WO2017123518A1 - Immunomodulateurs d'aminotriazole pour traiter des maladies auto-immunes - Google Patents

Immunomodulateurs d'aminotriazole pour traiter des maladies auto-immunes Download PDF

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WO2017123518A1
WO2017123518A1 PCT/US2017/012796 US2017012796W WO2017123518A1 WO 2017123518 A1 WO2017123518 A1 WO 2017123518A1 US 2017012796 W US2017012796 W US 2017012796W WO 2017123518 A1 WO2017123518 A1 WO 2017123518A1
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compound according
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triazol
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Jan L. BRESLOW
Manish P. PONDA
Harold Selnick
Melissa Egbertson
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The Rockefeller University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the invention relates to l-acyl-3-(heteroaryl)-lH-l,2,4-triazol-5-amines that selectively inhibit Coagulation Factor Xlla in the presence of thrombin and other coagulation factors. These compounds are useful to treat autoimmune diseases.
  • Chemotaxis is directional movement in response to a specific chemical gradient. This cellular ability is necessary for immune homeostasis and the response to inflammation, among other critical biologic processes.
  • chemokines have been identified along with their receptors, providing a molecular mechanism to orchestrate movement of distinct cell types in response to diverse stimuli.
  • CCR7 and its ligands, CCL19 and CCL21 comprise a signaling axis required for chemotaxis of T-cells into and within lymphoid organs.
  • CCR7 -mediated chemotaxis is important in developing adaptive immunity, as well as maintaining tolerance and memory.
  • Chemokines are broadly grouped as homeostatic or inflammatory. For the latter, acutely increasing production may be sufficient to control a chemotactic response.
  • homeostatic chemokines such as CCL 19/21
  • signal modulation occurs by altering receptor density or effective ligand concentration. This is achieved either directly (e.g. increased receptor expression) or indirectly (e.g. atypical chemokine receptor scavenging of ligands).
  • CCR7 exposure to serum promotes cell migration, and there is an enhanced chemotactic response of T-cells to CCL19/21 in the presence of serum, although the basis for this acceleration has not been previously described in the literature.
  • HK high molecular weight kininogen
  • FXIIa active coagulation factor XII
  • a circulating cofactor that is activated at sites of inflammation and injury to enhance lymphocyte chemotaxis represents a new and powerful mechanism coupling inflammation to adaptive immunity.
  • small molecule therapeutic agents that can modulate FXIIa function - and thereby production of the HK fragment - without significantly affecting thrombin activation offer a means of safely regulating immune cell chemotaxis through humoral cofactors.
  • the invention relates to method for treating inflammation in a patient comprising administering to the patient a therapeutically effective amount of a compound of formula I
  • Ar/A is a fused bicycle in which Ar is an aromatic 5 or 6-membered ring and A is a non- aromatic 5, 6 or 7-membered ring and the point of attachment to the acyl triazole is on the non-aromatic ring;
  • R 1 is phenyl or an aromatic monocyclic heterocycle, said phenyl or heterocycle optionally substituted with one or more of: halogen, (Ci-C4)alkyl, (Ci-C4)alkoxy, (Ci-C4)fluoroalkyl, (Ci-C4)fluoroalkoxy and di(Ci-C4)alkylamino;
  • R 2 and R 3 are attached to Ar/A at a carbon and are chosen independently from hydrogen, halogen, hydroxy, amino, (Ci-C4)alkyl, (Ci-C4)alkoxy, (Ci-C4)alkylamino, di(Ci- C4)alkylamino, (Ci-C4)acylamino, (Ci-C4)fluoroalkyl and (Ci-C4)fluoroalkoxy;
  • R 4 is hydrogen or, when Ar/A contains a nitrogen, R 4 is attached to nitrogen and is chosen from hydrogen, (Ci-Cio)hydrocarbyl, and benzyl substituted with one to three substituents chosen from halogen, hydroxy, amino, (Ci-C4)alkyl, (Ci-C4)alkoxy, (Ci-C4)alkylamino, di(Ci-C4)alkylamino, (Ci-C4)acylamino, (Ci-C4)fluoroalkyl and (Ci-C4)fluoroalkoxy; with the proviso that if R 2 or R 3 is other than hydrogen, no non-hydrogen substituent may be attached to the same carbon as the acyl triazole group.
  • the invention relates to a method for treating an immunological disorder comprising administering a compound of formula I.
  • the invention in another aspect, relates to a method for treating vasodilatation comprising administering a compound of formula I.
  • the invention relates to compounds of formula I.
  • the invention relates to pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a compound of formula I.
  • the invention relates to compounds of formula I:
  • Ar/A is a fused bicycle in which Ar is an aromatic 5 or 6-membered ring and A is a non-aromatic 5, 6 or 7-membered ring and the point of attachment to the acyl triazole is on the non-aromatic ring.
  • A is a 5, 6 or 7-membered nitrogenous heterocycle, preferably an N-alkylated heterocycle.
  • the acyltriazole is attached to A at a carbon and one of R 2 , R 3 and R 4 is (Ci-C4)alkyl and is attached to the nitrogen of A.
  • A is a 5, 6 or 7-membered oxygen heterocycle; in some A is a 5, 6 or 7-membered sulfur heterocycle; in some, A is a 5, 6 or 7- membered carbocycle, and in particular, a 6-membered carbocycle.
  • Ar may be chosen from benzene, pyridine, pyrrole, thiophene and furan.
  • Exemplary embodiments of the Ar/A fused bicycle include:
  • Q is O, S or NR 4 ;
  • W 1 , W 2 and W 3 is chosen from O, S and NR 5 and the other two of W 1 , W 2 and W 3 are saturated carbons to which any of R 2 , R 3 and R 4 may be attached;
  • R 5 is hydrogen or (Ci-Cio)hydrocarbon, particularly compounds wherein one of W 1 and W 3 is chosen from -O- and -N(CH 3 )-;
  • R 1 may be an aromatic monocyclic heterocycle, optionally substituted with one or more of: halogen, (Ci-C4)alkyl, (Ci-C4)alkoxy, (Ci- C4)fluoroalkyl and (Ci-C4)fluoroalkoxy.
  • exemplary aromatic heterocyclic rings include furanyl, thiophenyl, pyrrolyl, pyrimidinyl, pyridazinyl, pyrazinyl, and, preferably, pyridinyl.
  • R 1 may also be optionally substituted phenyl.
  • R 1 is optionally substituted phenyl are those in which A is a six-membered carbocycle or heterocycle, and particularly those in which the triazolylcarbonyl is attached at a carbon of A, and the carbon bearing the triazolylcarbonyl is of the (S) configuration.
  • R 2 and R 3 are chosen independently from hydrogen, halogen, hydroxy, amino, (Ci-C4)alkyl, (Ci-C4)alkoxy, (Ci-C4)alkylamino, di(Ci- C4)alkylamino, (Ci-C4)acylamino, (Ci-C4)fluoroalkyl and (Ci-C4)fluoroalkoxy.
  • R 2 , and R 3 are chosen independently from hydrogen, halogen, (Ci-C4)alkyl, (Ci-C4)alkoxy, di(Ci-C4)alkylamino, (Ci-C4)acylamino, (Ci-C4)fluoroalkyl and (Ci-C4)fluoroalkoxy.
  • at least two of R 2 , R 3 and R 4 are hydrogen.
  • Ar/A contains a nitrogen
  • Ar/A is a tetrahydroindole (see example 8)
  • R 4 is attached to nitrogen
  • R 4 is hydrogen, (Ci-Cio)hydrocarbyl, or substituted benzyl.
  • Preferred benzyl substituents are halogen, (Ci-C4)alkyl, (Ci-C4)alkoxy, di(Ci-C4)alkylamino, (Ci- C4)acylamino, (Ci-C4)fluoroalkyl and (Ci-C4)fluoroalkoxy.
  • Ci to C20 hydrocarbon includes alkyl, cycloalkyl, polycycloalkyl, alkenyl, alkynyl, aryl and combinations thereof. Examples include benzyl, phenethyl, cyclohexylmethyl, adamantyl, camphoryl and naphthyl ethyl. Hydrocarbyl refers to any substituent comprised of hydrogen and carbon as the only elemental constituents. Aliphatic hydrocarbons are hydrocarbons that are not aromatic; they may be saturated or unsaturated, cyclic, linear or branched.
  • aliphatic hydrocarbons examples include isopropyl, 2-butenyl, 2-butynyl, cyclopentyl, norbornyl, etc.
  • Aromatic hydrocarbons include benzene (phenyl), naphthalene (naphthyl), anthracene, etc.
  • alkyl (or alkylene) is intended to include linear or branched saturated hydrocarbon structures and combinations thereof.
  • Alkyl refers to alkyl groups from 1 to 20 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, s- butyl, t-butyl and the like.
  • Cycloalkyl is a subset of hydrocarbon and includes cyclic hydrocarbon groups of from 3 to 8 carbon atoms. Examples of cycloalkyl groups include cy-propyl, cy-butyl, cy-pentyl, norbornyl and the like.
  • carbocycle is intended to include ring systems in which the ring atoms are all carbon but of any oxidation state.
  • C3-C 10 carbocycle refers to both non-aromatic and aromatic systems, including such systems as cyclopropane, benzene and cyclohexene;
  • Cs-Co carbopolycycle refers to such systems as norbornane, decalin, indane and naphthalene.
  • Carbocycle if not otherwise limited, refers to monocycles, bicycles and polycycles.
  • Heterocycle means an aliphatic or aromatic carbocycle residue in which from one to four carbons is replaced by a heteroatom selected from the group consisting of N, O, and S.
  • the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized.
  • a heterocycle may be non- aromatic (heteroaliphatic) or aromatic (heteroaryl).
  • heterocycles include pyrrolidine, pyrazole, pyrrole, indole, quinoline, isoquinoline, tetrahydroisoquinoline, benzofuran, benzodioxan, benzodioxole (commonly referred to as methylenedioxyphenyl, when occurring as a substituent), tetrazole, morpholine, thiazole, pyridine, pyridazine, pyrimidine, thiophene, furan, oxazole, oxazoline, isoxazole, dioxane, tetrahydrofuran and the like.
  • heterocyclyl residues include piperazinyl, piperidinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, tetrahydrofuryl, tetrahydropyranyl, thienyl (also historically called thiophenyl), benzothienyl, thiamorpholinyl, oxadiazolyl, triazolyl and
  • Hydrocarbyloxy refers to groups of from 1 to 20 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms attached to the parent structure through an oxygen.
  • Alkoxy is a subset of hydrocarbyloxy and includes groups of a straight or branched configuration. Examples include methoxy, ethoxy, propoxy, isopropoxy and the like.
  • Lower-alkoxy refers to groups containing one to four carbons.
  • halogen means fluorine, chlorine, bromine or iodine atoms.
  • acyl refers to formyl and to groups of 1, 2, 3, 4, 5, 6, 7 and 8 carbon atoms of a straight, branched, cyclic configuration, saturated, unsaturated and aromatic and combinations thereof, attached to the parent structure through a carbonyl functionality. Examples include acetyl, benzoyl, propionyl, isobutyryl and the like. Lower- acyl refers to groups containing one to four carbons.
  • the double bonded oxygen, when referred to as a substituent itself is called "oxo".
  • substituted refers to the replacement of one or more hydrogen atoms in a specified group with a specified radical.
  • cycloalkylaminoalkyl dialkylaminoalkyl, dialkylaminoalkoxy, heterocyclylalkoxy, mercapto, alkylthio, sulfoxide, sulfone, sulfonyl amino, alkylsulfinyl, alkylsulfonyl, acylaminoalkyl, acylaminoalkoxy, acylamino, amidino, aryl, benzyl, heterocyclyl, heterocyclylalkyl, phenoxy, benzyloxy, heteroaryloxy, hydroxyimino, alkoxyimino, oxaalkyl, aminosulfonyl, trityl, amidino, guanidino, ureido, benzyl oxyphenyl, and benzyloxy.
  • Oxo is also included among the substituents referred to in "optionally substituted”; it will be appreciated by persons of skill in the art that, because oxo is a divalent radical, there are circumstances in which it will not be appropriate as a substituent (e.g. on phenyl).
  • 1, 2, or 3 hydrogen atoms are replaced with a specified radical.
  • more than three hydrogen atoms can be replaced by fluorine; indeed, all available hydrogen atoms could be replaced by fluorine.
  • substituents are halogen, halo(Ci-C4)hydrocarbyl, halo(Ci-C4)hydrocarbyloxy, cyano, thiocyanato, (Ci-C4)hydrocarbylsulfinyl, (Ci-C4)hydrocarbyl-sulfonyl, aminosulfonyl, nitro, acetyl, and acetamido.
  • Preferred substituents are halogen, (Ci-C4)alkyl, (Ci-C4)alkoxy, (Ci- C4)fluoroalkyl, (Ci-C4)fluoroalkoxy, hydroxy, amino, (Ci-C4)alkylamino, di(Ci- C4)alkylamino, (Ci-C4)acylamino, (Ci-C4)fluoroalkyl and (Ci-C4)fluoroalkoxy.
  • Preparation of compounds can involve the protection and deprotection of various chemical groups.
  • the need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art. Suitable groups for that purpose are discussed in standard textbooks in the field of chemistry, such as Protective Groups in Organic Synthesis by T.W.Greene and P.G.M.Wuts [John Wiley & Sons, New York, 1999], in Protecting Group Chemistry, 1 st Ed., Oxford University Press, 2000; and in March 's Advanced Organic chemistry: Reactions, Mechanisms, and Structure, 5 th Ed., Wiley-Interscience Publication, 2001.
  • acyltriazolamines may also be found in PCT WO2014/145986, particularly pages 85-101.
  • enantiomerically pure compounds used herein are taken from Maehr J. Chem. Ed. 62, 114- 120 (1985): solid and broken wedges are used to denote the absolute configuration of a chiral element; wavy lines indicate disavowal of any stereochemical implication which the bond it represents could generate; solid and broken bold lines are geometric descriptors indicating the relative configuration shown but denoting racemic character; and wedge outlines and dotted or broken lines denote enantiomerically pure compounds of indeterminate absolute configuration.
  • R* and S* as indicating single enantiomers of unknown absolute configuration.
  • salts may be prepared from pharmaceutically acceptable non-toxic acids including inorganic and organic acids.
  • Suitable pharmaceutically acceptable acid addition salts for the compounds of the present invention include acetic, adipic, alginic, ascorbic, aspartic, benzenesulfonic (besylate), benzoic, boric, butyric, camphoric, camphorsulfonic, carbonic, citric,
  • ethanedi sulfonic ethanesulfonic, ethylenediaminetetraacetic, formic, fumaric, glucoheptonic, gluconic, glutamic, hydrobromic, hydrochloric, hydroiodic, hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulfonic, maleic, malic, mandelic, methanesulfonic, mucic, naphthylenesulfonic, nitric, oleic, pamoic, pantothenic, phosphoric, pivalic, polygalacturonic, salicylic, stearic, succinic, sulfuric, tannic, tartaric acid, teoclatic, p-toluenesulfonic, and the like.
  • suitable pharmaceutically acceptable base addition salts for the compounds of the present invention include, but are not limited to, metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from lysine, arginine, N,N'-dibenzylethylenediamine,
  • chloroprocaine choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium cations and carboxylate, sulfonate and phosphonate anions attached to alkyl having from 1 to 20 carbon atoms.
  • composition comprising a compound disclosed above, or a pharmaceutically acceptable salt form thereof, and a pharmaceutically acceptable carrier or diluent.
  • the present invention provides a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically carriers thereof and optionally one or more other therapeutic ingredients.
  • the carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • the formulations include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous and intraarticular), rectal and topical (including dermal, buccal, sublingual and intraocular) administration.
  • the most suitable route may depend upon the condition and disorder of the recipient.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association a compound of formula I or a pharmaceutically acceptable salt thereof ("active ingredient”) with the carrier which constitutes one or more accessory ingredients.
  • active ingredient a compound of formula I or a pharmaceutically acceptable salt thereof
  • the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
  • Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a
  • the active ingredient may also be presented as a bolus, electuary or paste.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricating, surface active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and may be formulated so as to provide sustained, delayed or controlled release of the active ingredient therein.
  • Formulations for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti -oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient.
  • Formulations for parenteral administration also include aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickening agents.
  • the formulations may be presented in unit-dose of multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of a sterile liquid carrier, for example saline, phosphate-buffered saline (PBS) or the like, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
  • LCMS analyses were performed on a SHIMADZU LCMS consisting of an UFLC 20- AD and LCMS 2020 MS detector.
  • the column used was a Shim-pack XR-ODS, 2.2 ⁇ , 3.0 x 50 mm.
  • a linear gradient was applied, starting at 95 % A (A: 0.05% TFA in water) and ending at 100% B (B: 0.05% TFA in MeCN) over 2.2 min with a total run time of 3.6 min.
  • the column temperature was at 40 °C with the flow rate of 1.0 mL/min.
  • the Diode Array Detector was scanned from 190-400 nm.
  • the mass spectrometer was equipped with an electrospray ion source (ESI) operated in a positive or negative mode. The mass spectrometer was scanned between m/z 90-900 with a scan time from 0.5 to 0.7 s.
  • ESI electrospray ion source
  • HPLC analyses were performed on a SHFMADZU UFLC with two LC20 AD pump and a SPD-M20A Photodiiode Array Detector.
  • the column used was an XBridge C 18 , 3.5 ⁇ , 4 60 x 100 mm. A linear gradient was applied, starting at 90 % A (A: 0.05% TFA in water) and ending at 95% B (B: 0.05% TFA in MeCN) over 10 min with a total run time of 15 min.
  • the column temperature was at 40 °C with the flow rate of 1.5 mL/min.
  • the Diode Array Detector was scanned from 200-400 nm.
  • TLC Thin layer chromatography
  • Flash chromatography was performed using 40-63 ⁇ (230-400 mesh) silica gel from Silicycle following analogous techniques to those disclosed in Still, W.C.; Kahn, M.; and Mitra, M. Journal of Organic Chemistry, 1978, 43, 2923.
  • Typical solvents used for flash chromatography or thin layer chromatography were mixtures of chloroform/methanol, dichloromethane/methanol, ethyl acetate/methanol and hexanes/ethyl acetate.
  • Example 1 3-(Pyridin-4-yl)-l-[(l, 2, 3, 4-tetrahydronaphthalen-l-yl) carbonyl]-lH-l, 2, 4-triazol-5-amine.
  • the reaction mixture was diluted with DCM (80 mL), washed with H 2 0 (50mL x3) and brine (50mL x3) and dried with Na 2 S0 4 . After filtration, the filtrate was concentrated under reduced pressure.
  • the crude product was purified by Prep-HPLC with the following conditions (Analyse HPLC-SHEVIADZU): Column, XBridge Shield RP18 OBD Column, 5um, 19mm xl50mm; mobile phase, Waters (0.1%FA) and ACN (20.0% ACN up to 70.0% in 7 min); Detector, 254 & 220nm.
  • Example 4 (5-Amino-3-(pyridin-4-yl)-lH-l,2,4-triazol-l-yl)(2,3-dihydro-lH-inden- l-yl)meth
  • the reaction mixture was diluted with DCM (80 mL), washed with H 2 0 (50 mL x3) and brine (50 mL x3) and dried with Na 2 S04. After filtration, the filtrate was concentrated under reduced pressure.
  • the crude product was purified by Prep-HPLC with the following conditions (2#- Analyse HPLC-SHIMADZU(HPLC-IO)): Column, XBridge Shield RP18 OBD Column, 5um, 19mm xl50mm; mobile phase, WatersQO mmol/L H4HCO3) and ACN (30.0% ACN up to 60.0% in 7 min); Detector, 254nm
  • the collected fraction was lyophilized to give 14.5 mg (19%) of l-[(2,3-dihydro-lH-inden-l-yl)carbonyl]-3-(pyridin-4-yl)-lH-l,2,4-triazol-5-amine as a white solid.
  • Example 7 (5-Amino-3-(furan-2-yl)-lH-l, 2, 4-triazol-l-yl)(2, 3-dihydro-lH-inden- l-yl)methanone.
  • the reaction mixture was diluted with EA (80 mL), washed with brine (3x120 mL) and dried with Na 2 S04. After filtration, the filtrate was concentrated under reduced pressure.
  • the crude product was purified by Prep-HPLC with the following conditions (2#-AnalyseHPLC- SHIMADZU(HPLC-IO)): Column, XBridge CI 8 OBD Prep Column, 100 A 5 um, 19mm x250 mm; mobile phase, Waters(0.1%FA) and ACN (hold 45.0% ACN in 9 min); Detector, 254nm.
  • Example 8 (5-Amino-3-(pyridin-4-yl)-lH-l,2,4-triazol-l-yl)(l-(4-methoxybenzyl)- 4,5,6,7-tetrahydro-lH-indol-4-yl)methanone.
  • Step 1 l-(4-Methoxybenzyl)-lH-pyrrole-2-carbaldehyde.
  • Step 2 l-(4-Methoxybenzyl)-2-vinyl-lH-pyrrole.
  • methyltriphenylphosphoium bromide (8.28 g, 23.3 mmol, 1.0 eq) was added. The resulting mixture was heated with stirring at 70 °C for 1 h. Upon cooled below 35 °C, a solution of 1 - (4-methoxybenzyl)-lH-pyrrole-2-carbaldehyde(5.0 g, 23.2 mmol, 1.0 eq) in dry THF was added dropwise into the mixture with stirring, then heated to 70 °C and stirred for 3 h. The reaction mixture was filtered through neutral alumina with PE.
  • Step 3 Methyl l-(4-methoxybenzyl)-4,5,6,7-tetrahydro-lH-indole-4-carboxylate.
  • Step 5 (5-Amino-3-(pyridin-4-yl)-lH-l,2,4-triazol-l-yl)(l-(4-methoxybenzyl)- 4,5,6,7-tetrah dro-lH-indol-4-yl)methanone.
  • the crude product was further purified by Prep-HPLC with the following conditions (Analyse HPLC-SHIMADZU): Column, XBridge Shield RP18 OBD Column, 5um, 19mm xl 50mm; mobile phase, Waters(0.1%FA) and ACN (35.0% ACN up to 60.0% in 7 min); Detector, 254 & 220nm.
  • Step 2 l-[(2-chloro-4,5,6,7-tetrahydro-lH-indol-4-yl)carbonyl]-3-(pyridin-4-yl)-lH- l,2,4-triazol-5-amine
  • 6-fluoro-l,2,3,4-tetrahydroquinoline-4- carboxylic acid (2.0 g, 10.25 mmol, 1.00 equiv) in DMF (60 mL)
  • HOBt (2.10 g, 15.54 mmol, 1.50 equiv
  • EDCI (2.94 g, 15.34 mmol, 1.50 equiv
  • TEA 3.11 g, 30.73 mmol, 3.00 equiv
  • 3-(pyridin-4-yl)-lH-l,2,4-triazol-5-amine (1.66 g, 10.30 mmol, 1.00 equiv).
  • 6-fluoro- 1,2,3, 4-tetrahydroquinoline-4- carboxylic acid (366 mg, 1.88 mmol, 1.00 equiv) in DMF (20 mL), 3-(pyridin-2-yl)-lH- l,2,4-triazol-5-amine (300 mg, 1.86 mmol, 1.00 equiv), HOBT (381 mg, 2.82 mmol, 1.50 equiv), EDCI (534 mg, 2.79 mmol, 1.50 equiv) and TEA (939.6 g, 9.29 mol, 5.00 equiv).
  • Example 17 (5-amino-3-phenyl-lH-l,2,4-triazol-l-yl)(6-fluoro-l,2,3,4- tetrahydroquinolin-4-yl)methanone
  • Example 20 (5-amino-3-(4-methoxyphenyl)-lH-l,2,4-triazol-l-yl)(6-fluoro-l,2,3,4- tetrahydroquinolin-4-yl)methanone
  • Example 21 (5-amino-3-(l-methylpiperidin-4-yl)-lH-l,2,4-triazol-l-yl)(6-fluoro- l,2,3,4-tetrahydroquinolin-4-yl)methanone
  • N-benzyl-3-bromo-l-[[2-(trimethylsilyl)ethoxy]methyl]-lH-l,2,4- triazol-5-amine (1.36 g, 3.55 mmol, 1.00 equiv) in dioxane (20 mL), Pd(dppf)Ch CH2CI2 (873 mg, 1.07 mmol, 0.30 equiv), potassium carbonate (1.47 g, 10.64 mmol, 3.00 equiv), water(5 mL) and l-methyl-4-(tetramethyl-l,3,2-dioxaborolan-2-yl)-l,2,3,6- tetrahydropyridine (1.19 g, 5.33 mmol, 1.50 equiv).
  • Step 7 (5-amino-3-(l-methylpiperidin-4-yl)-lH-l,2,4-triazol-l-yl)(6-fluoro-l,2,3,4- tetrahydroquinolin-4-yl)methanone
  • the reaction mixture was diluted with DCM (80 mL), washed with H 2 0 (50 mL x 3) and brine (50 mL x 3), dried with anhydrous Na 2 S0 4 , filtered and concentrated under reduced pressure.
  • the crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, C18 silica gel; mobile phase, water (lOmmol/L H4HCO3) and ACN (5.0% ACN up to 75.0% in 45 min); Detector, UV 254/220 nm. The collected fraction was extracted with 5 x 180 mL of dichloromethane and the organic layers combined.
  • Example 22 (5-amino-3-(5-chlorothiophen-3-yl)-lH-l,2,4-triazol-l-yl)(6-fluoro- l,2,3,4-tetrahydroquinolin-4-yl)methanone
  • Step 1 Tert-butyl 2-form l-lH-pyrrole-l-carboxylate.
  • Step 3 1-tert-but l 4-methyl 4,5,6,7-tetrahydroindole-l,4-dicarboxylate.
  • Step 6 (5-amino-3-(pyridin-4-yl)-lH-l,2,4-triazol-l-yl)(4,5,6,7-tetrahydro-lH-indol- 4-yl)methanone.
  • Example 24 Synthesis of (5-amino-3-(pyridin-4-yl)-lH-l,2,4-triazol-l-yl)(l-methyl- l,2,3,4-tetrahydroquinolin-4-yl methanone
  • Step 1 Meth l l-methyl-l,2,3,4-tetrahydroquinoline-4-carboxylate.
  • Step 2 1-m eth l- 1, 2,3, 4-tetrahydroquinoline-4-carboxylic acid.
  • Step 3 (5-amino-3-(pyridin-4-yl)-lH-l,2,4-triazol-l-yl)(l-methyl-l,2,3,4- tetrahydroquinolin-4 l)methanone.
  • Example 28 Synthesis of (5-amino-3-(pyridin-4-yl)-lH-l,2,4-triazol-l-yl)(7- methoxy- 1,2,3 , 4-tetrahy dronaphthal en- 1 -yl )methanone
  • Step 1 7-methoxy-l-(trimethylsilyloxy)-l,2,3,4-tetrahydronaphthalene-l-carbonitrile
  • Step 3 (5-amino-3-(pyridin-4-yl)-lH-l,2,4-triazol-l-yl)(7-methoxy-l,2,3,4- tetrahydronaphthalen- 1 -yl)methanone
  • the resulting solution was stirred overnight at room temperature (19 °C).
  • the resulting solution was diluted with 30 mL of EA, washed with H 2 0 (50 mL x 3) and brine (50 mL x 3), dried with Na 2 S0 4 filtered and concentrated under reduced pressure.
  • the crude product was purified by Prep-TLC with ethyl acetate/petroleum ether (1/1).
  • 6-fluoro-l,2,3,4-tetrahydronaphthalen-l-one 500 mg, 3.05 mmol, 1.00 equiv
  • dichloromethane 18 mL
  • TMSCN 905 mg, 9.14 mmol, 3.00 equiv
  • Znl 2 195 mg, 0.61 mmol, 0.20 equiv
  • Step 3 (5-amino-3-(pyridin-4-yl)-lH-l,2,4-triazol-l-yl)(6-fluoro-l,2,3,4- tetrahydronaphthalen- 1 -yl)methanone
  • 6-fluoro-l,2,3,4-tetrahydronaphthalene-l- carboxylic acid 60 mg, 0.31 mmol, 0.90 equiv
  • N,N-dimethylformamide 3 mL
  • HATU HATU
  • DIEA 132 mg, 1.02 mmol, 3.00 equiv
  • the resulting solution was stirred overnight at room temperature (19 °C).
  • the resulting solution was diluted with EA (30 mL), washed with H 2 0 (50mL x 3) and brine (50mL x 3), dried with Na 2 S0 4 , filtered and concentrated under reduced pressure.
  • the crude product was purified by Prep-TLC with ethyl acetate/petroleum ether (1/1).
  • the crude product was repurified by Prep-HPLC with the following conditions (2#-AnalyseHPLC- SHIMADZU (HPLC-10)): Column, XBridge Shield RP18 OBD Column, 5 um, 19 x 150 mm; mobile phase, water (0.1%FA) and ACN (18.0% ACN up to 40.0% in 12 min); Detector, UV 254/220nm.
  • 2#-AnalyseHPLC- SHIMADZU (HPLC-10) Column, XBridge Shield RP18 OBD Column, 5 um, 19 x 150 mm; mobile phase, water (0.1%FA) and ACN (18.0% ACN up to 40.0% in 12 min); Detector, UV 254/220nm.
  • Example 30 Synthesis of (5-amino-3-(pyridin-4-yl)-lH-l,2,4-triazol-l-yl)(6- methoxy- 1,2,3 , 4-tetrahy dronaphthal en- 1 -yl )methanone
  • 6-methoxy-l,2,3,4-tetrahydronaphthalen-l-one 500 mg, 2.84 mmol, 1.00 equiv
  • tetrahydrofuran 14 mL
  • LHMDS 1M in tetrahydrofuran
  • 6-methoxy-3,4-dihydronaphthalen-l-yl trifluoromethanesulfonate 300 mg, 0.97 mmol, 1.00 equiv
  • Pd(dppf)Cl 2 CH2CI2 400 mg, 0.49 mmol, 0.50 equiv
  • TEA 492 mg, 4.86 mmol, 5.00 equiv
  • MeOH 8 mL
  • Step 5 (5-amino-3-(pyridin-4-yl)-lH-l,2,4-triazol-l-yl)(6-methoxy-l,2,3,4- tetrahydronaphthalen- 1 -yl)methanone
  • the resulting solution was diluted with EA (30 mL), washed with H 2 0 (50 mL x 3) and brine (50mL x 3), dried with Na 2 S0 4 , filtered and concentrated under reduced pressure.
  • the crude product was purified by Prep-HPLC with the following conditions (2#-AnalyseHPLC-SHFMADZU(HPLC-10)): Column, XBridge C18 OBD Prep Column, 100A, 5 urn, 19 mm x 250 mm; mobile phase, waters(0.1%FA) and ACN (25.0% ACN up to 50.0% in 8 min); Detector, UV 254nm.
  • Example 31 As a negative control, N-benzyl-l-[(naphthalen-l-yl)carbonyl]-3- (pyridin-2-yl)-lH-l,2,4-triazol-5-amine was synthesized according to the procedures described in PCT WO 2011/126903, where it is example 269.
  • Assay buffer consists of 0.5x Hank's Balanced Salt Solution (Invitrogen), buffered with 25mM HEPES pH 7.4 (Invitrogen) and 0.5x Tris-buffered saline with Tween-20 0.05% (Santa Cruz
  • Test compounds were first dissolved in DMSO (Sigma) and then 4 ⁇ 1 were added to test wells containing assay buffer. Serial dilutions using an automated multi -channel pipette were used to generate a concentration range of approximately l- ⁇ .
  • Human FXIIa (Enzyme Research Labs) was diluted in assay buffer to a final concentration of 12.5nM. 80 ⁇ 1 of this enzyme solution was added to the assay wells. The enzyme/compound mixtures were incubated for 10 minutes at room temperature. Chromogenic substrate (Pefachrome Xlla; Enzyme Research Labs) was added to assay wells at a final concentration of 400 ⁇ .
  • Thrombin In a 96-well white opaque plate, 80 ⁇ 1 of assay buffer was added to each well. Test compounds were added, and serially diluted as above, to generate a concentration range of approximately l- ⁇ . Human alpha-thrombin (Enzyme Research Labs) was diluted in assay buffer to a final concentration of 12.5nM. 80 ⁇ 1 of this enzyme solution was added to the assay wells. The enzyme/compound mixtures were incubated for 10 minutes at room temperature. Fluorogenic substrate (Boc-Val-Pro-Arg-7-amido-4-methylcoumarin; Sigma) was added to assay wells at a final concentration of 20 ⁇ .
  • Fluorogenic substrate Boc-Val-Pro-Arg-7-amido-4-methylcoumarin
  • concentration of inhibitor that produced 50% of the rate of change of control wells without any inhibitor was repeated with a lower concentration range, typically from 10-lOOOnM.
  • Factor IXa Factor IXa.
  • Assay buffer 80 ⁇ 1 of assay buffer was added to each well. Test compounds were added, and serially diluted as above, to generate a concentration range of approximately l- ⁇ .
  • Human FIXa-beta (Enzyme Research Labs) was diluted in assay buffer to a final concentration of 12.5nM. 80 ⁇ 1 of this enzyme solution was added to the assay wells. The enzyme/compound mixtures were incubated for 10 minutes at room temperature. Fluorogenic substrate (Pefafluor FIXa; Enzyme Research Labs) was added to assay wells at a final concentration of ⁇ .
  • Factor Xa Factor Xa.
  • Assay buffer 80 ⁇ 1 of assay buffer was added to each well. Test compounds were added, and serially diluted as above, to generate a concentration range of approximately l- ⁇ .
  • Human FXa Enzyme Research Labs
  • 80 ⁇ 1 of this enzyme solution was added to the assay wells. The enzyme/compound mixtures were incubated for 10 minutes at room temperature. Fluorogenic substrate (Pefafluor FXa; Enzyme Research Labs) was added to assay wells at a final concentration of 80 ⁇ .
  • Factor XIa Factor XIa.
  • Assay buffer 80 ⁇ 1 of assay buffer was added to each well. Test compounds were added, and serially diluted as above, to generate a concentration range of approximately l- ⁇ .
  • Human FXIa Enzyme Research Labs
  • 80 ⁇ 1 of this enzyme solution was added to the assay wells. The enzyme/compound mixtures were incubated for 10 minutes at room temperature. Chromogenic substrate (Pefachrome FXIa 3371; Enzyme Research Labs) was added to assay wells at a final concentration of ⁇ .
  • Plasma Kallikrein In a 96-well white opaque plate, 80 ⁇ 1 of assay buffer was added to each well. Test compounds were added, and serially diluted as above, to generate a concentration range of approximately l- ⁇ . Human plasma kallikrein (Enzyme Research Labs) was diluted in assay buffer to a final concentration of 12.5nM.
  • Example 31 was tested as described above and exhibited an IC50 of 20 ⁇ versus Factor Xlla and an IC50 of ⁇ 0.5 ⁇ versus thrombin. Example 31 was highly selective for thrombin.
  • the compounds provided herein can be used for treating inflammation, for treating an immunological disorder, or for treating pathologies associated with vasodilatation.
  • the method comprises administering to a patient a therapeutically effective amount of a compound of formula I.
  • EAE experimental autoimmune encephalomyelitis
  • This is a standard and well-validated animal model of multiple sclerosis. Briefly, female mice approximately 10 weeks old are immunized with a fragment of brain protein, such as myelin oligodendrocyte glycoprotein (MOG), residues 35-55 in an emulsion with Freund's Complete adjuvant.
  • MOG myelin oligodendrocyte glycoprotein
  • Test compounds are administered either with MOG inoculation (prophylactic model), or beginning at the earliest sign of disease (therapeutic model). Compound efficacy is assessed by determining the EAE severity score 4 weeks after inoculation, as well as by determining EAE onset and peak severity in relation to comparator and/or control groups. The compound of Example 2 was evaluated in this test with the following results:

Abstract

L'invention concerne des composés 1-Acyl-3-(hétéroaryl)-1H-1,2,4-triazol-5-amines de formule (I). Ces composés inhibent le facteur de coagulation XIIa en présence de thrombine et d'autres facteurs de coagulation. Ces composés sont utiles pour traiter des maladies auto-immunes.
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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019108565A1 (fr) * 2017-11-29 2019-06-06 The Rockefeller University Immunomodulateurs à base de pyranopyrazole et de pyrazolopyridine pour le traitement de maladies auto-immunes
WO2021032934A1 (fr) 2019-08-21 2021-02-25 Kalvista Pharmaceuticals Limited Inhibiteurs d'enzyme
WO2021032938A1 (fr) 2019-08-21 2021-02-25 Kalvista Pharmaceuticals Limited Inhibiteurs d'enzyme
WO2021032933A1 (fr) 2019-08-21 2021-02-25 Kalvista Pharmaceuticals Limited Inhibiteurs d'enzymes
WO2021032936A1 (fr) 2019-08-21 2021-02-25 Kalvista Pharmaceuticals Limited Inhibiteurs d'enzymes
WO2022118016A2 (fr) 2020-12-01 2022-06-09 Kalvista Pharmaceuticals Limited Inhibiteurs enzymatiques
WO2022175675A1 (fr) 2021-02-19 2022-08-25 Kalvista Pharmaceuticals Limited Inhibiteurs du facteur xiia
WO2024038282A1 (fr) 2022-08-18 2024-02-22 Kalvista Pharmaceuticals Limited Dérivés de 2-aza- et 2-oxabicyclo[2.1.1]hexane utilisés comme inhibiteurs de l'enzyme du facteur xiia
WO2024084217A1 (fr) 2022-10-19 2024-04-25 Kalvista Pharmaceuticals Limited Dérivés de 3a,4,5,6-tétrahydro-1h-pyrazolo[3,4-c]pyridin-7(7ah)-one utilisés en tant qu'inhibiteurs du facteur xiia

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080161373A1 (en) * 2005-12-14 2008-07-03 Pinto Donald J P Arylpropionamide, arylacrylamide, arylpropynamide, or arylmethylurea analogs as factor xia inhibitors
US20130040950A1 (en) * 2010-03-30 2013-02-14 Verseon Corporation Multisubstituted aromatic compounds as inhibitors of thrombin
US20140274960A1 (en) * 2011-10-14 2014-09-18 Bristol-Myers Squibb Company Substituted tetrahydroisoquinoline compounds as factor xia inhibitors
US20150152048A1 (en) * 2012-05-24 2015-06-04 Ono Pharmaceutical Co., Ltd. Substituted pyrrolidines as factor xia inhibitors for the treatment thromboembolic diseases

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080161373A1 (en) * 2005-12-14 2008-07-03 Pinto Donald J P Arylpropionamide, arylacrylamide, arylpropynamide, or arylmethylurea analogs as factor xia inhibitors
US20130040950A1 (en) * 2010-03-30 2013-02-14 Verseon Corporation Multisubstituted aromatic compounds as inhibitors of thrombin
US20140274960A1 (en) * 2011-10-14 2014-09-18 Bristol-Myers Squibb Company Substituted tetrahydroisoquinoline compounds as factor xia inhibitors
US20150152048A1 (en) * 2012-05-24 2015-06-04 Ono Pharmaceutical Co., Ltd. Substituted pyrrolidines as factor xia inhibitors for the treatment thromboembolic diseases

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CIRINO ET AL.: "Thrombin Functions as an Inflammatory Mediator through Activation of Its Receptor", THE JOURNAL OF EXPERIMENTAL MEDICINE, vol. 183, 1 March 1996 (1996-03-01), pages 821 - 827, XP055400608 *
ZOLLER ET AL.: "Autoimmune diseases and venous thromboembolism: a review of the literature", AMERICAN JOURNAL OF CARDIOVASCULAR DISEASE, vol. 2, 15 August 2012 (2012-08-15), pages 171 - 183, XP055400612 *

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019108565A1 (fr) * 2017-11-29 2019-06-06 The Rockefeller University Immunomodulateurs à base de pyranopyrazole et de pyrazolopyridine pour le traitement de maladies auto-immunes
CN111670034A (zh) * 2017-11-29 2020-09-15 洛克菲勒大学 用于治疗自身免疫性疾病的吡喃并吡唑类和吡唑并吡啶类免疫调节剂
US11312723B2 (en) 2017-11-29 2022-04-26 The Rockefeller University Pyranopyrazole and pyrazolopyridine immunomodulators for treatment of autoimmune diseases
WO2021032935A1 (fr) 2019-08-21 2021-02-25 Kalvista Pharmaceuticals Limited Inhibiteurs d'enzyme
WO2021032933A1 (fr) 2019-08-21 2021-02-25 Kalvista Pharmaceuticals Limited Inhibiteurs d'enzymes
WO2021032936A1 (fr) 2019-08-21 2021-02-25 Kalvista Pharmaceuticals Limited Inhibiteurs d'enzymes
WO2021032938A1 (fr) 2019-08-21 2021-02-25 Kalvista Pharmaceuticals Limited Inhibiteurs d'enzyme
WO2021032937A1 (fr) 2019-08-21 2021-02-25 Kalvista Pharmaceuticals Limited Inhibiteurs d'enzyme
WO2021032934A1 (fr) 2019-08-21 2021-02-25 Kalvista Pharmaceuticals Limited Inhibiteurs d'enzyme
WO2022118016A2 (fr) 2020-12-01 2022-06-09 Kalvista Pharmaceuticals Limited Inhibiteurs enzymatiques
WO2022175675A1 (fr) 2021-02-19 2022-08-25 Kalvista Pharmaceuticals Limited Inhibiteurs du facteur xiia
WO2024038282A1 (fr) 2022-08-18 2024-02-22 Kalvista Pharmaceuticals Limited Dérivés de 2-aza- et 2-oxabicyclo[2.1.1]hexane utilisés comme inhibiteurs de l'enzyme du facteur xiia
WO2024084217A1 (fr) 2022-10-19 2024-04-25 Kalvista Pharmaceuticals Limited Dérivés de 3a,4,5,6-tétrahydro-1h-pyrazolo[3,4-c]pyridin-7(7ah)-one utilisés en tant qu'inhibiteurs du facteur xiia

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