Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
  • A61K31/52—Purines, e.g. adenine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P33/00—Antiparasitic agents
  • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
  • C07C211/33—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings
  • C07C211/34—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of a saturated carbon skeleton
  • C07C211/36—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of a saturated carbon skeleton containing at least two amino groups bound to the carbon skeleton
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
  • C07C211/43—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
  • C07C211/57—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings being part of condensed ring systems of the carbon skeleton
• • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D473/00—Heterocyclic compounds containing purine ring systems
  • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
  • C07D473/32—Nitrogen atom
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C13/00—Cyclic hydrocarbons containing rings other than, or in addition to, six-membered aromatic rings
  • C07C13/02—Monocyclic hydrocarbons or acyclic hydrocarbon derivatives thereof
  • C07C13/06—Monocyclic hydrocarbons or acyclic hydrocarbon derivatives thereof with a four-membered ring
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C13/00—Cyclic hydrocarbons containing rings other than, or in addition to, six-membered aromatic rings
  • C07C13/02—Monocyclic hydrocarbons or acyclic hydrocarbon derivatives thereof
  • C07C13/08—Monocyclic hydrocarbons or acyclic hydrocarbon derivatives thereof with a five-membered ring
  • C07C13/10—Monocyclic hydrocarbons or acyclic hydrocarbon derivatives thereof with a five-membered ring with a cyclopentane ring
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
  • C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
  • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
  • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
  • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
  • G01N33/569—Immunoassay; Biospecific binding assay; Materials therefor for microorganisms, e.g. protozoa, bacteria, viruses
  • G01N33/56905—Protozoa

Definitions

• compositions comprising an effective amount of such compounds, and methods for treating or preventing trypanosomosis, trypanosomiasis, or leishmaniasis, comprising administering an effective amount of such aminopurine compounds to a subject in need thereof.
• Protozoa of the genus Trypanosoma and Leishmania are known to cause a number of diseases in animals and humans. These protozoa can be transmitted by blood feeding invertebrates, by mechanical vectors or venereally, and are responsible for a number of diseases known as trypanosomosis or trypanosomiasis and leishmaniasis.
• Animal African Trypanosomosis (AAT), Human African Trypanosomiasis (HAT), Chagas disease and leishmaniasis are such parasitic diseases, which result in significant morbidity and mortality.
• AAT African animal trypanosomosis
• AAT African animal trypanosomosis
• AAT remains one of the biggest infectious disease constraints to productive livestock rearing in sub-Saharan Africa.
• AAT is also becoming increasingly prevalent beyond this region and is an established threat to animal health in South America and Asia.
• Trypanosomes are spread by the bite of infected tsetse flies (Glossina species). Certain Trypanoxome species can be mechanically transmitted by biting flies or by venereal transmission.
• HAT Human African trypanosomiasis
• tsetse fly Greek trypanosomiasis
• tsetse fly Greek trypanosomiasis
• the trypanosomes multiply in subcutaneous tissues, blood and lymph. This is also called the hemo-lymphatic stage, which produces bouts of fever, headaches, joint pains and itching.
• the parasites cross the blood-brain barrier to infect the central nervous system, known as the neurological or meningo- encephalic stage. Symptoms include changes of behavior, confusion, sensory
• Chagas disease caused by the T. cruzi trypanosome species. Chagas is vector-borne by contact with feces or urine of blood-sucking triatomine bugs (insects), known as kissing bugs. Chagas disease occurs mainly in the continental part of Latin America, but has been increasingly detected in the United States, Canada, and many European and some Western Pacific countries. Chagas disease presents itself in two phases. The initial, acute phase lasts for about 2 months after infection. During the acute phase, a high number of parasites circulate in the blood but in most cases symptoms are absent or mild.
• characteristic first visible signs may be a skin lesion or a purplish swelling of the lids of one eye. Additionally patients may present with fever, headache, enlarged lymph glands, pallor, muscle pain, difficulty in breathing, swelling, and abdominal or chest pain. During the chronic phase, the parasites are hidden mainly in the heart and digestive muscles. Up to 30% of patients suffer from cardiac disorders and up to 10%) suffer from digestive (typically enlargement of the esophagus or colon), neurological or mixed alterations. In later years the infection may lead to sudden death or heart failure caused by progressive destruction of the heart muscle and the nervous system. Chagas disease can be treated with benznidazole and also nifurtimox. Both medicines are effective in curing the disease if given soon after infection at the onset of the acute phase including the cases of congenital transmission. The efficacy of both drugs diminishes, however, the longer a person has been infected.
• Leishmaniasis is a disease caused by protozoa of the genus Leishmania.
• Leishmaniasis results from Leishmania transmission by the bite of certain species of sand fly (e.g.
• VL Visceral leishmaniasis
• kala-azar is fatal if left untreated in over 95% of cases. It is characterized by irregular bouts of fever, weight loss, enlargement of the spleen and liver, and anemia. It is highly endemic in the Indian subcontinent and in East Africa. An estimated 200,000 to 400,000 new cases of VL occur worldwide each year.
• Post-kala-azar dermal leishmaniasis is a sequel of visceral leishmaniasis that appears as macular, papular or nodular rash usually on face, upper arms, trunks and other parts of the body. It occurs mainly in East Africa and the Indian subcontinent. It usually appears 6 months to 1 or more years after kala-azar has apparently been cured, but may occur earlier. People with PKDL are considered to be a potential source of kala-azar infection.
• Cutaneous leishmaniasis is the most common form of leishmaniasis and causes skin lesions, mainly ulcers, on exposed parts of the body, leaving life-long scars and serious disability. About 95% of CL cases occur in the Americas, the Mediterranean basin, the Middle East and Central Asia. Over two thirds of new CL cases occur in 6 countries: Afghanistan, Norway, Brazil, Colombia, Iran and the Syrian Arab Republic.
• Mucocutaneous leishmaniasis leads to partial or total destruction of mucous membranes of the nose, mouth and throat. Almost 90% of mucocutaneous leishmaniasis cases occur in Cambodia, Brazil and Peru. The current treatments suffer from safety/toxicity concerns (including cardiotoxicty), incomplete cure rates, difficult administration, long duration of treatment, lack of compliance and developing resistance. (Disease descriptions and facts were obtained from www.who.org).
• R 1 , R 2 and R 3 are as defined herein.
• Aminopurine Compounds as described in the instant disclosure, such as, for example, an Aminopurine Compound of formula (I), or a compound from Table 1 or Table 2.
• compositions comprising an effective amount of an Aminopurine 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 uses of Aminopurine Compounds for treating or preventing trypanosomosis, trypanosomiasis, and/or leishmaniasis, wherein the methods comprise administering to a subject in need thereof an effective amount of an Aminopurine Compound as described herein.
• the methods comprise administering to a subject in need thereof an effective amount of an Aminopurine Compound as described herein.
• an Aminopurine Compound for use as a medicament.
• the Aminopurine Compound for use in a method for the treatment or prevention of trypanosomosis, trypanosomiasis, or leishmaniasis, the method comprising administering to a subject in need thereof an effective amount of the
• Aminopurine Compound for use in a method of treating or preventing Animal trypanosomosis or African animal
• trypanosomosis AAT
• the method comprising administering to a subject in need thereof an effective amount of the Aminopurine Compound.
• HAT Human African trypanosomiasis
• an Aminopurine Compound for use in a method of treating or preventing American trypanosomiasis or Chagas disease comprising administering to a subject in need thereof an effective amount of the Aminopurine
• an Aminopurine Compound for use in a method of treating or preventing Leishmaniasis, comprising administering to a subject in need thereof an effective amount of the Aminopurine Compound.
• the terms “comprising” and “including” can be used interchangeably.
• the terms “comprising” and “including” are to be interpreted as specifying the presence of the stated features or components as referred to, but does not preclude the presence or addition of one or more features, or components, or groups thereof. Additionally, the terms “comprising” and “including” are intended to include examples encompassed by the term “consisting of. Consequently, the term “consisting of can be used in place of the terms “comprising” and “including” to provide for more specific embodiments of the invention.
• 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,
• An alkyl group can 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
• alkoxyamine alkoxyamine; aralkoxyamine; N-oxide; hydrazine; hydrazide; hydrazone; azide;
• 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,
• cycloalkyl groups include cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl,
• a cycloalkyl group can be substituted or unsubstituted.
• 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 even 6 to 10 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).
• 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
• 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
• 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 tolO 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
• 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
• 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, oxathiany
• benzimidazolyl e.g., lH-benzo[d]imidazolyl or
• benzoxadiazolyl benzoxazinyl, benzodithiinyl, benzoxathiinyl, benzothiazinyl, benzoxazolyl (i.e., benzo[d]oxazolyl), benzothiazolyl, benzothiadiazolyl, benzo[l,3]dioxolyl, pyrazol opyridyl (for example, lH-pyrazolo[3,4-b]pyridyl, lH-pyrazolo[4,3-b]pyridyl), imidazopyridyl
• azabenzimidazolyl or lH-imidazo[4,5-b]pyridyl triazol opyridyl, isoxazol opyridyl, 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, t
• 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 (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.
• piperazinyl e.g., piperazin-2-onyl
• morpholinyl thiomorpholinyl
• tetrahydropyranyl e.g., tetrahydro-2H-pyranyl
• tetrahydrothiopyranyl tetrahydrothiopyranyl
• oxathianyl dithi
• 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 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.
• 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.
• 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.
• a "halogen” is fluorine, chlorine, bromine or iodine.
• 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.
• amino group is a radical of the formula: - H 2 .
• alkylamino is a radical of the formula: -NH-alkyl or -N(alkyl) 2 , wherein each alkyl is independently as defined above.
• a "carboxy” group is a radical of the formula: -C(0)OH.
• aminocarbonyl is a radical of the
• each R ff is independently a substituted or unsubstituted alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl or heterocyclyl group as defined herein.
• acylamino is a radical of the formula: - HC(0)( R # )
• a "sulfonylamino” group is a radical of the formula: - HS0 2 (R # )
• a "urea” group is a radical of the
• substituents are those found in the exemplary compounds and embodiments disclosed herein, as well as halogen (chloro, iodo, bromo, or fluoro); alkyl;
• 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, pyridyl, quinolinyl, isoquinolinyl, acridinyl, pyrazinyl, pyridazinyl, pyrimidyl, benzimidazolyl, benzothiophenyl, or benzofuranyl) aryloxy; aralkyloxy; heterocyclyloxy; and heterocyclyl alkoxy.
• aryl or heteroaryl e.g., phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thiopheny
• the term "Aminopurine Compound” refers to compounds of formula (I) as well as to further embodiments of compounds of formula (I) provided herein.
• the term “Aminopurine Compound” refers to deuterated compounds of formula (I).
• an "Aminopurine Compound” is a compound set forth in Table 1 or Table 2.
• the term “Aminopurine Compound” includes pharmaceutically acceptable salts, tautomers, isotopologues, and/or stereoisomers of the Aminopurine 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) include, but are not limited to metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from lysine, ⁇ , ⁇ '-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine,
• 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,
• stereomerically pure means one stereoisomer of an Aminopurine 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.
• 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 Aminopurine 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 Aminopurine Compounds can include E and Z isomers, or a mixture thereof, and cis and trans isomers or a mixture thereof.
• the Aminopurine Compounds are isolated as either the E or Z isomer. In other embodiments, the Aminopurine 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:
• the Aminopurine Compounds can contain unnatural proportions of atomic isotopes at least one 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 carbon-13 ( 13 C), or nitrogen- 15 ( 15 N).
• 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 Aminopurine 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 Aminopurine Compounds, for example, the isotopologues are carbon-13, or nitrogen- 15 enriched Aminopurine Compounds.
• deuterated means a compound wherein at least one hydrogen (H) has been replaced by deuterium (indicated by D or 2 H), that is, the compound is enriched in deuterium in at least one position.
• inhibitor and “inhibition” mean that a specified response of a designated activity (e.g., parasite growth ) is comparatively decreased in the presence of an
• Aminopurine Compound Inhibition of parasite growth, for example growth of T. congolensce,
• T. vivax and/or T. evansi can be determined by the assays described herein.
• Treating means 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.
• 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.
• an effective amount in connection with an Aminopurine Compound means an amount capable of treating or preventing a disorder, disease or condition, or symptoms thereof, disclosed herein.
• subject or patient includes an animal, including, but not limited to, an animal such a bull, camel, cat, cattle, chicken, cow, deer, dog, donkey, duck, elephant, gerbil, goat, goose, guinea fowl, guinea pig, honey bee, horse, ostrich, otter, pig, pigeon, rabbit, reindeer, sheep, swan, turkey, water buffalo, or yak, in one embodiment a mammal, in another embodiment a human, in another embodiment a cell from any one of the foregoing subjects.
• a subject or patient is a non-human animal.
• a subject or patient is a non-human mammal.
• the term "consecutive" means that more than 10 minutes have passed between the administration of the anti-MIF antibody and the administration of the chemotherapeutic agent.
• the time period can then be more than 10 minutes, more than 30 minutes, more than 1 hour, more than 3 hours, more than 6 hours or more than 12 hours.
• a subject or patient is a human having or at risk for having trypanosomiasis, and/or leishmaniasis. In some such embodiments, the subject or patient is a human having or at risk for having leishmaniasis. In some such embodiments, the subject or patient is a human having or at risk for having Chagas Disease.
• a subject is a bull, camel, cat, cattle, chicken, cow, deer, dog, donkey, duck, elephant, gerbil, goat, goose, guinea fowl, guinea pig, honey bee, horse, ostrich, otter, pig, pigeon, rabbit, reindeer, sheep, swan, turkey, water buffalo, or yak having or at risk for having trypanosomosis, .
• a subject is cattle, having or at risk for having trypanosomosis.
• R 2 is cycloalkyl or aryl, substituted with at least one R 2 , OR, CN, RC(0)R, CH 2 OR, CH 2 R 2 , CH 2 RCOR, CH 2 RCOOR', or heterocyclylalkyl;
• R 3 is phenyl or pyridyl, optionally substituted with at least one halogen, CN, (Ci -2 )alkyl, or 0(Ci -2 )alkyl, wherein the alkyl is optionally fluorinated;
• R is H or (C M) alkyl
• R' is (Ci -4 )alkyl; provided the Aminopurine Compound is not
• R 1 is CR la R lb R lc , wherein each of R la , R lb and R lc is independently (Ci -2 )alkyl.
• R 1 is t-butyl
• R 1 is t-butyl. In other embodiment, R 1 is C(CH 3 ) 2 CH 2 CH 3 . In other embodiment, R 1 is C(CH 3 ) 2 CH 2 OH. In other embodiments of compounds of formula (I), R 1 is CR la R lb R lc , wherein R la and R lb and the carbon to which they are attached form a 3-6 membered cycloalkyl or 3-6 membered heterocyclyl, and R lc is (Ci. 4 )alkyl.
• R la and R lb and the carbon to which they are attached form a cyclopropyl, cyclobutyl, cyclohexyl, or tetrahydropyranyl.
• R lc is CH 3 .
• R 1 is 1-methylcyclopropyl, 1-methylcyclobutyl, 1-methylcyclpentyl, 1- methyl-tetrahydropyranyl, 4-methyl-tetrahydropyranyl or 2,2-dimethyltetrahydropyranyl.
• R 1 is 1-methylcyclopropyl.
• R 1 is 1-methylcyclobutyl.
• R 1 is 1-methylcyclpentyl.
• R 1 is 1-methyl-tetrahydropyranyl. In one embodiment, R 1 is 4-methyl-tetrahydropyranyl. In a specific embodiment, R 1 is 4-methyl- tetrahydropyran-4-yl. In one embodiment, R 1 is 2,2-dimethyltetrahydropyranyl. In a specific embodiment, R 1 is 2,2-dimethyltetrahydropyran-4-yl.
• R 2 is (C3-7)cycloalkyl, substituted with at least one NR 2 , OR, CN, NRC(0)R, CH 2 OR, CH 2 NR 2 , CH 2 NRC(0)R, CH 2 NRC(0)OR' or heterocyclylalkyl.
• R 2 is cyclobutyl
• R 2 is substituted with at least one NH 2 , NHCH 3 , N(CH 3 ) 2 , OH, OCH3, CN, NHC(0)CH 3 , N(CH 3 )C(0)CH 3 , CH 2 OH, CH 2 OCH 3 , CH 2 NH 2 , CH 2 NHCH 3 , CH 2 N(CH 3 ) 2 , CH 2 NHC(0)CH 3 , CH 2 N(CH 3 )C(0)CH 3 ,
• R 2 is cyclobutyl, substituted with NH 2 .
• R 2 is cyclohexyl, substituted with NH 2 , OH, CN, NHC(0)CH 3 , CH 2 OH, CH 2 NH 2 , CH 2 NHCH 3 , CH 2 N(CH 3 ) 2 , CH 2 NHC(0)CH 3 , CH 2 NHC(0)OCH 3 , CH 2 -piperidyl, or CH 2 -morpholinyl.
• R 2 is cyclobutyl substituted with NH 2 . In one embodiment, R 2 is cyclohexyl, substituted with OH. In one embodiment, R 2 is cyclohexyl, substituted with CN, NHC(0)CH 3 . In one
• R 2 is cyclohexyl, substituted with CH 2 OH. In one embodiment, R 2 is cyclohexyl, substituted with CH 2 NH 2 . In one embodiment, R 2 is cyclohexyl, substituted with CH 2 NHCH 3 . In one embodiment, R 2 is cyclohexyl, substituted with CH 2 N(CH 3 ) 2 . In one embodiment, R 2 is cyclohexyl, substituted with CH 2 NHC(0)CH 3 . In one embodiment, R 2 is cyclohexyl, substituted with CH 2 NHC(0)OCH 3 . In one embodiment, R 2 is cyclohexyl, substituted with CH 2 -piperidyl. In one embodiment, R 2 is cyclohexyl, substituted with CH 2 -morpholinyl. In yet other
• R 2 is aryl, substituted with at least one NR 2 , OR, CN, NRC(0)R, CH 2 OR, CH 2 NR 2 , CH 2 NRCOR, or CH 2 NRCOOR' .
• R 2 is phenyl, substituted with at least one NH 2 , NHCH 3 , N(CH 3 ) 2 , OH, OCH 3 , CN, NHC(0)CH 3 ,
• R 2 is phenyl, substituted with CH 2 NH 2 .
• R 3 is phenyl, substituted with at least one halogen, fluorinated (Ci -2 )alkyl, or 0-fluorinated(Ci -2 )alkyl. In some such embodiments, R 3 is substituted with at least one F, CI, CHF 2 , CF 3 , or OCF 3 . In other such embodiments, R 3 is meta-substituted phenyl, for example, R 3 is meta-F-phenyl, meta-Cl-phenyl, meta-CF 3 -phenyl, or meta-OCF 3 -phenyl. In one embodiment, R 3 is meta-F-phenyl.
• R 3 is meta-Cl-phenyl. In one embodiment, R 3 is meta-CF 3 -phenyl. In one embodiment, R 3 is meta-OCF 3 -phenyl. In still other embodiments, R 3 is bis-meta-substituted phenyl, wherein each substituent is independently F, CI, or CF 3 . In one embodiment, R is bis- meta-substituted phenyl, wherein each substituent is F. In one embodiment, R 3 is bis-meta- substituted phenyl, wherein each substituent is CI. In one embodiment, R 3 is bis-meta-substituted phenyl, wherein one substituent is F and one substituent is CI.
• R 3 is bis- meta-substituted phenyl, wherein one substituent is F and one substituent is CF 3 . In one embodiment, R 3 is bis-meta-substituted phenyl, wherein one substituent is CI and one substituent is CF 3 . In some embodiments, R 3 is para-substituted phenyl, for example, para-OCF 3 -phenyl, para-CF 3 -phenyl or para-Cl-phenyl. In one embodiment, R 3 is para-Cl-phenyl. In one
• R 3 is para-CF 3 -phenyl. In one embodiment, R 3 is para-OCF 3 -phenyl. In some embodiments, R 3 is ortho-F, meta-CF 3 -phenyl, ortho-F, meta-Cl-phenyl, or meta-Cl, para-Cl- phenyl. In one embodiment, R 3 is ortho-F, meta-F -phenyl. In one embodiment, R 3 is ortho-F, meta-CF 3 -phenyl. In one embodiment, R 3 is ortho-F, meta-Cl-phenyl. In one embodiment, R 3 is meta-Cl, para-Cl-phenyl.
• R 3 is pyridyl substituted with at least one halogen, fluorinated (Ci -2 )alkyl, 0-fluorinated(Ci -2 )alkyl or CF 3 .
• R 3 is pyridyl substituted with CI.
• R 3 is pyridyl substituted with CF 3 .
• R 3 is substituted with at least one F, CI, CHF 2 , CF 3 , or OCF 3 .
• R 3 is substituted with at least one CI, or CF 3 .
• R 1 is CR la R lb R lc , wherein R la and R lb and the carbon to which they are attached form a 3-6 membered cycloalkyl or 3-6 membered heterocyclyl
• R lc is R 2 is cyclohexyl, substituted with H 2 , OH, CN, HC(0)CH 3 , CH 2 OH, CH 2 H 2 , CH 2 HCH 3 , CH 2 N(CH 3 ) 2 , CH 2 HC(0)CH 3 , CH 2 HC(0)OCH 3 , CH 2 -piperidyl, or CH 2 -morpholinyl.
• R 3 is meta-substituted phenyl, or bis-meta-substituted phenyl.
• R 1 is 1-methylcyclopropyl, 1-methylcyclobutyl, 1-methylcyclpentyl or 1-methyl-tetrahydropyranyl.
• R 3 is meta-F -phenyl, meta-Cl-phenyl, meta-CF 3 -phenyl, or meta-OCF 3 -phenyl, or R 3 is bis-meta-substituted phenyl, wherein each substituent is independently F, CI, or CF 3 .
• the compound is 9-((ls,4s)-4-(aminomethyl)cyclohexyl)-N8-
• the compound is 9-((ls,4s)-4-(aminomethyl)cyclohexyl)-N8-
• the compound is 9-((ls,4s)-4-(aminomethyl)cyclohexyl)-N8-
• the compound is 9-((ls,4s)-4-(aminomethyl)cyclohexyl)-N8-
• the compound is N8-(3-chlorophenyl)-9-((ls,4s)-4-
• the compound is 9-((ls,4s)-4-(aminomethyl)cyclohexyl)-N2- tert-butyl-N8-(pyridin-2-yl)-9H-purine-2,8-diamine.
• the compound is 9-((lr,4r)-4-(aminomethyl)cyclohexyl)-N8-
• the compound is 9-((ls,4s)-4-(aminomethyl)cyclohexyl)-N2-
• the compound is 9-((ls,4s)-4-(aminomethyl)cyclohexyl)-N8-
• the compound is (ls,4s)-4-(8-(3-chlorophenylamino)-2-(l- methylcyclopentylamino)-9H-purin-9-yl)cyclohexanol.
• the compound is N-(((ls,4s)-4-(8-(3-chlorophenylamino)-2-
• the compound is 9-((ls,4s)-4-(aminomethyl)cyclohexyl)-N2-
• the compound is 9-((ls,4s)-4-(aminomethyl)cyclohexyl)-N2- tert-pentyl-N8-(3-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine.
• the compound is methyl ((ls,4s)-4-(8-(3- chlorophenylamino)-2-(4-methyltetrahydro-2H-pyran-4-ylamino)-9H-purin-9- yl)cyclohexyl)methylcarbamate.
• the compound is 9-((ls,4s)-4-(aminomethyl)cyclohexyl)-N2- tert-butyl-N8-(3-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine.
• the compound is 9-((ls,4s)-4-(aminomethyl)cyclohexyl)-N2- (l-methylcyclopentyl)-N8-(4-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine.
• the compound is 9-((lr,4r)-4-(aminomethyl)cyclohexyl)-N2- tert-butyl-N8-(3-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine.
• the compound is 9-((lr,4r)-4-(aminomethyl)cyclohexyl)-N2- tert-butyl-N8-p-tolyl-9H-purine-2,8-diamine.
• the compound is ((ls,4s)-4-(8-(3-chlorophenylamino)-2-(4- methyltetrahydro-2H-pyran-4-ylamino)-9H-purin-9-yl)cyclohexyl)methanol.
• the compound is 9-((lR,3S)-3-(aminomethyl)cyclohexyl)-
• the compound is N8-(3-chlorophenyl)-9-((ls,4s)-4-
• the compound is 9-((ls,4s)-4-(aminomethyl)cyclohexyl)-N2- tert-butyl-N8-(4-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine.
• the compound is 9-((ls,4s)-4-(aminomethyl)cyclohexyl)-N2- tert-pentyl-N8-(4-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine.
• the compound is (ls,4s)-4-(2-(4-methyltetrahydro-2H-pyran-
• the compound is (3-(trifluoromethyl)phenylamino)-9H-purin- 9-yl)cyclohexanecarbonitrile.
• the compound is N-((ls,4s)-4-(8-(3-chlorophenylamino)-2-
• the compound is ((lr,4r)-4-(8-(3-chlorophenylamino)-2-(4- methyltetrahydro-2H-pyran-4-ylamino)-9H-purin-9-yl)cyclohexyl)methanol.
• the compound is 9-((ls,4s)-4-aminocyclohexyl)-N8-(3- chlorophenyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine.
• the compound is 9-((ls,4s)-4-(aminomethyl)cyclohexyl)-N2-
• the compound is 9-((ls,4s)-4-aminocyclohexyl)-N2-tert- butyl-N8-(3-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine.
• the compound is 9-((lr,4r)-4-aminocyclohexyl)-N2-tert- butyl-N8-(3-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine. [0094] In one embodiment, the compound is 9-((ls,4s)-4-(aminomethyl)cyclohexyl)-N2-
• the compound is 9-(4-(aminomethyl)phenyl)-N8-(3- chlorophenyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine.
• the compound is 9-((ls,4s)-4-(aminomethyl)cyclohexyl)-N8-
• the compound is 9-((ls,4s)-4-(aminomethyl)cyclohexyl)-N2-
• the compound is 9-((ls,4s)-4-(aminomethyl)cyclohexyl)-N8-
• the compound is 9-((ls,4s)-4-(aminomethyl)cyclohexyl)-N2-
• the compound is 9-((ls,4s)-4-(aminomethyl)cyclohexyl)-N2-
• the compound is 9-(3-aminocyclobutyl)-N2-tert-butyl-N8-
• the compound is N8-(3-chlorophenyl)-N2-(4- methyltetrahydro-2H-pyran-4-yl)-9-((ls,4s)-4-(piperidin-l-ylmethyl)cyclohexyl)-9H-purine-2,8- diamine.
• the compound is N8-(3-chlorophenyl)-N2-(4- methyltetrahydro-2H-pyran-4-yl)-9-((ls,4s)-4-(morpholinomethyl)cyclohexyl)-9H-purine-2,8- diamine.
• the compound is 9-((ls,4s)-4-(aminomethyl)cyclohexyl)-N8-
• the compound is 9-((ls,4s)-4-(aminomethyl)cyclohexyl)-N8-
• the compound is 9-((ls,4s)-4-(aminomethyl)cyclohexyl)-N8-
• the compound is 9-((ls,4s)-4-(aminomethyl)cyclohexyl)-N2-
• the compound is 9-((ls,4s)-4-(aminomethyl)cyclohexyl)-N8-
• the compound is 9-((ls,4s)-4-(aminomethyl)cyclohexyl)-N8-
• the compound is 9-((ls,4s)-4-(aminomethyl)cyclohexyl)-N2- tert-butyl-N8-(3,5-dichlorophenyl)-9H-purine-2,8-diamine.
• the compound is 9-((ls,4s)-4-(aminomethyl)cyclohexyl)-N8-
• the compound is 9-((ls,4s)-4-(aminomethyl)cyclohexyl)-N8-
• the compound is 9-((ls,4s)-4-(aminomethyl)cyclohexyl)-N8-
• the compound is 3-(9-((lr,4r)-4-aminocyclohexyl)-2-(tert- butylamino)-9H-purin-8-ylamino)benzonitrile.
• the compound is 9-((lr,4r)-4-aminocyclohexyl)-N2-tert- butyl-N8-(3-chloro-5-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine.
• the compound is 2-(9-((ls,4s)-4-(aminomethyl)cyclohexyl)-
• the compound is 9-((ls,4s)-4-(aminomethyl)cyclohexyl)-N8-
• the compound is 9-((ls,4s)-4-
• the compound is 9-((ls,4s)-4-(aminomethyl)cyclohexyl)-N2-
• the compound is 9-((ls,4s)-4-
• the compound is 9-(4-aminocyclohexyl)-N8-(2-fluoro-5-
• the compound is N2-tert-butyl-N8-(3-chloro-2- fluorophenyl)-9-((ls,4s)-4-((dimethylamino)methyl)cyclohexyl)-9H-purine-2,8-diamine.
• the compound is 9-((ls,4s)-4-(aminomethyl)cyclohexyl)-N8-
• the compound is 9-((ls,4s)-4-(aminomethyl)cyclohexyl)-N8-
• the compound is 9-((lr,4r)-4-aminocyclohexyl)-N8-(3- chlorophenyl)-N2-cyclopropyl-9H-purine-2,8-diamine.
• the compound is 9-((lr,4r)-4-aminocyclohexyl)-N8-(3- chlorophenyl)-N2-(cyclopropylmethyl)-9H-purine-2,8-diamine.
• the compound is 9-((lr,4r)-4-aminocyclohexyl)-N8-(3- chlorophenyl)-N2-(2,2,2-trifluoroethyl)-9H-purine-2,8-diamine.
• the compound is 9-((ls,4s)-4-(aminomethyl)cyclohexyl)-N8-
• the compound is ((1 s,4s)-4-(8-(3-chlorophenylamino)-2-
• the compound is 9-((ls,4s)-4-(aminomethyl)cyclohexyl)-N8-
• the compound is 9-((ls,4s)-4-(aminomethyl)cyclohexyl)-N8-
• the compound is 9-((ls,4s)-4-(aminomethyl)cyclohexyl)-N8-
• the compound is 9-((ls,4s)-4-(aminomethyl)cyclohexyl)-N8-
• the compound is 4-(9-((ls,4s)-4-(aminomethyl)cyclohexyl)-
• the compound is 9-((ls,4s)-4-(aminomethyl)cyclohexyl)-N8-
• the compound is 9-((ls,4s)-4-(aminomethyl)cyclohexyl)-N8-
• the compound is 9-((ls,4s)-4-(aminomethyl)cyclohexyl)-N8-
• the compound is 9-((ls,4s)-4-(aminomethyl)cyclohexyl)-N-
• the compound is 9-((ls,4s)-4-(aminomethyl)cyclohexyl)-N8-
• the compound is 9-((ls,4s)-4-(aminomethyl)cyclohexyl)-N8-
• Aminopurine Compounds of Formula I can be made using conventional organic syntheses and commercially available starting materials.
• Aminopurine Compounds of formula (I) can be prepared as described in U.S. Patent No. 7,723,340, and U.S. Patent No. 8,158,635, 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 products.
• the aminopyrimidine derivative was treated with R 3 NCS, in a solvent, such as THF, DMF, NMP, dioxane, or EtOH, to obtain the (optionally isolated) thiourea derivative, which was cyclized, using for example, EDC or DIC, in a solvent, for example, THF, dioxane, NMP or DMF, optionally at elevated temperature (for example, 40- 80 °C), to provide compounds of formula (I).
• a solvent such as THF, DMF, NMP, dioxane, or EtOH
• R 2 is cycloalkyl or aryl, substituted with at least one R 2 , OR, CN, RC(0)R, CH 2 OR, CH 2 R 2 , CH 2 RCOR, CH 2 RCOOR', or heterocyclylalkyl;
• R 3 is phenyl or pyridyl, optionally substituted with at least one halogen, CN, (Ci -2 )alkyl, or 0(Ci -2 )alkyl, wherein the alkyl is optionally fluorinated;
• R is H or (Ci -4 ) alkyl
• R' is (Ci -4 )alkyl
• the solvent is THF, dioxane, NMP or DMF.
• the contacting is optionally performed at elevated temperature, for example, from about 40 °C to about 80 °C.
• the methods further comprise preparing a compound of formula (la):
• the solvent is THF, DMF, MP, dioxane, or EtOH.
• the methods further comprise preparing a compound of formula (lb):
• the reducing agent is H 2 in the presence of a catalyst.
• the catalyst Pd/C.
• the solvent is MeOH or ethyl acetate.
• the reducing agent is iron in the presence of ammonium chloride.
• the solvent is EtOH, MeOH or water.
• the methods further comprise preparing a compound of formula (Ic):
• the base is DIEA, TEA, sodium carbonate, sodium bicarbonate, or pyridine.
• the solvent is DCM, DMF, dioxane or THF.
• the contacting is performed at elevated temperature, for example, from about 0 °C to about 60 °C.
• the methods further comprise preparing a compound of formula (Id):
• the base is DIEA, TEA, sodium carbonate, sodium bicarbonate, or pyridine.
• the solvent is DCM, DMF, dioxane or THF.
• the contacting is performed at reduced temperature, for example, about -78 °C.
• Aminopurine Compounds provided herein are for use as a medicament. Accordingly, provided herein are the Aminopurine Compounds for use in methods of treatment or prevention of trypanosomosis, trypanosomiasis and/or leishmaniasis.
• the methods provided herein comprise the administration of an effective amount of at least one Aminopurine Compound(s) to a subject in need thereof.
• the Aminopurine Compounds provided herein can be administered in combination with a second active agent. Accordingly, the Aminopurine Compounds provided herein and the second active agent provided herein can be used in the treatment or prevention of all diseases, disorders or conditions provided herein.
• Aminopurine Compounds for use in methods of treating or preventing trypanosomosis, trypanosomiasis and/or leishmaniasis, comprising administering to a subject in need thereof an effective amount of an Aminopurine Compound, as described herein.
• compounds for treating or preventing trypanosomosis, trypanosomiasis and/or leishmaniasis comprising administering to a subject in need thereof an effective amount of an Aminopurine Compound, as described herein.
• the trypanosomosis or trypanosomiasis is caused by
• the trypanosomosis or trypanosomiasis is caused by T. congolense, T. vivax or T. evansi.
• the subject is an animal, and the trypanosomosis or trypanosomiasis is caused by T. congolense, T. vivax, T. brucei brucei, T. evansi or T. simiae.
• the subject is a human, and the trypanosomosis or trypanosomiasis is caused by T. brucei
• the leishmaniasis is caused by L. donovani, L. infantum, L. chagasi; L. mexicana, L. amazonensis, L. venezuelensis, L. tropica, L. major, L. aethiopica, L. (V.) braziliensis, L. (V.) guyanensis, L. (V.) panamensis, or L. (V.) peruviana.
• L. donovani L. infantum
• L. chagasi L. mexicana
• L. amazonensis L. venezuelensis
• L. tropica L. major
• L. aethiopica L. (V.) braziliensis
• L. (V.) guyanensis L. (V.) panamensis
• L. (V.) peruviana In one
• the subject is a human and the leishmaniasis is caused by L. major, L. tropica, L. aethiopica, L. mexicana, L. donovani or L. infantum.
• the trypanosomosis is Animal trypanosomosis or African animal trypanosomosis (AAT).
• the trypanosomiasis is Human African trypanosomiasis (HAT, also known as sleeping sickness).
• HAT Human African trypanosomiasis
• trypanosomiasis is American trypanosomiasis or Chagas disease.
• trypanosomosis or African animal trypanosomosis comprising administering to a subject in need thereof an effective amount of an Aminopurine Compound, as described herein.
• the subject is selected from cattle, sheep, goats, pigs, and dogs, and the Animal trypanosomosis or African animal trypanosomosis is caused by T. vivax, T. congolense, T. brucei, or T. evansi.
• the subject is selected from horses and donkeys, and the Animal trypanosomosis or African animal
• trypanosomosis is caused by T. equiperdum.
• the subject is selected from dogs, horses and cats, and the Animal trypanosomosis or African animal trypanosomosis is caused by T. brucei brucei.
• the subject is selected from horses, camels, water buffalo and cattle, and the Animal trypanosomosis or African animal
• trypanosomosis is caused by T. brucei evansi. [00163] In some embodiments, the trypanosomosis is Nagana and is caused by T.
• the trypanosomosis is Surra and is caused by T. evansi. In yet other embodiments, the trypanosomosis is Dourine and is caused by T.
• the second active agent is at least one of diminazene in various salt forms, including diminazene di-aceturate (i.e. Berenil®, Veriben®, Trypan®, Trypadim®, Trypazene®, Trypamyl®, Diamyl® Diminazen®); quinapyramine sulphate (Triquin®,
• the methods additionally may comprise administering at least one of an antibiotic, an anti-parasitic, an anti-inflammatory and/or a vitamin.
• HAT Human African trypanosomiasis
• Aminopurine Compounds for use in methods of treating or preventing Human African trypanosomiasis (HAT), comprising administering to a subject in need thereof an effective amount of an Aminopurine Compound, as described herein.
• HAT Human African trypanosomiasis
• the Human African trypanosomiasis is caused by T. brucei gambiense, T. brucei brucei, or T. brucei rhodesiense.
• the second active agent is selected from pentamidine, suramin, melarsoprol (arsenic-derived), eflornithine and nifurtimox.
• trypanosomiasis or Chagas disease comprising administering to a subject in need thereof an effective amount of an Aminopurine Compound, as described herein.
• Aminopurine Compounds, as described herein, for use in methods of treating or preventing American trypanosomiasis or Chagas disease comprising administering to a subject in need thereof an effective amount of an Aminopurine Compound, as described herein.
• the American trypanosomiasis or Chagas disease is caused by T. cruzi.
• the second active agent is selected from benznidazole and nifurtimox.
• the leishmaniasis is caused by Leishmania.
• the subject is a mammal, for example, a human or a rodent.
• the leishmaniasis is visceral leishmaniasis (also known as kala-azar) and is caused by L. donovani or L. infantum.
• the Leishmaniasis is post-kala-azar dermal leishmaniasis (PKDL).
• PKDL post-kala-azar dermal leishmaniasis
• the Leishmaniasis is cutaneous and is caused by L. major, L. tropica, L. aethiopica or L. Mexicana.
• the leishmaniasis is mucocutaneous leishmaniasis.
• the second active agent is selected from pentavalent antimonials (meglumine antimoniate and sodium stibogluconate; Pentostam®), Amphotericin B deoxycholate (also AmBisome®), pentamidine, paromomycin sulfate (aminosidine), miltefosine
• ketoconazole (hexadecylphosphocholine) and ketoconazole.
• compositions comprising an effective amount of an Aminopurine compound, as described herein, and a pharmaceutically acceptable carrier, excipient or vehicle.
• the Aminopurine Compounds can be administered to a subject enterally (for example, orally, rectally), topically, or parenterally (for example, intravenously,
• 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 (e.g., sucrose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate or calcium carbonate), a binder (e.g., cellulose, methylcellulose, hydroxymethylcellulose, polypropylpyrrolidone, polyvinylpyrrolidone, gelatin, gum arabic, polyethyleneglycol, sucrose or starch), a disintegrator (e.g., starch,
• an excipient e.g., sucrose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate or calcium carbonate
• a binder e.g., cellulose, methylcellulose, hydroxymethylcellulose, polypropylpyrrolidone, polyvinylpyrrolidone, gelatin, gum arabic, poly
• a lubricant e.g., magnesium
• the effective amount of the Aminopurine Compounds in the pharmaceutical composition may be at a level that will exercise the desired effect; for example, about 0.005 mg/kg of a subject's body weight to about 20 mg/kg of a subject's body weight in unit dosage for both oral and parenteral administration.
• the dose of an Aminopurine Compound to be administered to a subject is rather widely variable and can be subject to the judgment of a health-care practitioner.
• the Aminopurine 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 20 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 dose is about 0.01 mg/kg of a subject's body weight to about 5 mg/kg of a subject's body weight, about 0.05 mg/kg of a subject's body weight to about 1 mg/kg of a subject's body weight, about 0.1 mg/kg of a subject's body weight to about 0.75 mg/kg of a subject's body weight or about 0.25 mg/kg of a subject's body weight to about 0.5 mg/kg of a subject's body weight. In one embodiment, the dose is about 0.01 mg/kg of a subject's body weight to about 5 mg/kg of a subject's body weight.
• the dose is about 0.05 mg/kg of a subject's body weight to about 1 mg/kg of a subject's body weight. In one embodiment, the dose is about 0.1 mg/kg of a subject's body weight to about 0.75 mg/kg of a subject's body weight. In one embodiment, the dose is about 0.25 mg/kg of a subject's body weight to about 0.5 mg/kg of a subject's body weight. In one embodiment, one dose is given per day. In any given case, the amount of the Aminopurine 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 ⁇ .
• 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.
• methods for the treatment or prevention of a disease or disorder comprising the administration of about 0.375 mg/day to about 750 mg/day, about 0.75 mg/day to about 375 mg/day, about 3.75 mg/day to about 75 mg/day, about 7.5 mg/day to about 55 mg/day or about 18 mg/day to about 37 mg/day of an Aminopurine Compound to a subject in need thereof.
• the methods for the treatment of a disease or disorder comprise the administration of about 0.375 mg/day to about 750 mg/day of an Aminopurine Compound to a subject in need thereof. In one embodiment, the methods for the treatment of a disease or disorder comprise the administration of about 0.75 mg/day to about 375 mg/day of an Aminopurine Compound to a subject in need thereof. In one embodiment, the methods for the treatment of a disease or disorder comprise the administration of about 3.75 mg/day to about 75 mg/day of an Aminopurine Compound to a subject in need thereof.
• the methods for the treatment of a disease or disorder comprise the administration of about 7.5 mg/day to about 55 mg/day of an Aminopurine Compound to a subject in need thereof. In one embodiment, the methods for the treatment of a disease or disorder comprise the administration of about 18 mg/day to about 37 mg/day of an Aminopurine Compound to a subject in need thereof.
• kits for the treatment or prevention of a disease or disorder comprising the administration of about 1 mg/day to about 1200 mg/day, about 10 mg/day to about 1200 mg/day, about 100 mg/day to about 1200 mg/day, about 400 mg/day to about 1200 mg/day, about 600 mg/day to about 1200 mg/day, about 400 mg/day to about 800 mg/day or about 600 mg/day to about 800 mg/day of an Aminopurine Compound to a subject in need thereof.
• the methods disclosed herein comprise the administration of 400 mg/day, 600 mg/day or 800 mg/day of an
• Aminopurine Compound to a subject in need thereof.
• the methods for the treatment of a disease or disorder comprising the administration of about 1 mg/day to about 1200 mg/day of an
• Aminopurine Compound to a subject in need thereof.
• the methods for the treatment of a disease or disorder comprising the administration of about 10 mg/day to about 1200 mg/day of an
• Aminopurine Compound to a subject in need thereof.
• the methods for the treatment of a disease or disorder comprising the administration of about 100 mg/day to about 1200 mg/day of an
• Aminopurine Compound to a subject in need thereof.
• the methods for the treatment of a disease or disorder comprising the administration of about 400 mg/day to about 1200 mg/day of an
• Aminopurine Compound to a subject in need thereof.
• the methods for the treatment of a disease or disorder comprising the administration of about 600 mg/day to about 1200 mg/day of an
• Aminopurine Compound to a subject in need thereof.
• the methods for the treatment of a disease or disorder comprising the administration of about 400 mg/day to about 800 mg/day of an
• Aminopurine Compound to a subject in need thereof.
• the methods for the treatment of a disease or disorder comprising the administration of about 600 mg/day to about 800 mg/day of an
• the methods disclosed herein comprise the administration of 400 mg/day of an Aminopurine Compound to a subject in need thereof. In another particular embodiment, the methods disclosed herein comprise the administration of 600 mg/day of an Aminopurine Compound to a subject in need thereof. In another particular embodiment, the methods disclosed herein comprise the administration of 800 mg/day of an Aminopurine Compound to a subject in need thereof. 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 Aminopurine Compound.
• a unit dosage formulation that comprise between about 1 mg and 500 mg of an Aminopurine Compound. In one embodiment, provided herein is a unit dosage formulation that comprise between about 500 mg and about 1000 mg of an Aminopurine Compound.
• unit dosage formulations that comprise between about 1 mg and 200 mg, about 35 mg and about 1400 mg, about 125 mg and about 1000 mg, about 250 mg and about 1000 mg, or about 500 mg and about 1000 mg of an Aminopurine Compound.
• the unit dosage formulations comprises between about 1 mg and 200 mg of an Aminopurine Compound.
• the unit dosage formulations comprises between about 35 mg and about 1400 mg of an Aminopurine Compound.
• the unit dosage formulations comprises between about 125 mg and about 1000 mg of an Aminopurine Compound.
• the unit dosage formulations comprises between about 250 mg and about 1000 mg of an Aminopurine Compound.
• the unit dosage formulations comprises between about 500 mg and about 1000 mg of an Aminopurine Compound.
• unit dosage formulations comprising about 100 mg or 400 mg of an Aminopurine Compound.
• unit dosage formulations that comprise 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 35 mg, 50 mg, 70 mg, 100 mg, 125 mg, 140 mg, 175 mg, 200 mg, 250 mg, 280 mg, 350 mg, 500 mg, 560 mg, 700 mg, 750 mg, 1000 mg or 1400 mg of an Aminopurine Compound.
• the unit dosage formulations comprise 1 mg of an Aminopurine Compound.
• the unit dosage formulations comprise 5 mg of an Aminopurine Compound.
• the unit dosage formulations comprise 10 mg of an Aminopurine Compound.
• the unit dosage formulations comprise 15 mg of an Aminopurine Compound.
• the unit dosage formulations comprise 20 mg of an Aminopurine Compound. In one embodiment the unit dosage formulations comprise 25 mg of an Aminopurine Compound. In one embodiment the unit dosage formulations comprise 30 mg of an Aminopurine Compound. In one embodiment the unit dosage formulations comprise 35 mg of an Aminopurine Compound. In one embodiment the unit dosage formulations comprise 40 mg of an Aminopurine Compound. In one embodiment the unit dosage formulations comprise 50 mg of an Aminopurine Compound. In one embodiment the unit dosage formulations comprise 70 mg of an Aminopurine Compound. In one embodiment the unit dosage formulations comprise 100 mg of an Aminopurine Compound. In one embodiment the unit dosage formulations comprise 20 mg of an Aminopurine Compound. In one embodiment the unit dosage formulations comprise 25 mg of an Aminopurine Compound. In one embodiment the unit dosage formulations comprise 30 mg of an Aminopurine Compound. In one embodiment the unit dosage formulations comprise 35 mg of an Aminopurine Compound. In one embodiment the unit
• formulations comprise 125 mg of an Aminopurine Compound. In one embodiment the unit dosage formulations comprise 140 mg of an Aminopurine Compound. In one embodiment the unit dosage formulations comprise 175 mg of an Aminopurine Compound. In one embodiment the unit dosage formulations comprise 200 mg of an Aminopurine Compound. In one
• unit dosage formulations comprise 250 mg of an Aminopurine Compound. In one embodiment the unit dosage formulations comprise 280 mg of an Aminopurine Compound. In one embodiment the unit dosage formulations comprise 350 mg of an Aminopurine
• the unit dosage formulations comprise 500 mg of an
• the unit dosage formulations comprise 560 mg of an Aminopurine Compound. In one embodiment the unit dosage formulations comprise 700 mg of an Aminopurine Compound. In one embodiment the unit dosage formulations comprise 750 mg of an Aminopurine Compound. In one embodiment the unit dosage formulations comprise 1000 mg of an Aminopurine Compound. In one embodiment the unit dosage formulations comprise 1400 mg of an Aminopurine Compound.
• An Aminopurine Compound can be administered once, twice, three, four or more times daily.
• doses of 600 mg or less are administered as a once daily dose and doses of more than 600 mg are administered twice daily in an amount equal to one half of the total daily dose.
• An Aminopurine Compound can be administered orally for reasons of convenience.
• an Aminopurine Compound when administered orally, is administered with a meal and water.
• the Aminopurine Compound is dispersed in water or juice (e.g., apple juice or orange juice) and administered orally as a suspension.
• the Aminopurine Compound can also be administered intradermally,
• 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.
• compositions comprising an effective amount of an Aminopurine 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, suspensions, gels, intra-ruminal devices (e.g. for prolonged prophylaxis or controlled release), implants, topical pour-ons, transdermal delivery gels, spot-ons, implants (including devices, gels, liquids (e.g. PLGA), 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
• Capsules can be prepared by mixing an Aminopurine Compound with a suitable carrier or diluent and filling the proper amount of the mixture in capsules.
• suitable 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.
• Tablets can be prepared by direct compression, by wet granulation, or by dry granulation. Their formulations usually incorporate diluents, binders, lubricants and
• Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such as sodium chloride and powdered sugar. Powdered cellulose derivatives are also useful.
• Typical tablet binders are substances such as starch, gelatin and sugars such as lactose, fructose, glucose and the like. Natural and synthetic gums are also convenient, including acacia, alginates, methylcellulose, polyvinylpyrrolidine and the like. Polyethylene glycol, ethylcellulose and waxes can also serve as binders.
• a lubricant might be necessary in a tablet formulation to prevent the tablet and punches from sticking in the dye.
• the lubricant can be chosen from such slippery solids as talc, magnesium and calcium stearate, stearic acid and hydrogenated vegetable oils.
• Tablet disintegrators are substances that swell when wetted to break up the tablet and release the compound. They include starches, clays, celluloses, algins and gums. More particularly, corn and potato starches, methylcellulose, agar, bentonite, wood cellulose, powdered natural sponge, cation-exchange resins, alginic acid, guar gum, citrus pulp and carboxymethyl cellulose, for example, can be used as well as sodium lauryl sulfate. Tablets can be coated with sugar as a flavor and sealant, or with film-forming protecting agents to modify the dissolution properties of the tablet.
• the compositions can also be formulated as chewable tablets, for example, by using substances such as mannitol in the formulation.
• Cocoa butter is a traditional suppository base, which can be modified by addition of waxes to raise its melting point slightly.
• Water-miscible suppository bases comprising, particularly, polyethylene glycols of various molecular weights are in wide use.
• the effect of the Aminopurine Compound can be delayed or prolonged by proper formulation.
• a slowly soluble pellet of the Aminopurine 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 Aminopurine Compound in oily or emulsified vehicles, or adding amounts of PLGA, that allow it to disperse slowly in the serum.
• Example 4 -((IS, 4S)-4-(Aminomethyl)cyclohexyl)-N8-(2-fluoro-5- (trifluoromethyl)phenyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine
• Example 7 9-((lS, 4S)-4-(Aminomethyl)cyclohexyl)-N2-(4-methyltetrahydro-2H-pyran-4- yl)-N8-(6-(trifluoromethyl)pyridin-2-yl)-9H-purine-2,8-diamine
• Example 8 9-((lS, 4S)-4-(Aminomethyl)cyclohexyl)-N8-(3,5-difluorophenyl)-N2-(4- methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine
• Example 9 9-((lS, 4S)-4-(Aminomethyl)cyclohexyl)-N8-(3,5-dichlorophenyl)-N2-(4- methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine;
• Example 13 9-((lS, 4S)-4-(Aminomethyl)cyclohexyl)-N8-(3-chloro-2-fluorophenyl)-N2-(4- methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine
• Example 15 ((IS, 4S)-4-(8-((3-Chlorophenyl)amino)-2-((4-methyltetrahydro-2H-pyran-4- yl)amino)-9H-purin-9-yl)cyclohexyl)methanol
• Example 18 Methyl (((IS, 4S)-4-(8-((3-chlorophenyl) amino)-2-((4-methyltetrahydro-2H- pyran-4-yl) amino)-9H-purin-9-yl)cyclohexyl)methyl)carbamate
• Example 25 9-((lS, 4S)-4-(Amino methyl)cyclohexyl)-N8-(3-chlorophenyl)-N2-(l- methylcyclopentyl)-9H-purine-2, 8-diamine
• Example 28 9-((lS, 4S)-4-(Aminomethyl)cyclohexyl)-N8-(5-chloropyridin-3-yl)-N2-(4- methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine
• terf-Butyl (3-(8-((3-chlorophenyl)amino)-2-((4-methyltetrahydro-2H-pyran-4- yl)amino)-9H-purin-9-yl)cyclobutyl)carbamate.
• tert-butyl (3-((5- amino-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4- yl)amino)cyclobutyl)carbamate (0.37 g, 1 mmol) and l-chloro-3-isothiocyanatobenzene
• Example 32 9-((lS, 4S)-4-(Aminomethyl)cyclohexyl)-N2-(4-methyltetrahydro-2H-pyran-4- yl)-N8-(3-(trifluoromethoxy)phenyl)-9H-purine-2,8-diamine
• Example 33 9-((lS, 4S)-4-(Aminomethyl)cyclohexyl)-N2-(4-methyltetrahydro-2H-pyran-4- yl)-N8-(4-(trifluoromethoxy)phenyl)-9H-purine-2,8-diamine
• Example 39 9-((lS, 4S)-4-(Aminomethyl)cyclohexyl)-N2-(4-methyltetrahydro-2H-pyran-4- yl)-N8-(3-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine
• Example 40 9-((lS, 4S)-4-Aminocyclohexyl)-N2-(teri-butyl)-N8-(3-(trifluoromethyl) phenyl)-9H-purine-2,8-diamine
• terf-Butyl ((IS, 4S)-4-((2-chloro-5-nitropyrimidin-4- yl)amino)cyclohexyl)carbamate To a stirred solution of 2, 4-dichloro-5-nitropyrimidine (0.8 g, 4 mmol) and DIPEA (2 mL, 12 mmol) in IPA (10 mL) was added portionwise tert-butyl ((I S, 4S)-4-aminocyclohexyl) carbamate (0.8 g, 4 mmol) at 0 °C under nitrogen The reaction mixture was slowly warmed to ambient temperature and stirred for 1 h. Completion of the reaction was confirmed by UPLC.
• terf-Butyl ((IS, 4S)-4-((2-(tert-butylamino)-5-nitropyrimidin-4- yl)amino)cyclohexyl) carbamate To a stirred solution of tert-butyl ((I S, 4S)-4-((2-chloro- 5-nitropyrimidin-4-yl)amino)cyclohexyl)carbamate (1 g, 3 mmol) in DMF (12 mL) was added tert butylamine (0.5 g, 7 mmol) and sodium bicarbonate (0.4 g, 5 mmol) at ambient temperature. The reaction mixture was heated to 60 °C for 4 h.
• terf-Butyl ((IS, 4S)-4-((5-amino-2-(ter ⁇ butylamino)pyrimidin-4- yl)amino)cyclohexyl) carbamate To a stirred solution of tert-butyl ((I S, 4S)-4-((2-(tert- butylamino)-5-nitropyrimidin-4-yl)amino)cyclohexyl)carbamate (0.9 g, 2 mmol) in ethanol: water (15 mL, 3 : 1) was added iron powder (1 g, 22 mmol) and ammonium chloride (0.1 g, 2 mmol) at ambient temperature. The reaction mixture was heated to 85 °C for 2 h.

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