBt.
• the coupling product can then be converted into an amidine after removing the protecting group by hydrogenation.
• a R 2 group can then be attached to the amidine.
• the deprotected product can then be converted into the final compound with a nucleophilic substitution reaction.
• the amide coupling reaction can use a standard peptide coupling method, for example, those mediated by an azide, a mixed acid anhydride, a carbodiimide (dicyclohexylcarbodiimide DCC, diisopropylcarbodiimide EDC), an active ester, a carbonyl diimidazole, a phosphorus reagent such as a BOP-C1.
• a standard peptide coupling method for example, those mediated by an azide, a mixed acid anhydride, a carbodiimide (dicyclohexylcarbodiimide DCC, diisopropylcarbodiimide EDC), an active ester, a carbonyl diimidazole, a phosphorus reagent such as a BOP-C1.
• Some of these methods (especially the carbodiimide method) can be facilitated by addition of l-hydroxybenzotriazole.
• the process can be carried out under an inert gas
• Suitable acid scavengers include organic tertiary amines such as diisopropylethylamine, triethylamine, trimethylamine, pyridine, N- methylmorpholine or the like, preferably N-methylmorpholine or diisopropylethylamine.
• the above coupling reaction is usually carried out in an anhydrous solvent.
• Examples of useful solvents include, but are not limited to, dichloromethane, tetrahydrofuran, diethyl ether, acetonitrile, dichloroethane, ethyl acetate, N,N- dimethylformamide, and dimethyl sulfoxide.
• the reaction temperature is usually not critical, preferably the reaction is carried out at 0 to 30 0 C for 2 to 24 hours.
• N-deprotection can be carried out by a conventional method such as acid mediated hydrolysis, such as using an organic acid such as trifluoroacetic acid, benzenesulfonic acid, formic acid or the like, or a mineral acid such as hydrochloric acid, sulfuric acid, hydrobromic acid or the like; a base-mediated hydrolysis, such as using an alkali metal or alkaline earth metal hydroxide, hydride, carbonate or hydrogencarbonate such as sodium hydroxide, potassium hydroxide, sodium hydride, potassium carbonate, sodium hydrogencarbonate, etc., or an organic base such as diisopropylethylamine, triethylamine, piperidine, etc.; or hydrogenolysis in the presence of a catalyst such as a metal catalyst such as palladium, platinum, or nickel. Suitable methods can also be found in "Protective Groups in Organic Synthesis" Third Edition, T.W. Green and Peter G.M. Wuts (1999), Publisher: John Wiley &
• removing the amino protecting group can be carried out in a solvent that does not adversely influence the reaction.
• useful solvents include:
• reaction temperature is usually not critical, preferably 0 to 40 °C.
• N-alkylation can be carried out with a nucleophilic substitution.
• nucleophilic substitution reagents include, but are not limited to, alkyl bromides, alkyl iodides, alkyl chlorides, alkyl sulfonates, alkyl benzene sulfonates, alkyl p-toluene sulfonates, alkyl mesylate or a reagent containing a sulfate group such as dimethyl sulfate. Alkyl iodide or alkyl p-toluenesulfonate is preferred.
• Nucleophilic substitution reactions are generally carried out in the presence of an acid scavenger, and appropriate acid scavengers can be an inorganic base, such as alkali or alkaline earth metal hydroxides, hydrides, carbonates, hydrogencarbonates, hydrogen phosphates such as sodium hydroxide, sodium hydride, potassium carbonate, dipotassium hydrogen phosphate, etc., or organic bases such as diisopropylethylamine, triethylamine, trimethylamine, pyridine, N-methylmorpholine or the like, preferably dibasic potassium hydrogen phosphate or diisopropylethylamine.
• an inorganic base such as alkali or alkaline earth metal hydroxides, hydrides, carbonates, hydrogencarbonates, hydrogen phosphates such as sodium hydroxide, sodium hydride, potassium carbonate, dipotassium hydrogen phosphate, etc.
• organic bases such as diisopropylethylamine, triethylamine, trimethylamine,
• Examples of useful solvents include, but are not limited to, tetrahydrofuran, dioxane, acetonitrile, acetone, N,N- dimethylformamide, and the like.
• the reaction temperature can be adjusted, preferably 20 to 80 °C.
• the product of each step can be purified by methods known in the art such as column chromatography and recrystallization.
• a third object of the present invention is to provide a use of compounds of the formula (I) for inhibiting thrombin and for the use in the prevention and/or treatment of thrombin-mediated and/or thrombin-related diseases.
• representative compounds of formula (I) were shown to have significant antithrombotic effects in animal models.
• the methods of using Compounds of the present invention typically include administering a compound of the present invention, such as a compound of formula (I), such as any one or more of compounds 1-19, or a pharmaceutically acceptable salt, to a subject in need thereof (e.g., in need of prevention or treatment of any of the thrombin-mediated or thrombin-related disease described herein) in an effective amount, such as in a therapeutically effective amount.
• a compound of the present invention such as a compound of formula (I), such as any one or more of compounds 1-19, or a pharmaceutically acceptable salt
• the Compounds of the present invention can be used in replacement of dabigatran etexilate for any of the indications that dabigatran etexilate is indicated as useful.
• Non-limiting indications that dabigatran etexilate is indicated as useful include any of the US FDA approved indications for dabigatran etexilate mesylate (Pradaxa), indications approved by similar agencies outside of the U.S., and any of such indications that dabigatran etexilate is indicated as useful as described in U.S. Patent Nos. 6,087,380, 7,866,474, 7,932,273, 9,034,822, and 9,925,174, the content of each of which is incorporated by reference in its entirety.
• Compounds of the present invention are useful in the prevention and/or treatment of thrombin-mediated and thrombin-related diseases.
• the present invention provides a use of a compound of the present invention, such as a compound of formula (I), such as any one or more of compounds 1-19, or a pharmaceutically acceptable salt, for the prevention and/or treatment of thrombotic diseases, especially venous or arterial thromboembolism, such as deep vein thrombosis in the lower limb, reocclusion after bypass surgery or angioplasty, obstruction of peripheral arterial disease, coronary thromboembolism, etc.
• a compound of the present invention such as a compound of formula (I), such as any one or more of compounds 1-19, or a pharmaceutically acceptable salt, for the prevention and/or treatment of thrombotic diseases, especially venous or arterial thromboembolism, such as deep vein thrombosis in the lower limb, reocclusion after bypass surgery or angioplasty, obstruction of peripheral arterial disease, coronary
• the present invention provides a method of treating or preventing a thrombotic disease, such as venous or arterial thromboembolism, such as deep vein thrombosis in the lower limb, reocclusion after bypass surgery or angioplasty, obstruction of peripheral arterial disease, coronary thromboembolism, the method comprising administering a compound of the present invention, such as a compound of formula (I), such as any one or more of compounds 1- 19, or a pharmaceutically acceptable salt, to a subject in need thereof in an effective amount, such as in a therapeutically effective amount.
• a thrombotic disease such as venous or arterial thromboembolism, such as deep vein thrombosis in the lower limb, reocclusion after bypass surgery or angioplasty, obstruction of peripheral arterial disease, coronary thromboembolism
• a compound of the present invention such as a compound of formula (I), such as any one or more of compounds 1- 19, or a pharmaceutically acceptable salt
• the present invention provides a use of a compound of the present invention, such as a compound of formula (I), such as any one or more of compounds 1-19, or a pharmaceutically acceptable salt, for the prevention and/or treatment of thrombosis related diseases or disorders such as stroke, pulmonary embolism, myocardial or cerebral infarction, atrial fibrillation and arrhythmia.
• a compound of the present invention such as a compound of formula (I), such as any one or more of compounds 1-19, or a pharmaceutically acceptable salt
• the present invention provides a method of treating or preventing a thrombosis related disease or disorder, such as one or more diseases or disorders selected from stroke, pulmonary embolism, myocardial or cerebral infarction, atrial fibrillation and arrhythmia, the method comprising administering a compound of the present invention, such as a compound of formula (I), such as any one or more of compounds 1- 19, or a pharmaceutically acceptable salt, to a subject in need thereof in an effective amount, such as in a therapeutically effective amount.
• a thrombosis related disease or disorder such as one or more diseases or disorders selected from stroke, pulmonary embolism, myocardial or cerebral infarction, atrial fibrillation and arrhythmia
• a compound of the present invention such as a compound of formula (I), such as any one or more of compounds 1- 19, or a pharmaceutically acceptable salt
• the present invention provides a use of a compound of the present invention, such as a compound of formula (I), such as any one or more of compounds 1-19, or a pharmaceutically acceptable salt, for the prevention and/or treatment of atherosclerotic diseases such as Coronary artery disease, cerebral arterial disease, and peripheral arterial disease.
• a compound of the present invention such as a compound of formula (I), such as any one or more of compounds 1-19, or a pharmaceutically acceptable salt, for the prevention and/or treatment of atherosclerotic diseases such as Coronary artery disease, cerebral arterial disease, and peripheral arterial disease.
• the present invention provides a method of treating or preventing an atherosclerotic disease or disorder, such as one or more diseases or disorders selected from Coronary artery disease, cerebral arterial disease, and peripheral arterial disease, the method comprising administering a compound of the present invention, such as a compound of formula (I), such as any one or more of compounds 1-19, or a pharmaceutically acceptable salt, to a subject in need thereof in an effective amount, such as in a therapeutically effective amount.
• an atherosclerotic disease or disorder such as one or more diseases or disorders selected from Coronary artery disease, cerebral arterial disease, and peripheral arterial disease
• a compound of the present invention such as a compound of formula (I), such as any one or more of compounds 1-19, or a pharmaceutically acceptable salt
• the present invention provides a use of a compound of the present invention, such as a compound of formula (I), such as any one or more of compounds 1-19, or a pharmaceutically acceptable salt, for the prevention and/or treatment of any oncological disease.
• the present invention provides a method of treating or preventing an oncological disease or disorder, the method comprising administering a compound of the present invention, such as a compound of formula (I), such as any one or more of compounds 1-19, or a
• Compounds of the present invention can also act as anticoagulants in in vitro or ex vivo blood lines.
• the present invention provides a method of inhibit coagulation in in vitro or ex vivo blood lines, the method comprising adding a compound of the present invention, such as a compound of formula (I), such as any one or more of compounds 1-19, or a pharmaceutically acceptable salt, to in vitro or ex vivo blood line in an effective amount.
• the present invention provides a method of reduce reperfusion time and/or prolong reocclusion time, the method comprising administering a compound of the present invention, such as a compound of formula (I), such as any one or more of compounds 1-19, or a pharmaceutically acceptable salt, to a subject in need thereof in an effective amount, wherein the subject is also administered a thrombolytic agent.
• a compound of the present invention such as a compound of formula (I), such as any one or more of compounds 1-19, or a pharmaceutically acceptable salt
• compounds of the present invention can be used to prevent the re-formation of thrombi after microsurgery.
• the present invention provides a method of preventing re-formation of thrombi after microsurgery, the method comprising administering a compound of the present invention, such as a compound of formula (I), such as any one or more of compounds 1-19, or a pharmaceutically acceptable salt, to a subject in need thereof in an effective amount.
• a compound of the present invention such as a compound of formula (I), such as any one or more of compounds 1-19, or a pharmaceutically acceptable salt
• the present invention provides a method of providing a hemodialysis and anticoagulant therapy for disseminated intravascular coagulation, the method comprising administering a compound of the present invention, such as a compound of formula (I), such as any one or more of compounds 1-19, or a pharmaceutically acceptable salt, to a subject in need thereof in an effective amount.
• a compound of the present invention such as a compound of formula (I), such as any one or more of compounds 1-19, or a pharmaceutically acceptable salt, to a subject in need thereof in an effective amount.
• Compounds of the present invention are also useful for the in vitro preservation of blood, plasma and other blood products.
• the present invention provides a method of preserving blood, plasma, or other blood products, the method comprising adding a compound of the present invention, such as a compound of formula (I), such as any one or more of compounds 1-19, or a pharmaceutically acceptable salt, to the blood, plasma or other blood product, e.g., in an effective amount to prevent coagulation of the blood, plasma or other blood product.
• a compound of the present invention such as a compound of formula (I), such as any one or more of compounds 1-19, or a pharmaceutically acceptable salt
• Compounds of the present invention can be administered orally.
• the amount will depend on the particular circumstances of the treated subject, including the route of administration, the frequency of administration, the condition being treated, and the like.
• a typical oral daily dose can be between about 0.01 mg/kg and about 1000 mg/kg. It can be a single daily dose, or multiple doses per day such as 2 to 4 times a day.
• the dosage and mode of administration can be adjusted depending on the age and weight of the patient as well as the severity of the condition treated.
• the subject herein is an animal, preferably a mammal, most preferably a human.
• a fourth object of the present invention is to provide a pharmaceutical
• composition which comprises a compound of the present invention, such as a compound of formula (I) (such as any one or more of compounds 1-19) or pharmaceutically acceptable salts, and optionally one or more pharmaceutically acceptable excipients.
• a compound of the present invention such as a compound of formula (I) (such as any one or more of compounds 1-19) or pharmaceutically acceptable salts, and optionally one or more pharmaceutically acceptable excipients.
• compounds of the present invention can be in the form of a tablet, a capsule, a powder, a granule, a liquid preparation (for example, an oral solution, a suspension, an emulsion, etc.) or a syrup, which can contain a pharmaceutically acceptable excipient such as a lubricant, a binder, a disintegrant, a filler, a dispersing agent, an emulsifier, a stabilizer, and the like.
• a pharmaceutically acceptable excipient such as a lubricant, a binder, a disintegrant, a filler, a dispersing agent, an emulsifier, a stabilizer, and the like.
• a suitable dilute acid or base or buffer salt can be added to adjust the pH, which can also include an antioxidant or a metal chelating agent.
• the solution can be sterilized by filtration and filled under sterile conditions in a sterile ampoules.
• tablets can be prepared by thoroughly mixing the compound(s) of the present invention with excipients (such as microcrystalline cellulose, sodium carboxymethyl starch, com starch, magnesium stearate, talc, etc.) to provide a mixture, which can then be sieved, and compressed using a tablet machine.
• excipients such as microcrystalline cellulose, sodium carboxymethyl starch, com starch, magnesium stearate, talc, etc.
• a hard capsule can be prepared by sieving the compound(s) of the present invention with an excipient (e.g., dry starch, magnesium stearate, etc.) and then filling the mixture into a hard gelatin capsule using suitable equipment.
• the compound(s) of the present invention can be sieved and mixed with excipients such as sodium carboxymethylcellulose and syrup to form a uniform paste.
• excipients such as sodium carboxymethylcellulose and syrup
• pigment, benzoic acid, etc. can be diluted with a portion of purified water, which can then be added to the paste with agitation. Water is then added to produce a desired volume.
• Other methods of preparing pharmaceutical compositions, excipients and the like can be found in Remington's Pharmaceutical Sciences, l8th Ed., Alfonso R. Gennaro (1990), publisher: Mack Publishing Company and its updates.
• the pharmaceutical composition of the present invention can be a solid, semi solid or liquid preparation made by conventional techniques. These methods include, for example, mixing, dissolving, granulating, grinding, emulsifying, embedding, spray drying or freeze drying.
• the active ingredient in such compositions can comprise from 0.1% to 99.9% by weight of the formulation.
• the carrier, diluent or excipient used in the compositions are compatible with the active ingredient and are pharmaceutically acceptable.
• Compounds of the present invention typically have improved properties, characterized by excellent solubility, rapid activation, good oral bioavailability, significant biological activity, and low toxicity.
• One advantage of compounds of the present invention is that they can be absorbed in the gastrointestinal tract.
• Compounds of the present invention have higher lipophilicity relative to the compound of formula (V), which enhances passive diffusion of the compounds of the present invention across the lipid bilayer cell membrane. Therefore, compounds of the present invention can have significantly improved oral bioavailability. Further, compounds of the present invention can be rapidly absorbed and metabolized into the active compound of formula (V).
• In vitro and in vivo studies show that representative compounds formula (I) can be hydrolyzed into a compound of formula (III) and/or formula (IV) with an esterase and ultimately converted into a compound of formula (V), without interaction with the cytochrome P450 enzyme system. Therefore, there is less risk of drug interactions.
• Example 22 shows that a single injection of the compound of formula (V) at 10 mg/kg of provided superior anti-thrombotic activity compared to dabigatran and melagatran; and a single oral dose of 10 mg/kg of the compounds of formula (I)
• solubility tests show that compounds of the present invention have very good water solubility at acidic pH, therefore can have various advantages to the production and application of the drug. For example, it is not necessary to use complex and costly formulation techniques and allows optimization of the mode of administration (e.g., oral) and patient compliance.
• Tetramethylsilane is used as the internal standard, and chemical shifts (d) are recorded in ppm.
• Thin-layer chromatography(TLC, using HSG-F254 high performance silica gel prefabricated panel for the chromatography, made in Yantai Zhifu Huangwu silica gel development and pilot plant) and HPLC are used for detection of the reaction and purity of the product. Iodine vapor or irradiation with 254A and 310A ultraviolet lamp or 1 % ninhydrin solution in ethanol is used for color development for visualization. Unless specially stated, all the reagents used are analytically pure, and anhydrous solvent and reagents are treated according to conventional methods. Melting points are determined by micrographic melting point apparatus, and the thermometer used is non- corrected.
• HPLC Agilent 1100; detection wavelength: 220 and 254nM; column temperature:
• Mobile Phase 1 A: 0.1% trifluoroacetic acid aqueous solution B: acetonitrile;
• Method 1 Chromatographic column: Sunfire Cl8(4.6x50mm, 3.5pm); flow rate: 2 ml/min; mobile phase A from 95% to 5%, gradient elution for 3 minutes;
• Method 2 Chromatographic column: XDB Cl8(4.6xl50mm, 5pm); flow rate
• rats in the model group were given either intravenous injection or intragastric administration with equivalent solvent, those in the positive or compound group were given either intravenous injection or intragastric administration in a dose of lOmg/kg.
• Intragastric solution preparation proper amount of the test chemical was weighed, and dissolved in DMSO to give the stock solution, which was then diluted serially with 0.5% CMC-Na solution to the required concentration of administration dosage.
• IV solution preparation proper amount of compound (V) was weighed, and
• Rats were orally given 10 mg/kg of the test compound via gavage for oral study or given 2 mg/kg of compound (V) via the femoral vein for intravenous (i.v.) study.
• Blood samples were collected from the orbitat at l5min, 30min, lh, l.5h, 2h, 4h, 6h, 8h, lOh, and 24h after dosing and were analyzed by LC-MS/MS after pretreatment.
• WPS software was used to calculate the mean value, standard deviation, precision and accuracy of each sample.
• IV solution preparation proper amount of compound (V) was weighed, and
• Dogs were orally given 5 mg/kg of the test compound via gavage for oral study or given 2 mg/kg of compound (V) via the femoral vein for intravenous (i.v.) study.
• Blood samples were collected at l5min, 30min, lh, l.5h, 2h, 4h, 6h, 8h, lOh, and 24h after dosing and were analyzed by LC-MS/MS after pretreatment.
• WPS software was used to calculate the mean value, standard deviation, precision and accuracy of each sample.

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