WO2016089977A1 - Substituted indazole compounds, compositions thereof, and methods of treatment therewith - Google Patents

Substituted indazole compounds, compositions thereof, and methods of treatment therewith Download PDF

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Publication number
WO2016089977A1
WO2016089977A1 PCT/US2015/063393 US2015063393W WO2016089977A1 WO 2016089977 A1 WO2016089977 A1 WO 2016089977A1 US 2015063393 W US2015063393 W US 2015063393W WO 2016089977 A1 WO2016089977 A1 WO 2016089977A1
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Prior art keywords
triazol
indazol
substituted
alkyl
cyclopropyl
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PCT/US2015/063393
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French (fr)
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Stacie S. CANAN
Joie Garfunkle
Deborah Mortensen
Sophie Perrin-Ninkovic
Matthew Wyvratt
Jerome Zeldis
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Celgene Corporation
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D403/04—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 directly linked by a ring-member-to-ring-member bond
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • indazole compounds comprising an effective amount of such compounds
  • methods for treating or preventing malaria and/or babesiosis comprising administering an effective amount of such indazole compounds to a subject in need thereof, as well as the inventive compounds and compositions for use in such methods.
  • Plasmodium falciparum is the dominant species in sub-Saharan Africa, and is responsible for the almost 1 million deaths each year. The disease burden is heaviest in African children under 5 years of age and in pregnant women. Plasmodium vivax causes 25-40% of the global malaria burden, particularly in South and Southeast Asia, and Central and South America. The other two main species that are known to infect humans are Plasmodium ovale and Plasmodium malariae. A fifth species Plasmodium knowlesi, a species that infects primates, has led to human malaria, but the exact mode of transmission remains unclear.
  • Malaria is a disease that is prevalent in many developing countries.
  • the most common drug for treating malaria is chloroquine.
  • Other drugs include quinine, melfloquine, atovaquone, proguanil, doxycycline, artesunate, hydroxychloroquine, halofantrine, pyrimethamine-sulfadoxine, and primaquine.
  • Human and animal babesiosis is a tick-borne infection that is malaria-like and can result in severe hemolysis and death.
  • the zoonotic disease is caused by hemotropic parasites of the genus Babesia.
  • Babesial parasites including Babesia microti, Babesia divergens, Babesia bovi, Babesia bigemina, Babesia caballi and Babesia burgdorferi (and those of the closely related genus Theileria, for example T. equi), are some of the most ubiquitous and widespread blood parasites in the world, and
  • babesiosis Various medications are presently used for the treatment of babesiosis in animals and humans. However, many of these medications are costly and some exhibit significant toxicity and undesirable side effects.
  • the most common drugs for treating babesiosis are the same as for treating malaria and include, for example, chloroquine, quinine, atovaquone, doxycycline, pyrimethamine-sulfadoxine, and primaquine.
  • Other drugs tested against babesiosis include staurosporine, purvalanol A, imidocarb, clindamycin, nimbolide, gedunin, ciprofloxacin, diminazene aceturate and epoxomicin.
  • methods for preventing malaria by administering a compound of Formula (I). [0013] Also provided are methods for treating or preventing babesiosis, comprising administering to a subject in need thereof an effective amount of a compound of Formula (II)
  • a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt, tautomer, isotopologue, or stereoisomer thereof (each being referred to herein as an "Indazole Compound") is useful for treating or preventing malaria and/or babesiosis.
  • Indazole Compounds of Formula (I), as described in the instant disclosure such as, for example, in Table 1 and Table 2.
  • compositions comprising an effective amount of an Indazole Compound as described herein, and a pharmaceutically acceptable carrier, excipient or vehicle.
  • the pharmaceutical composition is suitable for oral, parenteral, mucosal, transdermal or topical administration.
  • provided herein are methods for treating or preventing malaria and/or babesiosis, comprising administering to a subject in need thereof an effective amount of an Indazole Compound as described herein, and a pharmaceutically acceptable carrier, excipient or vehicle.
  • methods for treating or preventing malaria comprising administering to a subject in need thereof an effective amount of an Indazole Compound as described herein, and a pharmaceutically acceptable carrier, excipient or vehicle.
  • kits for treating or preventing babesiosis comprising administering to a subject in need thereof an effective amount of an Indazole Compound as described herein, and a pharmaceutically acceptable carrier, excipient or vehicle.
  • alkyl group is a saturated, partially saturated, or unsaturated straight chain or branched non-cyclic hydrocarbon having from 1 to 10 carbon atoms, typically from 1 to 8 carbons or, in some embodiments, from 1 to 6, 1 to 4, or 2 to 6 or carbon atoms.
  • alkyl groups include -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl and -n-hexyl; while saturated branched alkyls include -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, -neopentyl, tert-pentyl, -2-methylpentyl, -3-methylpentyl,
  • alkyl group can be substituted or unsubstituted.
  • the alkyl groups described herein may be substituted with any substituent or substituents as those found in the exemplary compounds and embodiments disclosed herein, as well as halogen (chloro, iodo, bromo, or fluoro); alkyl; hydroxyl; alkoxy; alkoxyalkyl; amino; alkylamino; carboxy; nitro; cyano; thiol; thioether; imine; imide; amidine; guanidine; enamine; aminocarbonyl; acylamino; phosphonate; phosphine; thiocarbonyl; sulfmyl; sulfone; sulfonamide; ketone; aldehyde; ester; urea; urethane; oxime; hydroxyl amine;
  • alkoxyamine aryloxyamine, aralkoxy amine; N-oxide; hydrazine; hydrazide; hydrazone; azide; isocyanate; isothiocyanate; cyanate; thiocyanate; B(OH) 2 , or
  • a "cycloalkyl” group is a saturated, or partially saturated cyclic alkyl group of from 3 to 10 carbon atoms having a single cyclic ring or multiple condensed or bridged rings which can be optionally substituted with from 1 to 3 alkyl groups.
  • the cycloalkyl group has 3 to 8 ring members, whereas in other
  • cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 1-methylcyclopropyl, 2- methylcyclopentyl, 2-methylcyclooctyl, and the like, or multiple or bridged ring structures such as l-bicyclo[l . l . l]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl,
  • cycloalkyl groups include cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, hexadienyl, among others.
  • a cycloalkyl group can be substituted or unsubstituted. Such substituted cycloalkyl groups include, by way of example, cyclohexanol and the like.
  • aryl group is an aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl). In some embodiments, aryl groups contain 6-14 carbons, and in others from 6 to 12 or 6 to 10 carbon atoms, or even 6 to 8 carbon atoms in the ring portions of the groups. Particular aryls include phenyl, biphenyl, naphthyl and the like. An aryl group can be substituted or unsubstituted. The phrase "aryl groups” also includes groups containing fused rings, such as fused aromatic-aliphatic ring systems (e.g., indanyl,
  • a "heteroaryl” group is an aryl ring system having one to four heteroatoms as ring atoms in a heteroaromatic ring system, wherein the remainder of the atoms are carbon atoms.
  • heteroaryl groups contain 3 to 6 ring atoms, and in others from 6 to 9 or even 6 to 10 atoms in the ring portions of the groups. Suitable heteroatoms include oxygen, sulfur and nitrogen.
  • the heteroaryl ring system is monocyclic or bicyclic.
  • Non-limiting examples include but are not limited to, groups such as pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, benzisoxazolyl (e.g., benzo[d]isoxazolyl), thiazolyl, pyrolyl, pyridazinyl, pyrimidyl, pyrazinyl, thiophenyl, benzothiophenyl, furanyl, benzofuranyl, indolyl
  • groups such as pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, benzisoxazolyl (e.g., benzo[d]isoxazolyl), thiazolyl, pyrolyl, pyridazinyl, pyrimidyl,
  • indolyl-2-onyl or isoindolin-l-onyl e.g., indolyl-2-onyl or isoindolin-l-onyl
  • azaindolyl pyrrolopyridyl or lH-pyrrolo[2,3- b]pyridyl
  • indazolyl benzimidazolyl (e.g., lH-benzo[d]imidazolyl), imidazopyridyl (e.g., azabenzimidazolyl or lH-imidazo[4,5-b]pyridyl)
  • pyrazolopyridyl triazolopyridyl
  • benzotriazolyl e.g., lH-benzo[d][l,2,3]triazolyl
  • benzoxazolyl e.g., benzo[d]oxazolyl
  • benzothiazolyl benzothiadiazolyl,
  • heterocyclyl is an aromatic (also referred to as heteroaryl) or non- aromatic cycloalkyl in which one to four of the ring carbon atoms are independently replaced with a heteroatom from the group consisting of O, S and N.
  • heterocyclyl groups include 3 to 10 ring members, whereas other such groups have 3 to 5, 3 to 6, or 3 to 8 ring members.
  • Heterocyclyls can also be bonded to other groups at any ring atom (i.e., at any carbon atom or heteroatom of the heterocyclic ring).
  • a heterocycloalkyl group can be substituted or unsubstituted.
  • Heterocyclyl groups encompass unsaturated, partially saturated and saturated ring systems, such as, for example, imidazolyl, imidazolinyl and imidazolidinyl (e.g., imidazolidin-4-one or imidazolidin-2,4-dionyl) groups.
  • heterocyclyl includes fused ring species, including those comprising fused aromatic and non-aromatic groups, such as, for example, 1-and 2-aminotetraline, benzotriazolyl (e.g., lH-benzo[d][l,2,3]triazolyl), benzimidazolyl (e.g., lH-benzo[d]imidazolyl), 2,3-dihydrobenzo[l,4]dioxinyl, and benzo[l,3]dioxolyl.
  • the phrase also includes bridged polycyclic ring systems containing a heteroatom such as, but not limited to, quinuclidyl.
  • heterocyclyl group examples include, but are not limited to, aziridinyl, azetidinyl, azepanyl, oxetanyl, pyrrolidyl, imidazolidinyl (e.g., imidazolidin-4-onyl or imidazolidin-2,4-dionyl), pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, dioxolyl, furanyl, thiophenyl, pyrrolyl, pyrrolinyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, benzisoxazolyl (e.g., benzo[d]isoxazolyl), thiazolyl, thiazol
  • non-aromatic heterocyclyl groups do not include fused ring species that comprise a fused aromatic group.
  • non- aromatic heterocyclyl groups include aziridinyl, azetidinyl, azepanyl, pyrrolidyl, imidazolidinyl (e.g., imidazolidin-4-onyl or imidazolidin-2,4-dionyl), pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, piperidyl, piperazinyl
  • substituted heterocyclyl groups may be mono-substituted or substituted more than once, such as, but not limited to, pyridyl or morpholinyl groups, which are 2-, 3-, 4-, 5-, or 6-substituted, or disubstituted with various substituents such as those listed below.
  • a "cycloalkylalkyl” group is a radical of the formula: -alkyl-cycloalkyl, wherein alkyl and cycloalkyl are as defined above. Substituted cycloalkylalkyl groups may be substituted at the alkyl, the cycloalkyl, or both the alkyl and the cycloalkyl
  • cycloalkylalkyl groups include but are not limited to methylcyclopropyl, methylcyclobutyl, methylcyclopentyl, methylcyclohexyl,
  • An "aralkyl” group is a radical of the formula: -alkyl-aryl, wherein alkyl and aryl are defined above. Substituted aralkyl groups may be substituted at the alkyl, the aryl, or both the alkyl and the aryl portions of the group. Representative aralkyl groups include but are not limited to benzyl and phenethyl groups and fused (cycloalkylaryl)alkyl groups such as 4-ethyl-indanyl.
  • heterocyclylalkyl is a radical of the formula: -alkyl- heterocyclyl, wherein alkyl and heterocyclyl are defined above. Substituted
  • heterocyclylalkyl groups may be substituted at the alkyl, the heterocyclyl, or both the alkyl and the heterocyclyl portions of the group.
  • Representative heterocylylalkyl groups include but are not limited to 4-ethyl-morpholinyl, 4-propylmorpholinyl, furan-2-yl methyl,
  • furan-3-yl methyl furan-3-yl methyl, pyridin-3-yl methyl, tetrahydrofuran-2-yl ethyl, and indol-2-yl propyl.
  • a "halogen” is chloro, iodo, bromo, or fluoro.
  • a "hydroxyalkyl” group is an alkyl group as described above substituted with one or more hydroxy groups.
  • alkoxy is -O-(alkyl), wherein alkyl is defined above.
  • alkoxyalkyl is -(alkyl)-O-(alkyl), wherein alkyl is defined above.
  • An "amine” group is a radical of the formula: -NH 2 .
  • a "hydroxyl amine” group is a radical of the formula: -N(R # )OH or -NHOH, wherein R # is a substituted or unsubstituted alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein.
  • alkoxyamine is a radical of the formula: -N(R # )0-alkyl or
  • An "aryloxyamine” group is a radical of the formula: -N(R # )0-aryl or -NHO-aryl, wherein R # is as defined above.
  • An "aralkoxyamine” group is a radical of the formula: -N(R )0-aralkyl or
  • alkylamine is a radical of the formula: -NH-alkyl or -N(alkyl) 2 , wherein each alkyl is independently as defined above.
  • An "0(alkyl)aminocarbonyl” group is a radical of the formula:
  • each R # is independently as defined above.
  • N-oxide group is a radical of the formula: -N -O " .
  • each R # is independently as defined above.
  • each R # is independently as defined above.
  • each R # is independently as defined above.
  • a "hydrazine” group is a radical of the formula: -N(R # )N(R # ) 2 , -NHN(R # ) 2 ,
  • each R # is independently as defined above.
  • each R # is independently as defined above.
  • An "azide” group is a radical of the formula: -N 3 .
  • a "cyanate” group is a radical of the formula: -OCN.
  • a "thiocyanate” group is a radical of the formula: -SCN.
  • a "thioether” group is a radical of the formula; -S(R # ), wherein R # is as defined above.
  • a "sulfonylamino" group is a radical of the formula: -NHS0 2 (R # ) or
  • each R # is independently as defined above.
  • each R # is independently as defined above.
  • a "phosphine” group is a radical of the formula: -P(R # ) 2 , wherein each R # is independently as defined above.
  • substituents are those found in the exemplary compounds and embodiments disclosed herein, as well as halogen (chloro, iodo, bromo, or fluoro); alkyl;
  • morpholinyl, or thiazinyl monocyclic or fused or non- fused polycyclic aryl or heteroaryl (e.g. , phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridinyl, quinolinyl, isoquinolinyl, acridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzothiophenyl, or benzofuranyl) aryloxy; aralkyloxy; heterocyclyloxy; and heterocyclyl alkoxy.
  • aryl or heteroaryl e.g. , phenyl, naphthyl, pyrrolyl,
  • Indazole Compound refers to compounds of
  • an “Indazole Compound” is a compound set forth in Table 1 or Table 2.
  • the term “Indazole Compound” includes pharmaceutically acceptable salts, tautomers, isotopologues, and stereoisomers of the compounds provided herein.
  • the term "pharmaceutically acceptable salt(s)” refers to a salt prepared from a pharmaceutically acceptable non-toxic acid or base including an inorganic acid and base and an organic acid and base.
  • Suitable pharmaceutically acceptable base addition salts of the compounds of Formula (I) or Formula (II) include, but are not limited to metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from lysine,
  • Suitable non-toxic acids include, but are not limited to, inorganic and organic acids such as acetic, alginic, anthranilic,
  • Specific non-toxic acids include hydrochloric, hydrobromic, maleic, phosphoric, sulfuric, and methanesulfonic acids.
  • salts thus include hydrochloride and mesylate salts.
  • Others are well-known in the art, see for example, Remington 's Pharmaceutical Sciences, 18 th eds., Mack Publishing, Easton PA (1990) or Remington: The Science and Practice of Pharmacy, 19 th eds., Mack Publishing, Easton PA (1995).
  • stereomerically pure means one stereoisomer of an Indazole Compound that is substantially free of other stereoisomers of that compound.
  • a stereomerically pure compound having one chiral center will be substantially free of the opposite enantiomer of the compound.
  • a stereomerically pure compound having two chiral centers will be substantially free of other diastereomers of the compound.
  • stereomerically pure compound comprises greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, greater than about 90%> by weight of one stereoisomer of the compound and less than about 10%> by weight of the other stereoisomers of the compound, greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of the other stereoisomers of the compound, or greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of the other stereoisomers of the compound.
  • the Indazole Compounds can have chiral centers and can occur as racemates, individual enantiomers or diastereomers, and mixtures thereof. All such isomeric forms are included within the embodiments disclosed herein, including mixtures thereof.
  • the Indazole Compounds can include E and Z isomers, or a mixture thereof, and cis and trans isomers or a mixture thereof.
  • the Indazole Compounds are isolated as either the E or Z isomer. In other embodiments, the Indazole Compounds are a mixture of the E and Z isomers.
  • Tautomers refers to isomeric forms of a compound that are in equilibrium with each other. The concentrations of the isomeric forms will depend on the environment the compound is found in and may be different depending upon, for example, whether the compound is a solid or is in an organic or aqueous solution. For example, in aqueous solution, pyrazoles may exhibit the following isomeric forms, which are referred to as tautomers of each other: [0080] As readily understood by one skilled in the art, a wide variety of functional groups and other stuctures may exhibit tautomerism and all tautomers of compounds of Formula (I) are within the scope of the present invention.
  • the Indazole Compounds can contain unnatural proportions of atomic isotopes at one or more of the atoms.
  • the compounds may be radiolabeled with radioactive isotopes, such as for example tritium ( 3 H), iodine-125 ( 125 I), sulfur-35 ( 35 S), or carbon-14 ( 14 C), or may be isotopically enriched, such as with deuterium ( 2 H), carbon-13 ( 13 C), or nitrogen-15 ( 15 N).
  • radioactive isotopes such as for example tritium ( 3 H), iodine-125 ( 125 I), sulfur-35 ( 35 S), or carbon-14 ( 14 C)
  • isotopically enriched such as with deuterium ( 2 H), carbon-13 ( 13 C), or nitrogen-15 ( 15 N).
  • isotopically enriched compound is an isotopically enriched compound.
  • isotopically enriched refers to an atom having an isotopic composition other than the natural isotopic composition of that atom.
  • isotopically enriched may also refer to a compound containing at least one atom having an isotopic composition other than the natural isotopic composition of that atom.
  • isotopic composition refers to the amount of each isotope present for a given atom.
  • Radiolabeled and isotopically encriched compounds are useful as therapeutic agents, e.g., cancer and inflammation therapeutic agents, research reagents, e.g., binding assay reagents, and diagnostic agents, e.g., in vivo imaging agents.
  • isotopic variations of the Indazole Compounds as described herein, whether radioactive or not, are intended to be encompassed within the scope of the embodiments provided herein.
  • isotopologues of the Indazole Compounds for example, the isotopologues are deuterium, carbon-13, or nitrogen-15 enriched Indazole Compounds.
  • Treatment and “Treating” as used herein mean an alleviation, in whole or in part, of a disorder, disease or condition, or one or more of the symptoms associated with a disorder, disease, or condition, or slowing or halting of further progression or worsening of those symptoms, or alleviating or eradicating the cause(s) of the disorder, disease, or condition itself.
  • the disorder is malaria and/or babesiosis.
  • Preventing means a method of delaying and/or precluding the onset, recurrence or spread, in whole or in part, of a disorder, disease or condition; barring a subject from acquiring a disorder, disease, or condition; or reducing a subject's risk of acquiring a disorder, disease, or condition.
  • the disorder is malaria and/or babesiosis, as described herein, or symptoms thereof.
  • preventing includes prophylaxis.
  • the term "effective amount" in connection with an Indazole Compound means an amount capable of treating or preventing a disorder, disease or condition, or symptoms thereof, disclosed herein.
  • the disorder is malaria and/or babesiosis.
  • the term "effective amount” includes "prophylaxis-effective amount” as well as “treatment-effective amount”.
  • prophylaxis-effective amount refers to a concentration of compound of this invention that is effective in inhibiting, decreasing the likelihood of the disease by malarial or babesia parasites, or preventing malarial or babesia infection by malarial or babesia parasites, when administered before infection, i.e. before, during and/or after the exposure period to malarial or babesia parasites.
  • prophylaxis includes causal prophylaxis, i.e. antimalarial or antibabesia activity comprising preventing the pre-erythrocytic development of the parasite, suppressive prophylaxis, i.e. antimalarial or antibabesia activity comprising suppressing the development of the blood stage infection, and, for malaria, terminal prophylaxis, i.e. antimalarial activity comprising suppressing the development of intrahepatic stage infection.
  • This term includes primary prophylaxis (i.e.
  • the antimalarial or antibabesia compound is administered before, during and/or after the exposure period to malarial or babesia parasites and terminal prophylaxis (i.e. to prevent relapses or onset of clinical symptoms of malaria or babesia) when the antimalarial or antibabesia compound is administered towards the end of and/or after the exposure period to malarial or babesia parasites but before the clinical symptoms.
  • suppressive prophylaxis is used whereas against P. falciparum infections, suppressive prophylaxis is used whereas against P. vivax or a combination of P. falciparum and P. vivax, terminal prophylaxis is used. Because babesia parasites have no exo-erythrocytic stages, suppressive prophylaxis is used for treatment of babesiosis infections.
  • treatment-effective amount refers to a concentration of compound that is effective in treating malaria or babesia infection, e.g. leads to a reduction in parasite numbers in blood following microscopic examination when administered after infection has occurred.
  • subject includes an animal, including, but not limited to, an animal such a cow, monkey, horse, sheep, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbit or guinea pig, in one embodiment a mammal, in another embodiment a human.
  • a subject is a human having or at risk for having malaria and/or
  • R 2 is or substituted or unsubstituted 5-membered nitrogen- containing heteroaryl, wherein the heteroaryl is optionally fused to a second ring;
  • Y is selected from:
  • phenyl substituted with one or more substituents selected from halogen, -CN, -(Ci-3 alkyl) optionally fluorinated, -S0 2 (Ci_ 3 alkyl), -(Ci_ 3 alkyl)NR(C 3 _ 6 cycloalkyl),
  • R is -H or substituted or unsubstituted (C 1-3 alkyl),
  • R' is substituted or unsubstituted (C 1-4 alkyl), substituted or unsubstituted
  • R" is substituted or unsubstituted (C 3-6 cycloalkyl), substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
  • R # is -H or -OH.
  • R 2 is substituted or unsubstituted imidazolyl, oxazolyl, triazolyl, tetrazolyl, triazolinonyl, or benzimidazolyl.
  • R 2 is substituted with substituted or unsubstituted (C 1-4 alkyl), substituted or unsubstituted
  • R 2 is substituted with (C 1-4 alkyl) substituted with one or more -F, -OH, or -NR 2 ; (C 1-4 cycloalkyl); (C 0-4 alkyl)pyrrolidinyl;
  • R 2 is substituted with -CH 2 CH 3 , -CH(CH 3 ) 2 , -C(CH 3 ) 3 , -CH 2 CH(CH 3 ) 2 , -CH 2 C(CH 3 ) 3 , -CH(CH 3 )CH 2 CH 3 , -C(CH 3 ) 2 CH 2 CH 3 ; -CF 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CHF 2 , -CH 2 CH 2 CF3,
  • R 2 is substituted with -CH(CH 3 ) 2 , -C(CH 3 ) 3 , -CH 2 CH(CH 3 ) 2 , -C(CH 3 ) 2 CH 2 CH 3 , -CF 3 , -CH 2 CH 2 F, -CH 2 CF 3 ,
  • R 2 is triazolyl.
  • R 2 is oxazolyl.
  • R 2 is oxazolyl, substituted with -CH 2 CF 3 , -CH 2 N(CH 3 ) 2 , pyrrolidinyl, or -CH 2 (morpholinyl).
  • Y is phenyl, substituted with one or more substituents selected from -F, -CI, -CN, -CF 3 , -S0 2 CH 3 , -CH 2 NH(cyclopropyl), -CH 2 (pyrrolidinyl), -OCH 2 CH 2 (morpholinyl),
  • R a is -H, -F, -CI, -CN, -CF 3 , -S0 2 CH 3 , -CH 2 NH(cyclopropyl),
  • R b is -H, -F, -CI, -CN, -CF3, -S0 2 CH 3 , -CH 2 NH(cyclopropyl),
  • R c is -H, or -F
  • R a is -H, -F, -CI, -CN, -S0 2 CH 3 ,
  • R c is -H or -F.
  • the Indazole Compound is a compound of Formula (I) as described herein, wherein the compound at a concentration of 2 ⁇ inhibits malaria parasite growth by at least about 50%.
  • R 1 is -H or -CH 3 ;
  • Y is selected from:
  • phenyl substituted with one or more substituents selected from halogen, -CN, -(C 1-3 alkyl) optionally fluorinated, -S0 2 (Ci_ 3 alkyl),
  • R is -H or substituted or unsubstituted (C 1-3 alkyl),
  • R' is substituted or unsubstituted (C 1-4 alkyl), substituted or unsubstituted (C 3 _6 cycloalkyl), substituted or unsubstituted aryl, or substituted or unsubstituted aralkyl;
  • R" is substituted or unsubstituted (C 3 _ 6 cycloalkyl), substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
  • R x is -H or -(Ci_4 alkyl)(non-aromatic heterocyclyl).
  • R 1 is -H.
  • R 3 is substituted or unsubstituted imidazolyl, oxazolyl, triazolyl, tetrazolyl, triazolinonyl, or benzimidazolyl.
  • R 3 is substituted with substituted or unsubstituted (C 1-4 alkyl), substituted or unsubstituted (C 3 _ 6 cycloalkyl), substituted or unsubstituted (C 0-4 alkyl)(heterocyclyl), or substituted or unsubstituted aryl.
  • R 3 is substituted with (Ci_4 alkyl) substituted with one or more -F, -OH, or -NR 2 ; (C 1-4 cycloalkyl);
  • R 3 is substituted with -CH 2 CH 3 , -CH(CH 3 ) 2 , -C(CH 3 ) 3 , -CH 2 CH(CH 3 ) 2 , -CH 2 C(CH 3 ) 3 ,
  • -CH 2 (pyrrolidinonyl); morpholinyl; -CH 2 (morpholinyl); piperidyl; -CH 2 (piperidyl);
  • R 3 is substituted with -CH(CH 3 ) 2 , -C(CH 3 ) 3 , -CH 2 CH(CH 3 ) 2 , -C(CH 3 ) 2 CH 2 CH 3 , -CF 3 , -CH 2 CH 2 F, -CH 2 CF 3 , -CH 2 CH 2 CF 3 , -CH(OH)CH 3 , -CH 2 N(CH 3 ) 2 ; cyclobutyl; pyrrolidinyl; -CH 2 (pyrrolidinyl);
  • R 3 is substituted with -CH 2 CF 3 , or -CH 2 (pyrrolidinyl).
  • R 3 is substituted with pyrrolidinyl, or -CH 2 (pyrrolidinyl).
  • R 3 is substituted with -CH 2 CH 2 F, -CH 2 CF 3 , -CH 2 CH 2 CF 3 , or piperidyl.
  • R 3 is substituted with -CH 2 CH(CH 3 ) 2 , -CH 2 N(CH 3 ) 2 , pyrrolidinyl, or -CH 2 (pyrrolidinyl). In one embodiment, R 3 is substituted with -CH 2 CH(CH 3 ) 2 ,
  • R 3 is triazolyl.
  • Y is phenyl substituted with one or more substituents selected from -F, -CI, -CN, -CF 3 , -S0 2 CH 3 , -CH 2 NH(C 3 _ 4 cycloalkyl), -CH 2 (non-
  • Y is phenyl, substituted with one or more substituents selected from -F, -CN, or
  • Y is phenyl, substituted with one or more
  • Y is phenyl, substituted with one or more
  • R c is -H, or -F
  • R a is -H, -F, -CI
  • R b is -H, -F, -CI, or -CN.
  • R b is -H, or -F.
  • R c is -H.
  • the Indazole Compound is a compound of Formula (II) as described herein, wherein the compound at a concentration of 2 ⁇ inhibits parasite growth by at least about 50%.
  • Representative compounds of Formula (II) are
  • the compound of Formula (II) is selected from 3-(5-(lH-l,2,4-triazol-3-yl)-lH-indazol-3-yl)-N-cyclopentylbenzamide;
  • the compound of Formula (II) is selected from:
  • the compound of Formula (II) is selected from:
  • the compound of Formula (II) is selected from:
  • the compound of formula (II) is selected from
  • the compound of formula (II) is selected from
  • Indazole Compounds can be made using conventional organic syntheses and commercially available starting materials.
  • Indazole Compounds of Formula (I) and Formula (II) can be prepared as described in International Patent Application Publication No. WO 02/10137, 2002; United States patent application publication No. US 2004/0127536; United States patent application publication No. US 2005/0107386; and United States patent application publication No. US 2005/0009876, or as outlined in Scheme 1, shown below, as well as in the examples set forth herein. It should be noted that one skilled in the art would know how to modify the procedures set forth in the illustrative schemes and examples to arrive at the desired roducts.
  • compounds of Formula (I) can be prepared starting with the P N protected and appropriately subsitituted 5-cyanoindazole (synthesis described in applications listed above) wherein Hal is halogen (for example CI, Br or I), and P N is a protecting group (for example SEM, Boc, Trityl, Tosyl, Benzyl, 4-methoxybenzyl,
  • the R 2 group can be installed by transformation of the nitrile to a carboxylate derivative (including carboxylic acid, ester or amide) or suitable cyclization precursor (including, for example, acid, ester, imidate, amide) and then further functionalization.
  • a carboxylate derivative including carboxylic acid, ester or amide
  • suitable cyclization precursor including, for example, acid, ester, imidate, amide
  • the nitrile starting material can be hydrolyzed by treatment with a base, such as sodium hydroxide, in a solvent, such as DMSO, with heating (60-100 °C).
  • R # is -H or -OH
  • a coupling agent such as, for example, HATU
  • a solvent such as DMF
  • a base such as DIEA
  • Cyclization can be achieved to afford compounds wherein R 2 is substituted or unsubstituted 5-membered nitrogen-containing heteroaryl (wherein the heteroaryl is optionally fused to a second ring), for example, first by conversion of the nitrile to a carbimidate (for example, by treatment of the starting material with an acid, such as for example, HC1 gas, in a solvent, such as for example ethanol, followed by addition of the appropriate hydrazide in the presence of a base, such as TEA, in a solvent, such as methanol, at elevated temperatue (for example, 60-85 °C).
  • an acid such as for example, HC1 gas
  • a solvent such as for example ethanol
  • a base such as TEA
  • a solvent such as methanol
  • a catalyzed coupling reaction to install Y can be achieved by treatment with the appropriate boronic acid or borate ester Y-BH(OR ) 2 (wherein R + is H, lower alkyl, or together with the boron atom and the atoms to which they are attached, form a cyclic boronate), in the presence of a palladium catalyst (such as, for example, tetrakis(triphenylphosphine) palladium(O) or bis(triphenylphosphine)palladium(II) dichloride), in a solvent (such as 1 ,4 dioxane/water) and a base (such as sodium carbonate, potassium carbonate, or potassium phosphate), at elevated temperature (for example, 60 °C-100 °C).
  • a palladium catalyst such as, for example, tetrakis(triphenylphosphine) palladium(O) or bis(triphenylphosphine)palladium(
  • Deprotection for example, when P N is THP, by treatment with an acid such TFA or HC1, in a solvent such as DCM, THF, or 1,4 dioxane
  • a solvent such as DCM, THF, or 1,4 dioxane
  • Indazole N-alkylation for instance with methyl iodide in THF
  • Indazole compounds of Formula (II) can similarly be prepared.
  • the Indazole Compounds have utility as pharmaceuticals to treat, prevent or improve conditions in animals or humans. Accordingly, provided herein are uses of the Indazole Compounds, including treatment of malaria and/or babesiosis. The methods provided herein comprise the administration of an effective amount of one or more
  • Indazole Compound(s) to a subject in need thereof.
  • kits for treating or preventing malaria comprising administering to a subject in need thereof an effective amound of a compound of Formula (I) as described herein, or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, or isotopologue thereof.
  • the compound of Formula (I) is selected from Table 1.
  • the compound of Formula (I) is selected from Table 2.
  • the malaria is caused by Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, Plasmodium knowlesi or Plasmodium malariae.
  • the malaria is caused by Plasmodium falciparum.
  • the methods additionally comprise administering an effective amount of one or more of chloroquine, quinine, quinidine, melfloquine, atovaquone, proguanil, doxycycline, artesunate, artemether, artemisinin, lumefantrine, amodiaquine, hydroxychloroquine, halofantrine, pyrimethamine, sulfadoxine, or primaquine.
  • Babesiosis comprising administering to a subject in need thereof an effective amound of a compound of Formula (II) as described herein, or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, or isotopologue thereof.
  • the Babesiosis is caused by Babesia microti, Babesia divergens, Babesia bovis, Babesia bigemina, Babesia caballi, Babesia burgdorferi, or Theileria equi.
  • the Babesiosis is caused by Babesia bovis, Babesia bigemina, or Theileria equi.
  • the methods additionally comprise administering an effective amount of one or more of chloroquine, quinine, atovaquone, azithromycin, doxycycline, pyrimethamine-sulfadoxine, primaquine, staurosporine, purvalanol A, imidocarb, clindamycin, nimbolide, gedunin, ciprofloxacin, diminazene aceturate or epoxomicin.
  • the methods additionally comprise administering an effective amount of one or more of quinine, atovaquone, azithromycin, or clindamycin.
  • the compound of Formula (II) is selected from
  • the compound of Formula (II) is selected from:
  • the compound of Formula (II) is selected from:
  • the compound of Formula (II) is selected from:
  • the compound of Formula (II) is selected from:
  • the Indazole Compounds can be administered to a subject orally, topically or parenterally in the conventional form of preparations, such as capsules, microcapsules, tablets, granules, powder, troches, pills, suppositories, injections, suspensions, syrups, patches, creams, lotions, ointments, gels, sprays, solutions and emulsions.
  • preparations such as capsules, microcapsules, tablets, granules, powder, troches, pills, suppositories, injections, suspensions, syrups, patches, creams, lotions, ointments, gels, sprays, solutions and emulsions.
  • formulations can be prepared by methods commonly employed using conventional,
  • the effective amount of the Indazole Compounds in the pharmaceutical composition may be at a level that will exercise the desired effect; for example, at about 0.005 mg/kg of a subject's body weight to about 10 mg/kg of a subject's body weight in unit dosage for both oral and parenteral administration.
  • the dose of an Indazole Compound to be administered to a subject is rather widely variable and can be subject to the judgment of a health-care practitioner.
  • the Indazole Compounds can be administered one to four times a day in a dose of about 0.005 mg/kg of a subject's body weight to about 10 mg/kg of a subject's body weight in a subject, but the above dosage may be properly varied depending on the age, body weight and medical condition of the subject and the type of administration.
  • the amount of the Indazole Compound administered will depend on such factors as the solubility of the active component, the formulation used and the route of administration.
  • application of a topical concentration provides intracellular exposures or concentrations of about 0.01 - 10 ⁇ .
  • kits for the treatment or prevention of a disease or disorder comprising the administration of about 1 mg/day to about 1200 mg/day.
  • unit dosage formulations that comprise between about 1 mg and 500 mg, or between about 500 mg and about 1000 mg of an Indazole Compound.
  • An Indazole Compound can be administered once, twice, three, four or more times daily.
  • An Indazole Compound can be administered orally for reasons of convenience.
  • the Indazole Compound can also be administered intradermally, intramuscularly, intraperitoneally, percutaneously, intravenously, subcutaneously, intranasally, epidurally, sublingually, intracerebrally, intravaginally, transdermally, rectally, mucosally, by inhalation, or topically to the ears, nose, eyes, or skin.
  • the mode of administration is left to the discretion of the health-care practitioner, and can depend in- part upon the site of the medical condition.
  • capsules containing an Indazole are provided herein are capsules containing an Indazole
  • compositions comprising an effective amount of an Indazole Compound and a pharmaceutically acceptable carrier or vehicle, wherein a pharmaceutically acceptable carrier or vehicle can comprise an excipient, diluent, or a mixture thereof.
  • a pharmaceutically acceptable carrier or vehicle can comprise an excipient, diluent, or a mixture thereof.
  • the composition is a pharmaceutical composition.
  • compositions can be in the form of tablets, chewable tablets, capsules, solutions, parenteral solutions, troches, suppositories and suspensions and the like.
  • compositions can be formulated to contain a daily dose, or a convenient fraction of a daily dose, in a dosage unit, which may be a single tablet or capsule or convenient volume of a liquid.
  • the solutions are prepared from water-soluble salts, such as the hydrochloride salt.
  • all of the compositions are prepared according to known methods in pharmaceutical chemistry.
  • Capsules can be prepared by mixing an Indazole Compound with a suitable carrier or diluent and filling the proper amount of the mixture in capsules.
  • the usual carriers and diluents include, but are not limited to, inert powdered substances such as starch of many different kinds, powdered cellulose, especially crystalline and microcrystalline cellulose, sugars such as fructose, mannitol and sucrose, grain flours and similar edible powders.
  • the effect of the Indazole Compound can be delayed or prolonged by proper formulation.
  • a slowly soluble pellet of the Indazole Compound can be prepared and incorporated in a tablet or capsule, or as a slow-release implantable device.
  • the technique also includes making pellets of several different dissolution rates and filling capsules with a mixture of the pellets. Tablets or capsules can be coated with a film that resists dissolution for a predictable period of time. Even the parenteral preparations can be made long-acting, by dissolving or suspending the Indazole
  • the Indazole Compounds can be administered alone or in combination with a co-agent useful in the treatment of malaria, such as substances useful in the treatment and/or prevention of malaria e.g. for example a co-agent including, but not limited to, one or more of chloroquine, quinine, quinidine, melfloquine, atovaquone, proguanil, doxycycline, artesunate, artemether, artemisinin, lumefantrine, amodiaquine, hydroxychloroquine, halofantrine, pyrimethamine, sulfadoxine, or primaquine.
  • a co-agent including, but not limited to, one or more of chloroquine, quinine, quinidine, melfloquine, atovaquone, proguanil, doxycycline, artesunate, artemether, artemisinin, lumefantrine, amodiaquine, hydroxychloroquine, hal
  • the Indazole Compounds can be administered alone or in combination with a co-agent useful in the treatment of babesiosis, such as substances useful in the treatment and/or prevention of babesiosis e.g. for example a co-agent including, but not limited to, one or more of chloroquine, quinine, atovaquone, azithromycin, doxycycline, pyrimethamine-sulfadoxine, primaquine, staurosporine, purvalanol A, imidocarb, clindamycin, nimbolide, gedunin, ciprofloxacin, diminazene aceturate or epoxomicin.
  • the co-agent is an effective amount of one or more of quinine, atovaquone, azithromycin, or clindamycin.
  • the Indazole Compound is administered to a subject prior to, simultaneously or sequentially with other therapeutic regimens or co- agents useful in the treatment of malaria or babesiosis (e.g. multiple drug regimens), in an effective amount
  • the Indazole Compounds that are administered simultaneously with said co-agents can be administered in the same or different composition(s) and by the same or different route(s) of administration.
  • Methyl iodide (6.43 g, 45.3 mmol) was added at 0 °C, then the reaction was allowed to warm to ambient temperature and stirred for 16 h. Completion of the reaction was confirmed by TLC. The product was isolated and purified via standard methods to afford l-(tert-butyl) 2-methyl pyrrolidine- 1,2-dicarboxylate (6.6 g, 95 %) as yellow oil.
  • tert-Butyl-2-(hydrazinecarbonyl)pyrrolidine-l-carboxylate To a stirred solution of l-(tert-butyl) 2-methyl pyrrolidine- 1,2-dicarboxylate (6.6 g, 34 mmol) in methanol (120 mL) was added hydrazine hydrate (8 mL) at 0 °C and the reaction was stirred at 60 °C for 16 h. Completion of the reaction was confirmed by TLC. The product was isolated and purified via standard methods to afford tert-butyl-2-(hydrazinecarbonyl)pyrrolidine-l-carboxylate (6.6 g, quant.) as a colorless oil.
  • reaction mixture was filtered through a Celite pad and the filtrate was concentrated and purified via standard methods to afford tert-butyl 2-(3-(3-(3-carbamoylphenyl)- lH-indazol-5-yl)-lH-l,2,4-triazol-5-yl)pyrrolidine-l-carboxylate (180 mg, 56%) as a white solid.
  • tert Butyl 2-(hydrazinecarbonyl) pyrrolidine-l-carboxylate To a stirred solution of l-(tert-butyl) 2-methyl pyrrolidine- 1 ,2-dicarboxylate (0.3 g, 1.31 mmol) in methanol (15 mL) was added anhydrous hydrazine hydrate (1 mL) and heated at reflux for 48 h. The reaction mixture was concentrated to afford tert butyl 2-(hydrazinecarbonyl) pyrrolidine-l- carboxylate (0.28 g, 93%) as pale yellow oil.
  • tert-Butyl 2-(3-(3-(4-cyanophenyl)- lH-indazol-5-yl)- 1H- 1 ,2,4-triazol-5- yl)pyrrolidine-l-carboxylate To a solution tert-butyl-2-(4-(3-bromo-lH-indazol-5-yl)-lH- pyrrol-2-yl) pyrrolidine-l-carboxylate (500 mg, 1.15 mmol) in methanol (10 mL) was added (4-cyanophenyl) boronic acid (255 mg, 1.73 mmol) followed by potassium acetate (338 mg, 3.45 mmol). The reaction was degassed for 10 minutes, and then
  • N-(2-Aminophenyl)-3-bromo-l-(tetrahydro-2H-pyran-2-yl)-lH-indazole-5- carboxamide To 3-bromo-l-(tetrahydro-2H-pyran-2-yl)-lH-indazole-5-carboxylic acid (3 g, 0.92mmol) in DMF (30 mL) was added DIEA (3.7 mL, 2.30 mmol) and HATU (5.26 g, 1.38 mmol) followed by benzene- 1,2-diamine (0.99 g, 0.92 mmol). The reaction was stirred for 16 h at ambient temperature.
  • reaction mixture was quenched with water (30 mL) and worked up and purified via standard methods to afford N-(2-aminophenyl)-3-bromo-l- (tetrahydro-2H-pyran-2-yl)-lH-indazole-5 -carboxamide (2 g, 52%) as off white solid.
  • N-Cyclopropyl-3-(5-(5-(3,3,3-trifluoropropyl)-lH-l,2,4-triazol-3-yl)-lH- indazol-3-yl)benzamide To a stirred solution 3-bromo-5-(5-(3,3,3-trifluoropropyl)-lH-l,2,4- triazol-3-yl)-lH-indazole (300 mg, 0.82 mmol) and (3-(cyclopropylcarbamoyl) phenyl) boronic acid (334 mg, 1.63 mmol) in methanol (5 mL) was added potassium acetate (240 mg,
  • the reaction was degassed for 10 minutes, and then bis(triphenylphosphine)palladium(II) dichloride (0.129 g, 0.02 mmol) was added and the mixture was degassed for another 5 minutes, then heated at 90 °C for 12 h.
  • the reaction was degassed for 10 minutes, and then bis(triphenylphosphine)palladium(II) dichloride (0.112 g, O.Olmmol) was added and the mixture was degassed for another 5 minutes, then heated at 90 °C for 16 h.
  • 1,4-dioxane (6 mL) was added 4.5 N HC1 in dioxane (0.5 mL) at 0 °C and the reaction was stirred for 16 h at room temperature. Completion of the reaction was monitored by LCMS. The reaction mixture was concentrated under vacuum and then coevaporated with diethyl ether under vacuum. The residue was dissolved in 10%> DCM in methanol (20 mL) and neutralized using sodium carbonate.
  • the reaction was degassed for 10 minutes, and then bis(triphenylphosphine)palladium(II) dichloride (36 mg, 0.05 mmol) was added and the reaction mixture was degassed for another 10 minutes.
  • the reaction mixture was irradiated at 150 °C under microwave irradiation for lh 30 min.
  • Tetrakis(triphenylphosphine)palladium(0) 80 mg, 0.069 mmol was added and the reaction was degassed for a further 10 minutes, then heated at 150 °C under microwave irradiation for 2 h. Completion of the reaction was confirmed by LCMS. The reaction mixture was filtered through a Celite pad and the filtrate was concentrated and purified via standard methods to afford tert- butyl-2-(3-(3-(3-(methylsulfonyl)phenyl)-lH-in ⁇
  • Tetrakis(triphenylphosphine)palladium(0) (213 mg, 0.185 mmol) was added and the reaction was degassed for a further 10 minutes, then heated at 150 °C under microwave irradiation for 2 h. Completion of the reaction was confirmed by LCMS. The reaction mixture was filtered through a Celite pad and the filtrate was concentrated and purified via standard methods to afford N- methyl-3-(5-(3-(pyrrolidin-2-yl)-lH-l,2,4-triazol-5-yl)-lH-indazol-3-yl)benzamide (41 mg, 11%). MS (ESI) m/z 388 [M + 1] + .
  • the reaction was degassed for 10 minutes, and then bis(triphenylphosphine)palladium(II) dichloride (162 mg, 0.23 mmol) was added and the reaction mixture was degassed for another 10 minutes.
  • the reaction mixture was heated to 90 °C for 16 h. Completion of the reaction was confirmed by LCMS.
  • the reaction mixture was filtered through a Celite pad and the filtrate was concentrated and purified via standard methods to afford tert- butyl 2-(3-(3-(3-formylphenyl)- lH-indazol-5-yl)- 1H- 1 ,2,4-triazol-5-yl)pyrrolidine- 1 -carboxylate (290 mg, 53%) as off-white solid.
  • tert-Butyl 4-(hydrazinecarbonyl)piperidine-l-carboxylate To a stirred solution of l-(tert-butyl)4-methyl piperidine-l,4-dicarboxylate (1.2 g, 0.49 mmol) in methanol (20 mL) was added hydrazine (2 mL) at room temperature. The reaction was stirred for 16 h at same temperature. The reaction was worked up via standard methods to afford tert-butyl 4- (hydrazinecarbonyl)piperidine-l -carboxylate (1.0 g, 83%) as an off white gummy solid.
  • tert-Butyl 4-(3-(3-(4-cyanophenyl)- lH-indazol-5-yl)- 1H- 1 ,2,4-triazol-5- yl)piperidine-l-carboxylate To tert-butyl 4-(3-(3-bromo-lH-indazol-5-yl)-lH-l,2,4-triazol-5- yl)piperidine-l-carboxylate (0.400 g, 0.09 mmol) in methanol (10 mL) was added
  • Tetrakis(triphenylphosphine)palladium(0) (240 mg, 0.21 mmol) was added and the reaction mixture was degassed for another 10 minutes. The reaction mixture was heated to 120 °C for 16 h. Completion of the reaction was confirmed by LCMS. The reaction mixture was filtered through a Celite pad and the filtrate was concentrated and purified via standard methods to afford tert-butyl 2-(3-(3-(3-(3-(methylsulfonamido)phenyl)-lH-indazol-5-yl)-lH-l,2,4-triazol-5- yl)pyrrolidine-l -carboxylate; (80 mg, 10%) as off white solid.
  • Tetrakis(triphenylphosphine)palladium(0) (95 mg, 0.083 mmol) was added and the reaction mixture was degassed for another 10 minutes. The reaction mixture was heated at 90 °C for 4 h in sealed tube. Completion of the reaction was confirmed by LCMS. The reaction mixture was filtered through a Celite pad and the filtrate was concentrated and purified via standard methods to afford 4-(5-(3-(morpholinomethyl)-lH-l,2,4- triazol-5-yl)-lH-indazol-3-yl)benzonitrile (70 mg, 22%). MS (ESI) m/z 386 [M + 1] + .
  • Ethyl dimethyl glycinate To a stirred solution of ethylbromoacetate (3 g, 20 mmol) in acetonitrile ( 30 mL) was added triethylamine (3.61 g, 30 mmol) at 0 °C. The suspension was stirred for 10 min and dimethylamine solution (0.96 g, 21 mmol) was added slowly at 0 °C The resulting reaction mixture was stirred for 16 h at room temperature.
  • the reaction was degassed for 5 minutes, and then bis(triphenylphosphine)palladium(II) dichloride (69 mg, 0.098 mmol) was added to the reaction mixture and further degassed for another 10 minutes.
  • the reaction mixture was heated at 90 °C for 16 h. Completion of the reaction was confirmed by LCMS.
  • reaction mixture was filtered through a Celite pad and the filtrate was concentrated and purified via standard methods to afford4-(5-(5-((dimethylamino)methyl)-l,3,4-oxadiazol-2-yl)-l- (tetrahydro-2H-pyran-2-yl)-lH-indazol-3-yl)benzonitrile (220 mg, 47%) as white solid.
  • Ethyl 3-bromo-lH-indazole-5-carbimidate hydrochloride salt Dry HC1 gas was purged into a stirred solution of 3-bromo-l-(tetrahydro-2H-pyran-2-yl)-lH-indazole-5- carbonitrile (15 g, 49 mmol) in ethanol (150 mL) at -15 °C for 30 min. The reaction mixture was then stirred for 16 h at ambient temperature. The product was isolated and purified via standard methods to afford ethyl 3-bromo-lH-indazole-5-carbimidate hydrochloride salt (12 g, 91%) as light brown solid.
  • reaction was degassed for 10 minutes, and then bis(triphenylphosphine)palladium(II) dichloride (95 mg, 0.13 mmol) was added and the reaction mixture was degassed for another 10 minutes.
  • the reaction mixture was heated at 90 °C for 16 h in sealed tube. Completion of the reaction was confirmed by HPLC.
  • reaction mixture was filtered through a Celite pad and the filtrate was concentrated and purified via standard methods to afford tert-butyl 2-(5-(3-(4-cyanophenyl)-l-(tetrahydro-2H-pyran-2-yl)- 1 H-indazol-5 -yl)-l, 3, 4-oxadiazol-2-yl)pyrrolidine-l -carboxylate (150 mg, 41%) as pale yellow solid.
  • RPMI 1640 medium to separate the erythrocytes from the plasma and buffy coat. Separation was achieved by centrifuging the blood at 500 x g for 5 minutes in a swing-out rotor.
  • Leukocyte-free erythrocytes were typically stored at 50% hematocrit (i.e. 1 volume of malaria culture media for 1 volume of packed erythrocytes, corresponding to approximately 5 x 109 cells/mL).
  • Parasite culture conditions P. falciparum asexual blood stage parasites were propagated at 37 °C in malaria culture media at 3-5% hematocrit in a reduced oxygen environment (e.g. a custom mixture of 5% C0 2 , 5% 0 2 and 90%> N 2 ). Lines were conveniently cultured in 6-24 well tissue culture plates in a modular chamber (Billups- Rothenberg, Del Mar, CA, www.brincubator.com), with plates containing sterile water on the bottom to increase humidity and minimize desiccation. These chambers were suffused with the low 0 2 gas and maintained at 37 °C in an incubator designed to minimize temperature fluctuations.
  • a reduced oxygen environment e.g. a custom mixture of 5% C0 2 , 5% 0 2 and 90%> N 2 .
  • Parasites could also be cultured in flasks that are individually gassed, or alternatively placed in flasks that permit gas exchange through the cap (in which case the incubator needs to be continuously infused with a low 0 2 gas mixture). Parasites typically propagated 3-8 fold every 48 h, thus care was taken to avoid parasite cultures attaining too high a parasitemia (i.e. percentage of erythrocytes that are parasitized) for healthy growth. Optimal growth was at 0.5 - 4% parasitemia. Parasites were most suitable for assays when they are 2-5% parasitemia, and mostly ring stages with few or no gametocytes.
  • Assay conditions Parasites were diluted to a 2x stock consisting of 0.6% to 0.9% parasitemia and 3.2% hematocrit in low hypoxanthine medium, and 100 mL were added per well already containing 100 mL of low hypoxanthine medium with or without compound (present at different concentrations). Plates were then incubated in a gassed modular chamber at 37 °C for 48 h. After this time, 100 mL of culture supernatant from each well was removed and replaced with 100 mL of low hypoxanthine medium containing a final concentration of 7.5 mCi/mL of [ 3 H]-hypoxanthine (1 mCi/mL stock, Amersham Biosciences).
  • the plates were placed at-80 °C for at least 1 h to freeze the cells. Plates are then thawed and the cells were harvested onto glass fiber filters (Wallac, Turku, Finland). Filters were dried for 30 minutes at 80 °C, placed in sample bags (Wallac), and immersed in scintillation fluid (Ecoscint A; National
  • Assay data analysis Assay data is analyzed using Graph pad prism ver.5 software. A variable sigmoid dose response curve is plotted keeping log concentrations at X-axis and % inhibition at Y-axis.
  • B. bovis (Texas strain) was maintained by using a microaerophilic stationary-phase culture system (Igarashi et al., 1994). Briefly, medium 199 was supplemented with 40 %> bovine serum, 60 U/mL of penicillin G, 60 ⁇ / ⁇ 1 of streptomycin, and 0.15 ⁇ g/mL of amphotericin B (Sigma- Aldrich) was used for the in vitro cultivation of B. bovis.
  • the culture plates which contain the medium, parasites-infected red blood cells (iRBCs), and normal bovine RBCs were incubated at 37 °C in an atmosphere of 5% C0 2 , 5% 0 2 , and 90% N 2 . The medium was replaced every day with fresh one.
  • iRBCs parasites-infected red blood cells
  • normal bovine RBCs normal bovine RBCs
  • B. bovis iRBCs were serially diluted with uninfected-RBCs to adjust the parasitemias ranging from 0.25 to 8%. Uninfected RBCs were used as a control. Thin blood smear was prepared from each dilution and stained with Giemsa to confirm the parasitemia by microscopy. In 96-wells plate, 100 of lysis buffer which contained 2x SYBR Green I was added to 100 ⁇ , of each dilution of the iRBCs in triplicate and incubated in dark place at room temperature for 1 hour.
  • fluorescence values were determined by using a fluorescence plate reader (Fluoroskan Ascent, Thermo Labsystems, USA) at 485 nm and 518 nm excitation and emission wavelengths, respectively. Gain values were set to 100. The fluorescence (after subtracted by the uninfected RBCs) and parasitemia values were plotted and analyzed by linear regression.
  • Antibabesial screening by fluorescence-based method The experiment was conducted by using 96-wells culture plates. Only sixty interior wells were used in this experiment, due to buffer-evaporation during incubation. Two hundred microliters of medium, medium with indicated compound concentrations, and 10% hematocrit with 1% B. bovis iRBCs or uninfected-RBCs as blank control were loaded into each well, in triplicate. The medium, and solvents were replaced every day.
  • Thin blood smears were prepared every day after initiation of the experiment to calculate the parasitemia by microscopy; 100 ⁇ , of culture from each well was separated to a new 96-wells plate and 100 ⁇ of lysis buffer which contained 2x SYBR Green I was added into each well and incubated in dark place at room temperature for 1 hour. Fluorescence values were determined as described above. The fluorescence values (after subtracted by the uninfected RBCs) were plotted against the logarithm of drug concentrations to monitor the rate of inhibition and to calculate IC 50 values by GraphPad Prism ver.5 (GraphPad Software, USA).

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Abstract

Provided herein are methods for treating and preventing malaria and/or Babesiosis, the methods comprising administering an effective amount of Indazole Compounds having the formulas: (I)[Formula (I) should be inserted here] or (II)[Formula (II) should be inserted here] wherein R1, R2, R3 and Y are as defined herein.

Description

SUBSTITUTED INDAZOLE COMPOUNDS, COMPOSITIONS THEREOF, AND METHODS OF TREATMENT THEREWITH
[0001] This application claims the benefit of U.S. provisional application no.
62/087,010, filed December 3, 2014, and U.S. provisional application no. 62/110,643, filed February 2, 2015, the contents of each of which are incorporated by reference herein in their entirety.
[0002] Provided herein are certain indazole compounds, compositions comprising an effective amount of such compounds, methods for treating or preventing malaria and/or babesiosis, comprising administering an effective amount of such indazole compounds to a subject in need thereof, as well as the inventive compounds and compositions for use in such methods.
BACKGROUND
[0003] Malaria is caused by protozoan parasites of the genus Plasmodium
(falciparum, vivax, ovale, malariae and knowlesi) that infect and destroy red blood cells, leading to fever, severe anemia, cerebral malaria and, if untreated, death. Plasmodium falciparum is the dominant species in sub-Saharan Africa, and is responsible for the almost 1 million deaths each year. The disease burden is heaviest in African children under 5 years of age and in pregnant women. Plasmodium vivax causes 25-40% of the global malaria burden, particularly in South and Southeast Asia, and Central and South America. The other two main species that are known to infect humans are Plasmodium ovale and Plasmodium malariae. A fifth species Plasmodium knowlesi, a species that infects primates, has led to human malaria, but the exact mode of transmission remains unclear.
[0004] Malaria is a disease that is prevalent in many developing countries.
Approximately 40% of the world's population lives in countries where the disease is endemic; approximately 247 million people suffer from the disease every year.
[0005] Various medications are presently used for the treatment of malaria.
However, many of these medications are costly and some exhibit significant toxicity and undesirable side effects in humans. The most common drug for treating malaria is chloroquine. Other drugs include quinine, melfloquine, atovaquone, proguanil, doxycycline, artesunate, hydroxychloroquine, halofantrine, pyrimethamine-sulfadoxine, and primaquine.
[0006] However, the widespread emergence of drug resistance of malaria parasites in many tropical countries has compromised many of the current chemotherapies and there is a continued need for new chemotherapeutic approaches. Accordingly, provide herein are novel potent anti-malarial agents and methodology of treating malaria using novel potent anti-malarial agents.
[0007] Human and animal babesiosis is a tick-borne infection that is malaria-like and can result in severe hemolysis and death. The zoonotic disease is caused by hemotropic parasites of the genus Babesia. Babesial parasites, including Babesia microti, Babesia divergens, Babesia bovi, Babesia bigemina, Babesia caballi and Babesia burgdorferi (and those of the closely related genus Theileria, for example T. equi), are some of the most ubiquitous and widespread blood parasites in the world, and
consequently have considerable worldwide economic, medical, human and veterinary impact. There is published evidence that many of the past cases of human babesiosis that were attributed to classic species such as B. divergens or B. microti, may indeed be due to species not yet known to cause such infections in humans. (K.-P. Hunfeld, A.
Hildebrandt, J.S. Gray, International Journal for Parasitology 38 (2008) 1219-1237.) The parasites are intraerythrocytic and are transmitted by ixodid ticks, among others, and are capable of infecting a wide variety of vertebrate hosts which are competent in maintaining the transmission cycle, including animals and humans. (Mary J. Homer, 1 Irma Aguilar- Delfm,2 Sam R. Telford, 111,3 Peter J. Krause,4 and David H. Persing, Clin. Microbiol. Rev. 2000, 13, pp. 451-469; Igarashi Katayama, Nasr El-Bahy, Naoaki Yokoyama and Ikuo, Yokoyama, Takeshi Yoshinari, Daisuke Nagano, Koji, Thillaiampalam Sivakumar, Akio Ueno, Yuki Nakano, Miki, Mahmoud AbouLaila, Tserendorj Munkhjargal,
Antimicrob. Agents Chemother. 2012, 56(6):3196.)
[0008] Various medications are presently used for the treatment of babesiosis in animals and humans. However, many of these medications are costly and some exhibit significant toxicity and undesirable side effects. The most common drugs for treating babesiosis are the same as for treating malaria and include, for example, chloroquine, quinine, atovaquone, doxycycline, pyrimethamine-sulfadoxine, and primaquine. Other drugs tested against babesiosis include staurosporine, purvalanol A, imidocarb, clindamycin, nimbolide, gedunin, ciprofloxacin, diminazene aceturate and epoxomicin.
[0009] The diversity of Babesia species and the high prevalence of ticks could enable the zoonotic pathogens to spread to a worldwide scale. Accordingly, provided herein are novel potent anti-babesia agents and methodology of treating babesiosis using novel potent anti-babesia agents.
[0010] Citation or identification of any reference in this application is not to be construed as an admission that the reference is prior art to the present application.
SUMMARY
[0011] Provided herein are methods for treating or preventing malaria, comprising administering to a subject in need thereof an effective amount of a compound of
Formula (I)
Figure imgf000004_0001
and pharmaceutically acceptable salts, tautomers, isotopologues, and stereoisomers thereof, wherein R1, R2, and Y are as defined herein.
[0012] In one embodiment provided herein are methods for treating malaria by administering a compound of Formula (I). In another embodiment provided herein are methods for preventing malaria by administering a compound of Formula (I). [0013] Also provided are methods for treating or preventing babesiosis, comprising administering to a subject in need thereof an effective amount of a compound of Formula (II)
Figure imgf000005_0001
and pharmaceutically acceptable salts, tautomers, isotopologues, and stereoisomers thereof, wherein R1, R3, and Y are as defined herein.
[0014] In one embodiment provided herein are methods for treating babesiosis by administering a compound of Formula (II). In another embodiment provided herein are methods for preventing babesiosis by administering a compound of Formula (II).
[0015] A compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt, tautomer, isotopologue, or stereoisomer thereof (each being referred to herein as an "Indazole Compound") is useful for treating or preventing malaria and/or babesiosis.
[0016] In one aspect, provided herein are Indazole Compounds of Formula (I), as described in the instant disclosure, such as, for example, in Table 1 and Table 2.
[0017] In another aspect, provided herein are pharmaceutical compositions comprising an effective amount of an Indazole Compound as described herein, and a pharmaceutically acceptable carrier, excipient or vehicle. In some embodiments the pharmaceutical composition is suitable for oral, parenteral, mucosal, transdermal or topical administration.
[0018] In one aspect, provided herein are methods for treating or preventing malaria and/or babesiosis, comprising administering to a subject in need thereof an effective amount of an Indazole Compound as described herein, and a pharmaceutically acceptable carrier, excipient or vehicle. [0019] In one aspect, provided herein are methods for treating or preventing malaria, comprising administering to a subject in need thereof an effective amount of an Indazole Compound as described herein, and a pharmaceutically acceptable carrier, excipient or vehicle.
[0020] In another aspect provided herein are methods for treating or preventing babesiosis, comprising administering to a subject in need thereof an effective amount of an Indazole Compound as described herein, and a pharmaceutically acceptable carrier, excipient or vehicle.
[0021] In a further empodiment provided herein are the inventive compounds and compositions for use in a method as described above.
[0022] The present embodiments can be understood more fully by reference to the detailed description and examples, which are intended to exemplify non-limiting embodiments.
DETAILED DESCRIPTION DEFINITIONS
[0023] An "alkyl" group is a saturated, partially saturated, or unsaturated straight chain or branched non-cyclic hydrocarbon having from 1 to 10 carbon atoms, typically from 1 to 8 carbons or, in some embodiments, from 1 to 6, 1 to 4, or 2 to 6 or carbon atoms. Representative alkyl groups include -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl and -n-hexyl; while saturated branched alkyls include -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, -neopentyl, tert-pentyl, -2-methylpentyl, -3-methylpentyl,
-4-methylpentyl, -2,3-dimethylbutyl and the like. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, allyl, -CH=CH(CH3), -CH=C(CH3)2, -C(CH3)=CH2, -C(CH3)=CH(CH3), -C(CH2CH3)=CH2, -C≡CH, -C≡C(CH3), -C≡C(CH2CH3), -CH2C≡CH, -CH2C≡C(CH3) and -CH2C≡C(CH2CH3), among others. An alkyl group can be substituted or unsubstituted. When the alkyl groups described herein are said to be "substituted," they may be substituted with any substituent or substituents as those found in the exemplary compounds and embodiments disclosed herein, as well as halogen (chloro, iodo, bromo, or fluoro); alkyl; hydroxyl; alkoxy; alkoxyalkyl; amino; alkylamino; carboxy; nitro; cyano; thiol; thioether; imine; imide; amidine; guanidine; enamine; aminocarbonyl; acylamino; phosphonate; phosphine; thiocarbonyl; sulfmyl; sulfone; sulfonamide; ketone; aldehyde; ester; urea; urethane; oxime; hydroxyl amine;
alkoxyamine; aryloxyamine, aralkoxy amine; N-oxide; hydrazine; hydrazide; hydrazone; azide; isocyanate; isothiocyanate; cyanate; thiocyanate; B(OH)2, or
0(alkyl)aminocarbonyl.
[0024] A "cycloalkyl" group is a saturated, or partially saturated cyclic alkyl group of from 3 to 10 carbon atoms having a single cyclic ring or multiple condensed or bridged rings which can be optionally substituted with from 1 to 3 alkyl groups. In some embodiments, the cycloalkyl group has 3 to 8 ring members, whereas in other
embodiments the number of ring carbon atoms ranges from 3 to 5, 3 to 6, or 3 to 7. Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 1-methylcyclopropyl, 2- methylcyclopentyl, 2-methylcyclooctyl, and the like, or multiple or bridged ring structures such as l-bicyclo[l . l . l]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl,
bicyclo[2.2.2]octyl, adamantyl and the like. Examples of unsaturared cycloalkyl groups include cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, hexadienyl, among others. A cycloalkyl group can be substituted or unsubstituted. Such substituted cycloalkyl groups include, by way of example, cyclohexanol and the like.
[0025] An "aryl" group is an aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl). In some embodiments, aryl groups contain 6-14 carbons, and in others from 6 to 12 or 6 to 10 carbon atoms, or even 6 to 8 carbon atoms in the ring portions of the groups. Particular aryls include phenyl, biphenyl, naphthyl and the like. An aryl group can be substituted or unsubstituted. The phrase "aryl groups" also includes groups containing fused rings, such as fused aromatic-aliphatic ring systems (e.g., indanyl,
tetrahydronaphthyl, and the like).
[0026] A "heteroaryl" group is an aryl ring system having one to four heteroatoms as ring atoms in a heteroaromatic ring system, wherein the remainder of the atoms are carbon atoms. In some embodiments, heteroaryl groups contain 3 to 6 ring atoms, and in others from 6 to 9 or even 6 to 10 atoms in the ring portions of the groups. Suitable heteroatoms include oxygen, sulfur and nitrogen. In certain embodiments, the heteroaryl ring system is monocyclic or bicyclic. Non-limiting examples include but are not limited to, groups such as pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, benzisoxazolyl (e.g., benzo[d]isoxazolyl), thiazolyl, pyrolyl, pyridazinyl, pyrimidyl, pyrazinyl, thiophenyl, benzothiophenyl, furanyl, benzofuranyl, indolyl
(e.g., indolyl-2-onyl or isoindolin-l-onyl), azaindolyl (pyrrolopyridyl or lH-pyrrolo[2,3- b]pyridyl), indazolyl, benzimidazolyl (e.g., lH-benzo[d]imidazolyl), imidazopyridyl (e.g., azabenzimidazolyl or lH-imidazo[4,5-b]pyridyl), pyrazolopyridyl, triazolopyridyl, benzotriazolyl (e.g., lH-benzo[d][l,2,3]triazolyl), benzoxazolyl (e.g., benzo[d]oxazolyl), benzothiazolyl, benzothiadiazolyl, isoxazolopyridyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl (e.g., 3,4-dihydroisoquinolin-l(2H)-onyl), tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups.
[0027] A "heterocyclyl" is an aromatic (also referred to as heteroaryl) or non- aromatic cycloalkyl in which one to four of the ring carbon atoms are independently replaced with a heteroatom from the group consisting of O, S and N. In some
embodiments, heterocyclyl groups include 3 to 10 ring members, whereas other such groups have 3 to 5, 3 to 6, or 3 to 8 ring members. Heterocyclyls can also be bonded to other groups at any ring atom (i.e., at any carbon atom or heteroatom of the heterocyclic ring). A heterocycloalkyl group can be substituted or unsubstituted. Heterocyclyl groups encompass unsaturated, partially saturated and saturated ring systems, such as, for example, imidazolyl, imidazolinyl and imidazolidinyl (e.g., imidazolidin-4-one or imidazolidin-2,4-dionyl) groups. The phrase heterocyclyl includes fused ring species, including those comprising fused aromatic and non-aromatic groups, such as, for example, 1-and 2-aminotetraline, benzotriazolyl (e.g., lH-benzo[d][l,2,3]triazolyl), benzimidazolyl (e.g., lH-benzo[d]imidazolyl), 2,3-dihydrobenzo[l,4]dioxinyl, and benzo[l,3]dioxolyl. The phrase also includes bridged polycyclic ring systems containing a heteroatom such as, but not limited to, quinuclidyl. Representative examples of a heterocyclyl group include, but are not limited to, aziridinyl, azetidinyl, azepanyl, oxetanyl, pyrrolidyl, imidazolidinyl (e.g., imidazolidin-4-onyl or imidazolidin-2,4-dionyl), pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, dioxolyl, furanyl, thiophenyl, pyrrolyl, pyrrolinyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, benzisoxazolyl (e.g., benzo[d]isoxazolyl), thiazolyl, thiazolinyl, isothiazolyl, thiadiazolyl, oxadiazolyl, piperidyl, piperazinyl (e.g., piperazin-2-onyl), morpholinyl, thiomorpholinyl, tetrahydropyranyl (e.g., tetrahydro-2H-pyranyl), tetrahydrothiopyranyl, oxathianyl, dioxyl, dithianyl, pyranyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, dihydropyridyl, dihydrodithiinyl, dihydrodithionyl, l,4-dioxaspiro[4.5]decanyl, homopiperazinyl, quinuclidyl, indolyl (e.g., indolyl-2-onyl or isoindolin-l-onyl), indolinyl, isoindolyl, isoindolinyl, azaindolyl (pyrrolopyridyl or lH-pyrrolo[2,3-b]pyridyl), indazolyl, indolizinyl, benzotriazolyl (e.g. lH-benzo[d][l,2,3]triazolyl), benzimidazolyl
(e.g., lH-benzo[d]imidazolyl or lH-benzo[d]imidazol-2(3H)-onyl), benzofuranyl, benzothiophenyl, benzothiazolyl, benzoxadiazolyl, benzoxazinyl, benzodithiinyl, benzoxathiinyl, benzothiazinyl, benzoxazolyl (i.e., benzo[d]oxazolyl), benzothiazolyl, benzothiadiazolyl, benzo[l,3]dioxolyl, pyrazolopyridyl (for example, lH-pyrazolo[3,4- b]pyridyl, lH-pyrazolo[4,3-b]pyridyl), imidazopyridyl (e.g., azabenzimidazolyl or lH-imidazo[4,5-b]pyridyl), triazolopyridyl, isoxazolopyridyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl (e.g., 3,4-dihydroisoquinolin-l(2H)-onyl), quinolizinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, pteridinyl, thianaphthalenyl, dihydrobenzothiazinyl, dihydrobenzofuranyl, dihydroindolyl, dihydrobenzodioxinyl, tetrahydroindolyl, tetrahydroindazolyl, tetrahydrobenzimidazolyl, tetrahydrobenzotriazolyl, tetrahydropyrrolopyridyl, tetrahydropyrazolopyridyl,
tetrahydroimidazopyridyl, tetrahydrotriazolopyridyl, tetrahydropyrimidin-2(lH)-one and tetrahydroquinolinyl groups. Representative non-aromatic heterocyclyl groups do not include fused ring species that comprise a fused aromatic group. Examples of non- aromatic heterocyclyl groups include aziridinyl, azetidinyl, azepanyl, pyrrolidyl, imidazolidinyl (e.g., imidazolidin-4-onyl or imidazolidin-2,4-dionyl), pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, piperidyl, piperazinyl
(e.g., piperazin-2-onyl), morpholinyl, thiomorpholinyl, tetrahydropyranyl (e.g., tetrahydro- 2H-pyranyl), tetrahydrothiopyranyl, oxathianyl, dithianyl, l,4-dioxaspiro[4.5]decanyl, homopiperazinyl, quinuclidyl, or tetrahydropyrimidin-2(lH)-one. Representative substituted heterocyclyl groups may be mono-substituted or substituted more than once, such as, but not limited to, pyridyl or morpholinyl groups, which are 2-, 3-, 4-, 5-, or 6-substituted, or disubstituted with various substituents such as those listed below. [0028] A "cycloalkylalkyl" group is a radical of the formula: -alkyl-cycloalkyl, wherein alkyl and cycloalkyl are as defined above. Substituted cycloalkylalkyl groups may be substituted at the alkyl, the cycloalkyl, or both the alkyl and the cycloalkyl
portions of the group. Representative cycloalkylalkyl groups include but are not limited to methylcyclopropyl, methylcyclobutyl, methylcyclopentyl, methylcyclohexyl,
ethylcyclopropyl, ethylcyclobutyl, ethylcyclopentyl, ethylcyclohexyl, propylcyclopentyl, propylcyclohexyl and the like.
[0029] An "aralkyl" group is a radical of the formula: -alkyl-aryl, wherein alkyl and aryl are defined above. Substituted aralkyl groups may be substituted at the alkyl, the aryl, or both the alkyl and the aryl portions of the group. Representative aralkyl groups include but are not limited to benzyl and phenethyl groups and fused (cycloalkylaryl)alkyl groups such as 4-ethyl-indanyl.
[0030] An "heterocyclylalkyl" group is a radical of the formula: -alkyl- heterocyclyl, wherein alkyl and heterocyclyl are defined above. Substituted
heterocyclylalkyl groups may be substituted at the alkyl, the heterocyclyl, or both the alkyl and the heterocyclyl portions of the group. Representative heterocylylalkyl groups include but are not limited to 4-ethyl-morpholinyl, 4-propylmorpholinyl, furan-2-yl methyl,
furan-3-yl methyl, pyridin-3-yl methyl, tetrahydrofuran-2-yl ethyl, and indol-2-yl propyl.
[0031] A "halogen" is chloro, iodo, bromo, or fluoro.
[0032] A "hydroxyalkyl" group is an alkyl group as described above substituted with one or more hydroxy groups.
[0033] An "alkoxy" group is -O-(alkyl), wherein alkyl is defined above.
[0034] An "alkoxyalkyl" group is -(alkyl)-O-(alkyl), wherein alkyl is defined above.
[0035] An "amine" group is a radical of the formula: -NH2.
[0036] A "hydroxyl amine" group is a radical of the formula: -N(R#)OH or -NHOH, wherein R# is a substituted or unsubstituted alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein.
[0037] An "alkoxyamine" group is a radical of the formula: -N(R#)0-alkyl or
-NHO-alkyl, wherein R# is as defined above.
[0038] An "aryloxyamine" group is a radical of the formula: -N(R#)0-aryl or -NHO-aryl, wherein R# is as defined above. [0039] An "aralkoxyamine" group is a radical of the formula: -N(R )0-aralkyl or
-NHO-aralkyl, wherein R# is as defined above.
[0040] An "alkylamine" group is a radical of the formula: -NH-alkyl or -N(alkyl)2, wherein each alkyl is independently as defined above.
[0041] An "aminocarbonyl" group is a radical of the formula: -C(=0)N(R#)2,
-C(=0)NH(R#) or -C(=0)NH2, wherein each R# is as defined above.
[0042] An "acylamino" group is a radical of the formula: -NHC(=0)(R#) or
-N(alkyl)C(=0)(R#), wherein each alkyl and R# are independently as defined above.
[0043] An "0(alkyl)aminocarbonyl" group is a radical of the formula:
-0(alkyl)C(=0)N(R#)2, -0(alkyl)C(=0)NH(R#) or -0(alkyl)C(=0)NH2, wherein each R# is independently as defined above.
[0044] An "N-oxide" group is a radical of the formula: -N -O".
[0045] A "carboxy" group is a radical of the formula: -C(=0)OH.
[0046] A "ketone" group is a radical of the formula: -C(=0)(R#), wherein R# is as defined above.
[0047] An "aldehyde" group is a radical of the formula: -CH(=0).
[0048] An "ester" group is a radical of the formula: -C(=0)0(R#) or -OC(=0)(R#), wherein R# is as defined above.
[0049] A "urea" group is a radical of the formula: -N(alkyl)C(=0)N(R#)2,
-N(alkyl)C(=0)NH(R#), -N(alkyl)C(=0)NH2, -NHC(=0)N(R#)2, -NHC(=0)NH(R#), or
-NHC(=0)NH2 #, wherein each alkyl and R# are independently as defined above.
[0050] An "imine" group is a radical of the formula: -N=C(R#)2 or -C(R#)=N(R#), wherein each R# is independently as defined above.
[0051] An "imide" group is a radical of the formula: -C(=0)N(R#)C(=0)(R#) or
-N((C=0)(R#))2, wherein each R# is independently as defined above.
[0052] A "urethane" group is a radical of the formula: -OC(=0)N(R#)2, -OC(=0)NH(R#),
-N(R#)C(=0)0(R#), or -NHC(=0)0(R#), wherein each R# is independently as defined above.
[0053] An "amidine" group is a radical of the formula: -C(=N(R#))N(R#)2,
-C(=N(R#))NH(R#), -C(=N(R#))NH2, -C(=NH)N(R#)2, -C(=NH)NH(R#), -C(=NH)NH2,
-N=C(R#)N(R#)2, -N=C(R#)NH(R#), -N=C(R#)NH2, -N(R#)C(R#)=N(R#), -NHC(R#)=N(R#), -N(R#)C(R#)=NH, or -NHC(R#)=NH, wherein each R# is independently as defined above. [0054] A "guanidine" group is a radical of the formula: -N(Rff)C(=N(Rff))N(Rff)2,
-NHC(=N(R#))N(R#)2, -N(R#)C(=NH)N(R#)2, -N(R#)C(=N(R#))NH(R#), -N(R#)C(=N(R#))NH2, -NHC(=NH)N(R#)2, -NHC(=N(R#))NH(R#), -NHC(=N(R#))NH2, -NHC(=NH)NH(R#), -NHC(=NH)NH2, -N=C(N(R#)2)2, -N=C(NH(R#))2, or -N=C(NH2)2, wherein each R# is independently as defined above.
[0055] A "enamine" group is a radical of the formula: -N(R#)C(R#)=C(R#)2,
-NHC(R#)=C(R#)2, -C(N(R#)2)=C(R#)2, -C(NH(R#))=C(R#)2, -C(NH2)=C(R#)2,
-C(R#)=C(R#)(N(R#)2), -C(R#)=C(R#)(NH(R#)) or -C(R#)=C(R#)(NH2), wherein each R# is independently as defined above.
[0056] An "oxime" group is a radical of the formula: -C(=NO(R#))(R#), -C(=NOH)(R#),
-CH(=NO(R#)), or -CH(=NOH), wherein each R# is independently as defined above.
[0057] A "hydrazide" group is a radical of the formula: -C(=0)N(R#)N(R#)2,
-C(=0)NHN(R#)2, -C(=0)N(R#)NH(R#), -C(=0)N(R#)NH2, -C(=0)NHNH(R#)2, or
-C(=0)NHNH2, wherein each R# is independently as defined above.
[0058] A "hydrazine" group is a radical of the formula: -N(R#)N(R#)2, -NHN(R#)2,
-N(R#)NH(R#), -N(R#)NH2, -NHNH(R#)2, or -NHNH2, wherein each R# is independently as defined above.
[0059] A "hydrazone" group is a radical of the formula: -C(=N-N(R#)2)(R#)2,
-C(=N-NH(R#))(R#)2, -C(=N-NH2)(R#)2, -N(R#)(N=C(R#)2), or -NH(N=C(R#)2), wherein each R# is independently as defined above.
[0060] An "azide" group is a radical of the formula: -N3.
[0061] An "isocyanate" group is a radical of the formula: -N=C=0.
[0062] An "isothiocyanate" group is a radical of the formula: -N=C=S.
[0063] A "cyanate" group is a radical of the formula: -OCN.
[0064] A "thiocyanate" group is a radical of the formula: -SCN.
[0065] A "thioether" group is a radical of the formula; -S(R#), wherein R# is as defined above.
[0066] A "thiocarbonyl" group is a radical of the formula: -C(=S)(R#), wherein R# is as defined above.
[0067] A "sulfmyl" group is a radical of the formula: -S(=0)(R#), wherein R# is as defined above. [0068] A "sulfone" group is a radical of the formula: -S(=0)2(R ), wherein R is as defined above.
[0069] A "sulfonylamino" group is a radical of the formula: -NHS02(R#) or
-N(alkyl)S02(R#), wherein each alkyl and R# are defined above.
[0070] A "sulfonamide" group is a radical of the formula: -S(=0)2N(R#)2, or
-S(=0)2NH(R#), or -S(=0)2NH2, wherein each R# is independently as defined above.
[0071] A "phosphonate" group is a radical of the formula: -P(=0)(0(R#))2, -P(=0)(OH)2,
-OP(=0)(0(R#))(R#), or -OP(=0)(OH)(R#), wherein each R# is independently as defined above.
[0072] A "phosphine" group is a radical of the formula: -P(R#)2, wherein each R# is independently as defined above.
[0073] When the groups described herein, with the exception of alkyl group, are said to be "substituted," they may be substituted with any appropriate substituent or substituents.
Illustrative examples of substituents are those found in the exemplary compounds and embodiments disclosed herein, as well as halogen (chloro, iodo, bromo, or fluoro); alkyl;
hydroxyl; alkoxy; alkoxyalkyl; amino; alkylamino; carboxy; nitro; cyano; thiol; thioether; imine; imide; amidine; guanidine; enamine; aminocarbonyl; acylamino; phosphonate; phosphine;
thiocarbonyl; sulfinyl; sulfone; sulfonamide; ketone; aldehyde; ester; urea; urethane; oxime; hydroxyl amine; alkoxyamine; aryloxyamine, aralkoxyamine; N-oxide; hydrazine; hydrazide; hydrazone; azide; isocyanate; isothiocyanate; cyanate; thiocyanate; oxygen (=0); B(OH)2, 0(alkyl)aminocarbonyl; cycloalkyl, which may be monocyclic or fused or non-fused polycyclic (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), or a heterocyclyl, which may be monocyclic or fused or non-fused polycyclic (e.g. , pyrrolidyl, piperidyl, piperazinyl,
morpholinyl, or thiazinyl); monocyclic or fused or non- fused polycyclic aryl or heteroaryl (e.g. , phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridinyl, quinolinyl, isoquinolinyl, acridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzothiophenyl, or benzofuranyl) aryloxy; aralkyloxy; heterocyclyloxy; and heterocyclyl alkoxy.
[0074] As used herein, the term "Indazole Compound" refers to compounds of
Formula (I) and Formula (II) as well as to further embodiments provided herein. In one embodiment, an "Indazole Compound" is a compound set forth in Table 1 or Table 2. The term "Indazole Compound" includes pharmaceutically acceptable salts, tautomers, isotopologues, and stereoisomers of the compounds provided herein.
[0075] As used herein, the term "pharmaceutically acceptable salt(s)" refers to a salt prepared from a pharmaceutically acceptable non-toxic acid or base including an inorganic acid and base and an organic acid and base. Suitable pharmaceutically acceptable base addition salts of the compounds of Formula (I) or Formula (II) include, but are not limited to metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from lysine,
Ν,Ν'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methyl-glucamine) and procaine. Suitable non-toxic acids include, but are not limited to, inorganic and organic acids such as acetic, alginic, anthranilic,
benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, formic, fumaric, furoic, galacturonic, gluconic, glucuronic, glutamic, glycolic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phenylacetic, phosphoric, propionic, salicylic, stearic, succinic, sulfanilic, sulfuric, tartaric acid, and p-toluenesulfonic acid. Specific non-toxic acids include hydrochloric, hydrobromic, maleic, phosphoric, sulfuric, and methanesulfonic acids.
Examples of specific salts thus include hydrochloride and mesylate salts. Others are well- known in the art, see for example, Remington 's Pharmaceutical Sciences, 18th eds., Mack Publishing, Easton PA (1990) or Remington: The Science and Practice of Pharmacy, 19th eds., Mack Publishing, Easton PA (1995).
[0076] As used herein and unless otherwise indicated, the term "stereoisomer" or
"stereomerically pure" means one stereoisomer of an Indazole Compound that is substantially free of other stereoisomers of that compound. For example, a stereomerically pure compound having one chiral center will be substantially free of the opposite enantiomer of the compound. A stereomerically pure compound having two chiral centers will be substantially free of other diastereomers of the compound. A typical
stereomerically pure compound comprises greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, greater than about 90%> by weight of one stereoisomer of the compound and less than about 10%> by weight of the other stereoisomers of the compound, greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of the other stereoisomers of the compound, or greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of the other stereoisomers of the compound. The Indazole Compounds can have chiral centers and can occur as racemates, individual enantiomers or diastereomers, and mixtures thereof. All such isomeric forms are included within the embodiments disclosed herein, including mixtures thereof.
[0077] The use of stereomerically pure forms of such Indazole Compounds, as well as the use of mixtures of those forms, are encompassed by the embodiments disclosed herein. For example, mixtures comprising equal or unequal amounts of the enantiomers of a particular Indazole Compound may be used in methods and compositions disclosed herein. These isomers may be asymmetrically synthesized or resolved using standard techniques such as chiral columns or chiral resolving agents. See, e.g., Jacques, J., et ah, Enantiomers, Racemates and Resolutions (Wiley-Interscience, New York, 1981); Wilen, S. H., et al, Tetrahedron 33:2725 (1977); Eliel, E. L., Stereochemistry of Carbon
Compounds (McGraw-Hill, NY, 1962); and Wilen, S. H., Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN, 1972).
[0078] It should also be noted the Indazole Compounds can include E and Z isomers, or a mixture thereof, and cis and trans isomers or a mixture thereof. In certain embodiments, the Indazole Compounds are isolated as either the E or Z isomer. In other embodiments, the Indazole Compounds are a mixture of the E and Z isomers.
[0079] "Tautomers" refers to isomeric forms of a compound that are in equilibrium with each other. The concentrations of the isomeric forms will depend on the environment the compound is found in and may be different depending upon, for example, whether the compound is a solid or is in an organic or aqueous solution. For example, in aqueous solution, pyrazoles may exhibit the following isomeric forms, which are referred to as tautomers of each other:
Figure imgf000015_0001
[0080] As readily understood by one skilled in the art, a wide variety of functional groups and other stuctures may exhibit tautomerism and all tautomers of compounds of Formula (I) are within the scope of the present invention.
[0081] It should also be noted the Indazole Compounds can contain unnatural proportions of atomic isotopes at one or more of the atoms. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium (3H), iodine-125 (125I), sulfur-35 (35S), or carbon-14 (14C), or may be isotopically enriched, such as with deuterium (2H), carbon-13 (13C), or nitrogen-15 (15N). As used herein, an
"isotopologue" is an isotopically enriched compound. The term "isotopically enriched" refers to an atom having an isotopic composition other than the natural isotopic composition of that atom. "Isotopically enriched" may also refer to a compound containing at least one atom having an isotopic composition other than the natural isotopic composition of that atom. The term "isotopic composition" refers to the amount of each isotope present for a given atom. Radiolabeled and isotopically encriched compounds are useful as therapeutic agents, e.g., cancer and inflammation therapeutic agents, research reagents, e.g., binding assay reagents, and diagnostic agents, e.g., in vivo imaging agents. All isotopic variations of the Indazole Compounds as described herein, whether radioactive or not, are intended to be encompassed within the scope of the embodiments provided herein. In some embodiments, there are provided isotopologues of the Indazole Compounds, for example, the isotopologues are deuterium, carbon-13, or nitrogen-15 enriched Indazole Compounds.
[0082] "Treatment" and "Treating" as used herein, mean an alleviation, in whole or in part, of a disorder, disease or condition, or one or more of the symptoms associated with a disorder, disease, or condition, or slowing or halting of further progression or worsening of those symptoms, or alleviating or eradicating the cause(s) of the disorder, disease, or condition itself. In one embodiment, the disorder is malaria and/or babesiosis.
[0083] "Preventing" as used herein, means a method of delaying and/or precluding the onset, recurrence or spread, in whole or in part, of a disorder, disease or condition; barring a subject from acquiring a disorder, disease, or condition; or reducing a subject's risk of acquiring a disorder, disease, or condition. In one embodiment, the disorder is malaria and/or babesiosis, as described herein, or symptoms thereof. In one embodiment, preventing includes prophylaxis.
[0084] The term "effective amount" in connection with an Indazole Compound means an amount capable of treating or preventing a disorder, disease or condition, or symptoms thereof, disclosed herein. In one embodiment, the disorder is malaria and/or babesiosis. The term "effective amount" includes "prophylaxis-effective amount" as well as "treatment-effective amount".
[0085] The term "prophylaxis-effective amount" refers to a concentration of compound of this invention that is effective in inhibiting, decreasing the likelihood of the disease by malarial or babesia parasites, or preventing malarial or babesia infection by malarial or babesia parasites, when administered before infection, i.e. before, during and/or after the exposure period to malarial or babesia parasites.
[0086] The term "prophylaxis" includes causal prophylaxis, i.e. antimalarial or antibabesia activity comprising preventing the pre-erythrocytic development of the parasite, suppressive prophylaxis, i.e. antimalarial or antibabesia activity comprising suppressing the development of the blood stage infection, and, for malaria, terminal prophylaxis, i.e. antimalarial activity comprising suppressing the development of intrahepatic stage infection. This term includes primary prophylaxis (i.e. preventing initial infection) where the antimalarial or antibabesia compound is administered before, during and/or after the exposure period to malarial or babesia parasites and terminal prophylaxis (i.e. to prevent relapses or onset of clinical symptoms of malaria or babesia) when the antimalarial or antibabesia compound is administered towards the end of and/or after the exposure period to malarial or babesia parasites but before the clinical symptoms.
Typically, against P. falciparum infections, suppressive prophylaxis is used whereas against P. vivax or a combination of P. falciparum and P. vivax, terminal prophylaxis is used. Because babesia parasites have no exo-erythrocytic stages, suppressive prophylaxis is used for treatment of babesiosis infections.
[0087] Likewise, the term "treatment-effective amount" refers to a concentration of compound that is effective in treating malaria or babesia infection, e.g. leads to a reduction in parasite numbers in blood following microscopic examination when administered after infection has occurred. [0088] The term "subject" includes an animal, including, but not limited to, an animal such a cow, monkey, horse, sheep, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbit or guinea pig, in one embodiment a mammal, in another embodiment a human. In one embodiment, a subject is a human having or at risk for having malaria and/or
babesiosis, or a symptom thereof.
INDAZOLE COMPOUNDS
[0089] Provided herein are compounds having the following Formula (I):
Figure imgf000018_0001
and pharmaceutically acceptable salts, tautomers, stereoisomers,
enantiomers, and isotopologues thereof,
wherein:
Figure imgf000018_0003
R2 is
Figure imgf000018_0002
or substituted or unsubstituted 5-membered nitrogen- containing heteroaryl, wherein the heteroaryl is optionally fused to a second ring;
Y is selected from:
a. pyridyl, optionally substituted with -NRC(=0)(Ci_4 alkyl), or
-NRC(=0)(C3_6 cycloalkyl);
b. quinolyl; or
c. phenyl, substituted with one or more substituents selected from halogen, -CN, -(Ci-3 alkyl) optionally fluorinated, -S02(Ci_3 alkyl), -(Ci_3 alkyl)NR(C3_6 cycloalkyl),
-(Ci-3 alkyl)heterocyclyl, -0(Ci_3 alkyl)heterocyclyl, -C(=0)NRR', -NRC(=0)R",
-NRS02(Ci_3 alkyl), or substituted or unsubstituted 5-membered heteroaryl; wherein
R is -H or substituted or unsubstituted (C1-3 alkyl),
R' is substituted or unsubstituted (C1-4 alkyl), substituted or unsubstituted
(C3-6 cycloalkyl), substituted or unsubstituted aryl, or substituted or unsubstituted aralkyl;
R" is substituted or unsubstituted (C3-6 cycloalkyl), substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and
R# is -H or -OH.
[0090] In one embodiment, provided herein are compounds of Formula (I), wherein R1 is
-H. In other embodiments, provided herein are compounds of Formula (I), wherein R2 is -C(=0)NH2 or -CONHOH. In some embodiments, R2 is substituted or unsubstituted imidazolyl, oxazolyl, triazolyl, tetrazolyl, triazolinonyl, or benzimidazolyl. In some such embodiments, R2 is substituted with substituted or unsubstituted (C1-4 alkyl), substituted or unsubstituted
(C3-6 cycloalkyl), substituted or unsubstituted (C0-4 alkyl)(heterocyclyl), or substituted or unsubstituted aryl. In other such embodiments, R2 is substituted with (C1-4 alkyl) substituted with one or more -F, -OH, or -NR2; (C1-4 cycloalkyl); (C0-4 alkyl)pyrrolidinyl;
(Co-4 alkyl)pyrrolidinonyl; (C0-4 alkyl)morpholinyl; (C0-4 alkyl)piperidyl; pyridyl; or phenyl, substituted with halogen. In still other such embodiments, R2 is substituted with -CH2CH3, -CH(CH3)2, -C(CH3)3, -CH2CH(CH3)2, -CH2C(CH3)3, -CH(CH3)CH2CH3, -C(CH3)2CH2CH3; -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3,
-CH(OH)CH3, -CH2N(CH3)2; cyclopropyl, cyclobutyl, cyclopentyl; pyrrolidinyl;
-CH2(pyrrolidinyl); pyrrolidinonyl; -CH2(pyrrolidinonyl); morpholinyl; -CH2(morpholinyl); piperidyl; -CH2(piperidyl); pyridyl; or chlorophenyl. For example, R2 is substituted with -CH(CH3)2, -C(CH3)3, -CH2CH(CH3)2, -C(CH3)2CH2CH3, -CF3, -CH2CH2F, -CH2CF3,
-CH2CH2CF3, -CH(OH)CH3, -CH2N(CH3)2; cyclobutyl; pyrrolidinyl; -CH2(pyrrolidinyl);
-CH2(pyrrolidinonyl); -CH2(morpholinyl); piperidyl; -CH2(piperidyl); pyridyl; or chlorophenyl. In some such embodiments, R2 is triazolyl. In others, R2 is oxazolyl. For example, R2 is oxazolyl, substituted with -CH2CF3, -CH2N(CH3)2, pyrrolidinyl, or -CH2(morpholinyl).
[0091] Also provided are compounds of Formula (I), wherein Y is phenyl, substituted with one or more substituents selected from -F, -CI, -CN, -CF3, -S02CH3,
-CH2NH(C3_4 cycloalkyl), -CH2(non-aromatic heterocyclyl), -0(Ci_2 alkyl)(non-aromatic heterocyclyl), -C(=0)NHR', -C(=0)N(CH3)R', -NHC(=0)R", -NRS02CH3, or substituted or unsubstituted imidazolyl, pyrazolyl, or triazolyl. In some embodiments, Y is phenyl substituted with one or more substituents selected from -F, -CI, -CN, -CF3, -S02CH3, -C(=0)NHR', or -NRS02CH3. In some other embodiments, Y is phenyl, substituted with one or more substituents selected from -F, -CI, -CN, -CF3, -S02CH3, -CH2NH(C3_4 cycloalkyl), -CH2(non-aromatic heterocyclyl), -0(Ci_2 alkyl)(non-aromatic heterocyclyl), -C(=0)NH(substituted or unsubstituted (Ci_4 alkyl)), -C(=0)NH(substituted or unsubstituted (C3_6 cycloalkyl)),
-C(=0)N(CH3)(substituted or unsubstituted (CM alkyl)), -C(=0)N(CH3)(substituted or unsubstituted (C3_6 cycloalkyl)), -NHC(=0)(substituted or unsubstituted (C3_6 cycloalkyl)), -NHS02CH3, or substituted or unsubstituted imidazolyl, pyrazolyl, or triazolyl. In yet other embodiments, Y is phenyl, substituted with one or more substituents selected from -F, -CI, -CN, -CF3, -S02CH3, -CH2NH(cyclopropyl), -CH2(pyrrolidinyl), -OCH2CH2(morpholinyl),
-C(=0)NH2, -C(=0)NHCH3, -C(=0)NHCH2CH3, -C(=0)NHCH2CH2CH3, -C(=0)N(CH3)2, -C(=0)NHCH2CH2OCH3, -C(=0)NH(cyclopropyl), -C(=0)NH(cyclobutyl),
-C(=0)NH(cyclopentyl), -C(=0)NH(hydroxycyclohexyl), -C(=0)N(CH3)(cyclopropyl),
-C(=0)NH(phenyl), -C(=0)NHCH2(fluorophenyl), -NHC(=0)(cyclopropyl),
-NHC(=0)(pyridyl), -NHC(=0)(methylphenyl), -NHS02CH3, imidazolyl, pyrazolyl, or triazolyl. For example, Y is phenyl substituted with one or more substituents selected from -F, -CI, -CN, -CF3, -S02CH3, -C(=0)NHCH3, -C(=0)NH(cyclopropyl), -C(=0)N(CH3)(cyclopropyl), or -NHS02CH3.
[0092] Also provided are compounds of Formula (I), wherein Y is
Figure imgf000020_0001
wherein:
Ra is -H, -F, -CI, -CN, -CF3, -S02CH3, -CH2NH(cyclopropyl),
-CH2(pyrrolidinyl), -OCH2CH2(morpholinyl), -C(=0)NH2, -C(=0)NHCH3,
-C(=0)NHCH2CH3, -C(=0)NHCH2CH2CH3, -C(=0)N(CH3)2, -C(=0)NH(cyclopropyl), -C(=0)NH(cyclobutyl), -C(=0)NH(cyclopentyl), -C(=0)NH(hydroxycyclohexyl), -C(=0)N(CH3)(cyclopropyl), -C(=0)NH(phenyl), -C(=0)NHCH2(fluorophenyl), -NHC(=0)(cyclopropyl), -NHC(=0)(pyridyl), -NHC(=0)(methylphenyl), -NHS02CH3, imidazolyl, pyrazolyl, or triazolyl;
Rb is -H, -F, -CI, -CN, -CF3, -S02CH3, -CH2NH(cyclopropyl),
-C(=0)NHCH3, -C(=0)NHCH2CH3, -C(=0)NHCH2CH2OCH3, -OCH2CH2(morpholinyl), -NHC(=0)(pyridyl); and
Rc is -H, or -F;
with the proviso that Ra, Rb and Rc are not simultaneously -H.
[0093] In some such embodiments, Ra is -H, -F, -CI, -CN, -S02CH3,
-CH2NH(cyclopropyl), -C(=0)NHCH3, -C(=0)NHCH2CH2CH3, -C(=0)NH(cyclopropyl), -C(=0)NH(cyclobutyl), -C(=0)NH(hydroxycyclohexyl), -C(=0)N(CH3)(cyclopropyl),
-C(=0)NH(phenyl), -NHC(=0)(pyridyl), or -NHS02CH3. In others, Rb is -H, -F, -CI, -CN, or -C(=0)NHCH3. In still others, Rc is -H or -F.
[0094] Representative compounds of Formula (I) are set forth in Table 1 and
Table 2.
[0095] Indazole Compounds set forth in Table 1 and Table 2 were tested in a
Plasmodium falciparum [3H]-hypoxanthine incorporation asexual blood-stage assay
described herein and were found to have activity therein. In one embodiment, the Indazole Compound is a compound of Formula (I) as described herein, wherein the compound at a concentration of 2 μΜ inhibits malaria parasite growth by at least about 50%.
[0096] Also provided herein are compounds having Formula (II):
Figure imgf000021_0001
and pharmaceutically acceptable salts, tautomers, stereoisomers, enantiomers, and isotopologues thereof, wherein: R1 is -H or -CH3;
R3 is -C(=0)NRRx, or substituted or unsubstituted 5-membered nitrogen- containing heteroaryl, wherein the heteroaryl is optionally fused to a second ring;
Y is selected from:
a. pyridyl, optionally substituted with -NRC(=0)(Ci_4 alkyl), or
Figure imgf000022_0001
cycloalkyl);
b. quinolyl; or
c. phenyl, substituted with one or more substituents selected from halogen, -CN, -(C1-3 alkyl) optionally fluorinated, -S02(Ci_3 alkyl),
-(C1-3 alkyl)NR(C3_6 cycloalkyl), -(C1-3 alkyl)heterocyclyl, -0(Ci_3 alkyl)heterocyclyl, -C(=0)NRR', -NRC(=0)R", -NRS02(Ci_3 alkyl), or substituted or unsubstituted
5-membered heteroaryl;
wherein
R is -H or substituted or unsubstituted (C1-3 alkyl),
R' is substituted or unsubstituted (C1-4 alkyl), substituted or unsubstituted (C3_6 cycloalkyl), substituted or unsubstituted aryl, or substituted or unsubstituted aralkyl;
R" is substituted or unsubstituted (C3_6 cycloalkyl), substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and
Rx is -H or -(Ci_4 alkyl)(non-aromatic heterocyclyl).
[0097] In some embodiments, of compounds of Formula (II), R1 is -H. In other embodiments of compounds of Formula (II), R3 is -C(=0)NH(Ci_2 alkyl)(5-membered non-aromatic heterocyclyl). In some such embodiments, R3 is
-C(=0)NH(Ci_2 alkyl)(pyrrolidinyl). In others, R3 is -C(=0)NHCH2CH2(pyrrolidinyl). In some embodiments of compounds of Formula (II), R3 is substituted or unsubstituted imidazolyl, oxazolyl, triazolyl, tetrazolyl, triazolinonyl, or benzimidazolyl. In some such embodiments, R3 is substituted with substituted or unsubstituted (C1-4 alkyl), substituted or unsubstituted (C3_6 cycloalkyl), substituted or unsubstituted (C0-4 alkyl)(heterocyclyl), or substituted or unsubstituted aryl. In some other such embodiments, R3 is substituted with (Ci_4 alkyl) substituted with one or more -F, -OH, or -NR2; (C1-4 cycloalkyl);
(Co-4 alkyl)pyrrolidinyl; (C0-4 alkyl)pyrrolidinonyl; (C0-4 alkyl)morpholinyl;
(Co-4 alkyl)piperidyl; pyridyl; or phenyl, substituted with halogen. For example, R3 is substituted with -CH2CH3, -CH(CH3)2, -C(CH3)3, -CH2CH(CH3)2, -CH2C(CH3)3,
-CH(CH3)CH2CH3, -C(CH3)2CH2CH3; -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3,
-CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -CH(OH)CH3, -CH2N(CH3)2; cyclopropyl, cyclobutyl, cyclopentyl; pyrrolidinyl; -CH2(pyrrolidinyl); pyrrolidinonyl;
-CH2(pyrrolidinonyl); morpholinyl; -CH2(morpholinyl); piperidyl; -CH2(piperidyl);
pyridyl; or chlorophenyl. In another embodiment, R3 is substituted with -CH(CH3)2, -C(CH3)3, -CH2CH(CH3)2, -C(CH3)2CH2CH3, -CF3, -CH2CH2F, -CH2CF3, -CH2CH2CF3, -CH(OH)CH3, -CH2N(CH3)2; cyclobutyl; pyrrolidinyl; -CH2(pyrrolidinyl);
-CH2(pyrrolidinonyl); -CH2(morpholinyl); piperidyl; -CH2(piperidyl); pyridyl; or chlorophenyl. For example, R3 is substituted with -CH2CF3, or -CH2(pyrrolidinyl). In another example, R3 is substituted with pyrrolidinyl, or -CH2(pyrrolidinyl). In another example, R3 is substituted with -CH2CH2F, -CH2CF3, -CH2CH2CF3, or piperidyl. In one embodiment, R3 is substituted with -CH2CH(CH3)2, -CH2N(CH3)2, pyrrolidinyl, or -CH2(pyrrolidinyl). In one embodiment, R3 is substituted with -CH2CH(CH3)2,
-CH2CH2F, -CH2CF3, -CH2CH2CF3, -CH2N(CH3)2, pyrrolidinyl, -CH2(pyrrolidinyl), or piperidyl. In some such embodiments, R3 is triazolyl. In other embodiments of compounds of Formula (II), Y is phenyl, substituted with one or more substituents selected from -F, -CI, -CN, -CF3, -S02CH3, -CH2NH(C3_4 cycloalkyl), -CH2(non-aromatic heterocyclyl), -0(Ci_2 alkyl)(non-aromatic heterocyclyl), -C(=0)NHR', -C(=0)N(CH3)R', -NHC(=0)R", -NRS02CH3, or substituted or unsubstituted imidazolyl, pyrazolyl, or triazolyl. In some such embodiments, Y is phenyl substituted with one or more
substituents selected from -F, -CI, -CN, -CF3, -S02CH3, -C(=0)NHR', or -NRS02CH3. In yet other embodiments, Y is phenyl, substituted with one or more substituents selected from -F, -CI, -CN, -CF3, -S02CH3, -CH2NH(C3_4 cycloalkyl), -CH2(non-aromatic heterocyclyl), -0(Ci_2 alkyl)(non-aromatic heterocyclyl), -C(=0)NH(substituted or unsubstituted (Ci_4 alkyl)), -C(=0)NH(substituted or unsubstituted (C3_6 cycloalkyl)), C(=0)N(CH3)(substituted or unsubstituted (Ci_4 alkyl)), -C(=0)N(CH3)(substituted or unsubstituted (C3_6 cycloalkyl)), -NHC(=0)(substituted or unsubstituted (C3_6 cycloalkyl)), -NHS02CH3, or substituted or unsubstituted imidazolyl, pyrazolyl, or triazolyl. For example, Y is phenyl substituted with one or more substituents selected from -F, -CI, -CN, -CF3, -S02CH3, -C(=0)NHR', or -NHS02CH3. In yet other embodiments, Y is phenyl, substituted with one or more substituents selected from -F, -CI, -CN, -CF3, -SO2CH3, -CH2NH(cyclopropyl), -CH2(pyrrolidinyl), -OCH2CH2(morpholinyl), -C(=0)NH2,
-C(=0)NHCH3, -C(=0)NHCH2CH3, -C(=0)NHCH2CH2CH3, -C(=0)N(CH3)2,
-C(=0)NHCH2CH2OCH3, -C(=0)NH(cyclopropyl), -C(=0)NH(cyclobutyl),
-C(=0)NH(cyclopentyl), -C(=0)NH(hydroxycyclohexyl), -C(=0)N(CH3)(cyclopropyl),
-C(=0)NH(phenyl), -C(=0)NHCH2(fluorophenyl), -NHC(=0)(cyclopropyl),
-NHC(=0)(pyridyl), -NHC(=0)(methylphenyl), -NHS02CH3, imidazolyl, pyrazolyl, or triazolyl. For example, Y is phenyl, substituted with one or more substituents selected from -F, -CI, -CN, -C(=0)NHCH3, or -C(=0)NH(cyclopentyl). In another example, Y is phenyl, substituted with one or more substituents selected from -F, -CN, or
-C(=0)NHCH3. In yet another example, Y is phenyl, substituted with one or more
substituents selected from -CN, -CH2(pyrrolidinyl), -C(=0)NHCH2CH3,
-C(=0)NHCH2CH2CH3, -C(=0)NH(cyclopropyl), -C(=0)NH(cyclobutyl),
-C(=0)NH(hydroxycyclohexyl), -C(=0)NH(phenyl),
Figure imgf000024_0001
or
-NHC(=0)(pyridyl). In one embodiment, Y is phenyl, substituted with one or more
substituents selected from -F, -CN, -C(=0)NHCH3, -C(=0)NH(cyclopropyl) or
-C(=0)NH(cyclopentyl). In one embodiment, Y is phenyl, substituted with one or more substituents selected from -F, -CN, -CH2(pyrrolidinyl), -C(=0)NHCH3,
-C(=0)NHCH2CH3, -C(=0)NHCH2CH2CH3, -C(=0)NH(cyclopropyl),
-C(=0)NH(cyclobutyl), -C(=0)NH(cyclopentyl), -C(=0)NH(hydroxycyclohexyl),
-C(=0)NH(phenyl), -C(=0)NHCH2(fluorophenyl), or -NHC(=0)(pyridyl).
[0098] In some embodiments of compounds of Formula (II), Y is
Figure imgf000024_0002
wherein:
Ra is -H, -F, -CI, -CN, -CF3, -S02CH3, -CH2NH(cyclopropyl), -CH2(pyrrolidinyl), -OCH2CH2(morpholinyl), -C(=0)NH2, -C(=0)NHCH3, -C(=0)NHCH2CH3, -C(=0)NHCH2CH2CH3, -C(=0)N(CH3)2, -C(=0)NH(cyclopropyl), -C(=0)NH(cyclobutyl), -C(=0)NH(cyclopentyl), -C(=0)NH(hydroxycyclohexyl), -C(=0)N(CH3)(cyclopropyl), -C(=0)NH(phenyl), -C(=0)NHCH2(fluorophenyl), -NHC(=0)(cyclopropyl),
-NHC(=0)(pyridyl), -NHC(=0)(methylphenyl), -NHS02CH3, imidazolyl, pyrazolyl, or triazolyl;
Rb is -H, -F, -CI, -CN, -CF3, -S02CH3, -CH2NH(cyclopropyl), -C(=0)NHCH3, -C(=0)NHCH2CH3, -C(=0)NHCH2CH2OCH3, -OCH2CH2(morpholinyl), -NHC(=0)(pyridyl); and
Rc is -H, or -F;
with the proviso that Ra, Rb and Rc are not simultaneously -H.
[0099] In some such embodiments of compounds of Formula (II), Ra is -H, -F, -CI,
-CN, -S02CH3, -CH2NH(cyclopropyl), -C(=0)NHCH3, -C(=0)NHCH2CH2CH3,
-C(=0)NH(cyclopropyl), -C(=0)NH(cyclobutyl), -C(=0)NH(cyclopentyl),
-C(=0)NH(hydroxycyclohexyl), -C(=0)N(CH3)(cyclopropyl), -C(=0)NH(phenyl),
-NHC(=0)(pyridyl), or -NHS02CH3. For example, Ra is -H, -F, -CN, -C(=0)NHCH3, or -C(=0)NH(cyclopentyl). In another example, Ra is -H, -CN, or -C(=0)NHCH3. In yet another example, Ra is -H, -CN, -CH2(pyrrolidinyl), -C(=0)NHCH2CH3, -C(=0)NHCH2CH2CH3, -C(=0)NH(cyclopropyl), -C(=0)NH(cyclobutyl), -C(=0)NH(hydroxycyclohexyl),
-C(=0)NH(phenyl), -C(=0)NHCH2(fluorophenyl), -NHC(=0)(pyridyl), or triazolyl. In another example, Ra is -H, -CN, -C(=0)NH(cyclopropyl) or -C(=0)NH(cyclopentyl). In yet another example, Ra is -H, -CN, -CH2(pyrrolidinyl), -C(=0)NHCH2CH3, -C(=0)NHCH2CH2CH3, -C(=0)NH(cyclopropyl), -C(=0)NH(cyclobutyl), or -C(=0)NH(cyclopentyl),
-C(=0)NH(hydroxycyclohexyl), -C(=0)NH(phenyl), -C(=0)NHCH2(fluorophenyl),
-NHC(=0)(pyridyl), or triazolyl. In other embodiments, Rb is -H, -F, -CI, or -CN. In another embodiment, Rb is -H, or -F. In still other embodiments, Rc is -H.
[00100] Select Indazole Compounds were tested or will be tested in B. bovis, and/or T. equi strains of Babesia in growth inhibition assays described herein and were found to have or will have activity therein. In one embodiment, the Indazole Compound is a compound of Formula (II) as described herein, wherein the compound at a concentration of 2 μΜ inhibits parasite growth by at least about 50%. Representative compounds of Formula (II) are
3-(5-(lH-l,2,4-triazol-3-yl)-lH-indazol-3-yl)-N-cyclopentylbenzamide; N-methyl-3-(5-(5-(pyrrolidin- 1 -ylmethyl)- 1H- 1 ,2,4-triazol-3-yl)- lH-indazol-3- yl)benzamide;
3-(4-fluorophenyl)-l-methyl-5-(3-(pyrrolidin-l -ylmethyl)- lH-l,2,4-triazol-5-yl)-lH- indazole;
3-(l-methyl-5-(3-(pyrrolidin-l -ylmethyl)- lH-l,2,4-triazol-5-yl)-lH-indazol-3- yl)benzonitrile;
3- (4-chlorophenyl)-N-(2-(pyrrolidin-l-yl)ethyl)-lH-indazole-5-carboxamide;
4- (5-(5-(2,2,2-trifluoroethyl)-lH-l,2,4-triazol-3-yl)-lH-indazol-3-yl)benzonitrile; and 3-(5-(lH-imidazol-2-yl)-lH-indazol-3-yl)-N-methylbenzamide; and pharmaceutically acceptable salts, tautomers, stereoisomers, enantiomers, and isotopologues thereof.
[00101] In one embodiment, the compound of Formula (II) is selected from 3-(5-(lH-l,2,4-triazol-3-yl)-lH-indazol-3-yl)-N-cyclopentylbenzamide;
N-methyl-3-(5-(5-(pyrrolidin- 1 -ylmethyl)- 1H- 1 ,2,4-triazol-3-yl)- lH-indazol-3- yl)benzamide;
3 -(4-fluorophenyl)- 1 -methyl-5 -(3 -(pyrrolidin- 1 -ylmethyl)- 1 H- 1 ,2,4-triazol-5 -yl)- 1 H- indazole;
3-(l-methyl-5-(3-(pyrrolidin-l -ylmethyl)- lH-l,2,4-triazol-5-yl)-lH-indazol-3- yl)benzonitrile;
3- (4-chlorophenyl)-N-(2-(pyrrolidin-l-yl)ethyl)-lH-indazole-5-carboxamide;
4- (5-(5-(2,2,2-trifluoroethyl)-lH-l,2,4-triazol-3-yl)-lH-indazol-3-yl)benzonitrile; 3-(5-(lH-imidazol-2-yl)-lH-indazol-3-yl)-N-methylbenzamide;
N-methyl-3-(5-(3-(pyrrolidin-2-yl)-lH-l,2,4-triazol-5-yl)-lH-indazol-3-yl)benzamide; N-cyclopropyl-3-(5-(3-((dimethylamino)methyl)-lH-l,2,4-triazol-5-yl)-lH-indazol-3- yl)benzamide;
N-cyclopropyl-3-(5-(5-isobutyl-lH-l,2,4-triazol-3-yl)-lH-indazol-3-yl)benzamide; and pharmaceutically acceptable salts, tautomers, stereoisomers, enantiomers, and isotopologues thereof.
[00102] In one embodiment, the compound of Formula (II) is selected from
3-(5-(lH-l,2,4-triazol-3-yl)-lH-indazol-3-yl)-N-cyclopentylbenzamide;
N-methyl-3 -(5 -(5 -(pyrrolidin- 1 -ylmethyl)- 1H- 1 ,2,4-triazol-3-yl)- lH-indazol-3- yl)benzamide; 3 -(4-fluorophenyl)- 1 -methyl-5 -(3 -(pyrrolidin- 1 -ylmethyl)- 1 H- 1 ,2,4-triazol-5 -yl)-lH- indazole;
3-(l-methyl-5-(3-(pyrrolidin-l -ylmethyl)- lH-l,2,4-triazol-5-yl)-lH-indazol-3- yl)benzonitrile;
3- (4-chlorophenyl)-N-(2-(pyrrolidin-l-yl)ethyl)-lH-indazole-5-carboxamide;
4- (5-(5-(2,2,2-trifluoroethyl)-lH-l,2,4-triazol-3-yl)-lH-indazol-3-yl)benzonitrile;
3 -(5 -(lH-imidazol-2-yl)-l H-indazol-3 -yl)-N-methylbenzamide;
N-methyl-3-(5-(3-(pyrrolidin-2-yl)-lH-l,2,4-triazol-5-yl)-lH-indazol-3-yl)benzamide;
N-cyclopropyl-3-(5-(3-((dimethylamino)methyl)-lH-l,2,4-triazol-5-yl)-lH-indazol-3- yl)benzamide;
N-cyclopropyl-3 -(5 -(5 -isobutyl- 1 H- 1 ,2,4-triazol-3 -yl)- 1 H-indazol-3 -yl)benzamide;
3-(3-(lH-pyrazol-3-yl)phenyl)-5-(lH-l,2,4-triazol-3-yl)-lH-indazole;
3-(5-(lH-l,2,4-triazol-3-yl)-lH-indazol-3-yl)-N-propylbenzamide;
3 -(5 -( 1 H- 1 ,2,4-triazol-3 -yl)- 1 H-indazol-3 -yl)-N-(( 1 r,4r)-4-hydroxycyclohexyl)benzamide;
N-(3-(5-(lH-l,2,4-triazol-3-yl)-lH-indazol-3-yl)phenyl)nicotinamide;
3 -(5 -( 1 H- 1 ,2,4-triazol-3 -yl)- 1 H-indazol-3 -yl)-N-cyclopropylbenzamide;
3-(5-(3-((dimethylamino)methyl)-lH-l,2,4-triazol-5-yl)-lH-indazol-3-yl)-N-(4- fluorophenyl)benzamide;
3-(5-(lH-l,2,4-triazol-3-yl)-lH-indazol-3-yl)-N-cyclobutylbenzamide;
N-phenyl-3 -(5 -(5 -(pyrrolidin- 1 -ylmethyl)- 1H- 1 ,2,4-triazol-3-yl)- 1 H-indazol-3 -yl)benzamide;
3 -(5 -(5 -(pyrrolidin- 1 -ylmethyl)- 1H- 1 ,2,4-triazol-3-yl)- 1 H-indazol-3 -yl)quino line;
3- (5-(lH-l,2,4-triazol-3-yl)-lH-indazol-3-yl)-N-ethylbenzamide;
N-cyclopropyl-3-(5-(3-(pyrrolidin-2-yl)-lH-l,2,4-triazol-5-yl)-lH-indazol-3-yl)benzamide; N-cyclopropyl-3-(5-(5-(2,2,2-trifluoroethyl)-lH-l,2,4-triazol-3-yl)-lH-indazol-3-yl)benzamide; N-cyclopropyl-3 -(5 -(5 -(3 ,3 ,3 -trifluoropropyl)- 1 H- 1 ,2,4-triazol-3 -yl)- 1 H-indazol-3 - yl)benzamide;
N-cyclopropyl-3-(5-(5-(2-fluoroethyl)-lH-l,2,4-triazol-3-yl)-lH-indazol-3-yl)benzamide; N-cyclopropyl-3-(5-(5-(pyrrolidin-3-yl)-lH-l,2,4-triazol-3-yl)-lH-indazol-3-yl)benzamide;
4- (5-(5-(piperidin-4-yl)-lH-l,2,4-triazol-3-yl)-lH-indazol-3-yl)benzonitrile;
3-(3-(pyrrolidin-l-ylmethyl)phenyl)-5-(5-(pyrrolidin-2-yl)-lH-l,2,4-triazol-3-yl)-lH-indazole; and pharmaceutically acceptable salts, tautomers, stereoisomers, enantiomers, and isotopologues thereof.
[00103] In one embodiment, the compound of Formula (II) is selected from
3-(5-(lH-l,2,4-triazol-3-yl)-lH-indazol-3-yl)-N-cyclopentylbenzamide;
N-methyl-3-(5-(5-(pyrrolidin- 1 -ylmethyl)- 1H- 1 ,2,4-triazol-3-yl)- 1 H-indazol-3 - yl)benzamide;
3 -(4-fluorophenyl)- 1 -methyl-5 -(3 -(pyrrolidin- 1 -ylmethyl)- 1 H- 1 ,2,4-triazol-5 -yl)- 1 H- indazole;
3-(l-methyl-5-(3-(pyrrolidin-l -ylmethyl)- lH-l,2,4-triazol-5-yl)-lH-indazol-3- yl)benzonitrile;
N-methyl-3-(5-(3-(pyrrolidin-2-yl)-lH-l,2,4-triazol-5-yl)-lH-indazol-3-yl)benzamide; N-cyclopropyl-3-(5-(3-((dimethylamino)methyl)-lH-l,2,4-triazol-5-yl)-lH-indazol-3- yl)benzamide;
N-cyclopropyl-3-(5-(5-isobutyl-lH-l,2,4-triazol-3-yl)-lH-indazol-3-yl)benzamide; and pharmaceutically acceptable salts, tautomers, stereoisomers, enantiomers, and
isotopologues thereof.
[00104] In one embodiment, the compound of Formula (II) is selected from
3-(5-(lH-l,2,4-triazol-3-yl)-lH-indazol-3-yl)-N-cyclopentylbenzamide;
N-methyl-3 -(5 -(5 -(pyrrolidin- 1 -ylmethyl)- 1H- 1 ,2,4-triazol-3-yl)- 1 H-indazol-3 - yl)benzamide;
3 -(4-fluorophenyl)- 1 -methyl-5 -(3 -(pyrrolidin- 1 -ylmethyl)- 1 H- 1 ,2,4-triazol-5 -yl)- 1 H- indazole;
3-(l-methyl-5-(3-(pyrrolidin-l -ylmethyl)- lH-l,2,4-triazol-5-yl)-lH-indazol-3- yl)benzonitrile;
N-methyl-3-(5-(3-(pyrrolidin-2-yl)-lH-l,2,4-triazol-5-yl)-lH-indazol-3-yl)benzamide; N-cyclopropyl-3-(5-(3-((dimethylamino)methyl)-lH-l,2,4-triazol-5-yl)-lH-indazol-3- yl)benzamide;
N-cyclopropyl-3 -(5 -(5 -isobutyl- 1 H- 1 ,2,4-triazol-3 -yl)- 1 H-indazol-3 -yl)benzamide;
3-(3-(lH-pyrazol-3-yl)phenyl)-5-(lH-l,2,4-triazol-3-yl)-lH-indazole;
3-(5-(lH-l,2,4-triazol-3-yl)-lH-indazol-3-yl)-N-propylbenzamide;
3 -(5 -( 1 H- 1 ,2,4-triazol-3 -yl)- 1 H-indazol-3 -yl)-N-(( 1 r,4r)-4-hydroxycyclohexyl)benzamide; N-(3-(5-(lH-l,2,4-triazol-3-yl)-lH-indazol-3-yl)phenyl)nicotinamide;
3 -(5 -( 1 H- 1 ,2,4-triazol-3 -yl)- 1 H-indazol-3 -yl)-N-cyclopropylbenzamide;
3-(5-(3-((dimethylamino)methyl)-lH-l,2,4-triazol-5-yl)-lH-indazol-3-yl)-N-(4- fluorophenyl)benzamide;
3-(5-(lH-l,2,4-triazol-3-yl)-lH-indazol-3-yl)-N-cyclobutylbenzamide;
N-phenyl-3-(5-(5-(pyrrolidin- 1 -ylmethyl)- 1H- 1 ,2,4-triazol-3-yl)- 1 H-indazol-3 -yl)benzamide; 3-(5-(5-(pyrrolidin- 1 -ylmethyl)- 1H- 1 ,2,4-triazol-3-yl)- 1 H-indazol-3 -yl)quino line;
3- (5-(lH-l,2,4-triazol-3-yl)-lH-indazol-3-yl)-N-ethylbenzamide;
N-cyclopropyl-3-(5-(3-(pyrrolidin-2-yl)-lH-l,2,4-triazol-5-yl)-lH-indazol-3-yl)benzamide; N-cyclopropyl-3-(5-(5-(2,2,2-trifluoroethyl)-lH-l,2,4-triazol-3-yl)-lH-indazol-3-yl)benzamide; N-cyclopropyl-3 -(5 -(5 -(3 ,3 ,3 -trifluoropropyl)- 1 H- 1 ,2,4-triazol-3 -yl)- 1 H-indazol-3 - yl)benzamide;
N-cyclopropyl-3-(5-(5-(2-fluoroethyl)-lH-l,2,4-triazol-3-yl)-lH-indazol-3-yl)benzamide;
N-cyclopropyl-3-(5-(5-(pyrrolidin-3-yl)-lH-l,2,4-triazol-3-yl)-lH-indazol-3-yl)benzamide;
4- (5-(5-(piperidin-4-yl)-lH-l,2,4-triazol-3-yl)-lH-indazol-3-yl)benzonitrile;
3-(3-(pyrrolidin-l-ylmethyl)phenyl)-5-(5-(pyrrolidin-2-yl)-lH-l,2,4-triazol-3-yl)-lH-indazole; and pharmaceutically acceptable salts, tautomers, stereoisomers, enantiomers, and
isotopologues thereof.
[00105] In one embodiment, the compound of formula (II) is selected from
N-methyl-3-(5-(5-(pyrrolidin-l -ylmethyl)- lH-l,2,4-triazol-3-yl)-lH-indazol-3-yl)benzamide; 3-(4-fluorophenyl)-l-methyl-5-(3-(pyrrolidin-l -ylmethyl)- lH-l,2,4-triazol-5-yl)-lH-indazole; 3-(l-methyl-5-(3-(pyrrolidin-l-ylmethyl)-lH-l,2,4-triazol-5-yl)-lH-indazol-3-yl)benzonitrile;
3- (4-chlorophenyl)-N-(2-(pyrrolidin-l-yl)ethyl)-lH-indazole-5-carboxamide;
4- (5-(5-(2,2,2-trifluoroethyl)-lH-l,2,4-triazol-3-yl)-lH-indazol-3-yl)benzonitrile;
3 -(5 -(lH-imidazol-2-yl)-l H-indazol-3 -yl)-N-methylbenzamide;
N-methyl-3-(5-(3-(pyrrolidin-2-yl)-lH-l,2,4-triazol-5-yl)-lH-indazol-3-yl)benzamide;
and pharmaceutically acceptable salts, tautomers, stereoisomers, enantiomers, and isotopologues thereof.
[00106] In one embodiment, the compound of formula (II) is selected from
N-methyl-3-(5-(5-(pyrrolidin-l -ylmethyl)- lH-l,2,4-triazol-3-yl)-lH-indazol-3-yl)benzamide; 3-(4-fluorophenyl)-l-methyl-5-(3-(pyrrolidin-l -ylmethyl)- lH-l,2,4-triazol-5-yl)-lH-indazole; 3 -( 1 -methyl-5 -(3 -(pyrrolidin- 1 -ylm
3- (4-chlorophenyl)-N-(2-(pyrrolidin-l-yl)ethyl)-lH-indazole-5-carboxamide;
4- (5-(5-(2,2,2-trifluoroethyl)-lH-l,2,4-triazol-3-yl)-lH-indazol-3-yl)benzonitrile;
3-(5-(lH-imidazol-2-yl)-lH-indazol-3-yl)-N-methylbenzamide;
N-methyl-3-(5-(3-(pyrrolidin-2-yl)-lH-l,2,4-triazol-5-yl)-lH-indazol-3-yl)benzamide;
3- (5-(lH-l,2,4-triazol-3-yl)-lH-indazol-3-yl)-N-ethylbenzamide;
N-cyclopropyl-3-(5-(3-(pyrrolidin-2-yl)-lH-l,2,4-triazol-5-yl)-lH-indazol-3-yl)benzamide; N-cyclopropyl-3-(5-(5-(2,2,2-trifluoroethyl)-lH-l,2,4-triazol-3-yl)-lH-indazol-3-yl)benzamide; N-cyclopropyl-3 -(5 -(5 -(3 ,3 ,3 -trifluoropropyl)- 1 H- 1 ,2,4-triazol-3 -yl)- 1 H-indazol-3 - yl)benzamide;
N-cyclopropyl-3-(5-(5-(2-fluoroethyl)-lH-l,2,4-triazol-3-yl)-lH-indazol-3-yl)benzamide;
N-cyclopropyl-3-(5-(5-(pyrrolidin-3-yl)-lH-l,2,4-triazol-3-yl)-lH-indazol-3-yl)benzamide;
4- (5-(5-(piperidin-4-yl)-lH-l,2,4-triazol-3-yl)-lH-indazol-3-yl)benzonitrile;
3-(3-(pyrrolidin-l-ylmethyl)phenyl)-5-(5-(pyrrolidin-2-yl)-lH-l,2,4-triazol-3-yl)-lH-m^ and pharmaceutically acceptable salts, tautomers, stereoisomers, enantiomers, and isotopologues thereof.
[00107] In yet another embodiment, the compound of formula (II) is
N-methyl-3-(5-(5-(pyrrolidin-l-ylmethyl)-lH-l,2,4-triazol-3-yl)-lH-indazol-3-yl)benzamide;
3-(4-fluorophenyl)-l-methyl-5-(3-(pyrrolidin-l-ylmethyl)-lH-l,2,4-triazol-5-yl)-lH-indazole;
3-(l-methyl-5-(3-(pyrrolidin-l-ylmethyl)-lH-l,2,4-triazol-5-yl)-lH-indazol-3-yl)benzonitrile;
N-methyl-3-(5-(3-(pyrrolidin-2-yl)-lH-l,2,4-triazol-5-yl)-lH-indazol-3-yl)benzamide;
and pharmaceutically acceptable salts, tautomers, stereoisomers, enantiomers, and
isotopologues thereof.
[00108] In yet another embodiment, the compound of formula (II) is
N-methyl-3-(5-(5-(pyrrolidin-l-ylmethyl)-lH-l,2,4-triazol-3-yl)-lH-indazol-3-yl)benzamide;
3-(4-fluorophenyl)-l-methyl-5-(3-(pyrrolidin-l-ylmethyl)-lH-l,2,4-triazol-5-yl)-lH-indazole;
3-(l-methyl-5-(3-(pyrrolidin-l-ylmethyl)-lH-l,2,4-triazol-5-yl)-lH-indazol-3-yl)benzonitrile;
N-methyl-3-(5-(3-(pyrrolidin-2-yl)-lH-l,2,4-triazol-5-yl)-lH-indazol-3-yl)benzamide;
3-(5-(lH-l,2,4-triazol-3-yl)-lH-indazol-3-yl)-N-ethylbenzamide;
N-cyclopropyl-3-(5-(3-(pyrrolidin-2-yl)-lH-l,2,4-triazol-5-yl)-lH-indazol-3-yl)benzamide; N-cyclopropyl-3-(5-(5-(2,2,2-trifluoroethyl)-lH-l,2,4-triazol-3-yl)-lH-indazol-3-yl)benzamide; N-cyclopropyl-3 -(5 -(5 -(3 ,3 ,3 -trifluoropropyl)- 1 H- 1 ,2,4-triazol-3 -yl)- 1 H-indazol-3 - yl)benzamide;
N-cyclopropyl-3-(5-(5-(2-fluoroethyl)-lH-l,2,4-triazol-3-yl)-lH-indazol-3-yl)benzamide; N-cyclopropyl-3-(5-(5-(pyrrolidin-3-yl)-lH-l,2,4-triazol-3-yl)-lH-indazol-3-yl)benzamide; 4-(5-(5-(piperidin-4-yl)-lH-l,2,4-triazol-3-yl)-lH-indazol-3-yl)benzonitrile;
3-(3-(pyrrolidin-l-ylmethyl)phenyl)-5-(5-(pyrrolidin-2-yl)-lH-l,2,4-triazol-3-yl)-lH-m^ and pharmaceutically acceptable salts, tautomers, stereoisomers, enantiomers, and isotopologues thereof.
METHODS FOR MAKING INDAZOLE COMPOUNDS
[00109] The Indazole Compounds can be made using conventional organic syntheses and commercially available starting materials. By way of example and not limitation, Indazole Compounds of Formula (I) and Formula (II) can be prepared as described in International Patent Application Publication No. WO 02/10137, 2002; United States patent application publication No. US 2004/0127536; United States patent application publication No. US 2005/0107386; and United States patent application publication No. US 2005/0009876, or as outlined in Scheme 1, shown below, as well as in the examples set forth herein. It should be noted that one skilled in the art would know how to modify the procedures set forth in the illustrative schemes and examples to arrive at the desired roducts.
Figure imgf000031_0001
Scheme 1
[00110] As shown in Scheme 1, compounds of Formula (I), can be prepared starting with the PN protected and appropriately subsitituted 5-cyanoindazole (synthesis described in applications listed above) wherein Hal is halogen (for example CI, Br or I), and PN is a protecting group (for example SEM, Boc, Trityl, Tosyl, Benzyl, 4-methoxybenzyl,
2,4-dimethoxybenzyl, or THP). The R2 group can be installed by transformation of the nitrile to a carboxylate derivative (including carboxylic acid, ester or amide) or suitable cyclization precursor (including, for example, acid, ester, imidate, amide) and then further functionalization. For example, the nitrile starting material can be hydrolyzed by treatment with a base, such as sodium hydroxide, in a solvent, such as DMSO, with heating (60-100 °C). For example, compounds wherein R2 is -C(=0)NRR# (wherein R is -H or substituted or unsubstituted (C1-3 alkyl), and R# is -H or -OH) can be obtained from the intermediate carboxylate via a coupling reaction using a coupling agent, such as, for example, HATU, with the appropriate amine HNRR# in a solvent, such as DMF, in the presence of a base, such as DIEA. Cyclization can be achieved to afford compounds wherein R2 is substituted or unsubstituted 5-membered nitrogen-containing heteroaryl (wherein the heteroaryl is optionally fused to a second ring), for example, first by conversion of the nitrile to a carbimidate (for example, by treatment of the starting material with an acid, such as for example, HC1 gas, in a solvent, such as for example ethanol, followed by addition of the appropriate hydrazide in the presence of a base, such as TEA, in a solvent, such as methanol, at elevated temperatue (for example, 60-85 °C). Other nitrile transformations and cyclizations are described herein. A catalyzed coupling reaction to install Y can be achieved by treatment with the appropriate boronic acid or borate ester Y-BH(OR )2 (wherein R+ is H, lower alkyl, or together with the boron atom and the atoms to which they are attached, form a cyclic boronate), in the presence of a palladium catalyst (such as, for example, tetrakis(triphenylphosphine) palladium(O) or bis(triphenylphosphine)palladium(II) dichloride), in a solvent (such as 1 ,4 dioxane/water) and a base (such as sodium carbonate, potassium carbonate, or potassium phosphate), at elevated temperature (for example, 60 °C-100 °C). Deprotection (for example, when PN is THP, by treatment with an acid such TFA or HC1, in a solvent such as DCM, THF, or 1,4 dioxane) provides compounds of Formula (I), wherein R1 is -H. Indazole N-alkylation (for instance with methyl iodide in THF) provides compounds of Formula (I), wherein R1 is -CH3. Indazole compounds of Formula (II) can similarly be prepared.
METHODS OF USE
[00111] The Indazole Compounds have utility as pharmaceuticals to treat, prevent or improve conditions in animals or humans. Accordingly, provided herein are uses of the Indazole Compounds, including treatment of malaria and/or babesiosis. The methods provided herein comprise the administration of an effective amount of one or more
Indazole Compound(s) to a subject in need thereof.
[00112] In one aspect provided herein are compounds for treating or preventing malaria and/or babesiosis, comprising administering to a subject in need thereof an
effective amount of an Indazole Compound, as described herein.
[00113] In another aspect provided herein are methods for treating or preventing malaria and/or babesiosis, comprising administering to a subject in need thereof an
effective amount of an Indazole Compound, as described herein.
[00114] In one embodiment, provided herein are methods for treating or preventing malaria, comprising administering to a subject in need thereof an effective amound of a compound of Formula (I) as described herein, or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, or isotopologue thereof. In one embodiment, the compound of Formula (I) is selected from Table 1. In another embodiment, the compound of Formula (I) is selected from Table 2. In some embodiments, the malaria is caused by Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, Plasmodium knowlesi or Plasmodium malariae. In one embodiment, the malaria is caused by Plasmodium falciparum. In some embodiments, the methods additionally comprise administering an effective amount of one or more of chloroquine, quinine, quinidine, melfloquine, atovaquone, proguanil, doxycycline, artesunate, artemether, artemisinin, lumefantrine, amodiaquine, hydroxychloroquine, halofantrine, pyrimethamine, sulfadoxine, or primaquine.
[00115] In one embodiment, provided herein are methods for treating or preventing
Babesiosis, comprising administering to a subject in need thereof an effective amound of a compound of Formula (II) as described herein, or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, or isotopologue thereof. In some embodiments, the Babesiosis is caused by Babesia microti, Babesia divergens, Babesia bovis, Babesia bigemina, Babesia caballi, Babesia burgdorferi, or Theileria equi. In one embodiment, the Babesiosis is caused by Babesia bovis, Babesia bigemina, or Theileria equi. In some embodiments, the methods additionally comprise administering an effective amount of one or more of chloroquine, quinine, atovaquone, azithromycin, doxycycline, pyrimethamine-sulfadoxine, primaquine, staurosporine, purvalanol A, imidocarb, clindamycin, nimbolide, gedunin, ciprofloxacin, diminazene aceturate or epoxomicin. In one embodiment, the methods additionally comprise administering an effective amount of one or more of quinine, atovaquone, azithromycin, or clindamycin. In one embodiment, the compound of Formula (II) is selected from
N-methyl-3-(5-(5-(pyrrolidin- 1 -ylmethyl)- 1H- 1 ,2,4-triazol-3-yl)- lH-indazol-3- yl)benzamide;
3 -(4-fluorophenyl)- 1 -methyl-5 -(3 -(pyrrolidin- 1 -ylmethyl)- 1 H- 1 ,2,4-triazol-5 -yl)- 1 H- indazole;
3-(l-methyl-5-(3-(pyrrolidin-l -ylmethyl)- lH-l,2,4-triazol-5-yl)-lH-indazol-3- yl)benzonitrile;
3- (4-chlorophenyl)-N-(2-(pyrrolidin-l-yl)ethyl)-lH-indazole-5-carboxamide;
4- (5-(5-(2,2,2-trifluoroethyl)-lH-l,2,4-triazol-3-yl)-lH-indazol-3-yl)benzonitrile;
3-(5-(lH-imidazol-2-yl)-lH-indazol-3-yl)-N-methylbenzamide;
and pharmaceutically acceptable salts, tautomers, stereoisomers, enantiomers, and isotopologues thereof.
[00116] In one embodiment, the compound of Formula (II) is selected from
3-(5-(lH-l,2,4-triazol-3-yl)-lH-indazol-3-yl)-N-cyclopentylbenzamide;
N-methyl-3 -(5 -(5 -(pyrrolidin- 1 -ylmethyl)- 1H- 1 ,2,4-triazol-3-yl)- lH-indazol-3- yl)benzamide;
3 -(4-fluorophenyl)- 1 -methyl-5 -(3 -(pyrrolidin- 1 -ylmethyl)- 1 H- 1 ,2,4-triazol-5 -yl)- 1 H- indazole;
3-(l-methyl-5-(3-(pyrrolidin-l -ylmethyl)- lH-l,2,4-triazol-5-yl)-lH-indazol-3- yl)benzonitrile;
3- (4-chlorophenyl)-N-(2-(pyrrolidin-l-yl)ethyl)-lH-indazole-5-carboxamide;
4- (5-(5-(2,2,2-trifluoroethyl)-lH-l,2,4-triazol-3-yl)-lH-indazol-3-yl)benzonitrile;
3-(5-(lH-imidazol-2-yl)-lH-indazol-3-yl)-N-methylbenzamide;
N-methyl-3-(5-(3-(pyrrolidin-2-yl)-lH-l,2,4-triazol-5-yl)-lH-indazol-3-yl)benzamide;
N-cyclopropyl-3-(5-(3-((dimethylamino)methyl)-lH-l,2,4-triazol-5-yl)-lH-indazol-3- yl)benzamide;
N-cyclopropyl-3-(5-(5-isobutyl-lH-l,2,4-triazol-3-yl)-lH-indazol-3-yl)benzamide; and pharmaceutically acceptable salts, tautomers, stereoisomers, enantiomers, and
isotopologues thereof. [00117] In one embodiment, the compound of Formula (II) is selected from
3-(5-(lH-l,2,4-triazol-3-yl)-lH-indazol-3-yl)-N-cyclopentylbenzamide;
N-methyl-3-(5-(5-(pyrrolidin- 1 -ylmethyl)- 1H- 1 ,2,4-triazol-3-yl)- 1 H-indazol-3 - yl)benzamide;
3 -(4-fluorophenyl)- 1 -methyl-5 -(3 -(pyrrolidin- 1 -ylmethyl)- 1 H- 1 ,2,4-triazol-5 -yl)- 1 H- indazole;
3-(l-methyl-5-(3-(pyrrolidin-l -ylmethyl)- lH-l,2,4-triazol-5-yl)-lH-indazol-3- yl)benzonitrile;
N-methyl-3-(5-(3-(pyrrolidin-2-yl)-lH-l,2,4-triazol-5-yl)-lH-indazol-3-yl)benzamide; N-cyclopropyl-3-(5-(3-((dimethylamino)methyl)-lH-l,2,4-triazol-5-yl)-lH-indazol-3- yl)benzamide; and
N-cyclopropyl-3 -(5 -(5 -isobutyl- 1 H- 1 ,2,4-triazol-3 -yl)- 1 H-indazol-3 -yl)benzamide;
and pharmaceutically acceptable salts, tautomers, stereoisomers, enantiomers, and isotopologues thereof.
[00118] In one embodiment, the compound of Formula (II) is selected from
3-(5-(lH-l,2,4-triazol-3-yl)-lH-indazol-3-yl)-N-cyclopentylbenzamide;
N-methyl-3 -(5 -(5 -(pyrrolidin- 1 -ylmethyl)- 1H- 1 ,2,4-triazol-3-yl)- 1 H-indazol-3 - yl)benzamide;
3 -(4-fluorophenyl)- 1 -methyl-5 -(3 -(pyrrolidin- 1 -ylmethyl)- 1 H- 1 ,2,4-triazol-5 -yl)- 1 H- indazole;
3-(l-methyl-5-(3-(pyrrolidin-l -ylmethyl)- lH-l,2,4-triazol-5-yl)-lH-indazol-3- yl)benzonitrile;
N-methyl-3-(5-(3-(pyrrolidin-2-yl)-lH-l,2,4-triazol-5-yl)-lH-indazol-3-yl)benzamide; N-cyclopropyl-3-(5-(3-((dimethylamino)methyl)-lH-l,2,4-triazol-5-yl)-lH-indazol-3- yl)benzamide;
N-cyclopropyl-3 -(5 -(5 -isobutyl- 1 H- 1 ,2,4-triazol-3 -yl)- 1 H-indazol-3 -yl)benzamide;
3-(3-(lH-pyrazol-3-yl)phenyl)-5-(lH-l,2,4-triazol-3-yl)-lH-indazole;
3-(5-(lH-l,2,4-triazol-3-yl)-lH-indazol-3-yl)-N-propylbenzamide;
3 -(5 -( 1 H- 1 ,2,4-triazol-3 -yl)- 1 H-indazol-3 -yl)-N-(( 1 r,4r)-4-hydroxycyclohexyl)benzamide;
N-(3-(5-(lH-l,2,4-triazol-3-yl)-lH-indazol-3-yl)phenyl)nicotinamide;
3 -(5 -( 1 H- 1 ,2,4-triazol-3 -yl)- 1 H-indazol-3 -yl)-N-cyclopropylbenzamide; 3-(5-(3-((dimethylamino)methyl)-lH-l,2,4-triazol-5-yl)-lH-indazol-3-yl)-N-(4- fluorophenyl)benzamide;
3-(5-(lH-l,2,4-triazol-3-yl)-lH-indazol-3-yl)-N-cyclobutylbenzamide;
N-phenyl-3-(5-(5-(pyrrolidin- 1 -ylmethyl)- 1H- 1 ,2,4-triazol-3-yl)- 1 H-indazol-3 -yl)benzamide; 3-(5-(5-(pyrrolidin- 1 -ylmethyl)- 1H- 1 ,2,4-triazol-3-yl)- 1 H-indazol-3 -yl)quino line;
3- (5-(lH-l,2,4-triazol-3-yl)-lH-indazol-3-yl)-N-ethylbenzamide;
N-cyclopropyl-3-(5-(3-(pyrrolidin-2-yl)-lH-l,2,4-triazol-5-yl)-lH-indazol-3-yl)benzamide; N-cyclopropyl-3-(5-(5-(2,2,2-trifluoroethyl)-lH-l,2,4-triazol-3-yl)-lH-indazol-3-yl)benzamide; N-cyclopropyl-3 -(5 -(5 -(3 ,3 ,3 -trifluoropropyl)- 1 H- 1 ,2,4-triazol-3 -yl)- 1 H-indazol-3 - yl)benzamide;
N-cyclopropyl-3-(5-(5-(2-fluoroethyl)-lH-l,2,4-triazol-3-yl)-lH-indazol-3-yl)benzamide; N-cyclopropyl-3-(5-(5-(pyrrolidin-3-yl)-lH-l,2,4-triazol-3-yl)-lH-indazol-3-yl)benzamide;
4- (5-(5-(piperidin-4-yl)-lH-l,2,4-triazol-3-yl)-lH-indazol-3-yl)benzonitrile;
3-(3-(pyrrolidin-l-ylmethyl)phenyl)-5-(5-(pyrrolidin-2-yl)-lH-l,2,4-triazol-3-yl)-lH-indazole; and pharmaceutically acceptable salts, tautomers, stereoisomers, enantiomers, and
isotopologues thereof.
[00119] In one embodiment, the compound of Formula (II) is selected from
3-(5-(lH-l,2,4-triazol-3-yl)-lH-indazol-3-yl)-N-cyclopentylbenzamide;
N-methyl-3-(5-(5-(pyrrolidin- 1 -ylmethyl)- 1H- 1 ,2,4-triazol-3-yl)- 1 H-indazol-3 - yl)benzamide;
3 -(4-fluorophenyl)- 1 -methyl-5 -(3 -(pyrrolidin- 1 -ylmethyl)- 1 H- 1 ,2,4-triazol-5 -yl)- 1 H- indazole;
3-(l-methyl-5-(3-(pyrrolidin-l -ylmethyl)- lH-l,2,4-triazol-5-yl)-lH-indazol-3- yl)benzonitrile;
N-methyl-3-(5-(3-(pyrrolidin-2-yl)-lH-l,2,4-triazol-5-yl)-lH-indazol-3-yl)benzamide;
N-cyclopropyl-3-(5-(3-((dimethylamino)methyl)-lH-l,2,4-triazol-5-yl)-lH-indazol-3- yl)benzamide; and
N-cyclopropyl-3 -(5 -(5 -isobutyl- 1 H- 1 ,2,4-triazol-3 -yl)- 1 H-indazol-3 -yl)benzamide;
3-(3-(lH-pyrazol-3-yl)phenyl)-5-(lH-l,2,4-triazol-3-yl)-lH-indazole;
3-(5-(lH-l,2,4-triazol-3-yl)-lH-indazol-3-yl)-N-propylbenzamide;
3 -(5 -( 1 H- 1 ,2,4-triazol-3 -yl)- 1 H-indazol-3 -yl)-N-(( 1 r,4r)-4-hydroxycyclohexyl)benzamide; N-(3-(5-(lH-l,2,4-triazol-3-yl)-lH-indazol-3-yl)phenyl)nicotinamide;
3 -(5 -( 1 H- 1 ,2,4-triazol-3 -yl)- 1 H-indazol-3 -yl)-N-cyclopropylbenzamide;
3-(5-(3-((dimethylamino)methyl)-lH-l,2,4-triazol-5-yl)-lH-indazol-3-yl)-N-(4- fluorophenyl)benzamide;
3-(5-(lH-l,2,4-triazol-3-yl)-lH-indazol-3-yl)-N-cyclobutylbenzamide;
N-phenyl-3-(5-(5-(pyrrolidin- 1 -ylmethyl)- 1H- 1 ,2,4-triazol-3-yl)- 1 H-indazol-3 -yl)benzamide; 3-(5-(5-(pyrrolidin- 1 -ylmethyl)- 1H- 1 ,2,4-triazol-3-yl)- 1 H-indazol-3 -yl)quino line;
3- (5-(lH-l,2,4-triazol-3-yl)-lH-indazol-3-yl)-N-ethylbenzamide;
N-cyclopropyl-3-(5-(3-(pyrrolidin-2-yl)-lH-l,2,4-triazol-5-yl)-lH-indazol-3-yl)benzamide; N-cyclopropyl-3-(5-(5-(2,2,2-trifluoroethyl)-lH-l,2,4-triazol-3-yl)-lH-indazol-3-yl)benzamide; N-cyclopropyl-3 -(5 -(5 -(3 ,3 ,3 -trifluoropropyl)- 1 H- 1 ,2,4-triazol-3 -yl)- 1 H-indazol-3 - yl)benzamide;
N-cyclopropyl-3-(5-(5-(2-fluoroethyl)-lH-l,2,4-triazol-3-yl)-lH-indazol-3-yl)benzamide; N-cyclopropyl-3-(5-(5-(pyrrolidin-3-yl)-lH-l,2,4-triazol-3-yl)-lH-indazol-3-yl)benzamide;
4- (5-(5-(piperidin-4-yl)-lH-l,2,4-triazol-3-yl)-lH-indazol-3-yl)benzonitrile;
3-(3-(pyrrolidin-l-ylmethyl)phenyl)-5-(5-(pyrrolidin-2-yl)-lH-l,2,4-triazol-3-yl)-lH-indazole; and pharmaceutically acceptable salts, tautomers, stereoisomers, enantiomers, and
isotopologues thereof.
[00120] In a further embodiment provided herein is a compound of Formula (I) or
Formula (II) for use in a method described herein.
PHARMACEUTICAL COMPOSITIONS AND ROUTES OF ADMINISTRATION
[00121] The Indazole Compounds can be administered to a subject orally, topically or parenterally in the conventional form of preparations, such as capsules, microcapsules, tablets, granules, powder, troches, pills, suppositories, injections, suspensions, syrups, patches, creams, lotions, ointments, gels, sprays, solutions and emulsions. Suitable
formulations can be prepared by methods commonly employed using conventional,
organic or inorganic additives, such as an excipient, a binder, a disintegrator, a lubricant, a flavoring agent, a preservative, a stabilizer, a suspending agent, a dispersing agent, a diluent, and base wax. The effective amount of the Indazole Compounds in the pharmaceutical composition may be at a level that will exercise the desired effect; for example, at about 0.005 mg/kg of a subject's body weight to about 10 mg/kg of a subject's body weight in unit dosage for both oral and parenteral administration.
[00122] The dose of an Indazole Compound to be administered to a subject is rather widely variable and can be subject to the judgment of a health-care practitioner. In general, the Indazole Compounds can be administered one to four times a day in a dose of about 0.005 mg/kg of a subject's body weight to about 10 mg/kg of a subject's body weight in a subject, but the above dosage may be properly varied depending on the age, body weight and medical condition of the subject and the type of administration. In any given case, the amount of the Indazole Compound administered will depend on such factors as the solubility of the active component, the formulation used and the route of administration. In one embodiment, application of a topical concentration provides intracellular exposures or concentrations of about 0.01 - 10 μΜ.
[00123] In another embodiment, provided herein are methods for the treatment or prevention of a disease or disorder comprising the administration of about 1 mg/day to about 1200 mg/day.
[00124] In another embodiment, provided herein are unit dosage formulations that comprise between about 1 mg and 500 mg, or between about 500 mg and about 1000 mg of an Indazole Compound.
[00125] An Indazole Compound can be administered once, twice, three, four or more times daily. An Indazole Compound can be administered orally for reasons of convenience.
[00126] The Indazole Compound can also be administered intradermally, intramuscularly, intraperitoneally, percutaneously, intravenously, subcutaneously, intranasally, epidurally, sublingually, intracerebrally, intravaginally, transdermally, rectally, mucosally, by inhalation, or topically to the ears, nose, eyes, or skin. The mode of administration is left to the discretion of the health-care practitioner, and can depend in- part upon the site of the medical condition. [00127] In one embodiment, provided herein are capsules containing an Indazole
Compound without an additional carrier, excipient or vehicle.
[00128] In another embodiment, provided herein are compositions comprising an effective amount of an Indazole Compound and a pharmaceutically acceptable carrier or vehicle, wherein a pharmaceutically acceptable carrier or vehicle can comprise an excipient, diluent, or a mixture thereof. In one embodiment, the composition is a pharmaceutical composition.
[00129] The compositions can be in the form of tablets, chewable tablets, capsules, solutions, parenteral solutions, troches, suppositories and suspensions and the like.
Compositions can be formulated to contain a daily dose, or a convenient fraction of a daily dose, in a dosage unit, which may be a single tablet or capsule or convenient volume of a liquid. In one embodiment, the solutions are prepared from water-soluble salts, such as the hydrochloride salt. In general, all of the compositions are prepared according to known methods in pharmaceutical chemistry. Capsules can be prepared by mixing an Indazole Compound with a suitable carrier or diluent and filling the proper amount of the mixture in capsules. The usual carriers and diluents include, but are not limited to, inert powdered substances such as starch of many different kinds, powdered cellulose, especially crystalline and microcrystalline cellulose, sugars such as fructose, mannitol and sucrose, grain flours and similar edible powders.
[00130] The effect of the Indazole Compound can be delayed or prolonged by proper formulation. For example, a slowly soluble pellet of the Indazole Compound can be prepared and incorporated in a tablet or capsule, or as a slow-release implantable device. The technique also includes making pellets of several different dissolution rates and filling capsules with a mixture of the pellets. Tablets or capsules can be coated with a film that resists dissolution for a predictable period of time. Even the parenteral preparations can be made long-acting, by dissolving or suspending the Indazole
Compound in oily or emulsified vehicles that allow it to disperse slowly in the serum.
[00131] In another embodiment, the Indazole Compounds can be administered alone or in combination with a co-agent useful in the treatment of malaria, such as substances useful in the treatment and/or prevention of malaria e.g. for example a co-agent including, but not limited to, one or more of chloroquine, quinine, quinidine, melfloquine, atovaquone, proguanil, doxycycline, artesunate, artemether, artemisinin, lumefantrine, amodiaquine, hydroxychloroquine, halofantrine, pyrimethamine, sulfadoxine, or primaquine.
[00132] In another embodiment, the Indazole Compounds can be administered alone or in combination with a co-agent useful in the treatment of babesiosis, such as substances useful in the treatment and/or prevention of babesiosis e.g. for example a co-agent including, but not limited to, one or more of chloroquine, quinine, atovaquone, azithromycin, doxycycline, pyrimethamine-sulfadoxine, primaquine, staurosporine, purvalanol A, imidocarb, clindamycin, nimbolide, gedunin, ciprofloxacin, diminazene aceturate or epoxomicin. In one embodiment, the co-agent is an effective amount of one or more of quinine, atovaquone, azithromycin, or clindamycin.
[00133] In another embodiment, wherein the Indazole Compound is administered to a subject prior to, simultaneously or sequentially with other therapeutic regimens or co- agents useful in the treatment of malaria or babesiosis (e.g. multiple drug regimens), in an effective amount, the Indazole Compounds that are administered simultaneously with said co-agents can be administered in the same or different composition(s) and by the same or different route(s) of administration.
EXAMPLES
[00134] The following Examples are presented by way of illustration, not limitation.
Compounds are named using the automatic name generating tool provided in Chemdraw Ultra 9.0 (Cambridgesoft), which generates systematic names for chemical structures, with support for the Cahn-Ingold-Prelog rules for stereochemistry. One skilled in the art can modify the procedures set forth in the illustrative examples to arrive at the desired products.
[00135] Abbreviations used:
Figure imgf000040_0001
Figure imgf000041_0001
Figure imgf000042_0002
COMPOUND SYNTHESIS
Example 1. 3-(5-(5-(Pyrrolidin-2-yl)- 1H- 1 ,2,4-triazol-3-yl)- lH-indazol-3-yl)benzamide
Figure imgf000042_0001
[00136] Ethyl 3-bromo-lH-indazole-5-carbimidate. To a stirred solution of 3-bromo-l- (tetrahydro-2H-pyran-2-yl)-lH-indazole-5-carbonitrile (10 g, 32 mmol) in ethanol (500 mL) was bubbled dry HC1 gas at -15 °C for 30 min and stirring was continued for 16 h at room
temperature. Completion of the reaction was confirmed by LCMS. The product was isolated and purified via standard methods to afford ethyl 3-bromo-lH-indazole-5-carbimidate (8 g, 91%) as pale yellow solid. [00137] l-(tert-Butyl) 2-methyl pyrrolidine- 1,2-dicarboxylate. To a stirred solution of (tert-butoxycarbonyl)proline (6.5 g, 30.2 mmol) in DMF was added potassium carbonate (12.5 g, 90.6 mmol) at room temperature and the reaction was stirred for 10 min. Methyl iodide (6.43 g, 45.3 mmol) was added at 0 °C, then the reaction was allowed to warm to ambient temperature and stirred for 16 h. Completion of the reaction was confirmed by TLC. The product was isolated and purified via standard methods to afford l-(tert-butyl) 2-methyl pyrrolidine- 1,2-dicarboxylate (6.6 g, 95 %) as yellow oil.
[00138] tert-Butyl-2-(hydrazinecarbonyl)pyrrolidine-l-carboxylate. To a stirred solution of l-(tert-butyl) 2-methyl pyrrolidine- 1,2-dicarboxylate (6.6 g, 34 mmol) in methanol (120 mL) was added hydrazine hydrate (8 mL) at 0 °C and the reaction was stirred at 60 °C for 16 h. Completion of the reaction was confirmed by TLC. The product was isolated and purified via standard methods to afford tert-butyl-2-(hydrazinecarbonyl)pyrrolidine-l-carboxylate (6.6 g, quant.) as a colorless oil.
[00139] tert-Butyl-2-(4-(3-bromo-lH-indazol-5-yl)-lH-pyrrol-2-yl) pyrrolidine-l- carboxylate. To a stirred solution of ethyl 3-bromo-lH-indazole-5-carbimidate (8 g, 29 mmol) and tert-butyl 2-(hydrazinecarbonyl)pyrrolidine-l-carboxylate (6.5 g, 29 mmol) in methanol (80 mL) was added triethylamine (8.7 g, 87 mmol) at room temperature. The reaction was heated to 90 °C for 16 h in a sealed tube. Completion of the reaction was confirmed by LCMS. The product was isolated and purified via standard methods to afford to afford tert-butyl-2-(4-(3- bromo-lH-indazol-5-yl)-lH-pyrrol-2-yl) pyrrolidine- 1-carboxylate (6.1 g, 47%) as off white solid.
[00140] tert-Butyl 2-(3-(3-(3-carbamoylphenyl)-lH-indazol-5-yl)-lH-l,2,4-triazol-5- yl)pyrrolidine-l-carboxylate. To a solution tert-butyl-2-(4-(3-bromo-lH-indazol-5-yl)-lH- pyrrol-2-yl) pyrrolidine- 1-carboxylate (0.3 g, 0.7 mmol) in methanol (5 mL) was added
(3-carbamoylphenyl)boronic acid (173 mg, 1.5 mmol) followed by potassium acetate (205 mg, 2.1 mmol). The reaction was degassed for 10 minutes, and bis(triphenylphosphine)palladium(II) dichloride (97 mg, 0.14 mmol) was added and the reaction mixture was degassed for another 10 minutes. The reaction mixture was heated at 90 °C for 16 h. Completion of the reaction was confirmed by LCMS. The reaction mixture was filtered through a Celite pad and the filtrate was concentrated and purified via standard methods to afford tert-butyl 2-(3-(3-(3-carbamoylphenyl)- lH-indazol-5-yl)-lH-l,2,4-triazol-5-yl)pyrrolidine-l-carboxylate (180 mg, 56%) as a white solid.
[00141] 3-(5-(5-(Pyrrolidin-2-yl)-lH-l,2,4-triazol-3-yl)-lH-indazol-3-yl)benzamide.
To a stirred solution of tert-butyl 2-(3-(3-(3-carbamoylphenyl)-lH-indazol-5-yl)-lH-l,2,4- triazol-5-yl)pyrrolidine-l-carboxylate (150 mg) in methanol (5 mL) was added 4.5 N HC1 in dioxane (4 mL) at 0 °C and the reaction was stirred for 12 h at ambient temperature. Completion of the reaction was confirmed by LCMS. The reaction mixture was worked-up and the product isolated and purified via standard methods to afford 3-(5-(5-(pyrrolidin-2-yl)-lH-l,2,4-triazol-3- yl)-lH-indazol-3-yl)benzamide (46 mg, 39%). MS (ESI) m/z 374 [M + 1]+.
Example 2. 4-(5-(5-(Pyrrolidin- -yl)-lH-l,2,4-triazol-3-yl)-lH-indazol-3-yl)benzonitrile
Figure imgf000044_0001
[00142] Ethyl 3-bromo-lH-indazole-5-carbimidate. To a stirred solution of 3-bromo-l- (tetrahydro-2H-pyran-2-yl)-lH-indazole-5-carbonitrile (10 g, 0.32mmol) in 500 mL of ethanol was bubbled dry HC1 gas at -15 °C for 30 min and stirring was continued for 16 h at room temperature. Completion of the reaction confirmed by LCMS. The reaction was concentrated to afford ethyl 3-bromo-lH-indazole-5-carbimidate (7 g, 81%).
[00143] Methyl prolinate. Thionyl chloride (3 mL) was added dropwise at 0 °C to a stirred solution of [DL]-proline (1 g, 8.6 mmol) in methanol (15 mL). The reaction was stirred at room temperature for 16 h. The reaction was monitored by TLC. After completion of the reaction, the mixture was concentrated and purified via standard methods to afford methyl prolinate as an off- white solid (1 g, 90%>).
[00144] l-(tert-Butyl) 2-methyl pyrrolidine- 1,2-dicarboxylate. To stirred solution of methyl prolinate (300 mg, 2.32mmol) in acetonitrile (5 mL) was added triethyl amine (0.55 g, 4.65mmol) and the reaction was stirred for 10 min. Di-t-butyl dicarbonate (0.43 g, 2.78 mmol) was added dropwise to the reaction mixture at 0 °C and stirred for 16 h at ambient temperature. The reaction mixture was concentrated and purified via standard methods to afford l-(tert-butyl) 2-methyl pyrrolidine- 1 ,2-dicarboxylate (0.35 g, 66%) as pale yellow oil.
[00145] tert Butyl 2-(hydrazinecarbonyl) pyrrolidine-l-carboxylate. To a stirred solution of l-(tert-butyl) 2-methyl pyrrolidine- 1 ,2-dicarboxylate (0.3 g, 1.31 mmol) in methanol (15 mL) was added anhydrous hydrazine hydrate (1 mL) and heated at reflux for 48 h. The reaction mixture was concentrated to afford tert butyl 2-(hydrazinecarbonyl) pyrrolidine-l- carboxylate (0.28 g, 93%) as pale yellow oil.
[00146] tert-Butyl-2-(4-(3-bromo-lH-indazol-5-yl)-lH-pyrrol-2-yl) pyrrolidine-l- carboxylate. To a stirred solution of ethyl 3-bromo-lH-indazole-5-carbimidate (4 g, 20 mol) and tert-butyl 2-(hydrazinecarbonyl)pyrrolidine-l -carboxylate (3.42 g, 20mmol; see Example 1) in methanol (40 mL) was added triethylamine (4.52 g, 50 mmol) at room temperature. The reaction was heated at 90 °C in a sealed tube for 16 h. Completion of the reaction was confirmed by LCMS. The reaction mixture was concentrated under vacuum and the product purified via standard methods to afford tert-butyl-2-(4-(3-bromo-lH-indazol-5-yl)-lH-pyrrol-2-yl) pyrrolidine-l-carboxylate (3.5 g, 54%) as an off-white solid.
[00147] tert-Butyl 2-(3-(3-(4-cyanophenyl)- lH-indazol-5-yl)- 1H- 1 ,2,4-triazol-5- yl)pyrrolidine-l-carboxylate. To a solution tert-butyl-2-(4-(3-bromo-lH-indazol-5-yl)-lH- pyrrol-2-yl) pyrrolidine-l-carboxylate (500 mg, 1.15 mmol) in methanol (10 mL) was added (4-cyanophenyl) boronic acid (255 mg, 1.73 mmol) followed by potassium acetate (338 mg, 3.45 mmol). The reaction was degassed for 10 minutes, and then
bis(triphenylphosphine)palladium(II) dichloride (80 mg, 0.115 mmol) was added and the mixture was degassed for another 5 minutes, then heated at 90 °C for 6 h. The reaction mixture was filtered through a Celite pad and the filtrate was concentrated and purified via standard methods to afford tert-butyl 2-(3-(3-(4-cyanophenyl)-lH-indazol-5-yl)-lH-l,2,4-triazol-5-yl)pyrrolidine- 1 -carboxylate (300 mg, 57%) as off white solid.
[00148] 4-(5-(5-(Pyrrolidin-2-yl)-lH-l,2,4-triazol-3-yl)-lH-indazol-3-yl)benzonitrile.
To tert-butyl 2-(3 -(3 -(4-cyanophenyl)- 1 H-indazol-5 -yl)- 1 H- 1 ,2,4-triazol-5 -yl)pyrrolidine- 1 - carboxylate (300 mg, 0.66 mmol) in methanol (1 ml) was added 4.5 N HC1 in dioxane (1 mL) at 0 °C and stirred at ambient temperature for 6 h. The reaction mixture was concentrated and the residue was stirred with saturated sodium bicarbonate solution (15 mL). The solid precipitate was filtered, washed with water, dried and purified via standard methods to afford 4-(5-(5- (pyrrolidin-2-yl)-lH-l, 2, 4-triazol-3-yl)-lH-indazol-3-yl) benzonitrile (65 mg, 27%). MS (ESI) m/z 356 [M + 1]+.
Example 3. 4-(5-(lH-benzo[d]imidazol-2-yl)-lH-indazol-3-yl)-N-methylbenzamide
Figure imgf000046_0001
[00149] 3-Bromo-l-(tetrahydro-2H-pyran-2-yl)-lH-indazole-5-carboxylic acid. To
3-bromo-l-(tetrahydro-2H-pyran-2-yl)-lH-indazole-5-carbonitrile (5 g, 1.63 mmol) in DMSO (50 mL) was added 5N sodium hydroxide solution (5 mL) at room temperature. The reaction was stirred in a sealed tube for 16 h at 100 °C. The reaction mixture was cooled to room temperature and neutralized slowly by addition of 1.5N HC1 solution at 0 °C. The solid obtained was dried under vacuum to afford 3-bromo-l-(tetrahydro-2H-pyran-2-yl)-lH-indazole-5-carboxylic acid (4.6 g, 87%) as an off white solid.
[00150] N-(2-Aminophenyl)-3-bromo-l-(tetrahydro-2H-pyran-2-yl)-lH-indazole-5- carboxamide. To 3-bromo-l-(tetrahydro-2H-pyran-2-yl)-lH-indazole-5-carboxylic acid (3 g, 0.92mmol) in DMF (30 mL) was added DIEA (3.7 mL, 2.30 mmol) and HATU (5.26 g, 1.38 mmol) followed by benzene- 1,2-diamine (0.99 g, 0.92 mmol). The reaction was stirred for 16 h at ambient temperature. The reaction mixture was quenched with water (30 mL) and worked up and purified via standard methods to afford N-(2-aminophenyl)-3-bromo-l- (tetrahydro-2H-pyran-2-yl)-lH-indazole-5 -carboxamide (2 g, 52%) as off white solid.
[00151] 5-(lH-Benzo[d]imidazol-2-yl)-3-bromo-lH-indazole. To N-(2-aminophenyl)-3- bromo-l-(tetrahydro-2H-pyran-2-yl)-lH-indazole-5 -carboxamide (2 g, 0.48 mmol) in DMF (20 mL) was added phosphoryl trichloride (2.21 g, 1.44 mmol) at 0 °C. The reaction was stirred for 16 h at 90 °C. After completion of reaction, the reaction mixture was concentrated under reduced pressure and neutralized slowly by using 10%> sodium bicarbonate solution. The precipitate was collected and purified via standard methods to afford 5-(lH-benzo[d]imidazol-2- yl)-3-bromo-lH-indazole (1.2 g, 80 %>) as an off white solid. [00152] 4-(5-(lH-Benzo[d]imidazol-2-yl)-lH-indazol-3-yl)-N-methylbenzamide. To
5-(lH-benzo[d]imidazol-2-yl)-3-bromo-lH-indazole (0.350 g, 0.11 mmol) in 10 mL DMF: water (9: 1) was added 4-(methylcarbamoyl) phenyl) boronic acid (0.413 g, 0.23 mmol) followed by sodium carbonate (0.588 g, 0.55 mmol). The reaction was degassed for 10 minutes, and then bis(triphenylphosphine)palladium(II) dichloride (0.324 g, 0.04 mmol) was added and the mixture was degassed for another 5 minutes, then heated at 120 °C with microwave irradiation for 2 h. Completion of the reaction was confirmed by LCMS. The reaction mixture was filtered through a Celite pad and the filtrate was concentrated and purified via standard methods to afford 4-(5- (lH-benzo[d]imidazol-2-yl)-lH-indazol-3-yl)-N-methylbenzamide (60 mg, 15%). MS (ESI) m/z 368 [M + 1]+.
Example 4. 4-(5-(lH-Benzo[d]imidazol-2-yl)-lH-indazol-3-yl)benzonitrile
Figure imgf000047_0001
[00153] 3-(5-(lH-Benzo[d]imidazol-2-yl)-lH-indazol-3-yl)benzonitrile. To 5-(lH- benzo[d]imidazol-2-yl)-3-bromo-lH-indazole (0.350 g, 0.11 mmol) in 10 mL DMF: water (9: 1) was added (4-cyanophenyl) boronic acid (0.328 g, 0.22 mmol) followed by sodium carbonate (0.588 g,0.55 mmol). The reaction was degassed for 10 minutes, and then
bis(triphenylphosphine)palladium(II) dichloride (0.324 g, 0.04 mmol) was added and the mixture was degassed for another 5 minutes, then heated at 120 °C with microwave irradiation for 2 h. Completion of the reaction was confirmed by LCMS. The reaction mixture was filtered through a Celite pad and the filtrate was concentrated and purified via standard methods to afford 3-(5- (lH-benzo[d]imidazol-2-yl)-lH-indazol-3-yl)benzonitrile (28 mg, 8%). MS (ESI) m/z 334 [M + 1]+.
Example 5. 3-(5-(lH-Benzo [d] imidazol-2-yl)-lH-indazol-3-yl)benzonitrile
Figure imgf000048_0001
[00154] 3-(5-(lH-Benzo[d]imidazol-2-yl)-lH-indazol-3-yl)benzonitrile. To 5-(lH- Benzo[d]imidazol-2-yl)-3-bromo-lH-indazole (0.350 g, 0.11 mmol) in 10 mL DMF: water (9: 1) was added (4-cyanophenyl) boronic acid (0.328 g, 0.22 mmol) followed by sodium carbonate (0.588 g, 0.55 mmol). The reaction was degassed for 10 minutes, and then
bis(triphenylphosphine)palladium(II) dichloride (0.324 g, 0.04 mmol) was added and the mixture was degassed for another 5 minutes, then heated at 120 °C with microwave irradiation for 2 h. Completion of the reaction was confirmed by LCMS. The reaction mixture was filtered through a Celite pad and the filtrate was concentrated and purified via standard methods to afford 3-(5-(lH-benzo[d]imidazol-2-yl)-lH-indazol-3-yl)benzonitrile (15 mg, 10%). MS (ESI) m/z 336 [M + 1]+.
Example 6. N-Cyclopropyl-3-(5-(3-(pyrrolidin-2-yl)-lH-l,2,4-triazol-5-yl)-lH-indazol-3-
Figure imgf000048_0002
[00155] N-Cyclopropyl-3-(5-(3-(pyrrolidin-2-yl)-lH-l,2,4-triazol-5-yl)-lH-indazol-3- yl)benzamide. To a solution tert-butyl 2-(4-(3-bromo-lH-indazol-5-yl)-lH-pyrrol-2-yl) pyrrolidine- 1-carboxylate (300 mg, 0.69 mmol) in 8 mL of DMF: water (3: 1) was added
(3-(cyclopropylcarbamoyl) phenyl) boronic acid (285 mg, 1.38 mmol) followed by potassium fluoride (161 mg, 2.77 mmol). The reaction was degassed for 10 minutes. Tetrakis(triphenylphosphine)palladium(0) (80 mg, 0.069 mmol) was added and the reaction was degassed for a further 10 minutes, then heated at 150 °C under microwave irradiation for 2 h. Completion of the reaction was confirmed by LCMS. The reaction mixture was filtered through a Celite pad and the filtrate was concentrated and purified via standard methods to afford N- cyclopropyl-3-(5-(5-(pyrrolidin-2-yl)-lH-l,2,4-triazol-3-yl)-lH-indazol-3-yl)benzamide (46 mg, 16%). MS (ESI) m/z 414 [M + 1]+.
Example 7. N-Cyclopropyl-3-(5-(5-(2,2,2-trifluoroethyl)-lH-l,2,4-triazol-3-yl)-lH-indazol- -yl)benzamide
Figure imgf000049_0001
[00156] N-Cyclopropyl-3-(5-(5-(2,2,2-trifluoroethyl)-lH-l,2,4-triazol-3-yl)-lH- indazol-3-yl)benzamide. To 3-(5-(3-(2,2,2-trifluoroethyl)-lH-l,2,4-triazol-5-yl)-lH-indazol-3- yl)benzoic acid (150 mg, 0.38 mmol) in DMF (2 mL) was added DIEA (0.13 mL, 0.77 mmol) and HATU (295 mg, 0.77 mmol) followed by cyclopropylamine (0.05 mL, 0.77 mmol) at room temperature, The reaction was stirred for 16 h at room temperature. The reaction mixture was concentrated and the residue was purified via standard methods to afford N-cyclopropyl-3-(5-(5- (2,2,2-trifiuoroethyl)-lH-l,2,4-triazol-3-yl)-lH-indazol-3-yl)benzamide (30 mg, 19%). MS (ESI) m/z 427 [M + 1]+.
Example 8. N-cyclopropyl-3-(5-(5-(3,3,3-trifluoropropyl)-lH-l,2,4-triazol-3-yl)-lH-indazol-
3-yl)benzamide
Figure imgf000050_0001
[00157] 4,4,4-Trifluorobutanehydrazide. To a stirred solution of methyl 4,4,4- trifluorobutanoate (1.0 g, 6.4 mmol) in methanol (10 mL) was added anhydrous hydrazine hydrate (1 mL) and the reaction was stirred for 16 h. The reaction was concentrated to afford 4,4,4-trifluorobutanehydrazide (0.9 g, 90%) as yellow solid.
[00158] 3-Bromo-5-(5-(3,3,3-trifluoropropyl)-lH-l,2,4-triazol-3-yl)-lH-indazole. To a stirred solution of ethyl 3-bromo-lH-indazole-5-carbimidate (0.6 g, 2.24 mmol) and
4,4,4-trifluorobutanehydrazide (0.35 g, 2.24mmol) in methanol (6 mL) was added triethyl amine (0.68 g, 6.7 mmol) at room temperature. The reaction was heated in a sealed tube at 90 °C for 16 h. Completion of the reaction was confirmed by LCMS. The reaction was concentrated and the residue purified via standard methods to afford 3-bromo-5-(5-(3,3,3-trifluoropropyl)-lH- l,2,4-triazol-3-yl)-lH-indazole (0.45 g, 56%) as off-white solid.
[00159] N-Cyclopropyl-3-(5-(5-(3,3,3-trifluoropropyl)-lH-l,2,4-triazol-3-yl)-lH- indazol-3-yl)benzamide. To a stirred solution 3-bromo-5-(5-(3,3,3-trifluoropropyl)-lH-l,2,4- triazol-3-yl)-lH-indazole (300 mg, 0.82 mmol) and (3-(cyclopropylcarbamoyl) phenyl) boronic acid (334 mg, 1.63 mmol) in methanol (5 mL) was added potassium acetate (240 mg,
2.45 mmol). The reaction was degassed for 10 minutes, and then
bis(triphenylphosphine)palladium(II) dichloride (0.324 g, 0.04 mmol) was added and the mixture was degassed for another 5 minutes, then heated at 90 °C for 12 h. Completion of the reaction was confirmed by LCMS. The reaction mixture was filtered through a Celite pad and the filtrate was concentrated and purified via standard methods to afford N-cyclopropyl-3-(5-(5-(3,3,3- trifluoropropyl)-lH-l,2,4-triazol-3-yl)-lH-indazol-3-yl)benzamide (85 mg, 23%). MS (ESI) m/z 441 [M + 1]+. Example 9. N-(3-(5-(5-(Pyrrolidin-2-yl)-lH-l,2,4-triazol-3-yl)-lH-indazol-3- yi)phenyl)cyclopropanecarboxamide
Figure imgf000051_0001
[00160] (3-(Cyclopropane carboxamido)phenyl)boronic acid. To
(3-aminophenyl)boronic acid (0.700 g, 0.4 mmol) in DCM (20 mL) was added triethyl amine (1.03 g, 1.01 mmol) and cyclopropanecarbonyl chloride (0.551 g, 0.52 mmol) at 0 °C. The reaction mixture was stirred for 16 h at room temperature. Completion of the reaction was confirmed by LCMS. The reaction was quenched with water (40 mL), the organic layer separated and concentrated under vacuum. The residue was purified via standard methods to afford (3 -(cyclopropane carboxamido)phenyl)boronic acid (0.5 g, 71%) as light brown gummy solid.
[00161] tert-Butyl-2-(5-(3-(3-(cyclopropanecarboxamido)phenyl)-lH-indazol-5-yl)- lH-l,2,4-triazol-3-yl) pyrrolidine-l-carboxylate. To tert-butyl 2-(5-(3-bromo-lH-indazol-5- yl)-lH-l,2,4-triazol-3-yl)pyrrolidine-l-carboxylate (0.4 g, 0.09mmol) in methanol (10 mL) was added (3-(cyclopropanecarboxamido)phenyl) boronic acid (0.226 g, 0.11 mmol) followed by potassium acetate (0.226 g, 0.23 mmol) at room temperature. The reaction was degassed for 10 minutes, and then bis(triphenylphosphine)palladium(II) dichloride (0.129 g, 0.02 mmol) was added and the mixture was degassed for another 5 minutes, then heated at 90 °C for 12 h.
Completion of the reaction was confirmed by LCMS. The reaction mixture was filtered through a Celite pad and the filtrate was concentrated and purified via standard methods to afford tert- butyl-2-(5-(3-(3-(cyclopropanecarboxamido)phenyl)-lH-indazol-5-yl)-lH-l,2,4-triazol-3-yl) pyrrolidine-l-carboxylate (0.2 g, 48%) as off white solid.
[00162] N-(3-(5-(3-(Pyrrolidin-2-yl)-lH-l,2,4-triazol-5-yl)-lH-indazol-3yl)phenyl) cyclopropanecarboxamide. To a stirred solution of tert-butyl 2-(5-(3-(3- (cyclopropanecarboxamido)phenyl)- 1 H-indazol-5 -yl)- 1 H- 1 ,2,4-triazol-3 -yl)pyrrolidine- 1 - carboxylate (0.2 g, 0.03 mmol) in DCM (8 mL) was added TFA (0.5 mL) at 0 °C and stirred for 16 h at room temperature. Completion of the reaction was monitored by LCMS. The reaction mixture was concentrated under vacuum and purified via standard methods to afford N-(3-(5-(3- (pyrrolidin-2-yl)- 1 H- 1 ,2,4-triazol-5 -y 1)- 1 H-indazol-3yl)phenyl) cyclopropanecarboxamide (65 mg, 40%). MS (ESI) m/z 414 [M + 1]+.
Example 10. N-Cyclopropyl-3-(5-(5-(pyrrolidin-3-yl)-lH-l, 2, 4-triazol-3-yl)-lH-indazol-3- yl) benzamide
Figure imgf000052_0001
[00163] tert-Butyl3-(3-(3-(3-(cyclopropylcarbamoyl)phenyl)-lH-indazol-5-yl)-lH- l,2,4-triazol-5yl) pyrrolidine-l-carboxylate. To tert-butyl 3-(3-(3-bromo-lH-indazol-5-yl)-lH- l,2,4-triazol-5-yl)pyrrolidine-l-carboxylate (0.350 g, 0.08 mmol) in methanol (10 mL) was added (3-(cyclopropylcarbamoyl)phenyl)boronic acid (0.196 g, O.Olmmol) followed by potassium acetate (0.196 g, 0.20mmol) at room temperature. The reaction was degassed for 10 minutes, and then bis(triphenylphosphine)palladium(II) dichloride (0.112 g, O.Olmmol) was added and the mixture was degassed for another 5 minutes, then heated at 90 °C for 16 h.
Completion of the reaction was confirmed by LCMS. The reaction mixture was filtered through a Celite pad and the filtrate was concentrated and purified via standard methods to afford tert- butyl3-(3-(3-(3-(cyclopropylcarbamoyl)phenyl)-lH-indazol-5-yl)-lH-l,2,4-triazol- 5yl)pyrrolidine-l-carboxylate (0.150 g, 36%) as off white solid.
[00164] N-Cyclopropyl-3-(5-(5-(pyrrolidin-3-yl)-lH-l, 2,4-triazol-3-yl)-lH-indazol-3- yl)benzamide. To a stirred solution of tert-butyl 3-(3-(3-(3-(cyclopropylcarbamoyl) phenyl)-lH- indazol-5-yl)-lH-l,2,4-triazol-5-yl)pyrrolidine-l-carboxylate (0.150 g, 0.03 mmol) in
1,4-dioxane (6 mL) was added 4.5 N HC1 in dioxane (0.5 mL) at 0 °C and the reaction was stirred for 16 h at room temperature. Completion of the reaction was monitored by LCMS. The reaction mixture was concentrated under vacuum and then coevaporated with diethyl ether under vacuum. The residue was dissolved in 10%> DCM in methanol (20 mL) and neutralized using sodium carbonate. The crude product was isolated and purified via standard methods to afford N-cyclopropyl-3 -(5 -(5 -(pyrrolidin-3 -yl)- 1 H- 1 , 2,4-triazol-3 -yl)- 1 H-indazol-3 -yl)benzamide (54 mg, 45%). MS (ESI) m/z 414 [M + 1]+.
Example 11. 4-(5-(5-(Pyrrolidin-l-ylmethyl)-lH-l,2,4-triazol-3-yl)-lH-indazol-3-
Figure imgf000053_0001
[00165] 4-(5-(5-(Pyrrolidin-l-ylmethyl)-lH-l,2,4-triazol-3-yl)-lH-indazol-3- yl)benzonitrile. To a solution of bromo-5-(5-(pyrrolidin-l-ylmethyl)-lH-l, 2, 4-triazol-3-yl)- lH-indazole (400 mg, 1.15 mmol) in 10 mL of DME: water (4: 1) was added (4-cyanophenyl) boronic acid (339 mg, 2.3 mmol) followed by sodium carbonate (609 mg, 5.57 mmol). The reaction was degassed for 10 minutes, and then bis(triphenylphosphine)palladium(II) dichloride (336 mg, 0.46 mmol) was added and the mixture was degassed for another 5 minutes, then heated at 150 °C under microwave irradiation for 2 h. Completion of the reaction was confirmed by LCMS. The reaction mixture was filtered through a Celite pad and the filtrate was concentrated and purified via standard methods to afford 4-(5-(5-(pyrrolidin-l-ylmethyl)-lH- l,2,4-triazol-3-yl)-lH-indazol-3-yl)benzonitrile (55 mg, 12.97 %). MS (ESI) m/z 370 [M + 1]+.
Example 12. 3-(l-Methyl-5-(3-(pyrrolidin-l-ylmethyl)-lH-l,2,4-triazol-5-yl)-lH-indazol-3-
Figure imgf000053_0002
[00166] 3-(l-Methyl-5-(3-(pyrrolidin-l-ylmethyl)-lH-l,2,4-triazol-5-yl)-lH-indazol-3- yl)benzonitrile. To a solution 3-bromo-l-methyl-5-(3-(pyrrolidin-l-ylmethyl)-lH-l,2,4-triazol- 5-yl)-lH-indazole (180 mg, 0.50 mmol) in 6 mL of DME: water (5: 1) was added 3-cyanophenyl boronic acid (102 mg, 0.60 mmol) followed by sodium carbonate (216 mg, 2.00 mmol). The reaction was degassed for 10 minutes, and then bis(triphenylphosphine)palladium(II) dichloride (36 mg, 0.05 mmol) was added and the reaction mixture was degassed for another 10 minutes. The reaction mixture was irradiated at 150 °C under microwave irradiation for lh 30 min.
Completion of the reaction was confirmed by LCMS. The reaction mixture was filtered through a Celite pad and the filtrate was concentrated and purified via standard methods to afford 3-(l- methyl-5-(3-(pyrrolidin-l-ylmethyl)-lH-l,2,4-triazol-5-yl)-lH-indazol-3-yl)benzonitrile (55 mg,
28.72%). MS (ESI) m/z 384 [M + if.
Example 13. 3-(3-(Methylsulfonyl)phenyl)-5-(3-(pyrrolidin-2-yl)-lH-l,2,4-triazol-5-yl)-lH- indazole
Figure imgf000054_0001
[00167] tert-Butyl-2-(3-(3-(3-(methylsulfonyl)phenyl)-lH-indazol-5-yl)-lH-l,2,4- triazol-5-yl)pyrrolidine-l-carboxylate. To a solution tert-butyl-2-(4-(3-bromo-lH-indazol-5- yl)-lH-pyrrol-2-yl) pyrrolidine- 1-carboxylate (300 mg, 0.69 mmol) in 6 mL of DMF: water (5:1) was added (3-(methylsulfonyl)phenyl)boronic acid (277 mg, 1.38 mmol) followed by potassium fluoride (161 mg, 2.77 mmol). The reaction was degassed for 10 min.
Tetrakis(triphenylphosphine)palladium(0) (80 mg, 0.069 mmol) was added and the reaction was degassed for a further 10 minutes, then heated at 150 °C under microwave irradiation for 2 h. Completion of the reaction was confirmed by LCMS. The reaction mixture was filtered through a Celite pad and the filtrate was concentrated and purified via standard methods to afford tert- butyl-2-(3-(3-(3-(methylsulfonyl)phenyl)-lH-in^
carboxylate (70 mg, 20%) as an off white solid.
[00168] 3-(3-(Methylsulfonyl)phenyl)-5-(3-(pyrrolidin-2-yl)-lH-l,2,4-triazol-5-yl)-lH- indazole. To a stirred solution of tert-butyl 2-(3-(3-(3-(methylsulfonyl)phenyl)-lH-indazol-5-yl)- lH-l,2,4-triazol-5-yl)pyrrolidine-l-carboxylate (70 mg, 0.13 mmol) in 1,4-dioxane (2 mL) was added 4.5 N HC1 in 1,4-dioxane (1.5 mL) at 0 °C and stirred for 16 h at ambient temperature. Completion of the reaction was monitored by LCMS. The reaction mixture was concentrated under vacuum and then coevaporated with diethyl ether under vacuum. The residue was dissolved in 10% DCM in methanol (20 mL) and neutralized using sodium carbonate. The crude product was isolated and purified via standard methods to afford 3-(3-(methylsulfonyl)phenyl)-5- (3-(pyrrolidin-2-yl)-lH-l,2,4-triazol-5-yl)-lH-indazole (70 mg, 87%). MS (ESI) m/z 409
[M + 1]+.
Example 14. N-Methyl-3-(5-(3-(pyrrolidin-2-yl)-lH-l,2,4-triazol-5-yl)-lH-indazol-3-
Figure imgf000055_0001
[00169] N-Methyl-3-(5-(3-(pyrrolidin-2-yl)-lH-l,2,4-triazol-5-yl)-lH-indazol-3- yl)benzamide. To a solution tert-butyl 2-(4-(3-bromo-lH-indazol-5-yl)-lH-pyrrol-2-yl) pyrrolidine- 1 -carboxylate (400 mg, 0.92 mmol) in 8 mL of DMF: water (3: 1) was added
(3-(methylcarbamoyl) phenyl) boronic acid (331 mg, 1.85 mmol) followed by potassium fluoride (215 mg, 3.70 mmol). The reaction was degassed for 10 minutes.
Tetrakis(triphenylphosphine)palladium(0) (213 mg, 0.185 mmol) was added and the reaction was degassed for a further 10 minutes, then heated at 150 °C under microwave irradiation for 2 h. Completion of the reaction was confirmed by LCMS. The reaction mixture was filtered through a Celite pad and the filtrate was concentrated and purified via standard methods to afford N- methyl-3-(5-(3-(pyrrolidin-2-yl)-lH-l,2,4-triazol-5-yl)-lH-indazol-3-yl)benzamide (41 mg, 11%). MS (ESI) m/z 388 [M + 1]+.
Example 15. N-(3-(5-(5-(pyrrolidin-2-yl)-lH-l,2,4-triazol-3-yl)-lH-indazol-3-
Figure imgf000056_0001
[00170] tert-Butyl 2-(3-(3-(3-formylphenyl)-lH-indazol-5-yl)-lH-l,2,4-triazol-5- yl)pyrrolidine-l-carboxylate. To a solution 3-bromo-lH-indazol-5-amine (0.5 g, 1.16 mmol) in 10 mL of methanol was added 3-formylphenylboronic acid (261 mg, 1.74 mmol) followed by potassium acetate (341 mg, 3.5 mmol). The reaction was degassed for 10 minutes, and then bis(triphenylphosphine)palladium(II) dichloride (162 mg, 0.23 mmol) was added and the reaction mixture was degassed for another 10 minutes. The reaction mixture was heated to 90 °C for 16 h. Completion of the reaction was confirmed by LCMS. The reaction mixture was filtered through a Celite pad and the filtrate was concentrated and purified via standard methods to afford tert- butyl 2-(3-(3-(3-formylphenyl)- lH-indazol-5-yl)- 1H- 1 ,2,4-triazol-5-yl)pyrrolidine- 1 -carboxylate (290 mg, 53%) as off-white solid.
[00171] tert-Butyl 2-(3-(3-(3-((cyclopropylamino)methyl)phenyl)-lH-indazol-5-yl)- lH-l,2,4-triazol-5-yl)pyrrolidine-l-carboxylate. To a stirred solution of tert-butyl 2-(3-(3-(3- formylphenyl)-lH-indazol-5-yl)-lH-l,2,4-triazol-5-yl)pyrrolidine-l -carboxylate (0.22 g, 0.48 mmol) and cyclopropanamine (0.08 g, 1.4 mmol) in methanol (5 mL) were added resin bound sodium cyanotrihydroborate (0.2 g).The resulting mixture was stirred at 60 °C for 40 h. Completion of the reaction was confirmed by LCMS. The reaction was worked-up and the product isolated and purified via standard methods to afford tert-butyl 2-(3-(3-(3- ((cyclopropylamino)methyl)phenyl)- 1 H-indazol-5-yl)- 1 H- 1 ,2,4-triazol-5-yl)pyrrolidine- 1 - carboxylate (0.1 lg, 46%>) as off white solid. [00172] N-(3-(5-(5-(Pyrrolidin-2-yl)-lH-l,2,4-triazol-3-yl)-lH-indazol-3- yl)benzyl)cyclopropanamine. To a stirred solution of tert-butyl 2-(3-(3-(3- ((cyclopropylamino)methyl)phenyl)- 1 H-indazol-5-yl)- 1 H- 1 ,2,4-triazol-5-yl)pyrrolidine- 1 - carboxylate (110 mg) in methanol (3 mL) was added 4.5 N HC1 in dioxane (1 mL) at 0 °C and the reaction was stirred for 16 h at room temperature. Completion of the reaction was monitored by LCMS. The reaction mixture was concentrated under vacuum and then coevaporated with diethyl ether under vacuum. The residue was dissolved in 10% DCM in methanol (20 mL) and neutralized using sodium carbonate. The crude product was isolated and purified via standard methods to afford N-(3-(5-(5-(pyrrolidin-2-yl)-lH-l,2,4-triazol-3-yl)-lH-indazol-3- yl)benzyl)cyclopropanamine (39 mg, 44%). MS (ESI) m/z 400 [M + 1]+.
Example 16. 4-(5-(5-(Piperidin-4-yl)-lH-l,2,4-triazol-3-yl)-lH-indazol-3-yl)benzonitrile
Figure imgf000057_0001
[00173] Ethyl 3-bromo-lH-indazole-5-carbimidate. To a stirred solution of 3-bromo-l- (tetrahydro-2H-pyran-2-yl)-lH-indazole-5-carbonitrile (10 g, 0.032 mmol) in ethanol (500 mL) was bubbled HC1 gas at -15 °C for 30 min. The reaction was stirred for 16 h at room
temperature. Completion of the reaction was confirmed by LCMS. The reaction was worked up via standard methods to afford ethyl 3-bromo-lH-indazole-5-carbimidate (7 g, 81%) as pale yellow solid.
[00174] tert-Butyl 4-(hydrazinecarbonyl)piperidine-l-carboxylate. To a stirred solution of l-(tert-butyl)4-methyl piperidine-l,4-dicarboxylate (1.2 g, 0.49 mmol) in methanol (20 mL) was added hydrazine (2 mL) at room temperature. The reaction was stirred for 16 h at same temperature. The reaction was worked up via standard methods to afford tert-butyl 4- (hydrazinecarbonyl)piperidine-l -carboxylate (1.0 g, 83%) as an off white gummy solid.
[00175] tert-Butyl 4-(3-(3-bromo-lH-indazol-5-yl)-lH-l,2,4-triazol-5-yl)piperidine-l- carboxylate. To a stirred solution of ethyl 3-bromo-lH-indazole-5-carbimidate (0.4 g, 0.15 mmol) and tert-butyl 4-(hydrazinecarbonyl)piperidine-l-carboxylate (0.362 g, 0.15 mmol) in methanol (10 mL) was added DIEA (0.578 g, 0.45 mmol) at room temperature. The reaction was heated at 90 °C for 16 h in a sealed tube. Completion of the reaction was confirmed by LCMS. The reaction was worked up via standard methods to afford tert-butyl 4-(3-(3-bromo-lH- indazol-5-yl)-lH-l,2,4-triazol-5-yl)piperidine-l-carboxylate (0.4 g, 60%) as off white solid.
[00176] tert-Butyl 4-(3-(3-(4-cyanophenyl)- lH-indazol-5-yl)- 1H- 1 ,2,4-triazol-5- yl)piperidine-l-carboxylate. To tert-butyl 4-(3-(3-bromo-lH-indazol-5-yl)-lH-l,2,4-triazol-5- yl)piperidine-l-carboxylate (0.400 g, 0.09 mmol) in methanol (10 mL) was added
(4-cyanophenyl) boronic acid (0.157 g, 0.01 mmol) followed by potassium acetate (0.218 g, 0.22 mmol) at room temperature. The reaction was degassed for 5 minutes, and then
bis(triphenylphosphine)palladium(II) dichloride (0.124 g, 0.02 mmol) was added and the reaction mixture was degassed for another 5 minutes. The reaction mixture was heated at 90 °C for 16 h in sealed tube. Completion of the reaction was confirmed by LCMS. The reaction mixture was filtered through a Celite pad and the filtrate was concentrated and purified via standard methods to afford tert-butyl 4-(3-(3-(4-cyanophenyl)-lH-indazol-5-yl)-lH-l,2,4-triazol-5-yl)piperidine-l- carboxylate (0.2 g, 48%) as off white solid.
[00177] 4-(5-(5-(Piperidin-4-yl)-lH-l,2,4-triazol-3-yl)-lH-indazol-3-yl)benzonitrile.
To a stirred solution of tert-butyl 4-(3-(3-(4-cyanophenyl)-lH-indazol-5-yl)-lH-l,2,4-triazol-5- yl)piperidine-l-carboxylate (0.2 g, 0.04 mmol) in 1, 4-dioxane (6 mL) was added 4.5 N HC1 in dioxane (1 mL) at 0 °C. The reaction was stirred for 16 h at room temperature. Completion of the reaction was monitored by LCMS. The reaction mixture was concentrated under vacuum and then coevaporated with diethyl ether under vacuum. The residue was dissolved in 10% DCM in methanol (20 mL) and neutralized using sodium carbonate. The product was isolated and purified via standard methods to afford 4-(5-(5-(piperidin-4-yl)-lH-l,2,4-triazol-3-yl)-lH-indazol-3- yl)benzonitrile (120 mg, 76%). MS (ESI) m/z 370 [M + 1]+.
Example 17. N-(3-(5-(3-(pyrrolidin-2-yl)-lH-l,2,4-triazol-5-yl)-lH-indazol-3- yl)phenyl)methanesulfonamide
Figure imgf000059_0001
[00178] tert-Butyl 2-(3-(3-(3-(methylsulfonamido)phenyl)-lH-indazol-5-yl)-lH-l,2,4- triazol-5-yl)pyrrolidine-l-carboxylate. To a solution tert-butyl 2-(4-(3-bromo-l-(tetrahydro- 2H-pyran-2-yl)-l H-indazol-5 -yl)-lH-pyrrol-2-yl)pyrrolidine-l -carboxylate (600 mg, 1.39 mmol) in DMF (13 mL) was added (3-(methylsulfonamido)phenyl)boronic acid (448 mg, 2.01 mmol) followed by K3PO4 (1.17 g, 5.55 mmol). The reaction was degassed for 10 minutes.
Tetrakis(triphenylphosphine)palladium(0) (240 mg, 0.21 mmol) was added and the reaction mixture was degassed for another 10 minutes. The reaction mixture was heated to 120 °C for 16 h. Completion of the reaction was confirmed by LCMS. The reaction mixture was filtered through a Celite pad and the filtrate was concentrated and purified via standard methods to afford tert-butyl 2-(3-(3-(3-(methylsulfonamido)phenyl)-lH-indazol-5-yl)-lH-l,2,4-triazol-5- yl)pyrrolidine-l -carboxylate; (80 mg, 10%) as off white solid.
[00179] N-(3-(5-(3-(Pyrrolidin-2-yl)-lH-l,2,4-triazol-5-yl)-lH-indazol-3- yl)phenyl)methanesulfonamide. To a stirred solution of tert-butyl 2-(3-(3-(3- (methylsulfonamido)phenyl)- 1 H-indazol-5 -yl)- 1 H- 1 ,2,4-triazol-5 -yl) pyrrolidine- 1 -carboxylate (80 mg, 0.15 mmol) in methanol (3 mL) was added HC1 in dioxane (1 mL) at 0 °C and the reaction was stirred for 16 h at ambient temperature. The reaction mixture was concentrated under vacuum and then coevaporated with diethyl ether under vacuum. The residue was dissolved in 10% DCM in methanol (20 mL) and neutralized using sodium carbonate. The product was isolated and purified via standard methods to afford N-(3-(5-(3-(pyrrolidin-2-yl)- lH-l,2,4-triazol-5-yl)-lH-indazol-3-yl)phenyl)methanesulfonamide (62 mg, 95%). MS (ESI) m/z 424 [M + 1]+. Example 18. 4-(5-(3-(Morpholinomethyl)-lH-l,2,4-triazol-5-yl)-lH-indazol-3-
Figure imgf000060_0001
[00180] Ethyl 3-bromo-lH-indazole-5-carbimidate. To a stirred solution of 3-bromo-l- (tetrahydro-2H-pyran-2-yl)-lH-indazole-5-carbonitrile (10 g, 32 mmol) in ethanol (500 mL) was bubbled dry HCl gas at -15 °C for 30 min. The reaction was stirred for 16 h at room temperature. Completion of the reaction was confirmed by LCMS. The reaction mixture was concentrated to afford ethyl 3-bromo-lH-indazole-5-carbimidate (7 g, 80%) as pale yellow solid.
[00181] 4-(3-(3-Bromo-lH-indazol-5-yl)-lH-l,2,4-triazol-5-yl)methyl)morpholine. To a stirred solution of ethyl 3-bromo-lH-indazole-5-carbimidate (0.5 g, 1.86 mmol) and
2-morpholinoacetohydrazide (0.29 g, 1.86 mmol; see International Patent Application
Publication No. WO 02/10137, 2002) in methanol (5 mL) were added triethylamine (0.56 g, 5.59 mmol). The reaction was heated at 90 °C for 16 h in a sealed tube. Completion of the reaction was confirmed by LCMS. The reaction mixture worked-up and the product isolated and purified via standard methods to afford 4-(3-(3-bromo-lH-indazol-5-yl)-lH-l,2,4-triazol-5- yl)methyl)morpholine (0.34 g, 50%) as white solid.
[00182] 4-(5-(3-(Morpholinomethyl)-lH-l,2,4-triazol-5-yl)-lH-indazol-3- yl)benzonitrile. To a solution 4-(3-(3-bromo-lH-indazol-5-yl)-lH-l,2,4-triazol-5-yl) methyl)morpholine (0.3 g, 0.83 mmol) in 5 mL of DMF: water (4: 1) was added (4-cyanophenyl) boronic acid (0.18 g, 1.24 mmol) followed by sodium carbonate (0.27 g, 2.48 mmol). The reaction was degassed for 10 minutes. Tetrakis(triphenylphosphine)palladium(0) (95 mg, 0.083 mmol) was added and the reaction mixture was degassed for another 10 minutes. The reaction mixture was heated at 90 °C for 4 h in sealed tube. Completion of the reaction was confirmed by LCMS. The reaction mixture was filtered through a Celite pad and the filtrate was concentrated and purified via standard methods to afford 4-(5-(3-(morpholinomethyl)-lH-l,2,4- triazol-5-yl)-lH-indazol-3-yl)benzonitrile (70 mg, 22%). MS (ESI) m/z 386 [M + 1]+.
Example 19. 4-(5-(5-((Dimethylamino)methyl)-l,3,4-oxadiazol-2-yl)-lH-indazol-3- yl)benzonitrile
Figure imgf000061_0001
[00183] 3-Bromo-l-(tetrahydro-2H-pyran-2-yl)-lH-indazole-5-carboxylic acid. To a stirred solution of 3-bromo-l-(tetrahydro-2H-pyran-2-yl)-lH-indazole-5-carbonitrile (1 g, 3 mmol) in DMSO (10 mL) was added 5N sodium hydroxide solution (3 mL) at room temperature and the reaction was heated at 100 °C for 16 h. Completion of the reaction was confirmed by TLC. The reaction mixture was acidified to pH = 2 with 1.5N HC1 solution. The resulting solid was isolated and purified via standard methods to afford 3-bromo-l-(tetrahydro- 2H-pyran-2-yl)-lH-indazole-5-carboxylic acid (1.05 g, 100%) as brown solid.
[00184] Ethyl dimethyl glycinate. To a stirred solution of ethylbromoacetate (3 g, 20 mmol) in acetonitrile ( 30 mL) was added triethylamine (3.61 g, 30 mmol) at 0 °C. The suspension was stirred for 10 min and dimethylamine solution (0.96 g, 21 mmol) was added slowly at 0 °C The resulting reaction mixture was stirred for 16 h at room temperature.
Completion of the reaction was confirmed by TLC. The product was isolated and purified via standard methods to afford ethyl dimethyl glycinate (1.3 g, 62%) as brown liquid.
[00185] 2-(Dimethylamino)acetohydrazide. To a stirred solution of ethyl
dimethylglycinate (1.3 g, 10 mmol) in ethanol (20 mL) was added hydrazine hydrate (1.5 mL) at 0 °C. The reaction was heated at reflux for 24 h. Completion of the reaction was confirmed by TLC. The product was isolated and purified via standard methods to afford
2-(dimethylamino)acetohydrazide (0.9 g, 69%) as brown liquid. [00186] 3-Bromo-N'-(dimethylglycyl)-l-(tetrahydro-2H-pyran-2-yl)-lH-indazole-5- carbohydrazide. To a stirred solution of 3-bromo-l-(tetrahydro-2H-pyran-2-yl)-lH-indazole-5- carboxylic acid (1 g, 3 mmol) and 2-(dimethylamino)acetohydrazide (0.36 g, 3 mmol) in DMF (15 mL) was added DIEA (1.58 g, 12 mmol) and the reaction was stirred for 10 min at ambient temperature. EDC- HCl (1.17 g, 6 mmol) and HOBt (0.94 g, 6 mmol) were added to the reaction mixture at room temperature and stirring continued at room temperature for 16 h. Completion of the reaction was confirmed by LCMS. The reaction mixture was concentrated and the product was isolated and purified via standard methods to afford 3-bromo-N'-(dimethylglycyl)-l- (tetrahydro-2H-pyran-2-yl)-lH-indazole-5-carbohydrazide (0.58 g, 45%) as dark brown gummy.
[00187] l-(5-(3-Bromo-l-(tetrahydro-2H-pyran-2-yl)-lH-indazol-5-yl)-l,3,4- oxadiazol-2-yl)-N,N-dimethylmethanamine. To a stirred solution of 3-bromo-N'- (dimethylglycyl)- 1 -(tetrahydro-2H-pyran-2-yl)- 1 H-indazole-5 -carbohydrazide (0.58 g,
1.35 mmol) in DCM was added triethylamine (0.416 g, 4.12 mmol) and the reaction was stirred for 10 min at ambient temperature. Tosylchloride (0.391 g, 2.06mmol) was added and stirring continued for 15 h. Completion of the reaction was confirmed by LCMS. The product was isolated and purified via standard methods to afford l-(5-(3-bromo-l-(tetrahydro-2H-pyran-2- yl)-lH-indazol-5-yl)-l,3,4-oxadiazol-2-yl)-N,N-dimethylmethanamine (0.45 g, 80%) as brown gummy solid.
[00188] 4-(5-(5-((Dimethylamino)methyl)-l,3,4-oxadiazol-2-yl)-l-(tetrahydro-2H- pyran-2-yl)-lH-indazol-3-yl)benzonitrile. To a solution l-(5-(3-bromo-l-(tetrahydro-2H- pyran-2-yl)-lH-indazol-5-yl)-l,3,4-oxadiazol-2-yl)-N,N-dimethylmethanamine (400 mg, 0.98 mmol) in 5 mL of 1,4-dioxane: water (4: 1) was added (4-cyanophenyl)boronic acid (170 g, 1.18 mmol) followed by potassium carbonate (407 mg, 2.95 mmol). The reaction was degassed for 5 minutes, and then bis(triphenylphosphine)palladium(II) dichloride (69 mg, 0.098 mmol) was added to the reaction mixture and further degassed for another 10 minutes. The reaction mixture was heated at 90 °C for 16 h. Completion of the reaction was confirmed by LCMS. The reaction mixture was filtered through a Celite pad and the filtrate was concentrated and purified via standard methods to afford4-(5-(5-((dimethylamino)methyl)-l,3,4-oxadiazol-2-yl)-l- (tetrahydro-2H-pyran-2-yl)-lH-indazol-3-yl)benzonitrile (220 mg, 47%) as white solid.
[00189] 4-(5-(5-((Dimethylamino)methyl)-l,3,4-oxadiazol-2-yl)-lH-indazol-3- yl)benzonitrile. To a stirred solution of 4-(5-(5-((dimethylamino)methyl)-l,3,4-oxadiazol-2-yl)- l-(tetrahydro-2H-pyran-2-yl)-lH-indazol-3-yl)benzonitrile (220 mg, 0.51 mmol) in 1,4-dioxane (3 mL) was added 4.5 N HC1 in 1,4-dioxane (2 mL) at 0 °C and the reaction was stirred for 12 h at ambient temperature. Completion of the reaction was confirmed by LCMS. The reaction mixture worked-up and the product isolated and purified via standard methods to afford
4-(5-(5-((dimethylamino)methyl)-l,3,4-oxadiazol-2-yl)-lH-indazol-3-yl)benzonitrile (70 mg, 40%) as a white solid. MS (ESI) m/z 345 [M + 1]+.
Example 20. 4-(5-(5-Oxo-4,5-dihydro-lH-l,2,4-triazol-3-yl)-lH-indazol-3-yl)benzonitrile
Figure imgf000063_0001
[00190] Ethyl 3-bromo-lH-indazole-5-carbimidate hydrochloride salt. Dry HC1 gas was purged into a stirred solution of 3-bromo-l-(tetrahydro-2H-pyran-2-yl)-lH-indazole-5- carbonitrile (15 g, 49 mmol) in ethanol (150 mL) at -15 °C for 30 min. The reaction mixture was then stirred for 16 h at ambient temperature. The product was isolated and purified via standard methods to afford ethyl 3-bromo-lH-indazole-5-carbimidate hydrochloride salt (12 g, 91%) as light brown solid.
[00191] 5-(3-Bromo-lH-indazol-5-yl)-2,4-dihydro-3H-l,2,4-triazol-3-one. To a stirred solution of ethyl 3-bromo-lH-indazole-5-carbimidate (0.5 g, 1.86 mmol) and methyl carbazate (0.17 g, 1.86 mmol) in methanol (5 mL) was added triethylamine (0.56 g, 5.59 mmol). The reaction was heated to 90 °C for 16 h in a sealed tube. Completion of the reaction was confirmed by LCMS. The product was isolated and purified via standard methods to afford 5-(3-bromo-lH- indazol-5-yl)-2,4-dihydro-3H-l,2,4-triazol-3-one (0.45 g, 86%>) as brown solid.
[00192] 4-(5-(5-Oxo-4,5-dihydro-lH-l,2,4-triazol-3-yl)-lH-indazol-3-yl)benzonitrile. To a solution 5-(3-bromo-lH-indazol-5-yl)-2,4-dihydro-3H-l,2,4-triazol-3-one (0.3 g,
1.07 mmol) in 5 mL of DMF: water (4: 1) was added (4-cyanophenyl)boronic acid (0.24 g, 0.61 mmol) followed by sodium carbonate (0.35 g, 3.22 mmol). The reaction was degassed for 10 minutes. Tetrakis(triphenylphosphine)palladium(0) (125 mg, 0.11 mmol) was added and the reaction mixture was degassed for another 10 minutes. The reaction mixture was heated to 120 °C for 16 h. Completion of the reaction was confirmed by LCMS. The reaction mixture was filtered through a Celite pad and the filtrate was concentrated and purified via standard methods to afford 4-(5-(5-oxo-4,5-dihydro-lH-l,2,4-triazol-3-yl)-lH-indazol-3-yl)benzonitrile (40 mg, 12%). MS (ESI) m/z 301 [M - 1]".
Example 21. 4-(5-(3-(Trifluoromethyl)-lH-l,2,4-triazol-l-yl)-lH-indazol-3-yl)benzonitrile
Figure imgf000064_0001
[00193] 3-Bromo-lH-indazol-5-amine. Tin (II) chloride dihydrate (100.4 g,
44.62 mmol) was added portionwise to a solution of 3-bromo-5-nitro-lH-indazole (18.0 g, 7.43 mmol) in ethanol (400 mL) at 0 °C. The reaction mixture was stirred for 14 h at 80 °C. The product was isolated and purified via standard methods to afford 3-bromo-lH-indazol-5-amine (14.5 g, 92%) as light brown solid.
[00194] 4-(5-Amino-lH-indazol-3-yl)benzonitrile. To 3-bromo-lH-indazol-5-amine (9 g, 4.24 mmol) in methanol (100 mL) was added (4-cyanophenyl) boronic acid (7.48 g, 5.08mmol) followed by potassium acetate (12.48 g, 12.72mmol). The reaction was degassed for 10 minutes, and then bis(triphenylphosphine)palladium(II) dichloride (5.94 g, 0.84mmol) was added and the reaction mixture was degassed for another 10 minutes. The reaction mixture was heated at 90 °C for 16 h in sealed tube. Completion of the reaction was confirmed by LCMS. The reaction mixture was filtered through a Celite pad and the filtrate was concentrated and purified via standard methods to afford 4-(5 -amino- lH-indazol-3-yl)benzonitrile (4.5 g, 45%) as off white solid.
[00195] 4-(5-Bromo-lH-indazol-3-yl)benzonitrile. To 4-(5 -amino- lH-indazol-3- yl)benzonitrile (4.5 g, 1.92mmol) in acetonitrile (90 mL) was added copper (I) bromide (11.2 g,7.68mmol) at room temperature. The reaction was stirred for 15 min then tert- butylnitrite (9.2 mL, 7.68mmol) was added to the reaction mixture. The reaction mixture was heated at 70 °C for 45 minutes. The product was isolated and purified via standard methods to afford 4-(5-bromo-lH-indazol-3-yl)benzonitrile (1.6 g, 28%) as an off white solid.
[00196] 4-(5-(3-(Trifluoromethyl)-lH-l,2,4-triazol-l-yl)-lH-indazol-3-yl)benzonitrile. To 4-(5-bromo-lH-indazol-3-yl)benzonitrile (0.2 g, 0.06mmol) in acetonitrile (10 mL) was added cesium flouride (0.203 g, 1.39mmol) and copper iodide (0.019 g, O.Olmmol), followed by N-methyl-2-(methylamino)ethylamine (0.009 g, O.Olmmol) and 3-(trifluoromethyl)-lH-l,2,4- triazole (0.137 g, O.Olmmol) at room temperature. The reaction was heated at 140 °C for 4 h under microwave irradiation. The reaction mixture was cooled to room temperature. The product was isolated and purified via standard methods to afford 4-(5-(3-(trifluoromethyl)-lH- l,2,4-triazol-l-yl)-lH-indazol-3-yl)benzonitrile (30 mg, 12%). MS (ESI) m/z 353 [M - 1]".
Example 22. 4-(5-(5-(Pyrrolidin-2-yl)-l,3,4-oxadiazol-2-yl)-lH-indazol-3-yl)benzonitrile
Figure imgf000065_0001
[00197] 3-Bromo-l-(tetrahydro-2H-pyran-2-yl)-lH-indazole-5-carboxylic acid. To a stirred solution of 3-bromo- l-(tetrahydro-2H-pyran-2-yl)-lH-indazole-5-carbonitrile (5 g, 16 mmol) in DMSO (50 mL) was added 5N sodium hydroxide solution (10 mL). The reaction was heated at 100 °C for 16 h. Completion of the reaction was confirmed by TLC. The product was isolated and purified via standard methods to afford 3-bromo-l-(tetrahydro-2H-pyran-2-yl)- lH-indazole-5-carboxylic acid (5 g, 94%>) as brown solid.
[00198] tert-Butyl 2-(2-(3-bromo-l-(tetrahydro-2H-pyran-2-yl)-lH-indazole-5- carbonyl) hydrazine-l-carbonyl) pyrrolidine-l-carboxylate. To a stirred solution of 3-bromo- l-(tetrahydro-2H-pyran-2-yl)-lH-indazole-5-carboxylic acid (1 g, 3 mmol) and tert-butyl 2- (hydrazinecarbonyl)pyrrolidine-l-carboxylate (0.7 g, 3 mmol; see Example 1) in N,N-dimethyl formamide (15 mL) was added DIEA (1.58 g, 12 mmol) and the reaction was stirred for 10 min at ambient temperature. EDC-HC1 (1.17 g, 6 mmol) and HOBt (0.94 g, 6 mmol) were added to the reaction mixture at room temperature and stirring continued at room temperature for 16 h. Completion of the reaction was confirmed by LCMS. The reaction mixture was concentrated and the product was isolated and purified via standard methods to afford tert-butyl 2-(2-(3-bromo-l- (tetrahydro-2H-pyran-2-yl)- 1 H-indazole-5 -carbonyl) hydrazine- 1 -carbonyl) pyrrolidine- 1 - carboxylate (0.6 g) as white gummy solid.
[00199] tert-Butyl 2-(5-(3-bromo-l-(tetrahydro-2H-pyran-2-yl)-lH-indazol-5-yl)- l,3,4-oxadiazol-2-yl) pyrrolidine-l-carboxylate. To a stirred solution of tert-butyl 2-(2-(3- bromo- 1 -(tetrahydro-2H-pyran-2-yl)- 1 H-indazole-5 -carbonyl)hydrazine- 1 -carbonyl)pyrrolidine- 1-carboxylate (0.6 g, 1.12 mmol) in DCM was added triethylamine (0.34 g, 3.35 mmol) and the reaction was stirred for 10 min. Tosylchloride (0.32 g, 1.68 mmol) was added and the stirring was continued for 15 h. The product was isolated and purified via standard methods to afford tert-butyl 2-(5-(3-bromo-l-(tetrahydro-2H-pyran-2-yl)-lH-indazol-5-yl)-l,3,4-oxadiazol-2-yl) pyrrolidine-l-carboxylate (0.6 g) as colorless gummy solid.
[00200] tert-Butyl 2-(5-(3-(4-cyanophenyl)-l-(tetrahydro-2H-pyran-2-yl)-lH-indazol- 5-yl)-l,3,4-oxadiazol-2-yl)pyrrolidine-l-carboxylate. To a solution tert-butyl 2-(5-(3-bromo-l- (tetrahydro-2H-pyran-2-yl)- 1 H-indazol-5 -yl)- 1 ,3 ,4-oxadiazol-2-yl)pyrrolidine- 1 -carboxylate (350 mg, 0.67 mmol) in methanol (10 mL) was added (4-cyanophenyl)boronic acid (150 g, 1.01 mmol) followed by potassium acetate (200 mg, 2.02 mmol). The reaction was degassed for 10 minutes, and then bis(triphenylphosphine)palladium(II) dichloride (95 mg, 0.13 mmol) was added and the reaction mixture was degassed for another 10 minutes. The reaction mixture was heated at 90 °C for 16 h in sealed tube. Completion of the reaction was confirmed by HPLC. The reaction mixture was filtered through a Celite pad and the filtrate was concentrated and purified via standard methods to afford tert-butyl 2-(5-(3-(4-cyanophenyl)-l-(tetrahydro-2H-pyran-2-yl)- 1 H-indazol-5 -yl)-l, 3, 4-oxadiazol-2-yl)pyrrolidine-l -carboxylate (150 mg, 41%) as pale yellow solid.
[00201] 4-(5-(5-(Pyrrolidin-2-yl)-l,3,4-oxadiazol-2-yl)-lH-indazol-3-yl)benzonitrile.
To a stirred solution of tert-butyl 2-(5-(3-(4-cyanophenyl)-l-(tetrahydro-2H-pyran-2-yl)-lH- indazol-5-yl)-l,3,4-oxadiazol-2-yl)pyrrolidine-l-carboxylate (130 mg, 0.24 mmol) in DCM (5 mL) was added TFA (0.5 mL) at 0 °C and the reaction was stirred for 12 h. Completion of the reaction was confirmed by HPLC. The product was isolated and purified via standard methods to afford 4-(5-(5-(pyrrolidin-2-yl)-l,3,4-oxadiazol-2-yl)-lH-indazol-3-yl)benzonitrile (38 mg, 45%) as a white solid. MS (ESI) m/z 357 [M + 1]+.
Example 23. 4-(5-(l -Imidazol-2-yl)-lH-indazol-3-yl)benzonitrile
Figure imgf000067_0001
[00202] 3-Bromo-5-(lH-imidazol-2-yl)-lH-indazole. To ethyl 3-bromo-lH-indazole-5- carbimidate hydrochloride (1.5 g, 5.59 mmol) in ethanol (20 mL) was added acetic acid (3.35 g, 5.59 mmol) and amino acetalaldehyde dimethyl acetal (0.705 g, 0.67mmol) at room temperature. The reaction mixture was stirred for 3 h at 70 °C. The mixture was cooled to room temperature and treated dropwise with 6N HC1 solution (15 mL). The reaction was then heated at 90 °C for 6 h. The product was isolated and purified via standard methods to afford 3-bromo-5-(lH- imidazol-2-yl)-lH-indazole (1.4 g, 95%) as pale brown solid.
[00203] 4-(5-(lH-Imidazol-2-yl)-lH-indazol-3-yl)benzonitrile. To 3-bromo-5-(lH- imidazol-2-yl)-lH-indazole (0.350 g, 1.32 mmol) in 10 mL of DMF: water (9: 1) was added (4- cyanophenyl)boronic acid (0.388 g, 2.64 mmol) followed by sodium carbonate (0.703 g, 6.64 mmol). The reaction was degassed for 10 minutes, and then
bis(triphenylphosphine)palladium(II) dichloride (0.388 g, 0.05 mmol) was added and the reaction was degassed for a further 10 minutes, then heated at 120 °C under microwave irradiation for 2 h. Completion of the reaction was confirmed by LCMS. The reaction mixture was filtered through a Celite pad and the filtrate was concentrated and purified via standard methods to afford 4-(5-(lH-imidazol-2-yl)-lH-indazol-3-yl)benzonitrile (20 mg, 5%). MS (ESI) m/z 286 [M + 1]+. Example 24. 3-(5-(lH-Imidazol-2-yl)-lH-indazol-3-yl)-N-methylbenzamide
Figure imgf000068_0001
[00204] 3-(5-(lH-Imidazol-2-yl)-lH-indazol-3-yl)-N-methylbenzamid. 3-Bromo-5-(lH- imidazol-2-yl)-lH-indazole (0.350 g, 1.32 mmol) in 10 mL of DMF: water (9: 1) was added (3-(methylcarbamoyl) phenyl) boronic acid (0.472 g, 2.64 mmol) followed by sodium carbonate (0.703 g, 6.64 mmol). The reaction was degassed for 10 minutes, and then
bis(triphenylphosphine)palladium(II) dichloride (0.388 g, 0.05 mmol) was added and the reaction mixture was degassed for another 10 minutes. The reaction mixture was heated at 120 °C for 2 h in sealed tube. Completion of the reaction was confirmed by LCMS. The reaction mixture was filtered through a Celite pad and the filtrate was concentrated and purified via standard methods to afford 3-(5-(lH-imidazol-2-yl)-lH-indazol-3-yl)-N-methylbenzamide (13 mg, 3%). MS (ESI) m/z 318 [M + 1]+.
Example 25. 3-(5-( -Imidazol-2-yl)-lH-indazol-3-yl)benzonitrile
Figure imgf000068_0002
[00205] 3-(5-(lH-Imidazol-2-yl)-lH-indazol-3-yl)benzonitrile. 3-Bromo-5-(lH- imidazol-2-yl)-lH-indazole (0.350 g, 1.32 mmol) in 10 mL of DMF: water (9: 1) was added (3-(methylcarbamoyl) phenyl)boronic acid (0.472 g, 2.64 mmol) followed by sodium carbonate (0.703 g, 6.64 mmol). The reaction was degassed for 10 minutes, and then bis(triphenylphosphine)palladium(II) dichloride (0.388 g, 0.05 mmol) was added and the reaction mixture was degassed for another 10 minutes. The reaction mixture was heated at 120 °C for 2 h in sealed tube. Completion of the reaction was confirmed by LCMS. The reaction mixture was filtered through a Celite pad and the filtrate was concentrated and purified via standard methods to afford 3-(5-(lH-imidazol-2-yl)-lH-indazol-3-yl) benzonitrile (45 mg, 12%). MS (ESI) m/z 284 [M - 1]".
Example 26. N-Cyclopropyl-3-(5-(5-(2,2,2-trifluoroethyl)-l,3,4-oxadiazol-2-yl)-lH-indazol-
3-yl)benzamide
Figure imgf000069_0001
[00206] 3,3,3-trifluoropropanehydrazide. To a stirred solution of methyl
3,3,3-trifluoropropanoate (3 g, 21 mmol) in methanol (30 mL) was added anhydrous hydrazine hydrate (3 mL) at 0 °C. The reaction was stirred at room temperature for 25 h. The product was isolated and purified via standard methods to afford 3,3,3-trifluoropropanehydrazide (2.1 g, 70%)) as pale brown solid.
[00207] 3-Bromo-l-(tetrahydro-2H-pyran-3-yl)-N'-(3,3,3-trifluoropropanoyl)-lH- indazole-5-carbohydrazide. To a stirred solution of 3-bromo-l-(tetrahydro-2H-pyran-2-yl)-lH- indazole-5-carboxylic acid (2.5 g, 7.6 mmol) and 3,3,3-trifluoropropanehydrazide (1.1 g, 7.6 mmol) in DMF (25 mL) was added DIEA (3.92 g, 30.4 mmol). EDC (2.9 g, 15 mmol) and HOBT (2.3 g, 15 mmol) were added to the reaction mixture at room temperature and stirring continued at room temperature for 16 h. Completion of the reaction was confirmed by LCMS. The product was isolated and purified via standard methods to afford 3-bromo-l-(tetrahydro-2H- pyran-3-yl)-N'-(3,3,3-trifluoropropanoyl)-lH-indazole-5-carbohydrazide (1.5 g, 43%>) as a white solid.
[00208] 2-(3-bromo-l-(tetrahydro-2H-pyran-2-yl)-lH-indazol-5-yl)-5-(2,2,2- trifluoroethyl)-l,3,4-oxadiazole. To a stirred solution 3-bromo-l-(tetrahydro-2H-pyran-3-yl)- N'-(3,3,3-trifluoropropanoyl)-lH-indazole-5-carbohydrazide (1.5 g, 3.3 mmol) in DCM was added triethylamine (1 g, 10 mmol). Tosylchloride (0.95 g, 5 mmol) was added and the reaction was stirred at room temparature for 15 h. Completion of the reaction was confirmed by LCMS. The product was isolated and purified via standard methods to afford 2-(3-bromo-l-(tetrahydro- 2H-pyran-2-yl)-lH-indazol-5-yl)-5-(2,2,2-trifluoroethyl)-l,3,4-oxadiazole (1 g, 69%) as white solid.
[00209] 2-(3-bromo-lH-indazol-5-yl)-5-(2,2,2-trifluoroethyl)-l,3,4-oxadiazole. To a stirred solution of 2-(3-bromo-l-(tetrahydro-2H-pyran-2-yl)-lH-indazol-5-yl)-5-(2,2,2- trifluoroethyl)-l,3,4-oxadiazole (1 g, 2.3 mmol) in DCM (20 mL) was added TFA (5 mL) at 0 °C. The reaction was stirred for 12 h. Completion of the reaction was confirmed by HPLC. The product was isolated and purified via standard methods to afford 2-(3-bromo-lH-indazol-5-yl)-5- (2,2,2-trifluoroethyl)-l,3,4-oxadiazole (0.7 g, 87%) as off-white solid
[00210] N-Cyclopropyl-3-(5-(5-(2,2,2-trifluoroethyl)-l,3,4-oxadiazol-2-yl)-lH-indazol- 3-yl)benzamide. To a solution of 2-(3-bromo-l-(tetrahydro-2H-pyran-2-yl)-lH-indazol-5-yl)-5- (2,2,2-trifluoroethyl)-l,3,4-oxadiazole (300 mg, 0.86 mmol) in methanol (6 mL) was added (3-(cyclopropylcarbamoyl)phenyl)boronic acid (266 g, 1.3 mmol) followed by potassium acetate (255 mg, 2.60 mmol). The reaction was degassed for 10 minutes, and then
bis(triphenylphosphine)palladium(II) dichloride (0.124 g, 0.02 mmol) was added and the reaction mixture was degassed for another 10 minutes. The reaction mixture was heated at 100 °C for 1 h under microwave irradiation. Completion of the reaction was confirmed by LCMS. The reaction mixture was filtered through a Celite pad and the filtrate was concentrated and purified via standard methods to afford N-cyclopropyl-3-(5-(5-(2,2,2-trifluoroethyl)-l,3,4- oxadiazol-2-yl)-lH-indazol-3-yl)benzamide (28 mg, 8%). MS (ESI) m/z 426 [M - 1]".
ANTI-MALARIAL and ANTI-BABESIA in vitro ASSAYS
[00211] Plasmodium falciparum in vitro [3H]-hypoxanthine parasite growth
inhibition assay.
[00212] Preparation of host erythrocytes: Human erythrocytes for parasite culture were prepared by drawing blood into heparin-treated tubes and washing several times in
RPMI 1640 medium to separate the erythrocytes from the plasma and buffy coat. Separation was achieved by centrifuging the blood at 500 x g for 5 minutes in a swing-out rotor. Leukocyte-free erythrocytes were typically stored at 50% hematocrit (i.e. 1 volume of malaria culture media for 1 volume of packed erythrocytes, corresponding to approximately 5 x 109 cells/mL).
[00213] Parasite culture conditions: P. falciparum asexual blood stage parasites were propagated at 37 °C in malaria culture media at 3-5% hematocrit in a reduced oxygen environment (e.g. a custom mixture of 5% C02, 5% 02 and 90%> N2). Lines were conveniently cultured in 6-24 well tissue culture plates in a modular chamber (Billups- Rothenberg, Del Mar, CA, www.brincubator.com), with plates containing sterile water on the bottom to increase humidity and minimize desiccation. These chambers were suffused with the low 02 gas and maintained at 37 °C in an incubator designed to minimize temperature fluctuations. Parasites could also be cultured in flasks that are individually gassed, or alternatively placed in flasks that permit gas exchange through the cap (in which case the incubator needs to be continuously infused with a low 02 gas mixture). Parasites typically propagated 3-8 fold every 48 h, thus care was taken to avoid parasite cultures attaining too high a parasitemia (i.e. percentage of erythrocytes that are parasitized) for healthy growth. Optimal growth was at 0.5 - 4% parasitemia. Parasites were most suitable for assays when they are 2-5% parasitemia, and mostly ring stages with few or no gametocytes.
[00214] Preparation of compounds for assay: The Indazole Compounds were dissolved in 100% dimethyl sulfoxide (DMSO) and stored at -80 °C (or -20 °C). For the assay, serial compound dilutions (either 2x or customized) were made in low hypoxanthine medium (see above) and added to 96-well culture plates at 100 mL per well. Compounds were added to columns 3-12 (test samples), with columns 1 and 2 reserved for wells with low hypoxanthine medium without compound. Once completed, plates were placed into their own modular chamber, gassed and placed at 37 °C. These plates were set up no more than three hours prior to addition of the parasites.
[00215] Assay conditions: Parasites were diluted to a 2x stock consisting of 0.6% to 0.9% parasitemia and 3.2% hematocrit in low hypoxanthine medium, and 100 mL were added per well already containing 100 mL of low hypoxanthine medium with or without compound (present at different concentrations). Plates were then incubated in a gassed modular chamber at 37 °C for 48 h. After this time, 100 mL of culture supernatant from each well was removed and replaced with 100 mL of low hypoxanthine medium containing a final concentration of 7.5 mCi/mL of [3H]-hypoxanthine (1 mCi/mL stock, Amersham Biosciences). After a further 24 h, the plates were placed at-80 °C for at least 1 h to freeze the cells. Plates are then thawed and the cells were harvested onto glass fiber filters (Wallac, Turku, Finland). Filters were dried for 30 minutes at 80 °C, placed in sample bags (Wallac), and immersed in scintillation fluid (Ecoscint A; National
Diagnostic, Atlanta, GA). Radioactive emissions are counted in a 1205 Betaplate reader (Wallac). Mean counts per minute (cpm) were generally in the range 20,000-60,000, with an acceptable minimum of 10,000. Percentage reduction in [3H]- hypoxanthine uptake was equal to lOOx ((geometric mean cpm of no compound samples) - (mean cpm of test samples)) / (geometric mean cpm of no compound samples). Percentage reductions were used to plot percentage inhibition of growth as a function of compound concentrations. IC50 values were determined by linear regression analyses on the linear segments of the curves. (D. A. Fidock, P. J. Rosenthal, S. L. Croft, R. Brun, S. Nwaka, Nature Rev. Drug Discovery, 2004, 3, 509-520.)
[00216] Assay data analysis. Assay data is analyzed using Graph pad prism ver.5 software. A variable sigmoid dose response curve is plotted keeping log concentrations at X-axis and % inhibition at Y-axis.
[00217] Babesia spp. in vitro SYBR Green fluorescence parasite growth inhibition assay. Assay is described for B. bovis and can be applied to other Babesia strains.
[00218] Reagents. SG I nucleic acid stain purchased from Lonza (USA) was stored frozen at -20 °C as lOOOOx stock solution, and freshly thawed before use. Lysis buffer consisted of Tris (20 mM; pH 7.5), EDTA (5 mM), saponin (0.008%; W/V), and Triton X-100 (0.08%; V/V) was prepared in advance and stored at 4 °C. The Indazole
Compounds were prepared as 10 mM, 50 mM, 20 mM, and 50 mM stock solutions, respectively.
[00219] In vitro cultivation of Babesia bovis. B. bovis (Texas strain) was maintained by using a microaerophilic stationary-phase culture system (Igarashi et al., 1994). Briefly, medium 199 was supplemented with 40 %> bovine serum, 60 U/mL of penicillin G, 60 μ§/ηι1 of streptomycin, and 0.15 μg/mL of amphotericin B (Sigma- Aldrich) was used for the in vitro cultivation of B. bovis. The culture plates which contain the medium, parasites-infected red blood cells (iRBCs), and normal bovine RBCs were incubated at 37 °C in an atmosphere of 5% C02, 5% 02, and 90% N2. The medium was replaced every day with fresh one.
[00220] Assessment of fluorescence linearity. B. bovis iRBCs were serially diluted with uninfected-RBCs to adjust the parasitemias ranging from 0.25 to 8%. Uninfected RBCs were used as a control. Thin blood smear was prepared from each dilution and stained with Giemsa to confirm the parasitemia by microscopy. In 96-wells plate, 100 of lysis buffer which contained 2x SYBR Green I was added to 100 μΐ, of each dilution of the iRBCs in triplicate and incubated in dark place at room temperature for 1 hour.
Subsequently, fluorescence values were determined by using a fluorescence plate reader (Fluoroskan Ascent, Thermo Labsystems, USA) at 485 nm and 518 nm excitation and emission wavelengths, respectively. Gain values were set to 100. The fluorescence (after subtracted by the uninfected RBCs) and parasitemia values were plotted and analyzed by linear regression.
[00221] Antibabesial screening by fluorescence-based method. The experiment was conducted by using 96-wells culture plates. Only sixty interior wells were used in this experiment, due to buffer-evaporation during incubation. Two hundred microliters of medium, medium with indicated compound concentrations, and 10% hematocrit with 1% B. bovis iRBCs or uninfected-RBCs as blank control were loaded into each well, in triplicate. The medium, and solvents were replaced every day. Thin blood smears were prepared every day after initiation of the experiment to calculate the parasitemia by microscopy; 100 μΐ, of culture from each well was separated to a new 96-wells plate and 100 μί of lysis buffer which contained 2x SYBR Green I was added into each well and incubated in dark place at room temperature for 1 hour. Fluorescence values were determined as described above. The fluorescence values (after subtracted by the uninfected RBCs) were plotted against the logarithm of drug concentrations to monitor the rate of inhibition and to calculate IC50 values by GraphPad Prism ver.5 (GraphPad Software, USA). (Guswanto, Azirwan; Sivakumar, Thillaiampalam; Abdo Rizk, Mohamed; Abd Elsalam Elsayed, Shimaa; Youssef, Mohamed Ahmed; ElSaid, ElSaid El Shirbini; Yokoyama, Naoaki; Igarashi, Ikuo, Antimicrobial Agents and Chemotherapy, 2014, 58, 4713-4717.)
ACTIVITY TABLES
[00222] Each of the compounds in Table 1 and Table 2 was tested in one or more of the malaria assays and was found to have activity therein, with all of the Indazole
Compounds of Formula (I) having an IC50 below or at 2 μΜ in the assay, with some compounds having an IC50 between 1 and 2 μΜ (activity level A), some having an IC50 between 0.5 μΜ and 1 μΜ (activity level B), and some having an IC50 below 0.5 μΜ (activity level C).
[00223] Table 1.
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0001
Figure imgf000077_0001
Figure imgf000078_0001
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000082_0001
Figure imgf000083_0002
0224] Table 2.
Figure imgf000083_0001
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000086_0001
Figure imgf000087_0001
Figure imgf000088_0001
Figure imgf000089_0001
Figure imgf000090_0001
Figure imgf000091_0001
Figure imgf000092_0001
[00225] Characterization of the compounds in Table 2 by observed MS is described in International Patent Application Publication No. WO 02/10137, 2002; United States patent application publication No. US 2004/0127536; United States patent application publication No. US 2005/0107386; or United States patent application publication No. US 2005/0009876.
[00226] A number of references have been cited, the disclosures of which are incorporated herein by reference in their entirety.

Claims

What is claimed is:
1. A method of treating or preventing malaria, comprising administering to a subject in need thereof an effective amount of a compound of Formula (I),
Figure imgf000093_0001
or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, or isotopologue thereof, wherein:
R1 is -H or -CH3;
R2 is -C(=0)NRR#, or substituted or unsubstituted 5-membered nitrogen- containing heteroaryl, wherein the heteroaryl is optionally fused to a second ring;
Y is selected from:
a. pyridyl, optionally substituted with -NRC(=0)(Ci_4 alkyl), or
-NRC(=0)(C3_6 cycloalkyl);
b. quinolyl; or
c. phenyl, substituted with one or more substituents selected from halogen, -CN, -(Ci-3 alkyl) optionally fluorinated, -S02(Ci_3 alkyl), -(Ci_3 alkyl)NR(C3_6 cycloalkyl), -(Ci-3 alkyl)heterocyclyl, -0(Ci_3 alkyl)heterocyclyl, -C(=0)NRR', -NRC(=0)R",
-NRS02(Ci_3 alkyl), or substituted or unsubstituted 5-membered heteroaryl;
wherein
R is -H or substituted or unsubstituted (C1-3 alkyl),
R' is substituted or unsubstituted (C1-4 alkyl), substituted or unsubstituted
(C3_6 cycloalkyl), substituted or unsubstituted aryl, or substituted or unsubstituted aralkyl;
R" is substituted or unsubstituted (C3_6 cycloalkyl), substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and Rff is -H or -OH.
2. The method of claim 1, wherein R1 is -H.
3. The method of claim 1 , wherein R2 is -C(=0)NH2 or -CONHOH.
4. The method of claim 1 , wherein R2 is substituted or unsubstituted imidazolyl, oxazolyl, triazolyl, tetrazolyl, triazolinonyl, or benzimidazolyl.
5. The method of claim 4, wherein R2 is substituted with substituted or unsubstituted (C1-4 alkyl), substituted or unsubstituted (C3-6 cycloalkyl), substituted or unsubstituted (C0-4 alkyl)(heterocyclyl), or substituted or unsubstituted aryl.
6. The method of claim 4, wherein R2 is substituted with (C1-4 alkyl) substituted with one or more -F, -OH, or -NR2; (C1-4 cycloalkyl); (C0-4 alkyl)pyrrolidinyl; (Co-4 alkyl)pyrrolidinonyl; (C0-4 alkyl)morpholinyl; (C0-4 alkyl)piperidyl; pyridyl; or phenyl, substituted with halogen.
7. The method of claim 4, wherein R2 is substituted with -CH2CH3,
-CH(CH3)2, -C(CH3)3, -CH2CH(CH3)2, -CH2C(CH3)3, -CH(CH3)CH2CH3,
-C(CH3)2CH2CH3; -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CH2F,
-CH2CH2CHF2, -CH2CH2CF3, -CH(OH)CH3, -CH2N(CH3)2; cyclopropyl, cyclobutyl, cyclopentyl; pyrrolidinyl; -CH2(pyrrolidinyl); pyrrolidinonyl; -CH2(pyrrolidinonyl); morpholinyl; -CH2(morpholinyl); piperidyl; -CH2(piperidyl); pyridyl; or chlorophenyl.
8. The method of claim 4, wherein R2 is substituted with -CH(CH3)2, -C(CH3)3, -CH2CH(CH3)2, -C(CH3)2CH2CH3, -CF3, -CH2CH2F, -CH2CF3, -CH2CH2CF3, -CH(OH)CH3, -CH2N(CH3)2; cyclobutyl; pyrrolidinyl; -CH2(pyrrolidinyl);
-CH2(pyrrolidinonyl); -CH2(morpholinyl); piperidyl; -CH2(piperidyl); pyridyl; or chlorophenyl.
9. The method of claim 8, wherein R2 is triazolyl.
10. The method of claim 8, wherein R2 is oxazolyl.
11. The method of claim 8, wherein R2 is oxazolyl, substituted with -CH2CF3, -CH2N(CH3)2, pyrrolidinyl, or -CH2(morpholinyl).
12. The method of claim 1 , wherein Y is phenyl, substituted with one or more substituents selected from -F, -CI, -CN, -CF3, -S02CH3, -CH2NH(C3_4 cycloalkyl), -CH2(non-aromatic heterocyclyl), -0(Ci_2 alkyl)(non-aromatic heterocyclyl),
-C(=0)NHR', -C(=0)N(CH3)R', -NHC(=0)R", -NRS02CH3, or substituted or unsubstituted imidazolyl, pyrazolyl, or triazolyl.
13. The method of claim 1, wherein Y is phenyl, substituted with one or more substituents selected from -F, -CI, -CN, -CF3, -S02CH3, -CH2NH(C3_4 cycloalkyl), -CH2(non-aromatic heterocyclyl), -0(Ci_2 alkyl)(non-aromatic heterocyclyl),
-C(=0)NH(substituted or unsubstituted (Ci_4 alkyl)), -C(=0)NH(substituted or
unsubstituted (C3_6 cycloalkyl)), -C(=0)N(CH3)(substituted or unsubstituted (Ci_4 alkyl)), -C(=0)N(CH3)(substituted or unsubstituted (C3_6 cycloalkyl)), -NHC(=0)(substituted or unsubstituted (C3_6 cycloalkyl)), -NHS02CH3, or substituted or unsubstituted imidazolyl, pyrazolyl, or triazolyl.
14. The method of claim 1 , wherein Y is phenyl, substituted with one or more substituents selected from -F, -CI, -CN, -CF3, -S02CH3, -CH2NH(cyclopropyl),
-CH2(pyrrolidinyl), -OCH2CH2(morpholinyl), -C(=0)NH2, -C(=0)NHCH3,
-C(=0)NHCH2CH3, -C(=0)NHCH2CH2CH3, -C(=0)N(CH3)2, -C(=0)NHCH2CH2OCH3, -C(=0)NH(cyclopropyl), -C(=0)NH(cyclobutyl), -C(=0)NH(cyclopentyl),
-C(=0)NH(hydroxycyclohexyl), -C(=0)N(CH3)(cyclopropyl), -C(=0)NH(phenyl), -C(=0)NHCH2(fiuorophenyl), -NHC(=0)(cyclopropyl), -NHC(=0)(pyridyl),
-NHC(=0)(methylphenyl), -NHS02CH3, imidazolyl, pyrazolyl, or triazolyl.
15. The method of claim 1 , wherein Y is
Figure imgf000096_0001
wherein:
Ra is -H, -F, -CI, -CN, -CF3, -S02CH3, -CH2NH(cyclopropyl), -CH2(pyrrolidinyl), -OCH2CH2(morpholinyl), -C(=0)NH2, -C(=0)NHCH3,
-C(=0)NHCH2CH3, -C(=0)NHCH2CH2CH3, -C(=0)N(CH3)2, -C(=0)NH(cyclopropyl), -C(=0)NH(cyclobutyl), -C(=0)NH(cyclopentyl), -C(=0)NH(hydroxycyclohexyl), -C(=0)N(CH3)(cyclopropyl), -C(=0)NH(phenyl), -C(=0)NHCH2(fluorophenyl),
-NHC(=0)(cyclopropyl), -NHC(=0)(pyridyl), -NHC(=0)(methylphenyl), -NHS02CH3, imidazolyl, pyrazolyl, or triazolyl;
Rb is -H, -F, -CI, -CN, -CF3, -S02CH3, -CH2NH(cyclopropyl), -C(=0)NHCH3, -C(=0)NHCH2CH3, -C(=0)NHCH2CH2OCH3, -OCH2CH2(morpholinyl), -NHC(=0)(pyridyl); and
Rc is -H, or -F;
with the proviso that Ra, Rb and Rc are not simultaneously -H.
16. The method of claim 15, wherein Ra is -H, -F, -CI, -CN, -S02CH3,
-CH2NH(cyclopropyl), -C(=0)NHCH3, -C(=0)NHCH2CH2CH3, -C(=0)NH(cyclopropyl), -C(=0)NH(cyclobutyl), -C(=0)NH(hydroxycyclohexyl), -C(=0)N(CH3)(cyclopropyl), -C(=0)NH(phenyl), -NHC(=0)(pyridyl), or -NHS02CH3.
17. The method of claim 15, wherein Rb is -H, -F, -CI, -CN, or -C(=0)NHCH3.
18. The method of claim 15, wherein Rc is -H or -F.
19. The method of claim 1, wherein the compound is a compound of Table 1.
20. The method of claim 1, wherein the compound is a compound of Table 2.
21. The method of claim 1 , wherein the malaria is caused by Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, Plasmodium knowlesi or Plasmodium malariae.
22. The method of claim 1, additionally comprising administering an effective amount of one or more of chloroquine, quinine, quinidine, melfloquine, atovaquone,
proguanil, doxycycline, artesunate, artemether, artemisinin, lumefantrine, amodiaquine, hydroxychloroquine, halofantrine, pyrimethamine, sulfadoxine, or primaquine.
23. A method of treating or preventing babesiosis, comprising administering to a subject in need thereof an effective amount of a compound of Formula (II),
Figure imgf000097_0001
or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, or isotopologue thereof, wherein:
R1 is -H or -CH3;
R3 is -C(=0)NRRx, or substituted or unsubstituted 5-membered nitrogen- containing heteroaryl, wherein the heteroaryl is optionally fused to a second ring;
Y is selected from:
a. pyridyl, optionally substituted with -NRC(=0)(Ci_4 alkyl), or
Figure imgf000097_0002
cycloalkyl);
b. quinolyl; or
c. phenyl, substituted with one or more substituents selected from halogen, -CN, -(Ci-3 alkyl) optionally fluorinated, -S02(Ci_3 alkyl), -(Ci_3 alkyl)NR(C3_6 cycloalkyl), -(Ci-3 alkyl)heterocyclyl, -0(Ci_3 alkyl)heterocyclyl, -C(=0)NRR', -NRC(=0)R", -NRS02(Ci_3 alkyl), or substituted or unsubstituted 5-membered heteroaryl;
wherein
R is -H or substituted or unsubstituted (C1-3 alkyl),
R' is substituted or unsubstituted (C1-4 alkyl), substituted or unsubstituted
(C3_6 cycloalkyl), substituted or unsubstituted aryl, or substituted or unsubstituted aralkyl;
R" is substituted or unsubstituted (C3_6 cycloalkyl), substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and
Rx is -H or -(Ci_4 alkyl)(non-aromatic heterocyclyl).
24. The method of claim 23, wherein R1 is -H.
25. The method of claim 23, wherein R3 is -C(=0)NH(Ci_2 alkyl)(5-membered non-aromatic heterocyclyl).
26. The method of claim 23, wherein R3 is -C(=0)NH(Ci_2 alkyl)(pyrrolidinyl).
27. The method of claim 23, wherein R3 is -C(=0)NHCH2CH2(pyrrolidinyl).
28. The method of claim 23, wherein R3 is substituted or unsubstituted
imidazolyl, oxazolyl, triazolyl, tetrazolyl, triazolinonyl, or benzimidazolyl.
29. The method of claim 28, wherein R3 is substituted with substituted or
unsubstituted (C1-4 alkyl), substituted or unsubstituted (C3_6 cycloalkyl), substituted or unsubstituted (C0-4 alkyl)(heterocyclyl), or substituted or unsubstituted aryl.
30. The method of claim 28, wherein R3 is substituted with (C1-4 alkyl)
substituted with one or more -F, -OH, or -NR2; (C1-4 cycloalkyl); (C0-4 alkyl)pyrrolidinyl;
(Co-4 alkyl)pyrrolidinonyl; (C0-4 alkyl)morpholinyl; (C0-4 alkyl)piperidyl; pyridyl; or
phenyl, substituted with halogen.
31. The method of claim 28, wherein R3 is substituted with -CH2CH(CH3)2,
-CH2CH2F, -CH2CF3, -CH2CH2CF3, -CH2N(CH3)2, pyrrolidinyl, -CH2(pyrrolidinyl), or piperidyl.
32. The method of claim 31, wherein R3 is triazolyl.
33. The method of claim 23, wherein Y is phenyl, substituted with one or more substituents selected from -F, -CI, -CN, -CF3, -S02CH3, -CH2NH(C3_4 cycloalkyl), -CH2(non-aromatic heterocyclyl), -0(Ci_2 alkyl)(non-aromatic heterocyclyl),
-C(=0)NHR', -C(=0)N(CH3)R', -NHC(=0)R", -NRS02CH3, or substituted or unsubstituted imidazolyl, pyrazolyl, or triazolyl.
34. The method of claim 23, wherein Y is phenyl, substituted with one or more substituents selected from -F, -CI, -CN, -CF3, -S02CH3, -CH2NH(cyclopropyl),
-CH2(pyrrolidinyl), -OCH2CH2(morpholinyl), -C(=0)NH2, -C(=0)NHCH3,
-C(=0)NHCH2CH3, -C(=0)NHCH2CH2CH3, -C(=0)N(CH3)2, -C(=0)NHCH2CH2OCH3, -C(=0)NH(cyclopropyl), -C(=0)NH(cyclobutyl), -C(=0)NH(cyclopentyl),
-C(=0)NH(hydroxycyclohexyl), -C(=0)N(CH3)(cyclopropyl), -C(=0)NH(phenyl), -C(=0)NHCH2(fluorophenyl), -NHC(=0)(cyclopropyl), -NHC(=0)(pyridyl),
-NHC(=0)(methylphenyl), -NHS02CH3, imidazolyl, pyrazolyl, or triazolyl.
35. The method of claim 23, wherein Y is phenyl, substituted with one or more substituents selected from -F, -CN, -CH2(pyrrolidinyl), -C(=0)NHCH3,
-C(=0)NHCH2CH3, -C(=0)NHCH2CH2CH3, -C(=0)NH(cyclopropyl),
-C(=0)NH(cyclobutyl), -C(=0)NH(cyclopentyl), -C(=0)NH(hydroxycyclohexyl), -C(=0)NH(phenyl), -C(=0)NHCH2(fluorophenyl), or -NHC(=0)(pyridyl).
36. The method of claim 23, wherein Y is.
Figure imgf000099_0001
wherein: Ra is -H, -F, -CI, -CN, -CF3, -S02CH3, -CH2NH(cyclopropyl),
-CH2(pyrrolidinyl), -OCH2CH2(morpholinyl), -C(=0)NH2, -C(=0)NHCH3,
-C(=0)NHCH2CH3, -C(=0)NHCH2CH2CH3, -C(=0)N(CH3)2, -C(=0)NH(cyclopropyl), -C(=0)NH(cyclobutyl), -C(=0)NH(cyclopentyl), -C(=0)NH(hydroxycyclohexyl),
-C(=0)N(CH3)(cyciopropyl), -C(=0)NH(phenyl), -C(=0)NHCH2(fluorophenyl),
-NHC(=0)(cyclopropyl), -NHC(=0)(pyridyl), -NHC(=0)(methylphenyl), -NHS02CH3, imidazolyl, pyrazolyl, or triazolyl;
Rb is -H, -F, -CI, -CN, -CF3, -S02CH3, -CH2NH(cyclopropyl), -C(=0)NHCH3, -C(=0)NHCH2CH3, -C(=0)NHCH2CH2OCH3, -OCH2CH2(morpholinyl), -NHC(=0)(pyridyl); and
Rc is -H, or -F;
with the proviso that Ra, Rb and Rc are not simultaneously -H.
37. The method of claim 36, wherein Ra is -H, -CN, -CH2(pyrrolidinyl),
-C(=0)NHCH2CH3, -C(=0)NHCH2CH2CH3, -C(=0)NH(cyclopropyl),
-C(=0)NH(cyclobutyl), or -C(=0)NH(cyclopentyl), -C(=0)NH(hydroxycyclohexyl),
-C(=0)NH(phenyl), -C(=0)NHCH2(fIuorophenyl), -NHC(=0)(pyridyl), or triazolyl.
38. The method of claim 36, wherein Rb is -H, or -F.
39. The method of claim 36, wherein Rc is -H.
40. The method of claim 23, wherein the compound of Formula (II) is selected from
3-(5-(lH-l,2,4-triazol-3-yl)-lH-indazol-3-yl)-N-cyclopentylbenzamide;
N-methyl-3-(5-(5-(pyrrolidin-l-ylmethyl)-lH-l,2,4-triazol-3-yl)-lH-indazol-3-yl)benzamide; 3-(4-fluorophenyl)- 1 -methyl-5-(3-(pyrrolidin-l -ylmethyl)- 1 H- 1 ,2,4-triazol-5-yl)- lH-indazole; 3 -( 1 -methyl-5 -(3 -(pyrrolidin- 1 -ylmethyl)- 1 H- 1 ,2,4-triazol-5 -yl)- 1 H-indazol-3 -yl)benzonitrile ; N-methyl-3 -(5 -(3 -(pyrrolidin-2-yl)- 1 H- 1 ,2 ,4-triazol-5 -yl)- 1 H-indazol-3 -yl)benzamide;
N-cyclopropyl-3-(5-(3-((dimethylamino)methyl)-lH-l,2,4-triazol-5-yl)-lH-indazol-3- yl)benzamide;
N-cyclopropyl-3 -(5 -(5 -isobutyl- 1 H- 1 ,2,4-triazol-3 -yl)- 1 H-indazol-3 -yl)benzamide; 3-(3-(lH-pyrazol-3-yl)phenyl)-5-(lH-l,2,4-triazol-3-yl)-lH-indazole;
3-(5-(lH-l,2,4-triazol-3-yl)-lH-indazol-3-yl)-N-propylbenzamide;
3 -(5 -( 1 H- 1 ,2,4-triazol-3 -yl)- 1 H-indazol-3 -yl)-N-(( 1 r,4r)-4-hydroxycyclohexyl)benzamide;
N-(3-(5-(lH-l,2,4-triazol-3-yl)-lH-indazol-3-yl)phenyl)nicotinamide;
3 -(5 -( 1 H- 1 ,2,4-triazol-3 -yl)- 1 H-indazol-3 -yl)-N-cyclopropylbenzamide;
3-(5-(3-((dimethylamino)methyl)-lH-l,2,4-triazol-5-yl)-lH-indazol-3-yl)-N-(4- fluorophenyl)benzamide;
3-(5-(lH-l,2,4-triazol-3-yl)-lH-indazol-3-yl)-N-cyclobutylbenzamide;
N-phenyl-3-(5-(5-(pyrrolidin- 1 -ylmethyl)- 1H- 1 ,2,4-triazol-3-yl)- 1 H-indazol-3 -yl)benzamide; 3-(5-(5-(pyrrolidin- 1 -ylmethyl)- 1H- 1 ,2,4-triazol-3-yl)- 1 H-indazol-3 -yl)quino line;
3- (5-(lH-l,2,4-triazol-3-yl)-lH-indazol-3-yl)-N-ethylbenzamide;
N-cyclopropyl-3-(5-(3-(pyrrolidin-2-yl)-lH-l,2,4-triazol-5-yl)-lH-indazol-3-yl)benzamide; N-cyclopropyl-3-(5-(5-(2,2,2-trifluoroethyl)-lH-l,2,4-triazol-3-yl)-lH-indazol-3-yl)benzamide; N-cyclopropyl-3 -(5 -(5 -(3 ,3 ,3 -trifluoropropyl)- 1 H- 1 ,2,4-triazol-3 -yl)- 1 H-indazol-3 - yl)benzamide;
N-cyclopropyl-3-(5-(5-(2-fluoroethyl)-lH-l,2,4-triazol-3-yl)-lH-indazol-3-yl)benzamide; N-cyclopropyl-3-(5-(5-(pyrrolidin-3-yl)-lH-l,2,4-triazol-3-yl)-lH-indazol-3-yl)benzamide;
4- (5-(5-(piperidin-4-yl)-lH-l,2,4-triazol-3-yl)-lH-indazol-3-yl)benzonitrile; or
3-(3-(pyrrolidin-l-ylmethyl)phenyl)-5-(5-(pyrrolidin-2-yl)-lH-l,2,4-triazol-3-yl)-lH-indazole
41. The method of claim 23, wherein the Babesiosis is caused by Babesia microti, Babesia divergens, Babesia bovis, Babesia bigemina, Babesia caballi, Babesia burgdorferi, or Theileria equi.
42. The method of claim 23, additionally comprising administering an effective amount of one or more of chloroquine, quinine, atovaquone, azithromycin, doxycycline, pyrimethamine-sulfadoxine, primaquine, staurosporine, purvalanol A, imidocarb,
clindamycin, nimbolide, gedunin, ciprofloxacin, diminazene aceturate or epoxomicin.
43. A compound selected from
N-methyl-3-(5-(5-(pyrrolidin-l -ylmethyl)- lH-l,2,4-triazol-3-yl)-lH-indazol-3-yl)benzamide; 3-(4-fluorophenyl)-l-methyl-5-(3-(pyrrolidin-l -ylmethyl)- lH-l,2,4-triazol-5-yl)-lH-indazole; 3 -( 1 -methyl-5 -(3 -(pyrrolidin- 1 -ylm
3- (4-chlorophenyl)-N-(2-(pyrrolidin-l-yl)ethyl)-lH-indazole-5-carboxamide;
4- (5-(5-(2,2,2-trifluoroethyl)-lH-l,2,4-triazol-3-yl)-lH-indazol-3-yl)benzonitrile;
3-(5-(lH-imidazol-2-yl)-lH-indazol-3-yl)-N-methylbenzamide;
N-methyl-3-(5-(3-(pyrrolidin-2-yl)-lH-l,2,4-triazol-5-yl)-lH-indazol-3-yl)benzamide;
3-(3-(lH-pyrazol-3-yl)phenyl)-5-(lH-l,2,4-triazol-3-yl)-lH-indazole;
3-(5-(lH-l,2,4-triazol-3-yl)-lH-indazol-3-yl)-N-propylbenzamide;
3 -(5 -( 1 H- 1 ,2,4-triazol-3 -yl)- 1 H-indazol-3 -yl)-N-(( 1 r,4r)-4-hydroxycyclohexyl)benzamide;
N-(3-(5-(lH-l,2,4-triazol-3-yl)-lH-indazol-3-yl)phenyl)nicotinamide;
3 -(5 -( 1 H- 1 ,2,4-triazol-3 -yl)- 1 H-indazol-3 -yl)-N-cyclopropylbenzamide;
3-(5-(3-((dimethylamino)methyl)-lH-l,2,4-triazol-5-yl)-lH-indazol-3-yl)-N-(4- fluorophenyl)benzamide;
3-(5-(lH-l,2,4-triazol-3-yl)-lH-indazol-3-yl)-N-cyclobutylbenzamide;
N-phenyl-3 -(5 -(5 -(pyrrolidin- 1 -ylmethyl)- 1H- 1 ,2,4-triazol-3-yl)- 1 H-indazol-3 -yl)benzamide;
3 -(5 -(5 -(pyrrolidin- 1 -ylmethyl)- 1H- 1 ,2,4-triazol-3-yl)- 1 H-indazol-3 -yl)quino line;
3- (5-(lH-l,2,4-triazol-3-yl)-lH-indazol-3-yl)-N-ethylbenzamide;
N-cyclopropyl-3-(5-(3-(pyrrolidin-2-yl)-lH-l,2,4-triazol-5-yl)-lH-indazol-3-yl)benzamide; N-cyclopropyl-3-(5-(5-(2,2,2-trifluoroethyl)-lH-l,2,4-triazol-3-yl)-lH-indazol-3-yl)benzamide; N-cyclopropyl-3 -(5 -(5 -(3 ,3 ,3 -trifluoropropyl)- 1 H- 1 ,2,4-triazol-3 -yl)- 1 H-indazol-3 - yl)benzamide;
N-cyclopropyl-3-(5-(5-(2-fluoroethyl)-lH-l,2,4-triazol-3-yl)-lH-indazol-3-yl)benzamide;
N-cyclopropyl-3-(5-(5-(pyrrolidin-3-yl)-lH-l,2,4-triazol-3-yl)-lH-indazol-3-yl)benzamide;
4- (5-(5-(piperidin-4-yl)-lH-l,2,4-triazol-3-yl)-lH-indazol-3-yl)benzonitrile;
3-(3-(pyrrolidin-l-ylmethyl)phenyl)-5-(5-(pyrrolidin-2-yl)-lH-l,2,4-triazol-3-yl)-lH-indazole; and pharmaceutically acceptable salts, tautomers, stereoisomers, enantiomers, and isotopologues thereof.
44. A pharmaceutical composition comprising an effective amount of a
compound of claim 43, and a pharmaceutically acceptable carrier, excipient or vehicle.
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