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WO2024173196A1 - Inhibiteurs de la kallicréine plasmatique - Google Patents

Inhibiteurs de la kallicréine plasmatique Download PDF

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Publication number
WO2024173196A1
WO2024173196A1 PCT/US2024/015306 US2024015306W WO2024173196A1 WO 2024173196 A1 WO2024173196 A1 WO 2024173196A1 US 2024015306 W US2024015306 W US 2024015306W WO 2024173196 A1 WO2024173196 A1 WO 2024173196A1
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mmol
mixture
methyl
stirred
added
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Inventor
Jacqueline D. Hicks
Rongze Kuang
Matthew J. LOMBARDO
Zhicai Wu
Zhiqiang Zhao
Song Yang
Jianming Bao
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Merck Sharp and Dohme LLC
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Merck Sharp and Dohme LLC
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Priority to EP24757471.8A priority Critical patent/EP4665330A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4192—1,2,3-Triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • C07D401/02—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
    • C07D401/10—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 aromatic rings
    • 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
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • Plasma kallikrein is a zymogen of a trypsin-like serine protease and is present in plasma. The gene structure is similar to that of factor XI. Overall, the amino acid sequence of plasma kallikrein has 58% homology to factor XI.
  • Proteolytic activation by factor XIIa at an internal I389-R390 bond yields a heavy chain (371 amino acids) and a light chain (248 amino acids).
  • the active site of plasma kallikrein is contained in the light chain.
  • the light chain of plasma kallikrein reacts with protease inhibitors, including alpha 2 macroglobulin and Cl-inhibitor.
  • heparin significantly accelerates the inhibition of plasma kallikrein by antithrombin III in the presence of high molecular weight kininogen (HMWK).
  • HMWK high molecular weight kininogen
  • Bradykinin release results in increase of vascular permeability and vasodilation (for review, Coleman, R., "Contact Activation Pathway", Hemostasis and Thrombosis, pp.103-122, Lippincott Williams & Wilkins (2001); Schmaier A.H., "Contact Activation", Thrombosis and Hemorrhage, pp.105-128 (1998)).
  • HAE hereditary angioedema
  • the plasma kallikrein-kinin system is abnormally abundant in patients diagnosed with advanced diabetic macular edema (DME).
  • DME advanced diabetic macular edema
  • Recent publications have shown that plasma kallikrein contributes to observed retinal vascular leakage and dysfunction in diabetic rodent models (A. Clermont, et al., Diabetes, 60:1590 (2011)), and that treatment with a small molecule plasma kallikrein inhibitor ameliorated the observed retinal vascular permeability and other abnormalities related to retinal blood flow.
  • the present invention relates to compounds of Formula I: I and pharmaceutically acceptable salts thereof.
  • the compounds of Formula I are inhibitors of plasma kallikrein, and as such may be useful in the treatment, inhibition or amelioration of one or more disease states that could benefit from inhibition of plasma kallikrein, including hereditary angioedema, uveitis, posterior uveitis, wet age-related macular degeneration, diabetic macular edema, diabetic retinopathy and retinal vein occlusion.
  • the compounds of this invention could further be used in combination with other therapeutically effective agents, including but not limited to, other drugs useful for the treatment of hereditary angioedema, uveitis, posterior uveitis, wet age-related macular degeneration, diabetic macular edema, diabetic retinopathy and retinal vein occlusion.
  • the invention furthermore relates to processes for preparing compounds of Formula I, and pharmaceutical compositions which comprise compounds of Formula I and pharmaceutically acceptable salts thereof.
  • the present invention relates to compounds of Formula I: I wherein is phenyl or heteroaryl, which can be monocyclic, bicyclic or tricyclic, wherein said phenyl and heteroaryl groups are optionally substituted with one or two substituents independently selected from the group consisting of halo, oxo, R x , OR x and SO 2 R x ; is a 5-membered heteroaryl ring which is optionally substituted with one or two substituents independently selected from the group consisting of halo, cyano, R x and OR x ; X is a bond or CR 5 R 6 ; each R 1 is independently selected from the group consisting of halo, cyano, R x and OR x ; R 2 is hydrogen, halo, cyclopropyl, C 1-3 alkyl, R 3 is hydrogen, halo, cyano or methyl; R 4 is hydrogen, halo,
  • pyrimidinyl In another class of the embodiment, is phenyl. In another class of the embodiment, is pyridinyl. In another class of the embodiment, is cyclopentapyridinyl. In another class of the embodiment, is tetrahydroisoquinolinyl. In another class of the embodiment, is tetrahydrothiazolopyridinyl In another class of the embodiment, is quinolinyl. In another class of the embodiment, is dihydroquinazolinyl. In another class of the embodiment, is imidazopyridinyl. In another class of the embodiment, dihydrospirocyclopropaneisoquinolinyl.
  • pyrazolyl or triazolyl In an embodiment of the invention, is pyrazolyl or triazolyl. In a class of the embodiment, is pyrazolyl. In another class of the embodiment, is triazolyl. [0010] In an embodiment of the invention, is azetidinyl, azabicyclohexanyl, azaspirohexanyl, oxopyridinyl, oxo-azabicyclo[3.1.0]hexanyl, oxopyrimidinyl, pyridinyl, pyrrolidinyl wherein said pyrrolidinyl is optionally substituted with CONR 9 R 10 , and azabicyclohexanyl is optionally substituted with oxo.
  • azetidinyl In a class of the embodiment, is azetidinyl. In another class of the embodiment, is azabicyclohexanyl. In a subclass of the embodiment, is oxo-azabicyclo[3.1.0]hexanyl. In another class of the embodiment, is azaspirohexanyl. In another class of the embodiment, is oxopyridinyl. In another class of the embodiment, is oxopyrimidinyl. In another class of the embodiment, is pyridinyl. In another class of the embodiment, is pyrrolidinyl, wherein said pyrrolidinyl is optionally substituted with CONR 9 R 10 .
  • azetidinyl or pyrrolidinyl wherein said azetidinyl and pyrrolidinyl groups are optionally substituted with one or two substituents independenly selected from the group consisting of and R x and hydroxyl.
  • azetidinyl which is optionally substituted with one or two substituents independenly selected from the group consisting of and R x and hydroxyl.
  • pyrrolidinyl which is optionally substituted with one or two substituents independenly selected from the group consisting of R x and hydroxyl.
  • R 1 is chloro, fluoro, difluoromethyl, methoxy or cyano. In a class of the embodiment, R 1 is chloro. In another class of the embodiment, R 1 is fluoro. In another class of the embodiment, R 1 is difluoromethyl. In another class of the embodiment, R 1 is methoxy. In another class of the embodiment, R 1 is cyano.
  • R 2 is hydrogen. In another embodiment invention, R 2 is halo. In another embodiment invention, R 2 is cyclopropyl. In another embodiment invention, R 2 is C 1-3 alkyl. In another embodiment invention, R 2 is . In another embodiment R 7 invention, R 2 is .
  • R 2 is or .
  • R 3 is hydrogen, fluoro or cyano. In a class of the embodiment, R 3 is hydrogen. In another class of the embodiment, R 3 is fluoro. In another class of the embodiment, R 3 is cyano.
  • R 4 is hydrogen, hydroxyl or CH 2 OH. In a class of the embodiment, R 4 is hydrogen. In another class of the embodiment, R 4 is hydroxyl. In another class of the embodiment, R 4 is CH 2 OH.
  • R 5 is hydrogen or methyl. In a class of the embodiment, R 5 is hydrogen. In another class of the embodiment, R 5 is methyl.
  • R 6 is hydrogen.
  • R 7 is hydrogen or methyl. In a class of the embodiment, R 7 is hydrogen. In another class of the embodiment, R 7 is methyl.
  • n is zero. In another embodiment of the invention, n is one. In another embodiment of the invention, n is two. In another embodiment of the invention, n is three. [0020] Reference to the preferred classes and subclasses set forth above is meant to include all combinations of particular and preferred groups unless stated otherwise. [0021] Specific embodiments of the present invention include, but are not limited to the compounds identified herein as Examples 1 to 95, or pharmaceutically acceptable salts thereof.
  • compositions for treating diseases or condition in which plasma kallikrein activity is implicated are also included within the scope of the present invention.
  • the invention is also contemplated to encompass a pharmaceutical composition which is comprised of a pharmaceutically acceptable carrier and any of the compounds specifically disclosed in the present application.
  • the invention includes compositions for treating impaired visual activity, diabetic retinopathy, wet age-related macular degeneration, diabetic macular edema, retinal vein occlusion, hereditary angioedema, diabetes, pancreatitis, cerebral hemorrhage, nephropathy, cardiomyopathy, neuropathy, inflammatory bowel disease, arthritis, inflammation, septic shock, hypotension, cancer, adult respiratory distress syndrome, disseminated intravascular coagulation, blood coagulation during cardiopulmonary bypass surgery, and bleeding from postoperative surgery in a mammal, comprising a compound of the invention in a pharmaceutically acceptable carrier.
  • a class of the invention includes 25208 compositions for treating hereditary angioedema, uveitis, posterior uveitis, wet age-related macular degeneration,diabetic macular edema, diabetic retinopathy and retinal vein occlusion.
  • These compositions may optionally include anti-inflammatory agents, anti-VEGF agents, immunosuppressive agents, anticoagulants, antiplatelet agents, and thrombolytic agents.
  • the compositions can be added to blood, blood products, or mammalian organs in order to effect the desired inhibitions.
  • the invention also includes compositions for preventing or treating retinal vascular permeability associated with diabetic retinopathy and diabetic macular edema in a mammal, comprising a compound of the invention in a pharmaceutically acceptable carrier.
  • These compositions may optionally include anti-inflammatory agents, anti-VEGF agents, immunosuppressive agents, anticoagulants, antiplatelet agents, and thrombolytic agents.
  • the invention also includes compositions for treating inflammatory conditions of the eye, which includes, but is not limited to, uveitis, posterior uveitis, macular edema, acute macular degeneration, wet age-related macular degeneration, retinal detachments, retinal vein occlusion, ocular tumors, fungal infections, viral infections, multifocal choroiditis, diabetic uveitis, diabetic macular edema, diabetic retinopathy, proliferative vitreoretinopathy, sympathetic opthalmia, Vogt Koyanagi-Harada syndrome, histoplasmosis and uveal diffusion.
  • compositions may optionally include anti-inflammatory agents, anti-VEGF agents, immunosuppressive agents, anticoagulants, antiplatelet agents, and thrombolytic agents.
  • the invention also includes compositions treating posterior eye disease, which includes, but is not limited to, uveitis, posterior uveitis, wet age-related macular degeneration, diabetic macular edema, diabetic retinopathy and retinal vein occlusion.
  • compositions may optionally include anti-inflammatory agents, anti-VEGF agents, immunosuppressive agents, anticoagulants, antiplatelet agents, and thrombolytic agents.
  • the invention is directed to the compounds of structural Formula I described herein, as well as the pharmaceutically acceptable salts of the compounds of structural Formula I and also salts that are not pharmaceutically acceptable when they are used as precursors to the free compounds or their pharmaceutically acceptable salts or in other synthetic manipulations.
  • the compounds of the present invention may be administered in the form of a pharmaceutically acceptable salt.
  • pharmaceutically acceptable salt refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids.
  • Salts of basic compounds encompassed within the term "pharmaceutically acceptable salt” refer to non-toxic salts of the compounds of this invention which are generally prepared by reacting the free base with a suitable organic or inorganic acid.
  • Representative salts of basic compounds of the present invention include, but are not limited to, the following: acetate, ascorbate, adipate, alginate, aspirate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, camphorate, camphorsulfonate, camsylate, carbonate, chloride, clavulanate, citrate, cyclopentane propionate, diethylacetic, digluconate, dihydrochloride, dodecylsulfanate, edetate, edisylate, estolate, esylate, ethanesulfonate, formic, fumarate, gluceptate, glucohept
  • suitable pharmaceutically acceptable salts thereof include, but are not limited to, salts derived from inorganic bases including aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, mangamous, potassium, sodium, zinc, and the like.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, cyclic amines, dicyclohexyl amines and basic ion-exchange resins, such as arginine, betaine, caffeine, choline, N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
  • the basic nitrogen-containing groups may be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides and others.
  • lower alkyl halides such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides
  • dialkyl sulfates like dimethyl, diethyl, dibutyl
  • diamyl sulfates long chain halides
  • salts can be obtained by known methods, for example, by mixing a compound of the present invention with an equivalent amount and a solution containing a desired acid, base, or the like, and then collecting the desired salt by filtering the salt or distilling off the solvent.
  • the compounds of the present invention and salts thereof may form solvates with a solvent such as water, ethanol, or glycerol.
  • the compounds of the present invention may form an acid addition salt and a salt with a base at the same time according to the type of substituent of the side chain.
  • the invention also includes, in addition to the salt forms mentioned, inner salts or betaines (zwitterions).
  • the present invention encompasses all stereoisomeric forms of the compounds of Formula I. Unless a specific stereochemistry is indicated, the present invention is meant to comprehend all such isomeric forms of these compounds. Centers of asymmetry that are present in the compounds of Formula I can all independently of one another have (R) configuration or (S) configuration. When bonds to the chiral carbon are depicted as straight lines in the structural Formulas of the invention, it is understood that both the (R) and (S) configurations of the chiral carbon, and hence both each individual enantiomer and mixtures thereof, are embraced within the Formula. When a particular configuration is depicted, that entantiomer (either (R) or (S), at that center) is intended.
  • the invention includes all possible enantiomers and diastereomers and mixtures of two or more stereoisomers, for example mixtures of enantiomers and/or diastereomers, in all ratios.
  • enantiomers are a subject of the invention in enantiomerically pure form, both as levorotatory and as dextrorotatory antipodes, in the form of racemates and in the form of mixtures of the two enantiomers in all ratios.
  • the invention includes both the cis form and the trans form as well as mixtures of these forms in all ratios.
  • the preparation of individual stereoisomers can be carried out, if desired, by separation of a mixture by customary methods, for example by chromatography or crystallization, by the use of stereochemically uniform starting materials for the synthesis or by stereoselective synthesis.
  • a derivatization can be carried out before 25208 a separation of stereoisomers.
  • the separation of a mixture of stereoisomers can be carried out at an intermediate step during the synthesis of a compound of Formula I, or it can be done on a final racemic product.
  • Absolute stereochemistry may be determined by X-ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary, with a reagent containing a stereogenic center of known configuration.
  • the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature.
  • the present invention is meant to include all suitable isotopic variations of the specifically and generically described compounds.
  • H isotopic forms of hydrogen
  • protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples.
  • Isotopically-enriched compounds can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the general process schemes and examples herein using appropriate isotopically- enriched reagents and/or intermediates.
  • R 1 , etc. occurs more than one time in any constituent, its definition on each occurrence is independent at every other occurrence. Also, combinations of substituents and variables are permissible only if such combinations result in stable compounds. Lines drawn into the ring systems from substituents represent that the indicated bond may be attached to any of the substitutable ring atoms. If the ring system is bicyclic, it is intended that the bond be attached to any of the suitable atoms on either ring of the bicyclic moiety.
  • one or more silicon (Si) atoms can be incorporated into the compounds of the instant invention in place of one or more carbon atoms by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art from readily available starting materials.
  • Carbon and silicon differ in their covalent radius leading to differences in bond distance and the steric arrangement when 25208 comparing analogous C-element and Si-element bonds. These differences lead to subtle changes in the size and shape of silicon-containing compounds when compared to carbon.
  • size and shape differences can lead to subtle or dramatic changes in potency, solubility, lack of off-target activity, packaging properties, and so on.
  • substituents and substitution patterns on the compounds of the instant invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art, as well as those methods set forth below, from readily available starting materials. If a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, so long as a stable structure results.
  • compounds of the present invention may exist in amorphous form and/or one or more crystalline forms, and as such all amorphous and crystalline forms and mixtures thereof of the compounds of Formula I are intended to be included within the scope of the present invention.
  • some of the compounds of the instant invention may form solvates with water (i.e., a hydrate) or common organic solvents.
  • Such solvates and hydrates, particularly the pharmaceutically acceptable solvates and hydrates, of the instant compounds are likewise encompassed within the scope of this invention, along with un-solvated and anhydrous forms.
  • pharmaceutically acceptable esters of carboxylic acid derivatives such as methyl, ethyl, or pivaloyloxymethyl, or acyl derivatives of alcohols, such as O-acetyl, O-pivaloyl, O-benzoyl, and O-aminoacyl, can be employed.
  • esters and acyl groups known in the art for modifying the solubility or hydrolysis characteristics for use as sustained-release or prodrug formulations are also within the scope of this invention.
  • esters can optionally be made by esterification of an available carboxylic acid group or by formation of an ester on an available hydroxy group in a compound.
  • labile amides can be made.
  • esters or amides of the compounds of this invention may be prepared to act as pro-drugs which can be hydrolyzed 25208 back to an acid (or -COO- depending on the pH of the fluid or tissue where conversion takes place) or hydroxy form particularly in vivo and as such are encompassed within the scope of this invention.
  • pro-drug modifications include, but are not limited to, -C 1-6 alkyl esters and –C 1-6 alkyl substituted with phenyl esters.
  • the compounds within the generic structural formulas, embodiments and specific compounds described and claimed herein encompass salts, all possible stereoisomers and tautomers, physical forms (e.g., amorphous and crystalline forms), solvate and hydrate forms thereof and any combination of these forms, as well as the salts thereof, pro-drug forms thereof, and salts of pro-drug forms thereof, where such forms are possible unless specified otherwise.
  • the terms "alkyl” and “alkylene” are intended to include both branched- and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
  • alkyl groups are used throughout the specification, e.g., methyl, may be represented by conventional abbreviations including “Me” or CH or a symbol that is an extended bond as the termina " 3 l group, e.g., , ethyl may be represented by “Et” or CH 2 CH 3 , propyl may be represented by “Pr” or CH 2 CH 2 CH 3 , butyl may be represented by “Bu” or CH2CH2CH2CH3, etc.
  • C1-4 alkyl (or “C1-C4 alkyl”) for example, means linear or branched chain alkyl groups, including all isomers, having the specified number of carbon atoms. For example, the structures have equivalent meanings.
  • C 1-4 alkyl includes n-, iso-, sec- and t-butyl, n- and isopropyl, ethyl and methyl. If no number is specified, 1-4 carbon atoms are intended for linear or branched alkyl groups.
  • cycloalkyl means a monocyclic or bicyclic saturated aliphatic hydrocarbon group having the specified number of carbon atoms.
  • cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and so on.
  • aryl represents a stable monocyclic or bicyclic ring system of up to 10 carbon atoms in each ring, wherein at least one ring is aromatic.
  • Bicyclic aryl ring systems include fused ring systems, where two rings share two atoms, and spiro ring systems, where two rings share one atom.
  • Aryl groups within the scope of this definition include, but are not limited to: phenyl, indene, isoindene, naphthalene, and tetralin.
  • heteroaryl represents a stable monocyclic or bicyclic ring system of up to 10 atoms in each ring, wherein at least one ring is aromatic, and at least one ring contains from 1 to 4 heteroatoms selected from the group consisting of O, N and S.
  • Bicyclic heteroaryl ring systems include fused ring systems, where two rings share two atoms, and spiro ring systems, where two rings share one atom.
  • Heteroaryl groups within the scope of this definition include but are not limited to: azaindolyl, benzoimidazolyl, benzisoxazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, dihydroindenyl, furanyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthalenyl, naphthpyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, pyranyl, pyrazinyl, pyrazolyl, pyrazolopyrimidinyl, pyr
  • heterocycle or “heterocyclyl” as used herein is intended to mean a stable nonaromatic monocyclic or bicyclic ring system of up to 10 atoms in each ring, unless otherwise specified, containing from 1 to 4 heteroatoms selected from the group consisting of O, N, S, SO, or SO 2 .
  • Bicyclic heterocyclic ring systems include fused ring systems, where two rings share two atoms, and spiro ring systems, where two rings share one atom.
  • Heterocyclyl therefore includes, but is not limited to the following: azabicyclohexanyl, azaspirohexanyl, azaspirononanyl, azaspirooctanyl, azetidinyl, dioxanyl, isochromanyl, oxadiazaspirodecenyl, oxaspirooctanyl, oxazolidinonyl, 2-oxo-azabicyclo[3.1.0]hexanyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, tetrahydrofurnayl, tetrahydropyranyl, 25208 dihydropiperidinyl, tetrahydrothiophenyl and the like.
  • heterocycle contains a nitrogen, it is understood that the corresponding N-oxides thereof are also encompassed by this definition.
  • halogen or “halo” means fluorine, chlorine, bromine or iodine.
  • Celite® (Fluka) diatomite is diatomaceous earth, and can be referred to as "celite”.
  • variable R shown in the above structure can be attached to any one of 6 bicyclic ring carbon atoms i, ii, iii, iv, v or vi.
  • bicyclic ring systems include fused ring systems, where two rings share two atoms, and spiro ring systems, where two rings share one atom.
  • the invention also relates to medicaments containing at least one compound of the Formula I and/or of a pharmaceutically acceptable salt of the compound of the Formula I and/or an optionally stereoisomeric form of the compound of the Formula I or a pharmaceutically acceptable salt of the stereoisomeric form of the compound of Formula I, together with a pharmaceutically suitable and pharmaceutically acceptable vehicle, additive and/or other active substances and auxiliaries.
  • patient used herein is taken to mean mammals such as primates, humans, sheep, horses, cattle, pigs, dogs, cats, rats, and mice.
  • the medicaments according to the invention can be administered by oral, inhalative, rectal or transdermal administration or by subcutaneous, intraarticular, intraperitoneal or intravenous injection. Oral administration is preferred. Coating of stents with compounds of the Formulas I and other surfaces which come into contact with blood in the body is possible.
  • the invention also relates to a process for the production of a medicament, which comprises bringing at least one compound of the Formula I or Ia into a suitable administration form using a pharmaceutically suitable and pharmaceutically acceptable carrier and optionally further suitable active substances, additives or auxiliaries.
  • Suitable solid or galenical preparation forms are, for example, granules, powders, coated tablets, tablets, (micro)capsules, suppositories, syrups, juices, suspensions, emulsions, drops or injectable solutions and preparations having prolonged release of active substance, in whose preparation customary excipients such as vehicles, disintegrants, binders, coating agents, swelling agents, glidants or lubricants, flavorings, sweeteners and solubilizers are used.
  • auxiliaries which may be mentioned are magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, lactose, gelatin, starch, cellulose and its derivatives, animal and plant oils such as cod liver oil, sunflower, peanut or sesame oil, polyethylene glycol and solvents such as, for example, sterile water and mono- or polyhydric alcohols such as glycerol.
  • the dosage regimen utilizing the plasma kallikrein inhibitors is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed.
  • Oral dosages of the plasma kallikrein inhibitors when used for the indicated effects, will range between about 0.01 mg per kg of body weight per day (mg/kg/day) to about 30 mg/kg/day, preferably 0.025-7.5 mg/kg/day, more preferably 0.1-2.5 mg/kg/day, and most preferably 0.1-0.5 mg/kg/day (unless specificed otherwise, amounts of active ingredients are on free base basis).
  • an 80 kg patient would receive between about 0.8 mg/day and 2.4 g/day, preferably 2-600 mg/day, more preferably 8-200 mg/day, and most preferably 8-40 mg/ day.
  • a suitably prepared medicament for once a day administration would thus contain between 0.8 mg and 2.4 g, preferably between 2 mg and 600 mg, more preferably between 8 mg and 200 mg, and most preferably 8 mg and 40 mg, e.g., 8 mg, 10 mg, 20 mg and 40 mg.
  • the plasma kallikrein inhibitors may be administered in divided doses of two, three, or four times daily.
  • a suitably prepared medicament would contain between 0.4 mg and 4 g, preferably between 1 mg and 300 mg, more preferably between 4 mg and 100 mg, and most preferably 4 mg and 20 mg, e.g., 4 mg, 5 mg, 10 mg and 20 mg.
  • the patient would receive the active ingredient in quantities sufficient to deliver between 0.025-7.5 mg/kg/day, preferably 0.1-2.5 mg/kg/day, and more preferably 0.1-0.5 mg/kg/day.
  • Such quantities may be administered in a number of suitable ways, e.g., large volumes of low concentrations of active ingredient during one extended period of time or several 25208 times a day, low volumes of high concentrations of active ingredient during a short period of time, e.g., once a day.
  • a conventional intravenous formulation may be prepared which contains a concentration of active ingredient of between about 0.01-1.0 mg/mL, e.g., 0.1 mg/mL, 0.3 mg/mL, and 0.6 mg/mL, and administered in amounts per day of between 0.01 mL/kg patient weight and 10.0 mL/kg patient weight, e.g., 0.1 mL/kg, 0.2 mL/kg, 0.5 mL/kg.
  • an 80 kg patient receiving 8 mL twice a day of an intravenous formulation having a concentration of active ingredient of 0.5 mg/mL, receives 8 mg of active ingredient per day.
  • Glucuronic acid, L-lactic acid, acetic acid, citric acid or any pharmaceutically acceptable acid/conjugate base with reasonable buffering capacity in the pH range acceptable for intravenous administration may be used as buffers.
  • the choice of appropriate buffer and pH of a formulation, depending on solubility of the drug to be administered, is readily made by a person having ordinary skill in the art.
  • Anti-inflammatory agent is any agent which is directly or indirectly effective in the reduction of inflammation when administered at a therapeutically effective level.
  • Anti-inflammatory agent includes, but is not limited to steroidal anti-inflammatory agents and glucocorticoids. Suitable anti-inflammatory agents include, but are not limited to, cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone and triamcinolone.
  • an “anti-VEGF agent” is any agent which is directly or indirectly effective in inhibiting the activity of VEGF (Vascular Endothelial Growth Factor). Suitable anti-VEGF agents include, but are not limited to, bevacizumab, ranibizumab, brolucizumab and aflibercept.
  • An “immunosuppressant agent” is any agent which is directly or indirectly effective in suppressing, or reducing, the strength of the body’s immune system.
  • Suitable immunosuppressant agents include, but are not limited to, corticosteroids (for example, prednisone, budesonide, prednisolone), janus kinase inhibitors (for example, tofacitinib), calcineurin inhibitors (for example, cyclosporin, tacrolimus), mTOR inhibitors (for example, sirolimus, everolimus), IMDH inhibitors (for example, azathioprine, leflunomide, mycophenolate), biologics (for example, abatacept, adalimumab, anakinra, certolizumab, etanercept, golimumab, infliximab, ixekizumab, 25208 natalizumab, rituximab, secukinumab, tocilizumab, ustekinumab, vedolizumab), and monoclonal antibodies (for example, basiliximab, da
  • Suitable anticoagulants include, but are not limited to, factor XIa inhibitors, thrombin inhibitors, thrombin receptor antagonists, factor VIIa inhibitors, factor Xa inhibitors, factor IXa inhibitors, factor XIIa inhibitors, adenosine diphosphate antiplatelet agents (e.g., P2Y12 antagonists), fibrinogen receptor antagonists (e.g. to treat or prevent unstable angina or to prevent reocclusion after angioplasty and restenosis), other anticoagulants such as aspirin, and thrombolytic agents such as plasminogen activators or streptokinase to achieve synergistic effects in the treatment of various vascular pathologies.
  • factor XIa inhibitors include, but are not limited to, factor XIa inhibitors, thrombin inhibitors, thrombin receptor antagonists, factor VIIa inhibitors, factor Xa inhibitors, factor IXa inhibitors, factor XIIa inhibitors, adenosine diphosphat
  • Such anticoagulants include, for example, apixaban, dabigatran, cangrelor, ticagrelor, vorapaxar, clopidogrel, edoxaban, mipomersen, prasugrel, rivaroxaban, and semuloparin.
  • apixaban dabigatran
  • cangrelor cangrelor
  • ticagrelor vorapaxar
  • clopidogrel clopidogrel
  • edoxaban mipomersen
  • prasugrel rivaroxaban
  • semuloparin semuloparin
  • the anti-inflammatory agents, anti-VEGF agents, immunosuppressant agents, anticoagulants, antiplatelet agents, and thrombolytic agents described herein are employed in their conventional dosage ranges and regimens as reported in the art, including, for example, the dosages described in editions of the Physicians' Desk Reference, such as the 70th edition (2016) and earlier editions.
  • the anti-inflammatory agents, anti-VEGF agents, immunosuppressant agents, anticoagulants, antiplatelet agents, and thrombolytic agents described herein are employed in lower than their conventional dosage ranges.
  • one or more additional pharmacologically active agents may be administered in combination with a compound of the invention.
  • the additional active agent is intended to mean a pharmaceutically active agent (or agents) that is active in the body, including pro-drugs that convert to pharmaceutically active form after administration, which is different from the compound of the invention, and also includes free-acid, free-base and pharmaceutically acceptable salts of said additional active agents when such forms are sold commercially or are otherwise chemically possible.
  • any suitable additional active agent or agents including but not limited to anti-hypertensive agents, additional diuretics, anti- atherosclerotic agents such as a lipid modifying compound, anti-diabetic agents and/or anti- obesity agents may be used in any combination with the compound of the invention in a single dosage formulation (a fixed dose drug combination), or may be administered to the patient in one or more separate dosage formulations which allows for concurrent or sequential administration of 25208 the active agents (co-administration of the separate active agents).
  • angiotensin converting enzyme inhibitors e.g., alacepril, benazepril, captopril, ceronapril, cilazapril, delapril, enalapril, enalaprilat, fosinopril, imidapril, lisinopril, moveltipril, perindopril, quinapril, ramipril, spirapril, temocapril, or trandolapril); angiotensin II receptor antagonists also known as angiotensin receptor blockers or ARBs, which may be in free-base, free-acid, salt or pro-drug form, such as azilsartan, e.g., azilsartan medoxomil potassium (EDARBI ⁇ ), candesartan, e.g., candesartan cilexetil (ATACAND).
  • angiotensin II receptor antagonists also known as
  • calcium channel blockers e.g., amlodipine, nifedipine, verapamil, diltiazem, felodipine, gallopamil, niludipine, nimodipine, nicardipine
  • potassium channel activators e.g., nicorandil, pinacidil, cromakalim, minoxidil, aprilkalim, loprazolam
  • sympatholitics e.g., beta- adrenergic blocking drugs (e.g., acebutolol, atenolol, betaxolol, bisoprolol, carvedilol, metoprolol, metoprolol tartate, nadolol, propranolol, sotalol, timolol); alpha adrenergic blocking drugs (e.g., doxazosin, prazosin or alpha methyldopa); central alpha a
  • lipid lowering agents e.g., HMG-CoA reductase inhibitors such as simvastatin and lovastatin which are marketed as ZOCOR® and MEVACOR® in lactone pro-drug form and function as inhibitors after administration, and pharmaceutically acceptable salts of dihydroxy open ring acid HMG-CoA reductase inhibitors such as atorvastatin (particularly the calcium salt sold in LIPITOR®), rosuvastatin (particularly the calcium salt sold in CRESTOR®), pravastatin (particularly the sodium salt sold in PRAVACHOL®), and fluvastatin (particularly the sodium salt sold in LESCOL®); a cholesterol absorption inhibitor such as ezetimibe (ZETIA®), and ezetimibe in combination with any other lipid lowering agents such as the HMG-CoA reductase inhibitors noted above and particularly with simvastatin 25208 (VYTORIN®) or with atorvastatin calcium; niacin
  • Typical doses of the plasma kallikrein inhibitors of the invention in combination with other suitable agents may be the same as those doses of plasma kallikrein inhibitors administered without coadministration of additional agents, or may be substantially less that those doses of plasma kallikrein inhibitors administered without coadministration of additional agents, depending on a patient’s therapeutic needs.
  • the compounds are administered to a mammal in a therapeutically effective amount.
  • terapéuticaally effective amount an amount of a compound of the present invention that, when administered alone or in combination with an additional therapeutic agent to a mammal, is effective to treat (i.e., prevent, inhibit or ameliorate) the disease condition or treat the progression of the disease in a host.
  • the compounds of the invention are preferably administered alone to a mammal in a therapeutically effective amount.
  • the compounds of the invention can also be administered in combination with an additional therapeutic agent, as defined below, to a mammal in a therapeutically effective amount.
  • the combination of compounds is preferably, but not necessarily, a synergistic combination. Synergy, as described for example by Chou and Talalay, Adv.
  • Enzyme Regul.1984, 22, 27-55 occurs when the effect (in this case, inhibition of the desired target) of the compounds when administered in combination is greater than the additive effect of each of the compounds when administered individually as a single agent.
  • a synergistic effect is most clearly demonstrated at suboptimal concentrations of the compounds. Synergy can be in terms of lower cytotoxicity, increased anticoagulant effect, or some other beneficial effect of the combination compared with the individual components.
  • administered in combination or “combination therapy” it is meant that the compound of the present invention and one or more additional therapeutic agents are administered concurrently to the mammal being treated. When administered in combination each component may be administered at the same time or sequentially in any order at different points in time.
  • each component may be administered separately but sufficiently closely in time so as to provide the desired therapeutic effect.
  • the administration of each component does not need to be via the same route of administration; for example, one component can be administered orally, and another can be delivered into the vitreous of the eye.
  • Chiral resolutions can be performed on either Waters Thar 80 SFC or Berger MG II preparative SFC systems.
  • LC-MS data can be recorded on SHIMADAZU LC-MS-2020, SHIMADAZU LC-MS-2010, or Agilent 1100 series LC-MS, Agilent Prime-1260, or Waters Acquity LC-MS instruments using C18 columns employing a MeCN gradient in water containing 0.02 to 0.1% TFA. UV detections were at 220 and/or 254 nm and ESI ionization was used for MS detection. [0072] When chiral resolution was achieved by chromatography using chiral columns, the chiral columns used for SFC chiral resolutions are listed in tables.
  • CHIRALPAK AD CHIRALCEL OJ
  • CHIRALPAK AS CHIRALPAK AY
  • CHIRALPAK IA CHIRALPAK AD-H
  • CHIRALPAK AS-H CHIRALPAK AS-H.
  • fast-eluting isomer from a chiral resolution is always listed first in this table followed immediately by the slower-eluting isomer from the same resolution. If more than two isomers were separated, they will be always listed in the tables in order they were eluted, such as Peak 1 followed by Peak 2, Peak 3 and so on.
  • UV ultraviolet
  • ⁇ angstroms
  • W watts
  • XANTPHOS is also known as 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene.
  • XANTPHOS NiG3 is also known as [(4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2′-amino-1,1′- biphenyl)]palladium(II) methanesulfonate.
  • “BrettPhos” is also known as 2- (dicyclohexylphosphino)3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl and the “BrettPhos Pd G3” is also known as [(2-Di-cyclohexylphosphino-3,6-dimethoxy-2′,4′,6′- triisopropyl-1,1 ′-biphenyl)-2-(2′-amino-1,1′ -biphenyl)]palladium(II) methanesulfonate. These catalysts and ligands are available from Millipore Sigma.
  • R is any suitable group a s defined in Formula I
  • Scheme 5 depicts the preparation of compounds V from intermediates 5a and 5b.
  • the Mitsunobu reaction product of alcohol 5a and pyrazole 5b was treated with an amine such as 5c under basic conditions to provide acid 5d.
  • Amide coupling of 5d with an amine such as 5e using 25208 a reagent such as N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (HATU) provide II.
  • Scheme 6 depicts the preparation of compounds V from intermediates 5a and 5b.
  • the Mitsunobu reaction product of alcohol 5a and pyrazole 5b was treated with an amine such as 5c under basic conditions to provide acid 5d.
  • Amide coupling of 5d with an amine such as 5e using 25208 a reagent such as N,N,N',N'-tetramethyl-O-
  • Step 3 1-((2-(Azetidin-1-yl)pyrimidin-5-yl)methyl)-1H-pyrazole-4-carboxylic acid: [0089] To a solution of ethyl 1-[[2-(azetidin-1-yl)pyrimidin-5-yl]methyl]-1H-pyrazole-4- carboxylate (50.0 g, 174 mmol, 1.00 equiv) in THF (600 mL) and H 2 O (200 mL) was added LiOH (16.7 g, 696 mmol, 4.00 equiv). The resulting solution was stirred for overnight at 25 o C. The resulting mixture was concentrated under vacuum.
  • Step 3 1-(4-((2-Oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazole-4-carboxylic acid
  • ethyl 1-(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazole-4- carboxylate 450 mg, 1.33 mmol
  • lithium hydroxide 280 mg, 6.67 mmol
  • Step 3 Methyl 3-(difluoromethyl)-4-(hydroxymethyl)benzoate [0095] To a solution of 2-(difluoromethyl)-4-(methoxycarbonyl)benzoic acid (7.00 g, 30.4 mmol) in THF (70 mL) was added BH 3 ⁇ THF (91 mL, 91 mmol) (1 M in THF) at 0 °C. The resulting mixture was stirred at rt for 3 h. Water was added into the mixture and the pH of the aqueous was adjusted to 3-4 by addition of 2 M HCl solution and extracted with DCM. The combined organic layers were dried (Na 2 SO 4 ) and concentrated to give the title compound which was used in next step directly.
  • Step 4 Methyl 4-(((tert-butyldimethylsilyl)oxy)methyl)-3-(difluoromethyl)benzoate [0096] To a solution of methyl 3-(difluoromethyl)-4-(hydroxymethyl)benzoate (5.50 g, 25.4 mmol) in THF (70 mL) was added imidazole (5.20 g, 76.0 mmol) and TBSCl (11.5 g, 76.0 mmol) at rt. The resulting mixture was stirred at rt for 3 h.
  • Step 5 (4-(((tert-Butyldimethylsilyl)oxy)methyl)-3-(difluoromethyl)phenyl)methanol
  • methyl 4-(((tert-butyldimethylsilyl)oxy)methyl)-3- (difluoromethyl)benzoate (6.50 g, 19.7 mmol) in THF (60 ml) was added diisobutylaluminum 25208 hydride (59.0 mL, 59.0 mmol) at 0 °C, then the mixture was stirred at 0 °C for 1 h. The mixture was diluted by THF and aq.
  • Step 6 Ethyl 1-(4-(((tert-butyldimethylsilyl)oxy)methyl)-3-(difluoromethyl)benzyl)-1H- pyrazole-4-carboxylate [0098]
  • a round bottom flask to a solution of (4-(((tert-butyldimethylsilyl)oxy)methyl)-3- (difluoromethyl)phenyl)methanol (4.60 g, 15.2 mmol), ethyl 1H-pyrazole-4-carboxylate (4.26 g, 30.4 mmol) and Ph 3 P (7.98 g, 30.4 mmol) in toluene (50 ml) was added DBAD (7.00 g, 30.4 mmol) at rt.
  • Step 7 Ethyl 1-(3-(difluoromethyl)-4-(hydroxymethyl)benzyl)-1H-pyrazole-4-carboxylate [0099]
  • a solution of ethyl 1-(4-(((tert- butyldimethylsilyl)oxy)methyl)-3-(difluoromethyl)benzyl)-1H-pyrazole-4-carboxylate 5.50 g, 13.0 mmol
  • MeOH 50 mL
  • HCl/MeOH 4N, 10 mL, 40.0 mmol
  • Step 2 tert-Butyl 1-(1-(trifluoro-l4-boranyl)ethyl)- pyrazole-4-carboxylate, potassium salt [0101] To a solution of (1-(4-(tert- - pyrazol-1-yl)ethyl)boronic acid (180 g, 750 mmol) in MeOH (1.80 L) at rt was added KHF 2 (234 g, 3.00 mmol) in H 2 O (900 mL). The solution was stirred at rt for 12 h and concentrated to give a residue. Acetone was added and the mixture at rt for 1 h.
  • tert-Butyl 7'-acetyl-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-carboxylate [0102] tert-Butyl 7'-bromo-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-carboxylate (1.10 g, 3.25 mmol) was mixed with tributyl(1-ethoxyvinyl)stannane (1.50 g, 4.23 mmol) and palladium-tetrakis(triphenylphosphine) (188 mg, 0.163 mmol) in a microwave reaction vial.
  • tert-Butyl 7'-(1-hydroxyethyl)-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)- carboxylate [0103] tert-Butyl 7'-acetyl-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-carboxylate (900 mg, 3.00 mmol) in MeOH (15 ml) was mixed with NaBH 4 (170 mg, 4.50 mmol). The resulting mixture was stirred at rt overnight.
  • tert-Butyl 7'-(1-azidoethyl)-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)- carboxylate [0104] tert-Butyl 7'-(1-hydroxyethyl)-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)- carboxylate (830 mg, 2.74 mmol) was mixed with DBU (0.50 mL, 3.3 mmol) in DCM (0.9 mL). DPPA (903 mg, 3.28 mmol) in DCM (0.9 mL) was added. The resulting mixture was stirred at rt overnight.
  • tert-Butyl 2-(azidomethyl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate 370 mg, 1.37 mmol
  • DBU 0.25 mL, 1.6 mmol
  • DPPA 450 mg, 1.64 mmol
  • DCM 1.4 mL
  • tert-Butyl 2-((4-(ethoxycarbonyl)-1H-1,2,3-triazol-1-yl)methyl)-6,7-dihydrothiazolo[5,4- c]pyridine-5 -carboxylate tert- 2-(azidomethyl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate (230 mg, 0.780 mmol) was mixed with ethyl propiolate (0.16 mL, 1.6 mmol) in EtOH (1.9 mL).
  • Step 2 tert-Butyl (3-(2-tosylhydrazono)cyclobutyl)carbamate: [0115] To a solution of 4-methylbenzene-1-sulfonohydrazide (254.4 g, 1365 mmol, 1.00 equiv) in MeOH (5.10 L, 125 mol, 91.5 equiv) was added tert-butyl N-(3-oxocyclobutyl)carbamate (253 25208 g, 1.37 mol, 1 equiv). The resulting solution was stirred for 3 h at rt.
  • Step 3 tert-Butyl (3-(3-chlorophenyl)cyclobutyl)carbamate: [0116] To a solution of tert-butyl N-[3-[(4-methylbenzenesulfonamido)imino]- cyclobutyl]carbamate (385 g, 1.0 mol, 1 equiv) in dioxane (5.8 L) was added potassium carbonate (228 g, 1.64 mmol, 1.50 equiv) and (3-chlorophenyl)boronic acid (256 g, 1.634 mmol, 1.50 equiv).
  • Step 3 tert-Butyl (3-oxocyclobutyl)carbamate: [0120] To a solution of 3-oxocyclobutane-1-carbonyl azide in toluene from the previous step, was added toluene (800 mL). The resulting solution was heated to 90 °C until the evolution of N 2 ceased. Next, t BuOH (1 L) was added into the reaction mixture and the resulting mixture was stirred overnight at 90 °C. The mixture was cooled and concentrated.
  • Step 4 tert-Butyl (3-hydroxycyclobutyl)carbamate: [0121] To a solution of tert-butyl N-(3-oxocyclobutyl)carbamate (95.0 g, 503 mmol, 1.0 eq) in THF (950 mL) and MeOH (475 mL) cooled to 0 o C was added NaBH 4 (38.0 g, 1.01 mol, 1.0 eq), in portions. The mixture was stirred for 1 h at rt.
  • Step 5 tert-Butyl (3-iodocyclobutyl)carbamate: [0122] To a solution of tert-butyl N-(3-hydroxycyclobutyl)carbamate (88.9 g, 473 mmol, 1.0 eq) in in DCM (900 mL) was added I 2 (144 g, 567 mmol, 1.2 eq), PPh 3 (148.6 g, 567.4 mmol, 1.2 eq), and imidazole (38.6 g, 567 mmol, 1.2 eq).
  • reaction mixture was stirred at rt 12 h.
  • the mixture was diluted with H 2 O, then filtered, and the liquid was extracted with DCM.
  • the organic layers were combined and washed with brine.
  • the organic layer was dried by Na 2 SO 4 and concentrated under vacuum.
  • the residue was purified by flash silica gel chromatography (3% EtOAc/petroleum ether) to afford title compound.
  • the vial was capped. Air was removed by vacuum and back-filled with nitrogen (three times).2-Propanol (0.4 mL) and sodium bis(trimethylsilyl)amide (0.20 mL, 0.20 mmol) were introduced. Air was removed and back-filled with nitrogen (three times). The mixture was heated at 60 °C for 15 h. The mixture was diluted with EtOAc and washed with water and brine. The organic layer was separated and dried over anhydrous sodium sulfate. After it was filtered and concentrated, the crude was purified by flash silica gel chromatography (0-20% EtOAc/hexane) to provide the title compound.
  • Step 2 3-(5-Chloro-2-fluorophenyl)cyclobut-2-enamine
  • Step 1 1-Amino-3-(3-chlorophenyl)cyclobutane-1-carbonitrile: [0130] To a solution of 3-(3-chlorophenyl)cyclobutanone (200 mg, 1.11 mmol) in MeOH (1.7 mL) and water (1.0 mL) was added ammonia (1.6 mL, 11 mmol, 7M in MeOH), NaCN (109 mg, 2.21 mmol), and ammonium chloride (118 mg, 2.21 mmol). The vial was stirred at rt for 3 days and the mixture was diluted with EtOAc and washed with brine.
  • Step 3 (1S,2S,4S)-2-Amino-4-(3-chlorophenyl)cyclobutan-1-ol and -2-Amino-4-(3- chlorophenyl)cyclobutan-1-ol (racemic 2-amino-4-(3-chlorophenyl) [0133]
  • TFA salt 110 mg, 0.375 mmol
  • THF 4 mL
  • Step 2 3-(3-Chlorophenyl)-2-(hydroxymethyl)cyclobutanone: [0135] To a solution of 3-(3-chlorophenyl)cyclobutanone (100 mg, 0.554 mmol) in water (0.5 mL) and ACN (1 mL) was added potassium carbonate (1.5 mg, 0.011 mmol) and formaldehyde (37 ⁇ L, 0.50 mmol) at rt, then the mixture was stirred at 40 °C for 30 min.
  • Step 4 ((1S,2S,4R)-2-Amino-4-(3-chlorophenyl)cyclobutyl)methanol and ( -2-Amino- 4-(3-chlorophenyl)cyclobutyl)methanol: [0137] To a solution of 3-(3-chlorophenyl)-2-(hydroxymethyl)cyclobutanone oxime (240 mg, 1.06 mmol) in THF (5 mL) was added LAH (121 mg, 3.19 mmol) at 0 °C, then the mixture was stirred at rt for 1 h.
  • Methyl 1-((2-(methylthio)pyrimidin-5-yl)methyl)-1H-pyrazole-4-carboxylate [0141] Methyl 1H-pyrazole-4-carboxylate (0.760 g, 6.02 mmol) and Cs 2 CO 3 (5.35 g, 16.4 mmol) were added to a stirred solution of starting material 5-(bromomethyl)-2- (methylthio)pyrimidine (1.20 g, 5.48 mmol) in DMF (36 mL) at rt. The mixture was stirred at rt for overnight. The mixture was diluted with water, extracted with DCM. The combined organic phases were washed with brine, dried (MgSO 4 ) and concentrated under reduced pressure.
  • Ethyl 1-((6-fluoropyridin-3-yl)methyl)-1H-pyrazole-4-carboxylate [0146] To a solution of ethyl 1H-pyrazole-4-carboxylate (300 mg, 2.14 mmol) and 5- (chloromethyl)-2-fluoropyridine (343 mg, 2.36 mmol) in ACN (13 mL) was added potassium carbonate (256 mg, 1.85 mmol). The reaction mixture was purged with nitrogen and heated at 100 °C for 24 h. The mixture was diluted with water and extracted with DCM. The combined organic layers were dried over magnesium sulfate, filtered and concentrated under reduced pressure.
  • Step 3 1-((6-(Azetidin-1-yl)pyridin-3-yl)methyl)-1H-pyrazole-4-carboxylic acid: [0148] To a solution of ethyl 1-((6-(azetidin-1-yl)pyridin-3-yl)methyl)-1H-pyrazole-4- carboxylate (166 mg, 0.580 mmol) in THF (2 mL) and water (1 mL) was added LiOH (41.6 mg, 1.74 mmol). The reaction mixture was stirred at rt for 16 h. Additional lithium hydroxide (69 mg, 25208 2.9 mmol) and water (0.5 mL) were added, and the reaction was stirred at rt for 4 h.
  • Step 4 1-((6-(Azetidin-1-yl)pyridin-3-yl)methyl)-N-((cis)-3-(5-chloro-2- cyanophenyl)cyclobutyl)-1H-pyrazole-4-carboxamide: [0149] To a solution of 1-((6-(azetidin-1-yl)pyridin-3-yl)methyl)-1H-pyrazole-4-carboxylic acid, 2,2,2-trifluoroacetate salt (6.3 mg, 0.017 mmol), N-ethyl-N-isopropylpropan-2-amine (11 mg, 0.085 mmol) and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (6.5 mg, 0.017 mmol) in DMF (1 mL), stirred at rt, was added 2-
  • Step 2 1-((2-(Methylthio)pyrimidin-5-yl)methyl)-1H-pyrazole-4-carboxylic acid.
  • Step 3 N-( -3-(3-Chlorophenyl)cyclobutyl)-1-((2-(methylthio)pyrimidin-5-yl)methyl)- pyrazole- [0152] To the solution of 1-((2-(methylthio)pyrimidin-5-yl)methyl)-1H-pyrazole-4-carboxylic acid (275 mg, 1.10 mmol) and (cis)-3-(3-chlorophenyl)cyclobutan-1-amine hydrochloride (240 mg, 1.10 mmol) in DCM (10 mL) was added DIEA (576 ⁇ l, 3.30 mmol) and 1- propanephosphonic anhydride (1.31 mL, 2.20 mmol).
  • Step 4 N-( -3-(3-Chlorophenyl)cyclobutyl)-1-((2-(methylsulfonyl)pyrimidin-5-yl)methyl)- 1H- carboxamide: [0153] To the solution of N-((cis)-3-(3-chlorophenyl)cyclobutyl)-1-((2-(methylthio)pyrimidin- 5-yl)methyl)-1H-pyrazole-4-carboxamide (211 mg, 0.510 mmol) in DCM (5 mL) was added mCPBA (231 mg, 1.02 mmol).
  • N-((cis)-3-(3-Chlorophenyl)cyclobutyl)-1-((2-((S)-2-(((R)-3-hydroxypyrrolidin-1- yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)methyl)-1H-pyrazole-4-carboxamide [0156] To the solution of N-((cis)-3-(3-chlorophenyl)cyclobutyl)-1-((2-((S)-2-formylpyrrolidin- 1-yl)pyrimidin-5-yl)methyl)-1H-pyrazole-4-carboxamide (17 mg, 0.037 mmol) in CH 2 Cl 2 (5% AcOH) was added (R)-pyrrolidin-3-ol (6.4 mg, 0.073 mmol) and the mixture was stirred at rt for 0.5 h.
  • Ethyl-1-(1-(6-fluoropyridin-3-yl)ethyl)-1H-1,2,3-triazole-4-carboxylate [0158] To a solution of 5-(1-azidoethyl)-2-fluoropyridine (1.30 g, 7.82 mmol) in EtOH(10 mL), stirred at rt, was added ethyl propiolate (1.59 mL, 15.7 mmol), followed by a solution of L- sodium ascorbate (287 mg, 1.57 mmol) in water (5 mL) and a solution of copper(II) sulfate pentahydrate (391 mg, 1.57 mmol) in water (5 mL) The reaction mixture was stirred for 45 min at rt.
  • Ethyl-1-(1-(6-(azetidin-1-yl)pyridin-3-yl)ethyl)-1H-1,2,3-triazole-4-carboxylate 25208 [0159] To a solution of ethyl 1-(1-(6-fluoropyridin-3-yl)ethyl)-1H-1,2,3-triazole-4-carboxylate (60 mg, 0.23 mmol) in dioxane (1.5 mL) was added DIEA (1.19 mL, 6.81 mmol) and azetidine (389 mg, 6.81 mmol). The reaction mixture was heated at 80 °C for 45 min.
  • reaction mixture was stirred for 3.5 h at rt, and the mixture was quenched with brine and extracted with EtOAc.
  • the combined organic layers were concentrated under reduced pressure and purified by reverse phase HPLC (ACN/water with 0.05% TFA modifier) to afford the mixture of diastereomers.
  • the enantiopure title compounds were resolved by Chiral SFC (OD-H, 21 x 250mm, 45% (MeOH + 0.2% DIPA)).
  • the compounds were purified by reverse phase HPLC (ACN/water with 0.05% TFA modifier).
  • Step 7 1-(1-(6-(3-Azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)-2-((tert- butyldiphenylsilyl)oxy)ethyl)-N-( -3-(5-chloro-2-cyanophenyl)cyclobutyl)-1H-pyrazole-4- carboxamide.
  • Step 2 Methyl 1-((2-(3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)methyl)-1H-pyrazole-4- carboxylate: 25208 [0183] Methyl 1H-pyrazole-4-carboxylate (107 mg, 0.847 mmol) and Ph 3 P (222 mg, 0.847 mmol) were added to a stirred solution of (2-(3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5- yl)methanol (81 mg, 0.42 mmol) in toluene (4.2 mL) at rt and the mixture was stirred at rt for 15 min.
  • Step 3 1-((2-(3-Azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)methyl)-1H-pyrazole-4-carboxylic acid: [0184] Lithium hydroxide (110 mg, 4.58 mmol) was added to a stirred solution of methyl 1-((2- (3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)methyl)-1H-pyrazole-4-carboxylate (137 mg, 0.458 mmol) in THF (2 mL) and water (0.5 mL) at rt, and the mixture was stirred at 60 °C overnight. The mixture was diluted with water and extracted with EtOAc.
  • Step 4 1-((2-(3-Azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)methyl)-N-((cis)-3-(5-chloro-2- cyanophenyl)cyclobutyl)-1H-pyrazole-4-carboxamide: [0185] Hunig's base (64 ⁇ l, 0.37 mmol) and 1-((2-(3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5- yl)methyl)-1H-pyrazole-4-carboxylic acid (18 mg, 0.061 mmol) were added to a stirred solution of 2-((cis)-3-aminocyclobutyl)-4-chlorobenzonitrile (2,2,2-trifluoroacetate) (53 mg, 0.12 mmol) in DMF (0.6 mL) at rt.
  • Step 3 Ethyl 2-amino-2-(2-(2-(4-((2-oxopyridin-1 - yl)methyl)phenyl)acetyl)hydrazono)acetate.
  • Ethyl 2-ethoxy-2-iminoacetate (575 mg, 3.96 mmol) was added to a stirred mixture of 2-(4-((2-oxopyridin-1(2H)-yl)methyl)phenyl)acetohydrazide (510 mg, 1.98 mmol) in EtOH (50 mL) and the mixture was stirred at rt for 12 h.
  • Step 5 N-(3-(3-Chlorophenyl)cyclobutyl)-5-(4-((2-oxopyridin-1 -yl)methyl)benzyl)-4H- 1,2,4-triazole-3-carboxamide.
  • Trimethyl aluminum (0.47 mL, 0.95 mmol) was added to a stirred mixture of 3-(3- chlorophenyl)cyclobutanamine (86 mg, 0.47 mmol) in toluene (1 mL) at rt, and the mixture was stirred at rt for 10 min.
  • Step 2 Ethyl 1-(3-(difluoromethyl)-4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazole-4- carboxylate.
  • ethyl 1-(3-(difluoromethyl)-4-(((methylsulfonyl)oxy)methyl)benzyl)- 1H-pyrazole-4-carboxylate 200 g, 0.515 mmol
  • DMF 4 mL
  • pyridin-2(1H)-one 98 mg, 1.0 mmol
  • potassium carbonate 142 mg, 1.03 mmol
  • Step 2 N-(3-(3-Chlorophenyl)cyclobutyl)-1-(3-(difluoromethyl)-4-(hydroxymethyl)benzyl)-1H- pyrazole-4-carboxamide.
  • 1-(3-(difluoromethyl)-4-(hydroxymethyl)benzyl)-1H-pyrazole- 4-carboxylic acid 150 mg, 0.531 mmol
  • DIPEA 0.28 mL, 1.6 mmol
  • EDC 122 mg, 0.638 mmol
  • HOBT 98 mg, 0.64 mmol
  • DMF 3-(3- chlorophenyl)cyclobutanamine
  • Step 2 N-((cis)-3-(3-Chlorophenyl)cyclobutyl)-1-(3-(difluoromethyl)-4-(((1R,5S)-2-oxo-3- azabicyclo[3.1.0]hexan-3-yl)methyl)benzyl)-1H-pyrazole-4-carboxamide and N-( -3-(3- Chlorophenyl)cyclobutyl)-1-(3-(difluoromethyl)-4-(((1S,5R)-2-oxo-3-azabicyclo hexan-3- yl)methyl)benzyl)-1H-pyrazole-4-carboxamide.
  • Step 2 Methyl 3-(methylsulfonyl)-4-((2-oxopyridin-1 -yl)methyl)benzoate.
  • DIAD 132 mg, 0.573 mmol
  • 1-(4-(hydroxymethyl)-2- (methylsulfonyl)benzyl)pyridin-2(1H)-one 84 mg, 0.29 mmol
  • ethyl 1H-pyrazole-4-carboxylate 80 mg, 0.57 mmol
  • Ph 3 P 150 mg, 0.573 mmol
  • Step 6 N-((cis)-3-(3-Chlorophenyl)cyclobutyl)-1-(3-(methylsulfonyl)-4-((2-oxopyridin-1 - yl)methyl)benzyl)-1H-pyrazole-4-carboxamide.
  • Step 5 1-(2-Hydroxy-1-(4-(pyridin-2-ylmethyl)phenyl)ethyl)-1H-pyrazole-4-carboxylic acid.
  • Lithium hydroxide monohydrate (14.3 mg, 0.341 mmol) was added to a stirred mixture of ethyl 1-(2-hydroxy-1-(4-(pyridin-2-ylmethyl)phenyl)ethyl)-1H-pyrazole-4-carboxylate (60 mg, 0.17 mmol) in THF (0.5 mL) and water (0.2 mL) at rt and the mixture was stirred at rt for 18 h.
  • Step 6 N-((cis)-3-(5-Chloro-2-cyanophenyl)cyclobutyl)-1-((S)-2-hydroxy-1-(4-(pyridin-2- ylmethyl)phenyl)ethyl)-1H-pyrazole-4-carboxamide and N-((cis)-3-(5-Chloro-2- cyanophenyl)cyclobutyl)-1-((R)-2-hydroxy-1-(4-(pyridin-2-ylmethyl)phenyl)ethyl)-1H-pyrazole- 4-carboxamide.
  • Step 2 1-((2-(3-Azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)methyl)-1H-pyrazole-3- carboxylate, lithium salt.
  • Step 3 2-((2-(Azetidin-1-yl)pyrimidin-5-yl)methyl)-2H-1,2,3-triazole-4-carboxylic acid.
  • Step 4 2-((2-(Azetidin-1-yl)pyrimidin-5-yl)methyl)-N-((cis)-3-(5-chloro-2- cyanophenyl)cyclobutyl)-2H-1,2,3-triazole-4-carboxamide.
  • the crude product was purified by flash silica gel chromatography (0-100% MeOH/EtOAc) to give methyl 1-((2-(azetidin-1- yl)pyrimidin-5-yl)methyl)-1H-1,2,4-triazole-5-carboxylate (faster-eluting peak) and a mixture of another two isomers (slower eluting peak).
  • the slower eluting peak was purified by prep-TLC (10% MeOH/DCM) to give the title compound.
  • Step 3 1-((2-(Azetidin-1-yl)pyrimidin-5-yl)methyl)-N-((cis)-3-(5-chloro-2- cyanophenyl)cyclobutyl)- triazole-3-carboxamide.
  • Step 2 tert-Butyl 6-((4-(ethoxycarbonyl)-1H-1,2,3-triazol-1-yl)methyl)-3,4-dihydroisoquinoline- 2 -carboxylate.
  • tert-Butyl 6-(azidomethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate 270 mg, 0.940 mmol
  • EtOH 2 mL
  • a solution of copper(II) sulfate pentahydrate 47 mg, 0.19 mmol) in water (1 mL) was added.
  • Lithium 1-((2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)methyl)-1H- 1,2,3-triazole-4-carboxylate 25208 [0224] tert-Butyl 6-((4-(ethoxycarbonyl)-1H-1,2,3-triazol-1-yl)methyl)-3,4- dihydroisoquinoline-2(1H)-carboxylate (310 mg, 0.800 mmol) was mixed with LiOH (38 mg, 1.6 mmol) in a mixed solvent of THF (2 mL) and water (0.7 mL).
  • Example 78 N-((cis)-3-(5-Chloro-2-cyanophenyl)cyclobutyl)-1-((5-methyl-4,5,6,7-tetrahydrothiazolo[5,4- c]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide Step 1. N-((cis)-3-(5-Chloro-2-cyanophenyl)cyclobutyl)-1-((5-methyl-4,5,6,7- tetrahydrothiazolo[5,4-c]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide.
  • Example 83 and 84 N-((cis)-3-(5-Chloro-2-cyanophenyl)cyclobutyl)-1-((R)-1-(3-methyl-4-oxo-3,4- dihydroquinazolin-6-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide and N-((cis)-3-(5-Chloro-2- cyanophenyl)cyclobutyl)-1-((S)-1-(3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)ethyl)-1H-1,2,3- triazole-4-carboxamide Step 1: 6-Bromo-3-methylquinazolin-4 -one.
  • Tetrakis (triphenylphosphine) (0) (1.45 g, 1.26 mmol) was dissolved in toluene (15 mL), then tributyl(1-ethoxyvinyl)stannane (5.05 mL, 15.0 mmol) and 6-bromo-3- methylquinazolin-4(3H)-one (3.00 g, 12.6 mmol) were added at rt. The resulting mixture was stirred for 18 h at 130 °C, cooled to rt, then 6M HCl was added, and the mixture was stirred at rt for 1 h. Water was added, and the mixture was extracted with DCM.
  • Step 3 6-(1-Hydroxyethyl)-3-methylquinazolin-4 -one.
  • NaBH 4 140 mg, 3.71 mmol was added to a mixture of 6-acetyl-3- methylquinazolin-4(3H)-one (1.50 g, 7.42 mmol) in THF (10 mL) at 0 °C, and the mixture was stirred at rt for 1 h. Satd.
  • Lithium hydroxide hydrate (33.5 mg, 0.798 mmol) was added to a stirred mixture of methyl 1-(1-(3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)ethyl)-1H-1,2,3-triazole-4-carboxylate (50 mg, 0.16 mmol) in THF (2 mL) and water (0.4 mL) at rt, and the mixture was stirred at rt for 2 h. The reaction was adjusted to pH 6 with 1M HCl and extracted with DCM. The combined organic fractions were washed with brine, dried over Na 2 SO 4 , filtered and the solvent was evaporated under reduced pressure to give the title compound.
  • Step 7 N-((cis)-3-(5-Chloro-2-cyanophenyl)cyclobutyl)-1-((R)-1-(3-methyl-4-oxo-3,4- dihydroquinazolin-6-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide and N-( 3-(5-Chloro-2- cyanophenyl)cyclobutyl)-1-((S)-1-(3-methyl-4-oxo-3,4- ethyl)-1H-1,2,3- triazole-4-carboxamide.
  • N-((ethylimino)methylene)- N,N-dimethylpropane-1,3-diamine hydrochloride (28.8 mg, 0.150 mmol) was added to a stirred mixture of 1-(1-(3-methyl-4-oxo-3,4-dihydroquinazolin-6- yl)ethyl)-1H-1,2,3-triazole-4-carboxylic acid (30 mg, 0.10 mmol), 2-((cis)-3-aminocyclobutyl)-4- chlorobenzonitrile 2,2,2-trifluoroacetate (32 mg, 0.10 mmol) in pyridine (2 mL) at rt, and the mixture was stirred at rt for 12 h.
  • Example 85 1-((2-(Azetidin-1-yl)pyrimidin-5-yl)methyl)-N-((trans)-3-(3-chlorophenyl)-3-fluorocyclobutyl)- 1H-pyrazole-4-carboxamide Step 1: tert-Butyl (3-(3-chlorophenyl)-3-hydroxycyclobutyl)carbamate. [0241] To a solution of 1-bromo-3-chlorobenzene (3.10 g, 16.2 mmol) in THF (20 mL) was added n-butyllithium (6.48 mL, 16.2 mmol, 3M in hexanes) dropwise at -78 °C.
  • Step 2 3-Amino-1-(3-chlorophenyl)cyclobutanol.
  • tert-butyl (3-(3-chlorophenyl)-3-hydroxycyclobutyl)carbamate 500 mg, 1.68 mmol
  • DCM 2 mL
  • TFA 0.2 mL
  • MS 198.0 (M+1).
  • Example 86 and 87 N-((cis)-3-(5-Chloro-2-cyanophenyl)cyclobutyl)-1-((S)-1-(2-cyclopropylimidazo[1,2- a]pyridin-6-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide and N-((cis)-3-(5-Chloro-2- 25208 cyanophenyl)cyclobutyl)-1-((R)-1-(2-cyclopropylimidazo[1,2-a]pyridin-6-yl)ethyl)-1H-1,2,3- triazole-4-carboxamide Step 1: 6-Bromo-2-cyclopropylimidazo[1,2-a]pyridine.
  • 6-Bromo-2-cyclopropylimidazo[1,2-a]pyridine (2.60 g, 11.0 mmol) was dissolved in toluene (40 mL), then tributyl(1-ethoxyvinyl)stannane (5.55 mL, 16.5 mmol) and (PPh 3 ) 2 PdCl 2 (770 mg, 1.10 mmol) were added at rt. The mixture was stirred at 90 °C for 16 h, then cooled to rt, and 6M HCl was added. The mixture was stirred at rt for 1 h. The mixture was extracted with EtOAc, the combined organic fractions were washed with satd. aq.
  • Step 3 1-(2-Cyclopropylimidazo[1,2-a]pyridin-6-yl)ethanol [0247] To a solution of 1-(2-cyclopropylimidazo[1,2-a]pyridin-6-yl)ethanone (1.00 g, 4.99 mmol) in THF (10 mL) and MeOH (2 mL) was added NaBH 4 (227 mg, 5.99 mmol) at 0 °C. The reaction was stirred at rt for 1 h, satd. aq. NH 4 Cl was added, then the aq. layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated to give the title compound.
  • Step 5 6-(1-Azidoethyl)-2-cyclopropylimidazo[1,2-a]pyridine.
  • Step 6 tert-Butyl 1-(1-(2-cyclopropylimidazo[1,2-a]pyridin-6-yl)ethyl)-1H-1,2,3-triazole-4- carboxylate.
  • tert-butyl propiolate (251 mg, 1.99 mmol) and 6-(1-azidoethyl)- 2-cyclopropylimidazo[1,2-a]pyridine (348 mg, 1.53 mmol) in tert-butanol (7 mL) and water (7 mL) were added sodium ascorbate (607 mg, 3.06 mmol) and Cu 2 SO 4 ⁇ 5H 2 O (38.2 mg, 0.153 mmol) at rt, then the reaction mixture was stirred at rt for 4 h.
  • Step 8 N-( -3-(5-Chloro-2-cyanophenyl)cyclobutyl)-1-((S)-1-(2-cyclopropylimidazo[1,2- a]pyridin- -1H-1,2,3-triazole-4-carboxamide and N-( -3-(5-Chloro-2- cyanophenyl)cyclobutyl)-1-((R)-1-(2-cyclopropylimidazo[1,2- 6-yl)ethyl)-1H-1,2,3- triazole-4-carboxamide.
  • the vial was capped, air was removed and the vial was back-filled with nitrogen (three times).1,4-Dioxane (2.6 mL) and water (1.3 mL) were introduced with syringe.
  • the mixture was heated by microwave reactor at 140 °C for 10 min, cooled to rt, diluted with EtOAc, and washed with brine.
  • the organic layer was separated, dried over anhydrous sodium sulfate, concentrated, and purified by flash silica gel chromatography (0-30% EtOAc/petroleum ether) to give the title compound.
  • Plasma Kallikrein assay The effectiveness of a compound of the present invention as an inhibitor of plasma kallikrein can be determined using a relevant purified serine protease, and an appropriate synthetic substrate. The rate of hydrolysis of the chromogenic or fluorogenic substrate by the relevant serine protease was measured both in the absence and presence of compounds of the present invention. Assays were conducted at rt or at 37 °C. Hydrolysis of the substrate resulted in release of amino trifluoromethylcoumarin (AFC), which was monitored spectrofluorometrically by measuring the increase in emission at 510 nm with excitation at 405 nm.
  • AFC amino trifluoromethylcoumarin
  • a decrease in the rate of fluorescence change in the presence of inhibitor is indicative of enzyme inhibition.
  • the results of this assay are expressed as the half- maximal inhibitory concentrations (IC 50 ), or the inhibitory constant, K i .
  • IC 50 half- maximal inhibitory concentrations
  • K i inhibitory constant
  • Determinations were made using purified Human plasma kallikrein at a final concentration of 0.5 nM (Enzyme Research Laboratories) and the synthetic substrate, Acetyl-K- P-R-AFC (Sigma # C6608) at a concentration of 100 mM.
  • Activity assays were performed by diluting a stock solution of substrate at least tenfold to a final concentration ⁇ 0.2 Km into a solution containing enzyme or enzyme equilibrated with inhibitor. Times required to achieve equilibration between enzyme and inhibitor were determined in control experiments. The reactions were performed under linear progress curve conditions and fluorescence increase measured at 405 Ex/510 Em nm. Values were converted to percent inhibition of the control reaction (after subtracting 100% Inhibition value).
  • X is a bond or CR 5 R 6 ; each R 1 is independently selected from the group consisting of halo, cyano, R x and OR x ;
  • R 3 is hydrogen, halo, cyano or methyl;
  • R 4 is hydrogen, halo, hydroxyl, methyl or CH 2 OH;
  • R 5 is hydrogen or C1-3 alkyl, which is optionally substituted with one to three substituents selected

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Abstract

La présente invention concerne un composé de formule I et des compositions pharmaceutiques comprenant un ou plusieurs desdits composés, et des procédés d'utilisation desdits composés pour traiter ou prévenir un ou plusieurs états pathologiques qui pourraient bénéficier de l'inhibition de la kallicréine plasmatique, y compris l'angio-oedème héréditaire, l'uvéite, l'uvéite postérieure, la dégénérescence maculaire humide liée à l'âge, l'oedème maculaire diabétique, la rétinopathie diabétique et l'occlusion veineuse rétinienne. Les composés sont des inhibiteurs sélectifs de la kallicréine plasmatique.
PCT/US2024/015306 2023-02-17 2024-02-12 Inhibiteurs de la kallicréine plasmatique Ceased WO2024173196A1 (fr)

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US20160157485A1 (en) * 2013-07-08 2016-06-09 Syngenta Participations Ag 4-membered ring carboxamides used as nematicides
US20160332968A1 (en) * 2014-02-06 2016-11-17 Harry CHOBANIAN Antidiabetic compounds
WO2020086533A1 (fr) * 2018-10-22 2020-04-30 Assembly Biosciences, Inc. Composés d'hétéroaryle carboxamide à 5 chaînons pour le traitement du vhb
WO2022010828A1 (fr) * 2020-07-10 2022-01-13 Merck Sharp & Dohme Corp. Inhibiteurs de la kallicréine plasmatique

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