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WO2025163522A1 - Composés de cyanotriazole et leurs utilisations - Google Patents

Composés de cyanotriazole et leurs utilisations

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Publication number
WO2025163522A1
WO2025163522A1 PCT/IB2025/050982 IB2025050982W WO2025163522A1 WO 2025163522 A1 WO2025163522 A1 WO 2025163522A1 IB 2025050982 W IB2025050982 W IB 2025050982W WO 2025163522 A1 WO2025163522 A1 WO 2025163522A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
pharmaceutically acceptable
acceptable salt
disease
stereoisomer
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/IB2025/050982
Other languages
English (en)
Inventor
Maxime DAUPHINAIS
Jan Jiricek
Dennis KOESTER
Qingshuo MENG
Sarah Louise MILLER
Olivier RENE
Zhicong SHI
Haihao Tang
Katarina VULIC
Lei Zhang
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Novartis AG
Original Assignee
Novartis AG
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Filing date
Publication date
Application filed by Novartis AG filed Critical Novartis AG
Publication of WO2025163522A1 publication Critical patent/WO2025163522A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • 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
    • C07D401/12—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 chain containing hetero atoms as chain links
    • 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
    • C07D405/14—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
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 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

Definitions

  • the present invention relates to cyanotriazoles compounds, compositions comprising such compounds, and their use for the treatment of kinetoplastid diseases, particularly Chagas disease, leishmaniasis and human African trypanosomiasis (HAT).
  • kinetoplastid diseases particularly Chagas disease, leishmaniasis and human African trypanosomiasis (HAT).
  • Chagas disease also called American trypanosomiasis, is a tropical parasitic disease caused by the flagellate protozoan Trypanosoma cruzi. T. cruzi is commonly transmitted to humans and other mammals by the blood-sucking "kissing bugs" of the subfamily Triatominae (family Reduviidae). Chagas disease is endemic in twenty one Central and Latin American countries; particularly in poor, rural areas of Mexico, Central America, and South America. Large-scale population movements from rural to urban areas of Latin America and to other regions of the world have increased the geographic distribution of Chagas disease, and cases have been noted in many countries including the United States, Canada and Europe.
  • Leishmaniasis is a disease caused by protozoan parasites that belong to the genus Leishmania and is transmitted by the bite of certain species of sand fly. Leishmaniasis is mostly a disease of the developing world, and is rarely known in the developed world outside a small number of cases, mostly where personnel are stationed away from their home countries. Cutaneous leishmaniasis is the most common form of leishmaniasis. Visceral leishmaniasis (also called kala-azar), caused by the parasite Leishmania donovani, is the most serious form in which the parasites migrate to the vital organs and is potentially fatal, if untreated.
  • Visceral leishmaniasis has an estimated incidence of 50,000 to 90,000 new cases worldwide annually. More than 90 percent of the world's cases of visceral leishmaniasis are in India, Bangladesh, Nepal, Sudan, and Brazil. Nearly 600,000 to 1 million estimated new cases of Cutaneous Leishmaniasis occur annually, with 95% cases occurring in Americas, the Mediterranean basin, the middle east and central Asia.
  • Existing drugs for visceral leishmaniasis have serious drawbacks in terms of safety, resistance, stability and cost; and have low tolerability, long treatment duration when used individually, and are difficult to administer.
  • no vaccines are in routine use.
  • HAT Human African trypanosomiasis
  • sleeping sickness is a parasitic disease caused by the protozoan parasite Trypanosoma brucei, which is transmitted by the bite of the tsetse fly. Over 95% of sleeping sickness cases reported is caused by T.b. gambiense and ⁇ 5% of cases are caused by T.b. rhodesiense. The disease is endemic in 36 sub-Saharan African countries and the WHO recently reported that there were ⁇ 1000 new cases of the disease in 2018 and continued to remain below that threshold a of 2022, but it is likely that significant numbers of cases remain unreported. Following transmission, HAT manifests itself in 2 stages as the parasite replicates and spreads within the host.
  • stage 1 Parasites first reside in the bloodstream (stage 1); if untreated, they eventually cross into the central nervous system (CNS) leading to stage 2 disease causing severe neurologic disturbances which eventually cause death.
  • CNS central nervous system
  • stage 2 The treatment of choice for HAT depends on the disease form and disease stage.
  • Fexinidizazole the first oral treatment, is effective against both first and second stage disease; however, the 10 day long dosing with high pill burden is still a challenging regimen under resource-poor settings.
  • Acoziborole a single dose regimen has showed promising result with success rates of 95% in a recent Phase ll/lll study against gambiense HAT.
  • Cyanotriazoles have been shown to inhibit growth of trypanosomatic parasites in vitro through selective kinetoplastid topoisomerase II inhibition. (Rao et al., Science 380, 1349-1356 (2023). However, there remains a need for new and better treatments and therapies for Chagas disease, leishmaniasis and/or HAT that are safer, more effective and shorter-duration.
  • Ring A is naphthalenyl, 1 ,2-dihydroisoquinolinyl or a 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S;
  • R 1 is cyano, halo, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy or oxo; and n is 0-3.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I) or subformulae thereof, or a stereoisomer, enantiomer, enantiomeric mixture or pharmaceutically acceptable salt thereof; and one or more pharmaceutically acceptable carriers.
  • the invention provides a combination, in particular a pharmaceutical combination, comprising a therapeutically effective amount of a compound of Formula (I) or subformulae thereof, or a stereoisomer, enantiomer, enantiomeric mixture or pharmaceutically acceptable salt thereof; and one or more therapeutically active agent(s).
  • compounds of Formula (I) or subformulae thereof, in free form or in pharmaceutically acceptable salt form, may be useful as a therapy for a disease or condition that can be benefit from inhibition of growth and proliferation of kinetoplastid parasites.
  • compounds of Formula (I) or subformulae thereof selectively inhibit the parasite topoisomerase II (Topo II) enzyme, thereby causing irreversible DNA damage, without affecting human topoisomerases (human topo I, Ila and 11 ).
  • compounds of the invention selectively inhibit trypanosomal Topo II.
  • the invention provides a compound of Formula (I) or subformulae thereof, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, for use in treating, preventing, inhibiting, ameliorating, or eradicating the pathology and/or symptomology of a disease caused by a kinetoplastid parasite.
  • the invention provides the use of a compound selected from Formula (I), or subformulae thereof, or a pharmaceutically acceptable salt or stereoisomer thereof, in the manufacture of a medicament for treating a disease in a subject caused by a kinetoplastid parasite.
  • the kinetoplastid parasites include, but is not limited to, a parasite of the Trypanosoma genus, for example, Trypanosoma cruzi and Trypanosoma brucer, and a parasite of the Leishmania genus, for example, Leishmania donovani, Leishmania infantum, Leishmania braziliensis, Leishmania panamensis, Leishmania guayanensis, Leishmania amazonensis, Leishmania mexicana, Leishmania tropica, Leishmania major. Accordingly, compounds of the invention may be useful for treating Chagas disease, leishmaniasis and human African trypanosomiasis.
  • Ci-Ce alkyl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to six carbon atoms, and which is attached to the rest of the molecule by a single bond.
  • Ci -ealkyl examples include, but are not limited to, methyl, ethyl, n-propyl, /so-propyl, n-butyl, isobutyl (-CH2CH(CHs)2), sec-butyl (- CH(CH 3 )CH 2 CH 3 ), t-butyl (-C(CH 3 ) 3 ), n-pentyl, isopentyl (-(CH 2 )2CH(CH 3 ) 2 ), neopentyl (-CH- 2 C(CH 3 ) 3 ), terf-pentyl (-C(CH 3 ) 2 CH 2 CH 3 ), 2-pentan-yl (-CH(CH 3 )(CH 2 ) 2 CH 3 ), n-hexyl, and the like.
  • Ci-Ce alkoxy refers to a radical of the formula -OR a , where R a is a Ci-ealkyl radical as generally defined above.
  • Examples of Ci-ealkoxy include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentoxy, and hexoxy.
  • halo refers to bromo, chloro, fluoro or iodo; preferably fluoro, chloro or bromo.
  • Ci-Ce haloalkyl refers to a Ci-ealkyl radical as defined above, substituted by one or more halo radicals as defined above.
  • Examples of Ci-ehaloalkyl include, but are not limited to, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2- trifluoroethyl, 1 ,3-dibromopropan-2-yl, 3-bromo-2-fluoropropyl and 1 ,4,4-trifluorobutan-2-yl.
  • heteroaryl refers to aromatic moieties containing at least one heteroatom (e.g., oxygen, sulfur, nitrogen or combinations thereof) within a 5- to 10-membered aromatic ring system.
  • the heteroaromatic moiety may consist of a single or fused ring system.
  • a typical single heteroaryl ring is a 5- to 6-membered ring containing one to four heteroatoms independently selected from N, O and S and a typical fused heteroaryl ring system is a 9- to 10- membered ring system containing one to four heteroatoms independently selected from N, O and S.
  • the fused heteroaryl ring system may consist of two heteroaryl rings fused together or a heteroaryl fused to an aryl (e.g., phenyl).
  • aryl e.g., phenyl
  • 9-10 membered fused heteroaryl include, but are not limited to quinolinyl, isoquinolinyl, indazolyl, quinazolinyl, quinoxalinyl, benzofuranyl, benzothiazolyl, benzimidazolyl, 1 H-pyrazolo[3,4-b]pyridinyl, 1 H-pyrazolo[3,4-c]pyridinyl, pyrazolo[1 ,5-a]pyridinyl, imidazo[1 ,2-a]pyridinyl or 1 H-pyrrolo[2,3-b]pyridinyl.
  • IC50 refers to the molar concentration of an inhibitor that produces 50% of the inhibition effect.
  • EC50 refers to the molar concentration of an inhibitor or modulator that produces 50% efficacy.
  • CC50 refers to the lowest concentration of the compound that inhibited 50% growth of the 3T3 cells compared to untreated controls.
  • composition refers to a compound of the invention, or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable carrier, in a form suitable for topical or parenteral administration.
  • the term "pharmaceutically acceptable carrier” refers to a substance useful in the preparation or use of a pharmaceutical composition and includes, for example, suitable diluents, solvents, dispersion media, surfactants, antioxidants, preservatives, isotonic agents, buffering agents, emulsifiers, absorption delaying agents, salts, drug stabilizers, binders, disintegration agents, lubricants, wetting agents, sweetening agents, flavoring agents, dyes, and combinations thereof, as would be known to those skilled in the art (see, for example, Remington The Science and Practice of Pharmacy, 22 nd Ed. Pharmaceutical Press, 2013, pp. 1049-1070).
  • the term “inhibit”, “inhibition” or “inhibiting” refers to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.
  • the term “prevent”, “preventing” or “prevention” of any disease or disorder refers to the prophylactic treatment of the disease or disorder; or delaying the onset or progression of the disease or disorder.
  • the term “subject” refers to primates (e.g., humans, male or female, dogs, rabbits, guinea pigs, pigs, rats and mice).
  • the subject is a primate.
  • the subject is a human.
  • the term “treat”, “treating” or “treatment” of any disease or disorder refers to alleviating or ameliorating the disease or disorder (i.e. , slowing or arresting the development of the disease or at least one of the clinical symptoms thereof); or alleviating or ameliorating at least one physical parameter or biomarker associated with the disease or disorder, including those which may not be discernible to the patient.
  • a therapeutically effective amount of a compound of the invention refers to an amount of the compound of the invention that will elicit the biological or medical response of a subject, for example, reduction or inhibition of an enzyme or a protein activity, or ameliorate symptoms, alleviate conditions, slow or delay disease progression, or prevent a disease, etc.
  • the term “a therapeutically effective amount” refers to the amount of the compound of the invention that, when administered to a subject, is effective to (1) at least partially alleviate, inhibit, prevent and/or ameliorate a condition, or a disorder or a disease caused by the proliferation of a kinetoplastid parasite; or (2) reduce or inhibit the proliferation of a kinetoplastid parasite.
  • the term “endothermic peak” refers to the melting peak in a differential scanning calorimetry (DSC) thermogram.
  • the term “about” means within a statistically meaningful range of a value. Such a range can be within an order of magnitude, typically within 10%, more typically within 5%, even more typically within 1%, and most typically within 0.1% of the indicated value or range. Sometimes, such a range can lie within experimental error, typical of standard methods used for the measurement and/or determination of a given value or range.
  • the terms “compounds of the present invention” and “compounds of the invention” refer to compounds of Formula I and subformulae thereof, salts of the compound, hydrates or solvates of the compounds, salts, as well as all stereoisomers (including diastereoisomers, enantiomers or enantiomeric mixtures), and isotopically labeled compounds (including deuterium substitutions).
  • Compounds of the invention further comprise polymorphs of compounds of Formula (I) (or subformulae thereof) and salts thereof.
  • the present invention relates to compounds having antiparasitic activity against kinatoplastid protozoa. It relates particularly to compounds that inhibit growth of kinatoplastid parasite cells through inhibition of the parasitic proteasome, and thereof useful as a therapy for leishmaniasis, Chagas disease and African sleeping sickness.
  • Embodiment 1 A compound of Formula (I) or a stereoisomer, enantiomer, enantiomeric mixture or pharmaceutically acceptable salt thereof, as described in the Summary of the Invention.
  • Embodiment 2 The compound according to Embodiment 1 , wherein said compound of Formula (I) is further characterized as Formula (IA) or (IB): or a pharmaceutically acceptable thereof.
  • Embodiment 3 The compound according to Embodiment 1 or Embodiment 2, wherein Ring A is pyridyl or a 9-10 membered fused heteroaryl containing 1-3 heteroatoms selected from N, O and S.
  • Embodiment 4 The compound according to any one of Embodiments 1-3, wherein Ring A and Ring A 1 and Ring A 2 are independently a fused aryl or fused heteroaryl.
  • Embodiment 5 The compound according to any one of Embodiments 1-4, wherein Ring A is quinolinyl, isoquinolinyl, indazolyl, quinazolinyl, quinoxalinyl, benzofuranyl, benzothiazolyl, benzimidazolyl, 1 H-pyrazolo[3,4-b]pyridinyl, 1 H-pyrazolo[3,4-c]pyridinyl, pyrazolo[1 , 5-a]pyridinyl , imidazo[1 ,2-a]pyridinyl or 1 H-pyrrolo[2,3-b]pyridinyl.
  • Ring A is quinolinyl, isoquinolinyl, indazolyl, quinazolinyl, quinoxalinyl, benzofuranyl, benzothiazolyl, benzimidazolyl, 1 H-pyrazolo[3,4-b]pyridinyl, 1 H-
  • Embodiment 6 The compound according to Embodiment 5, wherein Ring A is quinolinyl or isoquinolinyl.
  • Embodiment 7 The compound according to any one of Embodiments 1-6, wherein said compound of Formula (I) is further characterized as Formula (IC) or a stereoisomer, enantiomer, enantiomeric mixture or pharmaceutically acceptable salt thereof.
  • Embodiment 8 The compound according to Embodiment 7, wherein said compound of Formula (IC) is further characterized as Formula (1D) or a pharmaceutically acceptable salt thereof.
  • Embodiment 9 The compound according to any one of Embodiments 1-6, wherein said compound of Formula (I) is further characterized as Formula (IE) or a stereoisomer, enantiomer, enantiomeric mixture or pharmaceutically acceptable salt thereof.
  • Formula (IE) a stereoisomer, enantiomer, enantiomeric mixture or pharmaceutically acceptable salt thereof.
  • Embodiment 10 The compound according to Embodiment 9, wherein said compound of Formula (I) is further characterized as Formula (IF) or a pharmaceutically acceptable salt thereof.
  • Embodiment 11 The compound according to any one of Embodiments 1-6, wherein said compound of Formula (I) is further characterized as Formula (IG) or a stereoisomer, enantiomer, enantiomeric mixture or pharmaceutically acceptable salt thereof.
  • Embodiment 12 The compound according to Embodiment 11, wherein said compound of Formula (I) is further characterized as Formula (IH) or a pharmaceutically acceptable salt thereof.
  • Embodiment 13 The compound according to any one of Embodiments 1-12, wherein R 1 is C1-C4 alkyl, C1-C4 haloalkyl or C1-C4 alkoxy; and n is 0-2.
  • Embodiment 14 A compound or a pharmaceutically acceptable salt thereof, selected from Compounds 1-41 in Table 1 :
  • Embodiment 15 The compound according to Embodiment 14, wherein said compound is (S)-2-(3-cyano-1/7-1,2,4-triazol-1-yl)-/V-(1-(2-methylquinolin-6-yl)pyrrolidin-3-yl)acetamide or a pharmaceutically acceptable salt thereof.
  • Embodiment 16 The compound according to any one of Embodiments 1-15, wherein said compound is a hydrate.
  • Embodiment 17 The compound according to Embodiment 16, wherein said compound is a monohydrate.
  • Embodiment 18 The compound according to any one of Embodiments 1-15, wherein said compound is an anhydrate.
  • Embodiment 19 The compound according to any one of Embodiments 1-18, wherein said compound is a malate salt.
  • Embodiment 20 The compound according to any one of Embodiments 1-18, wherein said compound is a maleate salt.
  • Embodiment 21 The compound according to Embodiment 15, having an X-ray powder diffraction pattern that is substantially as shown in FIG. 1 and/or with corresponding peaks listed in Table 2; and/or a DSC thermogram that is substantially as shown in FIG. 2.
  • Embodiment 22 The compound according to Embodiment 15, having an X-ray powder diffraction pattern that is substantially as shown in FIG. 3 and/or with corresponding peaks listed in Table 3; and/or a DSC thermogram that is substantially as shown in FIG. 4.
  • Embodiment 23 The compound according to Embodiment 15, having an X-ray powder diffraction pattern that is substantially as shown in FIG. 5 and/or with corresponding peaks listed in Table 4; and/or a DSC thermogram that is substantially as shown in FIG. 6.
  • Embodiment 24 The compound according to Embodiment 15, having an X-ray powder diffraction pattern that is substantially as shown in FIG. 7 and/or with corresponding peaks listed in Table 5; and/or a DSC thermogram that is substantially as shown in FIG. 8.
  • Embodiment 25 The compound according to any one of Embodiments 1-24, wherein said compound inhibits topoisomerase II.
  • Embodiment 26 A pharmaceutical composition comprising a compound according to any one of Embodiments 1-24, and at least one pharmaceutically acceptable excipient.
  • Embodiment 27 A combination comprising a compound according to any one of Embodiments 1-24, or a pharmaceutical composition thereof according to Embodiment 26, and one or more therapeutically active agents.
  • Embodiment 28 A compound according to any one of Embodiments 1-24, or a pharmaceutical composition according to Embodiment 26, for use as a medicament.
  • Embodiment 29 A compound according to any one of Embodiments 1-24, or a pharmaceutical composition according to Embodiment 26, for use in the treatment of a disease selected from Chagas disease, leishmaniasis and human African trypanosomiasis.
  • Embodiment 30 Use of a compound according to any one of Embodiments 1-24, or a pharmaceutical composition according to Embodiment 26, in the manufacture of a medicament for the treatment of a disease selected from Chagas disease, leishmaniasis and human African trypanosomiasis.
  • Embodiment 31 A method of inhibiting growth and proliferation of a kinetoplastid parasite in a subject, comprising administering to a subject in need thereof, a therapeutically effective amount of a compound according to any one of Embodiments 1-24.
  • Embodiment 32 A method of treating or preventing a disorder or disease caused by a kinetoplastid parasite, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of Embodiments 1-24, and optionally in combination with a second agent; wherein the disease is selected from Chagas disease, leishmaniasis and human African trypanosomiasis.
  • Embodiment 33 The method according to Embodiment 32, wherein said disease is leishmaniasis selected from visceral leishmaniasis and cutaneous leishmaniasis; and said second agent selected from stibogluconate, meglumine antimoniate, amphotericin, miltefosine, and paromomycin.
  • leishmaniasis selected from visceral leishmaniasis and cutaneous leishmaniasis
  • said second agent selected from stibogluconate, meglumine antimoniate, amphotericin, miltefosine, and paromomycin.
  • Embodiment 34 The method according to Embodiment 32, wherein said disease is Chagas disease; and said second agent is selected from benznidazole, nifurtimox and amphotericin.
  • Embodiment 35 The method according to Embodiment 32, wherein said disease is human African trypanosomiasis; and said second agent is pentamidine, suramin, melarsoprol, eflornithine, and nifurtimox.
  • Embodiment 36 Kit comprising two or more separate pharmaceutical compositions, at least one of which contains compound according to any one of Embodiments 1-24.
  • Embodiment 37 Use of 2-(3-cyano-1 H-1 ,2,4-triazol-1-yl)acetic acid for manufacturing a compound of Formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof according to any one of Embodiments 1-24.
  • Embodiment 38 Use of terf-butyl (S)-pyrrolidin-3-ylcarbamate for manufacturing a stereoisomer of a compound of Formula (I) or a pharmaceutically acceptable salt thereof according to any one of Embodiments 1-24.
  • the compounds can be present in the form of one of the possible stereoisomers or as mixtures thereof, for example as pure optical isomers, or as stereoisomer mixtures, such as racemates and diastereoisomer mixtures, depending on the number of asymmetric carbon atoms.
  • the present invention is meant to include all such possible stereoisomers, including racemic mixtures, diasteriomeric mixtures and optically pure forms.
  • Optically active (F?)- and (S)- stereoisomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be E or Z configuration.
  • the cycloalkyl substituent may have a cis- or trans-configuration.
  • the terms “salt” or “salts” refers to an acid addition or base addition salt of a compound of the invention. “Salts” include in particular “pharmaceutical acceptable salts”.
  • pharmaceutically acceptable salts refers to salts that retain the biological effectiveness and properties of the compounds of this invention and, which typically are not biologically or otherwise undesirable. In many cases, the compounds of the invention are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto.
  • Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids.
  • Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, hippuric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, sulfosalicylic acid, lactic acid, and the like.
  • Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.
  • Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I to XII of the periodic table.
  • the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium and magnesium salts.
  • Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like.
  • Certain organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine and tromethamine.
  • any formula given herein represent unlabeled forms as well as isotopical ly labeled forms of the compounds.
  • Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number.
  • Isotopes that can be incorporated into compounds of the invention include, for example, isotopes of hydrogen.
  • isotopes particularly deuterium (i.e., 2 H or D) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements or an improvement in therapeutic index or tolerability.
  • deuterium in this context is regarded as a substituent of a compound of Formula (I).
  • concentration of deuterium may be defined by the isotopic enrichment factor.
  • isotopic enrichment factor as used herein means the ratio between the isotopic abundance and the natural abundance of a specified isotope.
  • a substituent in a compound of this invention is denoted as being deuterium, such compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).
  • isotopic enrichment factor can be applied to any isotope in the same manner as described for deuterium.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine, such as 3 H, 11 C, 13 C, 14 C, 15 N, 18 F 31 P, 32 P, 35 S, 36 CI, 123 l, 124 l, 125 l respectively. Accordingly, it should be understood that the invention includes compounds that incorporate one or more of any of the aforementioned isotopes, including for example, radioactive isotopes, such as 3 H and 14 C, or those into which non-radioactive isotopes, such as 2 H and 13 C are present.
  • Such isotopically labelled compounds are useful in metabolic studies (with 14 C), reaction kinetic studies (with, for example 2 H or 3 H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients.
  • PET positron emission tomography
  • SPECT single-photon emission computed tomography
  • an 18 F or labeled compound may be particularly desirable for PET or SPECT studies.
  • I sotopically- labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labeled reagents in place of the non-labeled reagent previously employed.
  • any asymmetric atom (e.g., carbon or the like) of the compound(s) of the invention can be present in racemic or enantiomerically enriched, for example the (F?)-, (S)- or (Reconfiguration.
  • each asymmetric atom has at least 50 % enantiomeric excess, at least 60 % enantiomeric excess, at least 70 % enantiomeric excess, at least 80 % enantiomeric excess, at least 90 % enantiomeric excess, at least 95 % enantiomeric excess, or at least 99 % enantiomeric excess in the (R)- or (S)- configuration.
  • Substituents at atoms with unsaturated double bonds may, if possible, be present in cis- (Z)- or trans- (E)- form.
  • a compound of the present invention can be in the form of one of the possible stereoisomers, rotamers, atropisomers, or mixtures thereof, for example, as substantially pure geometric (cis or trans) stereoisomers, diastereomers, optical isomers (antipodes), racemates or mixtures thereof.
  • Any resulting mixtures of stereoisomers can be separated on the basis of the physicochemical differences of the constituents, into the pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and/or fractional crystallization.
  • Any resulting racemates of final products or intermediates can be resolved into the optical antipodes by known methods, e.g., by separation of the diastereomeric salts thereof, obtained with an optically active acid or base, and liberating the optically active acidic or basic compound.
  • a basic moiety may thus be employed to resolve the compounds of the present invention into their optical antipodes, e.g., by fractional crystallization of a salt formed with an optically active acid, e.g., tartaric acid, dibenzoyl tartaric acid, diacetyl tartaric acid, di-O,O'-p- toluoyl tartaric acid, mandelic acid, malic acid or camphor-10-sulfonic acid. Racemic products can also be resolved by chiral chromatography, e.g., high pressure liquid chromatography (HPLC) using a chiral adsorbent.
  • HPLC high pressure liquid chromatography
  • the invention provides a compound of Formula (I) thereof: or a stereoisomer, enantiomer, enantiomeric mixture or pharmaceutically acceptable salt thereof, wherein:
  • Ring A is naphthalenyl, 1 ,2-dihydroisoquinolinyl or a 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S;
  • R 1 is cyano, halo, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy or oxo; and n is 0-3.
  • the invention provides a compound of Formula (IA) or (IB): or a pharmaceutically acceptable salt thereof.
  • Ring A in any of the above formulae is and
  • Ring A 1 and Ring A 2 are independently a fused aryl or fused heteroaryl.
  • Ring A is . In another embodiment, Ring A is
  • the invention provides a compound of Formula (IC)
  • R 1 is C1-C4 alkyl, C1-C4 haloalkyl or C1-C4 alkoxy; and n is 0-2.
  • n is 0. In another embodiment, n is 1. In yet another embodiment, n is 2.
  • the present invention relates to crystalline forms of the compounds.
  • Crystalline compounds of the invention may be characterized as having an X-ray powder diffraction pattern, differential scanning calorimetry (DSC) thermogram, or thermogravimetric analysis (TGA) diagram that is “substantially as shown in” a figure (e.g., FIG. 1).
  • the invention relates to a solid or salt form of (S)-2-(3-cyano-1/7-1 ,2,4-triazol-1-yl)- /V-(1-(2-methylquinolin-6-yl)pyrrolidin-3-yl)acetamide or a pharmaceutically acceptable salt thereof.
  • the invention provides a solid form of (S)-2-(3-cyano-1/7-1 ,2,4-triazol-1- yl)-/V-(1-(2-methylquinolin-6-yl)pyrrolidin-3-yl)acetamide having an X-ray diffraction pattern comprising three or more 20 peaks selected from about 11.2°, 12.6°, 15.1° and 15.3° ⁇ 0.2° (20); and more particularly comprising 20 peaks at about 11.2°, 12.6° and 15.1 ° ⁇ 0.2° (20) (“Form A”).
  • the invention provides a solid form of (S)-2-(3-cyano-1/7-1 ,2,4- triazol-1-yl)-/V-(1-(2-methylquinolin-6-yl)pyrrolidin-3-yl)acetamide having an X-ray diffraction pattern comprising three or more 20 peaks selected from about 14.3°, 19.6°, 23.0° and 26.0° ⁇ 0.2° (20); and more particularly comprising 20 peaks at about 14.3°, 19.6° and 26.0° ⁇ 0.2° (20) (“Form B”).
  • the invention provides a solid form of (S)-2-(3-cyano-1/7-1 ,2,4- triazol-1-yl)-/V-(1-(2-methylquinolin-6-yl)pyrrolidin-3-yl)acetamide malate having an X-ray diffraction pattern comprising three or more 20 peaks selected from about 13.6°, 15.2°, 15.9° and 22.9° ⁇ 0.2° (20); and more particularly comprising 20 peaks at about 13.6°, 15.2° and 15.9° ⁇ 0.2° (20) (“Form C”).
  • the molar ratio of (S)-2-(3-Cyano-1/7-1 ,2,4- triazol-1-yl)-/V-(1-(2-methylquinolin-6-yl)pyrrolidin-3-yl)acetamide to malic acid is 1 : 0.5.
  • the invention provides a solid form of (S)-2-(3-cyano-1/7-1,2,4- triazol-1-yl)-/V-(1-(2-methylquinolin-6-yl)pyrrolidin-3-yl)acetamide maleate having an X-ray diffraction pattern having three or more 20 peaks selected from about 19.0°, 21.6°, 25.3° and 26.3° ⁇ 0.2° (20); and more particularly comprising 20 peaks at about 19.0°, 21.6° and 25.3° ⁇ 0.2° (20) (“Form D”).
  • the molar ratio of (S)-2-(3-Cyano-1/7-1 ,2,4-triazol-1- yl)-/V-(1-(2-methylquinolin-6-yl)pyrrolidin-3-yl)acetamide to maleic acid is 1 :1.
  • FIG. 1 shows an XRPD pattern of (S)-2-(3-cyano-1/7-1 ,2,4-triazol-1-yl)-/V-(1-(2- methylquinolin-6-yl)pyrrolidin-3-yl)acetamide Form A.
  • FIG. 2 shows a DSC thermogram of (S)-2-(3-cyano-1/7-1 ,2,4-triazol-1-yl)-/V-(1-(2- methylquinolin-6-yl)pyrrolidin-3-yl)acetamide Form A.
  • FIG. 3 shows an XRPD pattern of (S)-2-(3-cyano-1/7-1 ,2,4-triazol-1-yl)-/V-(1-(2- methylquinolin-6-yl)pyrrolidin-3-yl)acetamide Form B.
  • FIG. 4 shows a DSC thermogram of (S)-2-(3-cyano-1/7-1 ,2,4-triazol-1-yl)-/V-(1-(2- methylquinolin-6-yl)pyrrolidin-3-yl)acetamide Form B.
  • FIG. 5 shows an XRPD pattern of (S)-2-(3-cyano-1/7-1 ,2,4-triazol-1-yl)-/V-(1-(2- methylquinolin-6-yl)pyrrolidin-3-yl)acetamide malate Form C.
  • FIG. 6 shows a DSC thermogram of (S)-2-(3-cyano-1/7-1 ,2,4-triazol-1-yl)-/V-(1-(2- methylquinolin-6-yl)pyrrolidin-3-yl)acetamide malate Form C.
  • FIG. 7 shows an XRPD pattern of (S)-2-(3-cyano-1/7-1 ,2,4-triazol-1-yl)-/V-(1-(2- methylquinolin-6-yl)pyrrolidin-3-yl)acetamide maleate Form D.
  • FIG. 8 shows a DSC thermogram of (S)-2-(3-cyano-1/7-1 ,2,4-triazol-1-yl)-/V-(1-(2- methylquinolin-6-yl)pyrrolidin-3-yl)acetamide maleate Form D.
  • the invention relates to compounds of Formula (I) or subformulae thereof, or a stereoisomer, enantiomer, enantiomeric mixture or pharmaceutically acceptable salt thereof, that target the proteasome of kinetoplastid parasites and are useful as a therapy.
  • the activity of a compound according to the present invention can be assessed by the in vitro and in vivo methods described in the Biological Assay section infra. It is understood that the assays illustrate the invention without in any way limiting the scope of the invention.
  • the invention provides a method for preventing or treating Chagas disease, leishmaniasis, or human African trypanosomiasis in a subject in need of such treatment, comprising administering to said subject a therapeutically effective amount of a compound selected from Formula (I) or subformulae thereof, or a stereoisomer, enantiomer, enantiomeric mixture or pharmaceutically acceptable salt thereof, and optionally in combination with a second agent.
  • a compound selected from Formula (I) or subformulae thereof, or a stereoisomer, enantiomer, enantiomeric mixture or pharmaceutically acceptable salt thereof and optionally in combination with a second agent.
  • the required dosage will vary depending on the mode of administration, the particular condition to be treated and the effect desired.
  • the invention provides a method for treating Chagas disease, including but not limited to chronic indeterminate and chronic Chagas disease without severe organ dysfunction; acute symptomatic Chagas disease; congenital Chagas disease and chronic Chagas disease with organ dysfunction in conjunction with host-directed therapy.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier.
  • the composition comprises at least two pharmaceutically acceptable carriers, such as those described herein.
  • the pharmaceutical composition can be formulated for particular routes of administration such as oral administration, parenteral administration (e.g. by injection, infusion, transdermal or topical administration), and rectal administration. Topical administration may also pertain to inhalation or intranasal application.
  • the pharmaceutical compositions of the invention can be made up in a solid form (including, without limitation, capsules, tablets, pills, granules, powders or suppositories), or in a liquid form (including, without limitation, solutions, suspensions or emulsions).
  • Tablets may be either film coated or enteric coated according to methods known in the art.
  • the pharmaceutical compositions are tablets or gelatin capsules comprising the active ingredient together with one or more of: a) diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; b) lubricants, e.g., silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol; for tablets also c) binders, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone; if desired d) disintegrants, e.g., starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and e) absorbents, colorants, flavors and sweeteners.
  • Compounds of the invention can be administered in therapeutically effective amounts in combination with one or more therapeutic agents (pharmaceutical combinations).
  • the compound of the invention may be administered either simultaneously with, or before or after, one or more other therapeutic agent.
  • the compound of the invention may be administered separately, by the same or different route of administration, or together in the same pharmaceutical composition as the other agents.
  • a therapeutic agent is, for example, a chemical compound, peptide, antibody, antibody fragment or nucleic acid, which is therapeutically active or enhances the therapeutic activity when administered to a patient in combination with a compound of the invention.
  • Products provided as a combined preparation include a composition comprising a compound of the present invention and another therapeutic agent(s) together in the same pharmaceutical composition, or in separate form, e.g. in the form of a kit.
  • the invention provides a pharmaceutical composition comprising a compound of Formula (I) or subformulae thereof, or a pharmaceutically acceptable salt stereoisomer thereof, and another therapeutic agent(s).
  • the pharmaceutical composition may comprise a pharmaceutically acceptable carrier, as described above.
  • the invention provides a product comprising a compound of Formula (I) or subformulae thereof, or a pharmaceutically acceptable salt or stereoisomer thereof, and at least one other therapeutic agent as a combined preparation for simultaneous, separate or sequential use in therapy.
  • the invention provides a kit comprising two or more separate pharmaceutical compositions, at least one of which contains a compound of Formula (I) or subformulae thereof, or a pharmaceutically acceptable salt or stereoisomer thereof.
  • the kit comprises means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet.
  • An example of such a kit is a blister pack, as typically used for the packaging of tablets, capsules and the like.
  • the kit of the invention may be used for administering different dosage forms, for example, oral and parenteral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another.
  • the kit of the invention typically comprises directions for administration.
  • the compound of the invention and the other therapeutic agent may be manufactured and/or formulated by the same or different manufacturers. Moreover, the compound of the invention and the other therapeutic may be brought together into a combination therapy: (i) prior to release of the combination product to physicians (e.g. in the case of a kit comprising the compound of the invention and the other therapeutic agent); (ii) by the physician themselves (or under the guidance of the physician) shortly before administration; (iii) in the patient themselves, e.g. during sequential administration of the compound of the invention and the other therapeutic agent.
  • the invention provides the use of a compound of the present invention for treating a disease or condition caused by the growth and proliferation of a kinetoplastid parasite, wherein the medicament is prepared for administration with another therapeutic agent.
  • the invention also provides the use of another therapeutic agent for treating a disease or condition caused by the growth and proliferation of a kinetoplastid parasite, wherein the medicament is administered with a compound of Formula (I) or subformulae thereof, or a pharmaceutically acceptable salt or stereoisomer thereof.
  • the invention also provides the use of a compound of the present invention for treating a disease or condition caused by the growth and proliferation of a kinetoplastid parasite, wherein the patient has previously ⁇ e.g., within 24 hours) been treated with another therapeutic agent.
  • the invention also provides the use of another therapeutic agent for treating a disease or condition caused by the growth and proliferation of a kinetoplastid parasite, wherein the patient has previously ⁇ e.g., within 24 hours) been treated with a compound of Formula (I) or subformulae thereof, or a pharmaceutically acceptable salt or stereoisomer thereof.
  • the other therapeutic agent is selected from tstibogluconate, meglumine antimoniate, amphotericin, miltefosine and paromomycin.
  • the other therapeutic agent is selected from benznidazole, nifurtimox and/or amphotericin.
  • the other therapeutic agent is selected from pentamidine, suramin, melarsoprol, eflornithine, and/or nifurtimox.
  • the compounds of the present invention can be prepared in a number of ways known to one skilled in the art of organic synthesis in view of the methods, reaction schemes and examples provided herein.
  • the reaction schemes depicted below provide potential routes for synthesizing the compounds of the present invention as well as key intermediates.
  • Examples section below For a more detailed description of the individual reaction steps, see the Examples section below.
  • Those skilled in the art will appreciate that other synthetic routes may be used to synthesize the inventive compounds.
  • specific starting materials and reagents are depicted in the schemes and discussed below, other starting materials and reagents can be substituted to provide a variety of derivatives and/or reaction conditions.
  • many of the compounds prepared by the methods described below can be further modified in light of this disclosure using conventional chemistry well known to those skilled in the art. All methods described herein can be performed in any suitable order, unless otherwise indicated or otherwise clearly contradicted by context.
  • Step 1 Buchwald-Hartwig coupling.
  • a vial was charged with a Boc-protected aminopyrrolidine (1.3 mmol), an aryl bromide (1.6 mmol), a palladium catalyst such as[(4,5- bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2'-amino-1 ,1'-biphenyl)]palladium(ll) methanesulfonate (0.10 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.10 mmol) and an inorganic base such as cesium carbonate (3.4 mmol), and the vial was purged with nitrogen for 30 seconds.
  • a palladium catalyst such as[(4,5- bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2'-amino-1 ,1'-biphenyl)]palladium(
  • 1,4-Dioxane was then added and the reaction was stirred at 110 °C for 16 hours.
  • the reaction mixture was diluted with dichloromethane, washed with water and brine, dried with anhydrous magnesium sulfate, and purified by silica gel column chromatography.
  • Step 2 Protecting group removal. Boc-protected amine (1.3 mmol) was dissolved in the presence of an acid such as hydrochloric acid (4N solution in 1,4-dioxane) or trifluoroacetic acid in aprotic solvents and the mixture was stirred at room temperature for 2 hours. A white precipitate formed and the solid was collected by filtration and dried under vacuum.
  • an acid such as hydrochloric acid (4N solution in 1,4-dioxane) or trifluoroacetic acid in aprotic solvents
  • Step 3 Amide coupling using an activating reagent in polar aprotic solvents.
  • 2-(3-cyano-1H-1 ,2,4-triazol-1-yl)acetic acid 1.5 mmol
  • triethylamine 6.2 mmol
  • 2,4,6-tripropyl-1 , 3, 5, 2,4,6- trioxatriphosphorinane-2,4,6-trioxide 50% solution in ethyl acetate, 1.6 mmol
  • the mixture was partitioned between dichloromethane and water, and the product was extracted with a 10:1 mixture of dichloromethane and methanol.
  • the organic extracts were dried with anhydrous magnesium sulfate, filtered, concentrated, and purified by silica gel column chromatography.
  • the starting materials are generally available from non-excluding commercial sources such as Aldrich Chemicals (Milwaukee, Wis.), TCI Fine Chemicals (Japan), Shanghai Chemhere Co., Ltd. (Shanghai, China), Aurora Fine Chemicals LLC (San Diego, CA), FCH Group (Ukraine), Lancaster Synthesis, Inc. (Windham, N.H.), Acros Organics (Fairlawn, N.J.), Maybridge Chemical Company, Ltd.
  • LCMS LCMS (m/z) ES + or ES' are recorded on a Waters Acquity UPLC system; Acquity Binary Gradient Manager with Degasser; Acquity Column Compartment set at 50°C; Acquity Diode Array Detector; Leap Technologies HTS Pal Autosampler; Waters Qda Mass Detector.
  • X-Ray diffraction The X-ray powder diffraction (XRPD) patterns described herein were recorded on a Bruker D8 Advance diffractometer using CuK a radiation at a wavelength of 0.15 nm at room temperature. The XRPD pattern was recorded between 2° and 40° (2-theta).
  • XRPD X-ray powder diffraction
  • diffraction angles (20) in an XRPD pattern are collected with a variance of about ⁇ 0.3° (20), preferably about ⁇ 0.2° (20), more preferably at about ⁇ 0.1° (20), and even more preferably at ⁇ 0.05° (20).
  • DSC Differential Scanning Calorimetry
  • the DSC instrument used to test the crystalline forms was a TA Discovery DSC.
  • the DSC cell/sample chamber was purged with 20-50 ml/min of ultra-high purity nitrogen gas.
  • the instrument was calibrated with high purity indium.
  • the sample was placed into a closed aluminum DSC pan with a pinhole and measured against an empty reference pan.
  • About 1-3 mg of sample powder was placed into the bottom of the pan and lightly tapped down to contact the pan.
  • the weight of the sample was measured and recorded to a hundredth of a milligram.
  • the instrument was programmed to heat at 10°C per minute in the temperature range between 0°C and 300°C. Melting point determinations based on DSC have a variability of ⁇ 3 °C, preferably ⁇ 2 °C, more preferably ⁇ 1 °C.
  • Step 1 terf-Butyl (S)-(1-(2-methylquinolin-6-yl)pyrrolidin-3-yl)carbamate.
  • a vial was charged with terf-butyl (S)-pyrrolidin-3-ylcarbamate (250 mg, 1.3 mmol), 5-bromo-1-methyl-1/7- pyrazolo[3,4-b]pyridine (358 mg, 1.6 mmol), [(4,5-bis(diphenylphosphino)-9,9- dimethylxanthene)-2-(2'-amino-1 ,T-biphenyl)]palladium(ll) methanesulfonate (93 mg, 0.10 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (58 mg, 0.10 mmol) and cesium carbonate (1.1 g, 3.4 mmol), and the vial was purged with nitrogen for 30 seconds.
  • 1,4-Dioxane (5 mL) was then added and the reaction was stirred at 110 °C for 16 hours.
  • the reaction mixture was diluted with dichloromethane, washed with water and brine, dried with anhydrous magnesium sulfate, and purified by silica gel column chromatography (50% to 100% ethyl acetate in heptane) to give the title compound as a white solid.
  • Step 2 (S)-1-(2-methylquinolin-6-yl)pyrrolidin-3-amine hydrochloride.
  • tert-Butyl (S)-(1-(2- methylquinolin-6-yl)pyrrolidin-3-yl)carbamate (439 mg, 1.3 mmol) was dissolved in hydrochloric acid (4N solution in 1 ,4-dioxane, 20 mL, 80 mmol) and the mixture was stirred at room temperature for 2 hours. A white precipitate formed and the solid was collected by filtration and dried under vacuum to give the title compound as a white solid.
  • Step 3 (S)-2-(3-Cyano-1/7-1,2,4-triazol-1-yl)-/V-(1-(2-methylquinolin-6-yl)pyrrolidin-3- yl)acetamide.
  • (S)-1-(2-methylquinolin-6-yl)pyrrolidin-3-amine hydrochloride (327 mg, 1.2 mmol)
  • 2-(3-cyano-1/7-1,2,4-triazol-1-yl)acetic acid (226 mg, 1.5 mmol)
  • triethylamine (0.86 mL, 6.20mmol) in /V,/V-dimethylformamide (10 mL) was added 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (50% solution in ethyl acetate, 1.0 g, 1.6 mmol) and the reaction was stirred at room temperature for 2 hours.
  • Form A having an XRPD pattern that is substantially as shown in FIG. 1 with corresponding peaks listed in Table 2.
  • Form A has a DSC thermogram that is substantially as shown in FIG. 2, with a melting point at about 220 °C on DSC at 10 K/min.
  • Form A (10 g) was suspended in 150 mL acetone/water (6:4 v/v) or in 200 mL water and stirred at 25 °C for several hours. Alternatively, Form A (500 mg) was added in 10 mL water and stirred overnight at room temperature. The compound was filtered and vacuum dried to give (S)-2-(3-Cyano-1/7-1 ,2,4-triazol-1-yl)-/V-(1-(2-methylquinolin-6-yl)pyrrolidin-3-yl)acetamide Form B having an XRPD pattern that is substantially as shown in FIG. 3 with corresponding peaks listed in Table 3.
  • Form B is a monohydrate with a DSC thermogram that is substantially as shown in FIG. 4, with two dehydration endothermic peaks between 80 and 120 °C. After dehydration, it recrystallized to Form A at about 130 °C followed by an endothermic peak at about 219 °C.
  • 3-yl)acetamide to maleic acid is 1 :1.
  • Form C and Form D are anhydrates with a DSC thermogram that is substantially as shown in FIG. 6 and FIG. 8 respectively. Both forms exhibit melting points above 180 °C without any pre-melting event in the DSC curve.
  • the title compound was synthesized using the same procedure as Example 1 , using 5- bromo-1-methyl-1/7-pyrazolo[3,4-b]pyridine as the starting material and chloro(2- dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,r-biphenyl)]palladium(ll) (42 mg, 0.054 mmol) as the catalyst for step 1, and purified by Method A.
  • the title compound was synthesized using the same procedure as Example 1, using 5- bromo-1-methyl-1 /-/-indazole as the starting material and (SP-4-3)-[Dicyclohexyl[2 , ,4',6'-tris(1- methylethyl)[1,T-biphenyl]-2-yl]phosphine](methanesulfonato-KO)[2'-(methylamino-K/ ⁇ /)[1,1'- biphenyl]-2-yl-KC]palladium (32 mg, 0.038 mmol) as the catalyst for step 1, and purified by Method A.
  • 2-alpyridin-6-yl)pyrrolidin-3- trifluoroacetic acid salt The title compound was synthesized using the same procedure as Example 1, using 6- bromoimidazo[1,2-a]pyridine as the starting material and (SP-4-3)-[Dicyclohexyl[2',4',6'-tris(1- methylethyl)[1,T-biphenyl]-2-yl]phosphine](methanesulfonato-KO)[2'-(methylamino-K/ ⁇ /)[1,1'- biphenyl]-2-yl-KC]palladium (11 mg, 0.013 mmol) as the catalyst for step 1 , and purified by Method A.
  • the title compound was synthesized using the same procedure as Example 1, using 5- bromo-1,3-dimethyl-1 /-/-indazole as the starting material for step 1, and purified by silica gel column chromatography (0 to 5% methanol in dichloromethane).
  • the title compound was synthesized using the same procedure as Example 1, using 6- chloro-1-methyl-1/7-pyrazolo[3,4-b]pyridine as the starting material for step 1 , and purified by Method A, followed by free basing by partitioning between dichloromethane and saturated aqueous sodium bicarbonate.
  • the title compound was synthesized using the same procedure as Example 1 , using 4- bromo-5-chloronicotinonitrile as the starting material for step 1 , and purified by silica gel column chromatography (0-70% ethyl acetate in heptane).
  • the title compound was synthesized using the same procedure as Example 1, using tertbutyl (R)-pyrrolidin-3-ylcarbamate as the starting material for step 1, and purified by silica gel column chromatography (0 to 10% methanol in dichloromethane).
  • Step 1 fert-butyl (S)-(1-(1-methyl-1/7-pyrrolo[2,3-b]pyridin-5-yl)pyrrolidin-3-yl)carbamate.
  • a vial was charged with tert-butyl (S)-pyrrolidin-3-ylcarbamate (50 mg, 0.27 mmol), 5-bromo-1- methyl-1/7-pyrrolo[2,3-b]pyridine (57 mg, 0.27 mmol), cesium carbonate (219 mg, 0.67 mmol) and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,T-biphenyl)[2-(2'-amino-1,T- biphenyl)]palladium(l I) (21 mg, 0.027 mmol), and the vial was purged with nitrogen.
  • Step 2 (S)-1-(1-methyl-1/7-pyrrolo[2,3-b]pyridin-5-yl)pyrrolidin-3-amine.
  • fert-butyl (S)-(1-(3-chloro-2-cyanophenyl)pyrrolidin-3-yl)carbamate 85 mg, 0.27 mmol
  • dichloromethane 0.75 mL
  • trifluoroacetic acid 0.25 mL
  • Step 3 (S)-2-(3-cyano-1/7-1 ,2,4-triazol-1-yl)-/V-(1-(1-methyl-1/7-pyrrolo[2,3-b]pyridin-5- yl)pyrrolidin-3-yl)acetamide trifluoroacetic acid salt.
  • the title compound was synthesized using the same procedure as Example 1 , step 3, and purified by Method A.
  • the title compound was synthesized using the same procedure as Example 29, using 6- bromo-2-(trifluoromethyl)quinoline as the starting material for step 1 , and purified by Method A, followed by free basing by partitioning between dichloromethane and saturated aqueous sodium bicarbonate.
  • Step 1 fert-butyl (S)-(1-(3-chloro-2-cyanophenyl)pyrrolidin-3-yl)carbamate.
  • a vial was charged with tert-butyl (S)-pyrrolidin-3-ylcarbamate (50 mg, 0.27 mmol), 5-bromo-1 ,3-dimethyl- 1/7-pyrazolo[3,4-b]pyridine (61 mg, 0.27 mmol), sodium tert-butoxide (65 mg, 0.67 mmol) and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1 ,1'-biphenyl)[2-(2'-amino-1,1'- biphenyl)]palladium(l I) (21 mg, 0.027 mmol), and the vial was purged with nitrogen for 30 seconds.
  • Step 2 (S)-/V-(1-(3-chloro-2-cyanophenyl)pyrrolidin-3-yl)-2-(3-cyano-1/7-1,2,4-triazol-1- yl)acetamide trifluoroacetic acid salt.
  • the title compound was synthesized using the same procedure as Example 1, step 3, and purified by Method A.
  • the activity of a compound according to the present invention can be assessed by the following in vitro methods.
  • the assays described herein illustrate and do not limit the scope of the invention.
  • Compounds of the invention can be assayed for inhibitor activity against Trypanosoma cruzi cultured in 3T3 fibroblast cells.
  • the assay is done using the mammalian stage of T. cruzi that replicates in the intracellular space of host cells.
  • the host cells are initially infected with the tissue culture-derived trypomastigotes that rapidly invade into cells and then transform in to replicating amastigote stage.
  • the protocol uses the Tulahuen strain of T. cruzi that has been engineered to express the E. coli beta-galactosidase gene (Lac-Z) (Antimicr. Agents Chemoth. 40:2592, 1996). This allows for a colorimetric readout by using the substrate CPRG and an absorbance plate reader.
  • 3T3 fibroblast cells are re-suspended in RPMI-1640 medium without phenol red medium supplemented with 10% FBS (heat inactivated), 100 pg/ml penicillin, and 100 pg /ml streptomycin. Forty pL of suspension (1,000 cells) is dispensed into 384-well plates and incubated overnight at 37 °C temperature and in atmosphere containing 5% CO2. The following day, 100 nL of compounds of the invention in DMSO are added to plate wells containing 3T3 cells. At the same time control compound (benznidazole, known T. cruzi anti-parasitic drug ) and DMSO are added to plates to serve as the positive and negative controls, respectively.
  • control compound benznidazole, known T. cruzi anti-parasitic drug
  • NIH 3T3 fibroblast cells were maintained in RPMI medium 1640 with glutamine (Life Technologies) supplemented with 5% heat-inactivated fetal bovine serum and 100 I U penicillin/100 p g/mL streptomycin (3T3 Medium) at 37 °C/ 5% CO2.
  • NIH 3T3 fibroblast cells were purchased from ATCC.
  • NIH 3T3 cells re-suspended in RPMI medium were seeded at 1,000 cells/ well (50 pL) in white 384-well plates (Greiner Bio-One) and incubated overnight at 37 °C/ 5% CO2. The following day, 100 nL of each test compound in DMSO were transferred to individual plate wells by Echo 555 acoustic liquid handling system. . At the same time control compound (puromycin, known cytotoxic compound) and DMSO are added to plates to serve as the positive and negative controls, respectively. Plates were incubated for four days at 37 °C 15% CO2. Cell numbers in individual plate wells were determined through quantification of intracellular ATP amount.
  • the CellTiter-Glo luminescent cell viability reagent was added to plate wells, and ATP-dependent luminescence signal was measured on an BMG Clariostar Plate Reader.
  • the CC50 values were determined by analyzing the data using HELIOS software. All compounds tested had CC50 > 10 pM.
  • the proliferation is quantified by the addition of Cell TiterGlo® (Promega®) a luminescent cell viability assay that measures the number of viable cells in culture based on the quantification of cellular ATP amount, which is an indicator of metabolically active cells.
  • Trypanosoma brucei brucei (Lister 427) strain was grown in Hirumi 9 (HMI-9) media supplemented with 10% v/v fetal bovine serum (FBS) and 10% v/v serum plus.
  • FBS v/v fetal bovine serum
  • test compounds were three fold serially diluted in duplicates to 384-well white plates, resulting in 10 dilutions for each compound. A volume of 40 pL of bloodstream form of T. b.
  • brucei culture 10,000 parasites/mL was added to each well, and the assay plates were incubated at 37°C for 2 days in a CO2 incubator. Growth inhibition was monitored by measuring ATP levels, which, is used as a surrogate marker for growth. Relative luminescence units were measured using BMG clariostar plate reader after 30min of adding 40pl of Cell TiterGlo®. EC50 values were determined by analyzing the data using HELIOS software. EC50 is defined as the lowest concentration of the compound that inhibited 50% growth of the T. b. brucei wild type strain compared to untreated controls.
  • Amastigotes of L. donovani were grown in axenic culture at 37 °C in SM medium at pH 5.4 supplemented with 10% heat-inactivated fetal bovine serum under an atmosphere of 5% CO2 in air.
  • One hundred microlitres of culture medium with 105 amastigotes from axenic culture with or without a serial drug dilution were seeded in 96-well microtitre plates.
  • Serial drug dilutions of eleven 3-fold dilution steps covering a range from 100 to 0.002 pg/ml were prepared. After 70 h of incubation the plates were inspected under an inverted microscope to assure growth of the controls and sterile conditions.
  • compounds of the invention have an EC50 against T cruzi (column 2) and T. brucei brucei (column 3) ranging from >1 pM (+); between 0.1 pM and 1 pM (++) and ⁇ 0.1 pM (+++).
  • Table 5 shows that compounds of the invention have an EC50 against T cruzi (column 2) and T. brucei brucei (column 3) ranging from >1 pM (+); between 0.1 pM and 1 pM (++) and ⁇ 0.1 pM (+++).

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Abstract

La présente invention concerne un composé de formule (I) (I) ou un stéréoisomère, un énantiomère, un mélange énantiomère ou un sel pharmaceutiquement acceptable de celui-ci, les variables étant telles que définies dans la description. L'invention concerne en outre des compositions pharmaceutiques comprenant de tels composés et des procédés d'utilisation de tels composés pour le traitement de maladies liées auxs kinétoplastidés.
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WO2019244049A1 (fr) * 2018-06-19 2019-12-26 Novartis Ag Composés de cyanotriazole et leurs utilisations

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019244049A1 (fr) * 2018-06-19 2019-12-26 Novartis Ag Composés de cyanotriazole et leurs utilisations

Non-Patent Citations (7)

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Title
"Beilsteins Handbuch der organischen Chemie", vol. 4, SPRINGER-VERLAG
"Methods of Organic Synthesis", vol. 21, 1952
"Remington The Science and Practice of Pharmacy", 2013, PHARMACEUTICAL PRESS, pages: 1049 - 1070
LOUIS F. FIESERMARY FIESER: "Comprehensive Organic Transformations", vol. 1-19, 1999, WILEY-VCH
RAO ET AL., SCIENCE, vol. 380, 2023, pages 1349 - 1356
RAO SRINIVASA P. ET AL: "Cyanotriazoles are selective topoisomerase II poisons that rapidly cure trypanosome infections", SCIENCE - AUTHOR MANUSCRIPT, vol. 380, no. 6652, 30 June 2023 (2023-06-30), US, pages 1349 - 1356, XP093266541, ISSN: 0036-8075, DOI: 10.1126/science.adh0614 *
T.W. GREENEP.G.M. WUTS: "Protecting Groups in Organic Synthesis", 1991, JOHN WILEY AND SONS

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