Compounds and compositions for the treatment of parasitic diseases

The present invention provides compounds of Formula I:or a pharmaceutically acceptable salt, tautomer, or stereoisomer, thereof, wherein the variables are as defined herein. The present invention further provides pharmaceutical compositions comprising such compounds and methods of using such compounds for treating, preventing, inhibiting, ameliorating, or eradicating the pathology and/or symptomology of a disease caused by a parasite, such as Leishmaniasis, Human African Trypanosomiasis and Chagas disease.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention provides a class of compounds, pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent Leishmaniasis.

Leishmaniasis is a disease caused by protozoan parasites that belong to the genusLeishmaniaand is transmitted by the bite of certain species of sand fly.

Leishmaniasis is mostly a disease of the developing world, and is rarely known in the developed world outside a small number of cases, mostly in instances where troops are stationed away from their home countries. Leishmaniasis can be transmitted in many tropical and subtropical countries, and is found in parts of about 88 countries. Approximately 350 million people live in these areas. The settings in which leishmaniasis is found range from rainforests in Central and South America to deserts in West Asia and the Middle East. It affects as many as 12 million people worldwide, with 1.5-2 million new cases each year. The visceral form of leishmaniasis has an estimated incidence of 500,000 new cases and 60,000 deaths each year. More than 90 percent of the world's cases of visceral leishmaniasis are in India, Bangladesh, Nepal, Sudan, and Brazil. Kabul is estimated as the largest center of cutaneous leishmaniasis in the world, with approximately 67,500 cases as of 2004.

There are four main forms of Leishmaniasis. Cutaneous leishmaniasis is the most common form of leishmaniasis. Visceral leishmaniasis, also called kala-azar, is the most serious form in which the parasites migrate to the vital organs. Visceral leishmaniasis is caused by the parasiteLeishmania donovani, and is potentially fatal if untreated.

Currently, no vaccines are in routine use.

The two main therapies for visceral leishmaniasis are the antimony derivatives sodium stibogluconate (Pentostam®) and meglumine antimoniate (Glucantim®). Sodium stibogluconate has been used for about 70 years and resistance to this drug is a growing problem. In addition, the treatment is relatively long and painful, and can cause undesirable side effects. Amphotericin (AmBisome) is now the treatment of choice. Miltefosine (Impavido), and paromomycin are the other treatment alternatives. These drugs are known to produce a definitive cure in >90% of patients. Amphotericin (AmBisome) is expansive and has to be given intravenously; it is not affordable to most patients affected. Paromomycin, although affordable, requires intramuscular injections for 3 weeks; compliance is a major issue. Miltefosine is an oral drug and has shown to be more effective and better tolerated than other drugs. However, there are problems associated with the use of miltefosine that arise from its teratogenicity and pharmacokinetics. Miltefosine was shown to be much slower eliminated from the body and was still detectable five months after the end of treatment. The presence of subtherapeutic miltefosine concentrations in the blood beyond five months after treatment might contribute to the selection of resistant parasites and, moreover, the measures for preventing the teratogenic risks of miltefosine must be reconsidered. This led to some reluctance to taking Miltefosine by affected populations.

The Drugs for Neglected Diseases Initiative is actively facilitating the search for novel therapeutics. Our invention meets that needs.

Human African trypanosomiasis (HAT), also known as African sleeping sickness, is a vector-borne parasitic disease caused by the protozoaTrypanosoma brucei. There are two subspecies that infect humans,T.b. gambienseandT.b. rhodesiense, with the former accounting for over 95% of reported cases and the latter accounting for the remaining reported cases. The parasites are transmitted to humans by tsetse fly (Glossinagenus) bites which have acquired their infection from human beings or from animals harboring the human pathogenic parasites.

The disease has been recorded as occurring in 36 countries, all in subtropical and equatorial Africa. It is endemic in southeast Uganda and western Kenya. In 1995, the WHO estimated that 300,000 people were afflicted with the disease. In its 2001 report, the WHO set the figure of people at risk of infection at 60 million, of which only 4 to 5 million had access to any kind of medical monitoring. In 2006, the WHO estimated that about 70,000 people could have the disease, and many cases are believed to go unreported. About 48,000 people died of sleeping sickness in 2008. Public health efforts in prevention and the eradication of the tsetse fly population have proven to be successful in controlling the spread of the disease; under 10,000 new cases were reported in 2009 according to WHO figures, which represents a huge decrease from the estimated 300,000 new cases in 1998.

African trypanosomiasis symptoms occur in two stages. In the first stage, known as the haemolymphatic phase, the trypanosomes multiply in subcutaneous tissues, blood and lymph. The haemolymphatic phase is characterized by bouts of fever, headaches, joint pains and itching. In the second stage, the neurological phase, the parasites cross the blood-brain barrier to infect the central nervous system. It is in this stage when more obvious signs and symptoms of the disease appear: changes of behaviour, confusion, sensory disturbances and poor coordination. Disturbance of the sleep cycle, which gives the disease its name, is an important feature of the second stage of the disease. Without treatment, the disease is invariably fatal, with progressive mental deterioration leading to coma, systemic organ failure, and death.

Four drugs are registered for the treatment of sleeping sickness. The protocol depends on the stage of the disease. The current standard treatment for first-stage disease is intravenous or intramuscular pentamidine (forT.b. gambiense), or intravenous suramin (forT.b. rhodesiense). The current standard treatment for second-stage disease is: Intravenous melarsoprol, or interavenous melarsoprol in combination with oral nifurtimox, intravenous eflornithine only or eflornithine in combination with nifurtimox. All of the drugs have undesirable or sometime serious side effects. For example, 3-10% of patients those injected with Melarsoprol (Arsobal), an organoarsenical, developed reactive encephalopathy (convulsions, progressive coma, or psychotic reactions), and 10-70% of such cases result in death.

Chagas disease, also called American trypanosomiasis, is a tropical parasitic disease caused by the flagellate protozoanTrypanosoma cruzi. T. cruziis commonly transmitted to humans and other mammals by the blood-sucking “kissing bugs” of the subfamily Triatominae (family Reduviidae).

Chagas disease is contracted primarily in the Americas. It is endemic in twenty one Central and Latin American countries; particularly in poor, rural areas of Mexico, Central America, and South America. Large-scale population movements from rural to urban areas of Latin America and to other regions of the world have increased the geographic distribution of Chagas disease, and cases have been noted in many countries, particularly in Europe. Although there are triatomine bugs in the U.S., only very rarely vectorborne cases of Chagas disease have been documented.

Each year, an estimated 10 to 15 million people across the world are infected with Chagas disease, most of whom do not know they are infected. Every year, 14,000 people die as a consequence of the disease. In Central and South America, Chagas kills more people than any other parasite-borne disease, including malaria. By applying published seroprevalence figures to immigrant populations, CDC estimates that more than 300,000 persons withTrypanosoma cruziinfection live in the United States. Most people with Chagas disease in the United States acquired their infections in endemic countries.

Chagas disease has an acute and a chronic phase. If untreated, infection is lifelong. Acute Chagas disease occurs immediately after infection, may last up to a few weeks or months, and parasites may be found in the circulating blood. Infection may be mild or asymptomatic. There may be fever or swelling around the site of inoculation (where the parasite entered into the skin or mucous membrane). Rarely, acute infection may result in severe inflammation of the heart muscle or the brain and lining around the brain. The initial acute phase is responsive to antiparasitic treatments, with 60-90% cure rates. Following the acute phase, most infected people enter into a prolonged asymptomatic form of disease (called “chronic indeterminate”) during which few or no parasites are found in the blood. During this time, most people are unaware of their infection. Many people may remain asymptomatic for life and never develop Chagas-related symptoms.

However, an estimated 20-30% of infected people will develop debilitating and sometimes life-threatening medical problems over the course of their lives.

The symptoms of Chagas disease vary over the course of an infection. In the early, acute stage, symptoms are mild and usually produce no more than local swelling at the site of infection. The initial acute phase is responsive to antiparasitic treatments, with 60-90% cure rates. After 4-8 weeks, individuals with active infections enter the chronic phase of Chagas disease that is asymptomatic for 60-80% of chronically infected individuals through their lifetime.

There is no vaccine against Chagas disease. Treatment for Chagas disease focuses on killing the parasite and managing signs and symptoms.

During the acute phase of Chagas disease, the drugs currently available for treatment are benznidazole and nifurtimox. Once Chagas disease reaches the chronic phase, medications aren't effective for curing the disease. Instead, treatment depends on the specific signs and symptoms. However, problems with these current therapies include their diverse side effects, the length of treatment, and the requirement for medical supervision during treatment. Resistance to the two frontline drugs has already occurred. The antifungal agent Amphotericin b has been proposed as a second-line drug, but this drug is costly and relatively toxic.

In view of the foregoing, it is desirable to develop novel compounds as antiparasitic agents.

SUMMARY OF THE INVENTION

The invention therefore provides a compound of the formula (I):

In a second aspect, the present invention provides a pharmaceutical composition which contains a compound of the invention selected from Formula I, a N-oxide derivative, individual isomers and mixture of isomers thereof; or a pharmaceutically acceptable salt thereof, in admixture with one or more suitable excipients.

In a third aspect, the present invention provides a method of treating a disease in an animal in which a compound of the invention can prevent, inhibit or ameliorate the pathology and/or symptomology of a disease caused by a parasite of theLeishmaniagenus, for example,Leishmania donovani, Leishmania infantum, Leishmania braziliensis, Leishmania panamensis, Leishmania guayanensis, Leishmania amazonensis, Leishmania mexicana, Leishmania tropica, Leishmania major, Trypanosoma cruzi, andTrypanosoma bruceiand a parasite of theTrypanosomagenus, for example,Trypanosoma cruziandTrypanosoma brucei, which method comprises administering to the animal a therapeutically effective amount of a compound selected from Formula I, an N-oxide derivative, individual isomers and mixture of isomers thereof, or a pharmaceutically acceptable salt thereof.

In a fourth aspect, the present invention provides a compound of Formula I, an N-oxide derivative, individual isomers and mixture of isomers thereof, or a pharmaceutically acceptable salt thereof, for treating, preventing, inhibiting, ameliorating, or eradicating the pathology and/or symptomology of a disease caused by a parasite of theLeishmaniagenus, for example,Leishmania donovani, Leishmania infantum, Leishmania braziliensis, Leishmania panamensis, Leishmania guayanensis, Leishmania amazonensis, Leishmania mexicana, Leishmania tropica, Leishmania major, Trypanosoma cruzi, andTrypanosoma bruceiand a parasite of theTrypanosomagenus, such as, for example,Trypanosoma cruziandTrypanosoma brucei. Particularly, the parasite is aLeishmania, and the disease is Leishmanaisis.

In a fifth aspect, the present invention provides the use of a compound selected from Formula I, an N-oxide derivative, individual isomers and mixture of isomers thereof, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease caused by a parasite in an animal. The disease may be Leishmaniasis, Human African Trypanosomiasis and/or Chagas disease.

Unless specified otherwise, the term “compounds of the present invention” refers to compounds of Formula (I) and subformulae thereof, salts of the compound, hydrates or solvates of the compounds, salts, as well as all stereoisomers (including diastereoisomers and enantiomers), tautomers and isotopically labeled compounds (including deuterium substitutions). Compounds of the present invention further comprise polymorphs of compounds of formula I (or subformulae thereof) and salts thereof.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

For purposes of interpreting this specification, the following definitions will apply and whenever appropriate, terms used in the singular will also include the plural and vice versa.

“Acyl” as used herein refers to the radical C(═O)Ra, where Rais hydrogen or a non-hydrogen substituent on the carbonyl carbon, forming different carbonyl-containing groups including, but are not limited to, acids, acid halides, aldehydes, amides, esters, and ketones.

“Alkoxy” as used herein refers the radical —O-alkyl, wherein the alkyl is as defined herein. CXalkoxy and CX-Yalkoxy as used herein describe alkoxy groups where X and Y indicate the number of carbon atoms in the alkyl chain. Representative examples of C1-10alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy and decyloxy. The alkyl portion of the alkoxy may be optionally substituted, and the substituents include those described for the alkyl group below.

“Alkyl” as used herein refers to a fully saturated branched or unbranched hydrocarbon chain having up to 10 carbon atoms. CXalkyl and CX-Yalkyl as used herein describe alkyl groups where X and Y indicate the number of carbon atoms in the alkyl chain. For example, C1-10alkyl refers to an alkyl radical as defined above containing one to ten carbon atoms. C1-10alkyl includes, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, n-decyl and the like. Alkyl represented along with another radical like arylalkyl, heteroarylalkyl, alkoxyalkyl, alkoxyalkyl, alkylamino, where the alkyl portion shall have the same meaning as described for alkyl and is bonded to the other radical. For example, (C6-10)aryl(C1-3)alkyl includes, benzyl, phenylethyl, 1-phenylethyl, 3-phenylpropyl, 2-thienylmethyl, 2-pyridinylmethyl and the like.

Unless stated otherwise specifically in the specification, an alkyl group may be unsubstituted or substituted by one or more substituents to the extent that such substitution makes sense chemically. Typical substituents include, but are not limited to halo, hydroxyl, alkoxy, cyano, amino, acyl, aryl, arylalkyl, and cycloalkyl, or an heteroforms of one of these groups, and each of which can be substituted by the substituents that are appropriate for the particular group.

“Alkenyl” as used herein refers to a straight or branched, hydrocarbon chain having up to 10 carbon atoms and at least one carbon-carbon double bond. CXalkenyl and CX-Yalkenyl as used herein describe alkenyl groups where X and Y indicate the number of carbon atoms in the alkenyl chain. Examples of C2-7alkenyl include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl, and the like. The alkenyl may be optionally substituted, and the substituents include those described for the alkyl group descried herein.

“Alkynyl” as used herein refers to a straight or branched, hydrocarbon chain having up to 10 carbon atoms and at least one carbon-carbon triple bond. CXalkenyl and CX-Yalkenyl as used herein describe alkynyl groups, where X and Y indicate the number of carbon atoms in the alkynyl chain. For example, C2-7alkenyl include, but are not limited to, ethynyl, propargyl, 3-methyl-1-pentynyl, 2-heptynyl and the like. An alkynyl may be optionally substituted, and the substituents include those described for the alkyl group described herein.

“Alkylene” as used herein refers to a divalent alkyl group defined herein. Examples of C1-10alkylene includes, but are not limited to, methylene, ethylene, n-propylene, iso-propylene, n-butylene, sec-butylene, iso-butylene, tert-butylene, n-pentylene, isopentylene, neopentylene, n-hexylene, 3-methylhexylene, 2,2-dimethylpentylene, 2,3-dimethylpentylene, n-heptylene, n-octylene, n-nonylene and n-decylene. An alkylene group may be optionally substituted, and the substituents include those described for the alkyl group described herein.

“Alkenylene” as used herein refers to a divalent alkenyl group defined herein. Examples of C1-3alkenylene include, but are not limited to, ethene-1,2-diyl, propene-1,3-diyl, and methylene-1,1-diyl. An alkenylene may be optionally substituted, and the substituents include those described for the alkyl group described herein.

“Alkynylene” as used herein refers to a divalent alkynyl group defined herein. Examples of alkynylene include ethyne-1,2-diylene, propyne-1,3-diylene, and the like. An alkynylene may be optionally substituted, and the substituents include those described for the alkyl group described herein.

“Amino” as used herein refers to the radical —NH2. When an amino is described as “substituted” or “optionally substituted”, the term includes NR′R″ wherein each R′ and R″ is independently H, or is an alkyl, alkenyl, alkynyl, acyl, aryl, aryl, cycloalkyl, arylalkyl cycloalkylalkyl group or a heteroform of one of these groups, and each of the alkyl, alkenyl, alkynyl, acyl, aryl, arylalkyl or groups or heteroforms of one of these groups, each of which is optionally substituted with the substituents described herein as suitable for the corresponding group.

The term “amino” also includes forms wherein R′ and R″ are linked together to form a 3-8 membered ring which may be saturated, unsaturated or aromatic and which contains 1-3 heteroatoms independently selected from N, O and S as ring members, and which is optionally substituted with the substituents described as suitable for alkyl groups or, if NR′R″ is an aromatic group, it is optionally substituted with the substituents described as typical for heteroaryl groups.

Unless indicated otherwise, the compounds of the invention containing amino moieties may include protected derivatives thereof. Suitable protecting groups for amino moieties include acetyl, tert-butoxycarbonyl, benzyloxycarbonyl, and the like.

“Alkylamino” as used herein refers to the radical —NRaRb, where at least one of, or both, Raand Rbare an alkyl group as described herein. An C1-4alkylamino group includes —NHC1-4alkyl and —N(C1-4alkyl)2; e.g., —NHCH3, —N(CH3)2, —NH(CH2CH3), —N(CH2CH3)2, and the like.

“Aromatic” as used herein refers to a moiety wherein the constituent atoms make up an unsaturated ring system, where all atoms in the ring system are sp2hybridized and the total number of pi electrons is equal to 4n+2. An aromatic ring may be such that the ring atoms are only carbon atoms or may include carbon and non-carbon atoms (see Heteroaryl).

“Aryl” as used herein refers to a 6-14 membered monocyclic or polycyclic aromatic ring assembly where all the ring atoms are carbon atoms. Typically, the aryl is a 6 membered monocyclic, a 10-12 membered bicyclic or a 14-membered fused tricyclic aromatic ring system. CXaryl and CXaryl as used herein describe an aryl group where X and Y indicate the number of carbon atoms in the ring system. C6-14aryls include, but are not limited to, phenyl, biphenyl, naphthyl, azulenyl, and anthracenyl.

When an “aryl” is represented along with another radical like “arylalkyl”, “aryloxyalkyl”, “aryloxycarbonyl”, “aryloxy-carbonylalkyl”, the aryl portion shall have the same meaning as described in the above-mentioned definition of “aryl”.

“Aryloxy” as used herein, refers to the radical —O-aryl, wherein aryl is as defined herein.

“Bicyclic” or “bicyclyl” as used here in refers to a ring assembly of two rings where the two rings are fused together, linked by a single bond or linked by two bridging atoms. The rings may be a carbocyclyl, a heterocyclyl, or a mixture thereof.

“Bridging ring” as used herein refers to a polycyclic ring system where two ring atoms that are common to two rings are not directly bound to each other. One or more rings of the ring system may also comprise heteroatoms as ring atoms. Non-exclusive examples of bridging rings include norbornanyl, 7-oxabicyclo[2.2.1]heptanyl, adamantanyl, and the like.

“Carbamoyl” as used herein refers to the radical —C(O)NRa— where Rais H, or is an alkyl, alkenyl, alkynyl, acyl, aryl, or arylalkyl group or a heteroform of one of these groups, and each of the alkyl, alkenyl, alkynyl, acyl, aryl, arylalkyl or heteroforms of one of these groups is optionally substituted with the substituents described herein as suitable for the corresponding group.

“Carbamate” as used herein refers to the radical —OC(O)NRaRbwhere Raand Rbare each independently H, or is an alkyl, alkenyl, alkynyl, acyl, aryl, or arylalkyl group or a heteroform of one of these groups, and each of the alkyl, alkenyl, alkynyl, acyl, aryl, arylalkyl or heteroforms of one of these groups is optionally substituted with the substituents described herein as suitable for the corresponding group.

“Cycloalkyl”, as used herein, means a radical comprising a non-aromatic, saturated or partially unsaturated, monocyclic, bicyclic, tricyclic, fused, bridged or spiro polycyclic hydrocarbon ring system of 3-20 carbon atoms. CXcycloalkyl and CX-Ycycloalkyl are typically used where X and Y indicate the number of carbon atoms in the ring assembly. For example, C3-6cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2,5-cyclohexadienyl.

“Cycloalkylene”, as used herein, refers to a divalent radical comprising a cycloalkyl ring assembly as defined herein.

“Cyano”, as used herein, refers to the radical —CN.

“EC50”, refers to the molar concentration of an inhibitor or modulator that produces 50% efficacy.

“Fused ring”, as used herein, refers to a multi-ring assembly wherein the rings comprising the ring assembly are so linked that the ring atoms that are common to two rings are directly bound to each other. The fused ring assemblies may be saturated, partially saturated, aromatics, carbocyclics, heterocyclics, and the like. Non-exclusive examples of common fused rings include decalin, naphthalene, anthracene, phenanthrene, indole, benzofuran, purine, quinoline, and the like.

“Halo” or “halogen” as used herein refers to fluoro, chloro, bromo, and iodo.

“Haloalkyl”, or halo-substituted-alkyl” as used herein, refers to an alkyl as defined herein, which is substituted by one or more halo atoms defined herein. The haloalkyl can be mono-haloalkyl, dihaloalkyl or polyhaloalkyl including perhaloalkyl. A monohaloalkyl can have one iodo, bromo, chloro or fluoro within the alkyl group. Dihaloalky and polyhaloalkyl groups can have two or more of the same halo atoms or a combination of different halo groups within the alkyl. CXhaloalkyl and CX-Yhaloalkyl are typically used where X and Y indicate the number of carbon atoms in the alkyl chain. Non-limiting examples of C1-4haloalkyl include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. A C1-4perhaloalkyl group refers to a C1-4alkyl group having all hydrogen atoms replaced with halo atoms.

When a heteroaryl is represented along with another radical like “heteroaryloxy”, “heteroaryloxyalkyl”, “heteroaryloxycarbonyl”, the heteroaryl portion shall have the same meaning as described in the above-mentioned definition of “heteroaryl”.

“Heteroaryloxy”, as used herein, refers to an —O-heteroaryl group, wherein the heteroaryl is as defined in this Application.

“Heteroatom”, as used herein, refers to an atom that is not a carbon atom. Particular examples of heteroatoms include, but are not limited to nitrogen, oxygen, and sulfur.

“Heterocycloalkyl”, as used herein, refers to a 4-20 membered, non-aromatic, saturated or partially unsaturated, monocyclic or polycyclic ring system, comprising 1-8 heteroatoms as ring atoms and that the remaining ring atoms are carbon atoms. The heteroatoms are selected from N, O, and S, preferably O and N. The nitrogen atoms of the heterocycloalkyl can be optionally quaternerized and the sulfur atoms of the heterocycloalkyl can be optionally oxidized. The heterocycloalkyl can include fused or bridged rings as well as spirocyclic rings. CXheterocycloalkyl and CX-Yheterocycloalkyl are typically used where X and Y indicate the number of ring atoms in the ring. Typically, the heterocycloalkyl is 4-8-membered monocyclic ring containing 1 to 3 heteroatoms, a 7 to 12-membered bicyclic ring system containing 1-5 heteroatoms, or a 10-15-membered tricyclic ring system containing 1 to 7 heteroatoms. Examples of C4-6heterocycloalkyl include azetidinyl, tetrahydrofuran (THF), dihydrofuran, 1,4-dioxane, morpholine, 1,4-dithiane, piperazine, piperidine, 1,3-dioxolane, imidazolidine, imidazoline, pyrazolidinyl, pyrroline, pyrrolidine, tetrahydropyran, dihydropyran, oxathiolane, dithiolane, 1,3-dioxane, 1,3-dithiane, oxathiane, thiomorpholine, and the like

A heterocycloalkyl may be unsubstituted or substituted with 1-5 substituents (such as one, or two, or three) each independently selected from hydroxyl, thiol, cyano, nitro, oxo, alkylimino, C1-4alkyl, C1-4alkenyl, C1-4alkynyl, C1-4alkoxy, C1-4thioalkyl, C1-4alkenyloxy, C1-4alkynyloxy, halogen, C1-4alkylcarbonyl, carboxy, C1-4alkoxycarbonyl, amino, C1-4alkylamino, di-C1-4alkylamino, C1-4alkylaminocarbonyl, di-C1-4alkylaminocarbonyl, C1-4alkylcarbonylamino, C1-4alkylcarbonyl(C1-4alkyl)amino, sulfonyl, sulfamoyl, alkylsulfamoyl, C1-4alkylaminosulfonyl where each of the afore-mentioned hydrocarbon groups (e.g., alkyl, alkenyl, alkynyl, alkoxy residues) may be further substituted by one or more residues independently selected at each occurrence from halogen, hydroxyl or C1-4alkoxy groups. When a heterocycloalkyl forms part of other groups like “heterocycloalkyl-alkyl”, “heterocycloalkoxy”, “heterocycloalkyl-aryl”, the heteroaryl portion shall have the same meaning as described in the above-mentioned definition of “heteroaryl”

“Heterocycloalkylene”, as used herein, refers to a cycloalkylene, as defined in this Application, provided that one or more of the ring member carbon atoms is replaced by a heteroatom.

“Heterocycloalkyl fused to a phenyl” as used herein, refers to a bicyclic fused ring system that one of the ring is heterocycloalkyl as defined above and the other ring is a phenyl. A heterocycloalkyl fused to a phenyl includes but are not limited to benzo[b][1,4]oxazinyl, oxo-benzo[b][1,4]oxazinyl, tetrahydroquinoxalinyl, tetrahydroquinolinyl, indolinyl, benzo[d]imidazolyl, and the like.

“Heterocyclyl”, “heterocycle” or “heterocyclo”, as used herein, refers to a 3-20 membered, monocyclic or polycyclic ring system containing at least one heteroatom moiety selected from the group consisting of N, O, SO, SO2, (C═O), and S, and preferably N, O, S, optionally containing one to four additional heteroatoms in each ring. CXheterocyclyl and CX-Yheterocyclyl are typically used where X and Y indicate the number of ring atoms in the ring system. Unless otherwise specified, a heterocyclyl may be saturated, partially unsaturated, aromatic or partially aromatic.

Hydroxy, as used herein, refers to the radical —OH.

“Hydroxyalkyl” or “hydroxyl-substituted alkyl” as used herein, refers to an alkyl as defined herein, having one or more of the available hydrogen of the alkyl replaced by a hydroxyl group. For example, a hydroxyC1-4alkyl includes, but are not limited to, —CH2CH2OH, —CH(OH)CH2CH2OH, —CH(OH)CH2CH(OH)CH3.

“Nitro”, as used herein, refers to the radical —NO2.

“Oxo”, as used herein, refers to the divalent radical ═O

“Protected derivatives” means derivatives of inhibitors in which a reactive site or sites are blocked with protecting groups. Protected derivatives are useful in the preparation of inhibitors or in themselves may be active as inhibitors. Examples of protected group includes, but are not limited to, acetyl, tetrahydropyran, methoxymethyl ether, β-methoxyethoxymethyl ether, p-methoxybenzyl, methylthiomethyl ether, pivaloyl, silyl ether, carbobenzyloxy, benzyl, tert-butoxycarbonyl, p-methoxyphenyl, 9-fluorenylmethyloxycarbonyl, acetals, ketals, acylals, dithianes, methylesters, benzyl esters, tert-butyl esters, and silyl esters. A comprehensive list of suitable protecting groups can be found in T. W. Greene,Protecting Groups in Organic Synthesis,3rd edition, John Wiley & Sons, Inc. 1999.

“Unsubstituted or substituted” or “optionally substituted” as used herein indicate the substituent bound on the available valance of a named group or radical. “Unsubstituted” as used herein indicates that the named group or radical will have no further non-hydrogen substituents. “Substituted” or “optionally substituted” as used herein indicates that at least one of the available hydrogen atoms of named group or radical has been (or may be) replaced by a non-hydrogen substituent.

“Substituted terminally” as used herein referred to a substituent replacing a hydrogen at a terminal position of the parent molecule. For example C1-4alkyl substituted terminally by an amino means —C1-4alkylene-amino, which includes —(CH2)—NH2, —(CH2)2—NH2, —(CH2)3—NH2, —(CH2)CH2(CH2—NH2), —(CH2)4—NH2, —C(CH2)(CH2CH2—NH2), —C(CH3)2(CH2—NH2), and the like.

“Sulfamoyl” as used herein refers to the radical —S(O)2NRaRbwhere Raand Rbare independently H, or is an alkyl, alkenyl, alkynyl, acyl, aryl, aryl, cycloalkyl, arylalkyl cycloalkylalkyl group or a heteroform of one of these groups, and each of the alkyl, alkenyl, alkynyl, acyl, aryl, arylalkyl groups or heteroforms of one of these groups, is optionally substituted with the substituents described herein as suitable for the corresponding group.

“Sulfanyl” as used herein, means the radical —S—.

“Sulfinyl”, as used herein, means the radical —S(O)—. It is noted that the term “sulfinyl” when referring to a monovalent substituent can alternatively refer to a substituted sulfinyl group, —S(═O)R, where R is hydrogen or a non-hydrogen substituent on the sulfur atom forming different sulfinyl groups including sulfinic acids, sulfinamides, sulfinyl esters, and sulfoxides.

“Sulfonyl”, as used herein, means the radical —S(O)2—. It is noted that the term “sulfonyl” when referring to a monovalent substituent can alternatively refer to a substituted sulfonyl group, —S(═O)2R, where R is hydrogen or a non-hydrogen substituent on the sulfur atom forming different sulfonyl groups including sulfonic acids, sulfonamides, sulfonate esters, and sulfones.

“Thiocarbonyl”, as used herein, refers to the radical —C(═S)—. It is noted that the term thiocarbonyl when referring to a monovalent substituent can alternatively refer to a substituted thiocarbonyl group, —C(═S)R, where R is hydrogen or a non-hydrogen substituent on the carbon atom forming different thiocarbonyl groups including thioacids, thioamides, thioesters, and thioketones.

are symbols denoting the point of attachment of X, to other part of the molecule.

Any definition herein may be used in combination with any other definition to describe a composite structural group. By convention, the trailing element of any such definition is that which attaches to the parent moiety. For example, the composite group alkoxyalkyl would represent an alkoxy group attached to the parent molecule through an alkyl group.

It is noted in regard to all of the definitions provided herein that the definitions should be interpreted as being open ended in the sense that further substituents beyond those specified may be included. Hence, a C1alkyl indicates that there is one carbon atom but does not indicate what are the substituents on the carbon atom. Hence, a C1alkyl comprises methyl (i.e., —CH3) as well as —CRaRbRcwhere Ra, Rb, and Rcmay each independently be hydrogen or any other substituent where the atom attached to the carbon is not a hydrogen atom. Hence, —CF3, —CH2OH and —CH2CN, for example, are all C1alkyls.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The invention provides a novel class of compounds, pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent diseases or disorders associated with a parasite. In particular, the compounds can be used to treat leishmaniasis, Human Trypanosomiasis and/or Chagas disease. The compounds of the invention are effective in inhibiting, ameliorating, or eradicating the pathology and/or symptomology of the parasite.

In a first embodiment, the compound of the invention, or a pharmaceutical acceptable salt, tautomer or stereoisomer thereof, is of Formula I:

or a pharmaceutical acceptable salt, or a stereoisomer thereof; whereinX is O or NR4, wherein R4is selected from hydrogen, C1-4alkyl, haloC1-4alkyl, and —C(O)R10, wherein R10is hydroxy, C1-4alkyl, C1-4alkoxy, amino, C1-4alkylamino, C3-6cycloalkyl and C4-6heterocycloalkyl, each of which is independently optionally substituted by 1-2 substituents independently selected from hydroxyl, halo and C1-4alkyl;L1is —C(O)— or —S(O)2—;R1is selected from nitro, C1-4alkyl, C1-6alkoxy, amino, C5-9heteroaryl, C3-6cycloalkyl and C4-6heterocycloalkyl, each of which is optionally substituted by 1-2 substituent independently selected from halo, cyano, amino, C1-4alkyl, haloC1-4alkyl, C1-6alkoxy, and C1-4alkylcarbonyl; or —NHL1R1is nitro;R3is selected from hydrogen, halo, cyano, C1-4alkyl and haloC1-4alkyl;L2is selected from a bond, —C(O)— and —S(O)2—;R2is selected from hydrogen, C1-6alkyl, C1-4alkoxy, amino, C3-6cycloalkyl, C4-6heterocycloalkyl, and C5-6heteroaryl; whereinthe C1-6alkyl, C1-4alkoxy, C3-6cycloalkyl, and amino of R2are each optionally substituted by 1-2 substituents independently selected from halo, hydroxy, C1-4alkyl, C1-4alkoxy, —NR9aR9b, C3-6cycloalkyl, C5-6heterocycloalkyl, phenyl and C5-6heteroaryl, wherein R9ais hydrogen or C1-4alkyl and R9bis selected from hydrogen, C1-4alkyl, C1-4alkylcarbonyl and C1-4alkoxycarbonyl, and the C5-6heterocycloalkyl, phenyl or C5-6heteroaryl is further optionally substituted by 1-2 substituents independently selected from hydroxyl, C1-4alkyl and C1-4alkoxycarbonyl;the C5-6heteroaryl of R2is optionally substituted with 1-2 substituents selected from hydroxy, C1-4alkyl, and C1-4alkoxycarbonyl;the C3-6cycloalkyl or C4-6heterocycloalkyl of R2are each independently optionally substituted by 1-2 substituents independently selected from halo, cyano, hydroxy, C1-4alkyl, haloC1-4alkyl, C1-4alkoxylC1-4alkyl, aminocarbonyl, C1-4alkoxycarbonyl, and C1-4alkoxycarbonylaminoC1-4alkyl;R5is hydrogen or C1-4alkyl;or R2and R5together with L2and N to which R2and R5, respectively, attached are taken together to form a heteroC5-6cycloalkyl or a heteroC5-6cycloalkenyl, each of which is optionally substituted by 1 to 3 substituents independently selected from oxo, C1-4alkyl, —(CH2)1-4OH, —(CH2)1-4NRaRb, wherein Raand Rbare each independently hydrogen, C1-4alkyl or C3-6cycloalkyl;or —N(R5)L2R2is nitro or —N═CHN(CH3)2.

In another embodiment of the compound of the invention, X is O. In one variation, X is NR4, wherein R4is hydrogen, C1-4alkyl, haloC1-4alkyl, or C(O)R10, where R10is C1-4alkoxy or C1-4alkylamino. In one variation, X is NR4and R4is C1-4alkyl. In another variation, X is NR4and R4is hydrogen, ethyl, —C(O)OCH(CH3)(CH2CH3), and —C(O)OCH(CH3)2. In another variation, X is NH.

In another embodiment of the above embodiments and variations of the compound of the invention, L1is *—C(O)— or *—S(O)2—. In one variation, L1is *—C(O)—. In another variation, L1is *—S(O)2—.

In still another embodiment of the above embodiments and variations of the compound of the invention, R1is selected from C1-4alkyl, C1-6alkoxy, amino, C5-9heteroaryl, C3-6cycloalkyl and C4-6heterocycloalkyl, each is optionally substituted by 1-2 substituent independently selected from hydroxyl, halo, cyano, amino, C1-4alkyl, haloC1-4alkyl, C1-6alkoxy, C1-4alkylcarbonyl, phenyl and C5-6heteroaryl.

In another variation, R1is selected from C1-6alkoxy and C1-6alkylamino, wherein the C1-6alkoxy and C1-6alkylamino are each optionally substituted by 1-2 substituents independently selected from C1-4alkyl and C1-4alkoxy.

In still another variation, R1is selected from C5-9heteroaryl, C4-6heterocycloalkyl, and C3-6cycloalkyl, each of which is independently optionally substituted by 1-2 substituents independently selected from halo, cyano, C1-4alkyl and C1-4alkoxy.

In another embodiment of the above embodiments and variations of the compounds of the invention, in one variation, -L1-R1is selected from —NHC(O)N(CH3)CH2CH3, —NHC(O)N(CH3)OCH3, —NHC(O)N(CH3)2, —NHC(O)N(CH2CH3)2, —NHC(O)OCH2CH3, —NHC(O)OCH(CH3)2, and —NHC(O)O(CH2)2OCH3.

In still another variation, -L1-R1is selected from

In yet another variation, L1-R1is selected from —C(O)OCH2CH3, —C(O)O(CH2)2OCH3,

In a particular embodiment of the compound of the invention, —NHL1R1is nitro. R3is chloro or fluoro.

In another embodiment of above embodiments and variations of the compounds of the invention, R3is selected from hydrogen, halo, methyl, or trifluoromethyl. In one variation, R3is methyl or trifluoromethyl. In another variation, R3is hydrogen.

In another embodiment of above embodiments and variations of the compounds of the invention, R5is selected from hydrogen and C1-4alkyl. In one variation, R5is C1-4alkyl. In another variation, R5is methyl or ethyl. In still another variation, R5is hydrogen.

In another embodiment of above embodiments and variations of the compounds of the invention, L2is a bond, —C(O)— or —S(O)2—. In one variation, L2is a bond. In another variation, L2is —C(O)—. In still another variation, L2is —S(O)2—.

In another embodiment of above embodiments and variations of the compounds of the invention, R2is selected from hydrogen, C1-6alkyl, C1-4alkoxy, C3-6cycloalkoxy, amino, C3-6cycloalkyl, C5-6heterocycloalkyl, and C5-6heteroaryl, whereinthe C1-4alkyl, C1-4alkoxy, C3-6cycloalkoxy, and amino are each optionally substituted by 1-2 substituents independently selected from halo, hydroxy, C1-4alkyl, haloC1-4alkyl, C1-4alkoxy, —NR9aR9b, C5-6heterocycloalkyl, phenyl and C5-6heteroaryl, wherein R9ais hydrogen or C1-4alkyl, and R9bis selected from hydrogen, C1-4alkyl, and C1-4alkoxycarbonyl; and the C5-6heterocycloalkyl, phenyl or C5-6heteroaryl is each further optionally substituted by 1-2 substituents independently selected from halo, hydroxyl, C1-4alkyl and C1-4alkoxycarbonyl;the C5-6heteroaryl is optionally substituted with 1 to 2 C1-4alkyl;
the C3-6cycloalkyl or C4-6heterocycloalkyl are each independently optionally substituted by 1-2 substituents independently selected from halo, cyano, hydroxy, C1-4alkyl, haloC1-4alkyl, —CH2OCH3, —C(O)NH2, C1-4alkoxycarbonyl and C1-4alkoxycarbonylaminoC1-4alkyl.

In another variation, R2is C5-6heteroaryl optionally substituted with 1-2 substituents independently selected from hydroxyl and C1-4alkyl.

In one variation of the above embodiment, -L2-R2is selected from —C(O)OCH(CH3)2, —C(O)OCH2CH3, —C(O)OCH3,

In one particular variation, -L2-R2is —C(O)OCH(CH3)2.

In yet still another embodiment of above embodiments and variations of the compounds of the invention, R5and R2with N and L2to which they attached are taken together to form the C5-6heterocycloalkyl or C5-6heterocycloalkenyl selected from

Particular examples of compounds or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, according to the present invention include, but are not limited to:N-{2-[2-chloro-5-(furan-2-amido)phenyl]-1H-imidazo[4,5-b]pyridin-6-yl}-5-methyl-1,3-thiazole-2-carboxamide;propan-2-yl N-{2-[2-chloro-5-(furan-2-amido)phenyl]-1H-imidazo[4,5-b]pyridin-6-yl}carbamate;ethyl N-{2-[3-(5-fluorofuran-2-amido)phenyl]-1H-imidazo[4,5-b]pyridin-6-yl}carbamate;propan-2-yl N-[2-(2-chloro-5-{[(propan-2-yloxy)carbonyl]amino}phenyl)-1H-imidazo[4,5-b]pyridin-6-yl]carbamate;N-{2-[2-chloro-5-(furan-2-amido)phenyl]-1H-imidazo[4,5-b]pyridin-6-yl}-2,4-dimethyl-1,3-thiazole-5-carboxamide;ethyl N-{2-[2-chloro-5-(furan-2-amido)phenyl]-1H-imidazo[4,5-b]pyridin-6-yl}carbamate;propan-2-yl 2-[2-chloro-5-(furan-2-amido)phenyl]-6-{[(propan-2-yloxy)carbonyl]amino}-1H-imidazo[4,5-b]pyridine-1-carboxylate;N-(4-chloro-3-{6-nitro-1H-imidazo[4,5-b]pyridin-2-yl}phenyl)furan-2-carboxamide;methyl N-{2-[2-chloro-5-(furan-2-amido)phenyl]-1H-imidazo[4,5-b]pyridin-6-yl}carbamate;N-{4-chloro-3-[6-(2-methylpropanamido)-1H-imidazo[4,5-b]pyridin-2-yl]phenyl}furan-2-carboxamide;N-{4-chloro-3-[6-(methylamino)-1H-imidazo[4,5-b]pyridin-2-yl]phenyl}furan-2-carboxamide;N-{2-[2-chloro-5-(furan-2-amido)phenyl]-1H-imidazo[4,5-b]pyridin-6-yl}pyrrolidine-1-carboxamide;N-{4-chloro-3-[6-(dimethylamino)-1H-imidazo[4,5-b]pyridin-2-yl]phenyl}furan-2-carboxamide;N-{4-chloro-3-[6-(3-methylbutanamido)-1H-imidazo[4,5-b]pyridin-2-yl]phenyl}furan-2-carboxamide;tert-butyl N-{1-[({2-[2-chloro-5-(furan-2-amido)phenyl]-1H-imidazo[4,5-b]pyridin-6-yl}carbamoyl)oxy]-2-methylpropan-2-yl}carbamate;tert-butyl N-{2-[({2-[2-chloro-5-(furan-2-amido)phenyl]-1H-imidazo[4,5-b]pyridin-6-yl}carbamoyl)oxy]ethyl}carbamate;propan-2-yl N-{2-[2-chloro-5-(5-methylfuran-2-amido)phenyl]-1H-imidazo[4,5-b]pyridin-6-yl}carbamate;N-{4-chloro-3-[6-(2,3-dihydroxypropanamido)-1H-imidazo[4,5-b]pyridin-2-yl]phenyl}furan-2-carboxamide;N-{4-chloro-3-[6-(3-methoxypropanamido)-1H-imidazo[4,5-b]pyridin-2-yl]phenyl}furan-2-carboxamide;N-(3-{6-amino-1H-imidazo[4,5-b]pyridin-2-yl}-4-chlorophenyl)furan-2-carboxamide;

It is noted that the compounds of the present invention may be in the form of a pharmaceutically acceptable salt. It is further note that the compounds of the present invention may be a mixture of stereoisomers, or the compound may comprise a single stereoisomer.

Further compounds of the invention are detailed in the Examples, infra.

In another aspect, the present invention is directed to a pharmaceutical composition which includes as an active ingredient a compound according to any one of the above embodiments and variations in combination with a pharmaceutically acceptable carrier, diluent or excipient.

In another embodiment, the pharmaceutical composition is a solid formulation adapted for oral administration. In another embodiment, the composition is a liquid formulation adapted for oral administration. In yet another embodiment, the composition is a tablet. In still another embodiment, the composition is a liquid formulation adapted for parenteral administration.

In yet another embodiment, the pharmaceutical composition is adapted for administration by a route selected from the group consisting of orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraoccularly, via local delivery (for example by catheter or stent), subcutaneously, intraadiposally, intraarticularly, and intrathecally.

In another aspect, the present application is directed to a compound or a pharmaceutical composition according to any one of the above embodiments and variations for use in a therapeutic application.

In another aspect, the present application is directed to a compound or a pharmaceutical composition according to any one of the above embodiments and variations for use as a medicament.

In yet another aspect, the present invention is directed to a method for treating, preventing, inhibiting, ameliorating, or eradicating the pathology and/or symptomology of a disease caused by a parasite. The method involves administering to a subject a therapeutically effective amount of a compound or a pharmaceutical composition according to the above embodiments and variations.

In one embodiment of the method of the invention, the disease being treated is Leishmaniasis, Human African Trypanosomiasis, or Chagas disease.

In one embodiment of the method of the invention, the disease being treated is Leishmaniasis caused by the parasiteLeishmania donovani, Leishmania infantum, Leishmania braziliensis, Leishmania panamensis, Leishmania guayanensis, Leishmania amazonensis, Leishmania mexicana, Leishmania tropica, orLeishmania major.

In a embodiment, the disease being treated is visceral Leishmaniasis caused by the parasiteLeishmania donovani.

In another embodiment, the disease being treated is Human African Trypanosomiasis caused byTrypanosoma brucei, particularly, by the sub-speciesT.b. gambienseorT.b. rhodesiense.

In still another embodiment of the method of the invention, the disease being treated is Chagas disease, (also call American Trypanosomiasis) caused byTrypanosoma cruzi.

In the above method of the invention, the compounds or pharmaceutical compositions may be administered prior to, simultaneously with, or after a second agent. The second agent can be other drugs that are known for treating Leishmaniasis, Human African Trypanosomiasis, or Chagas diseases. In one particular variation for treating Leishmaniasis, the second agent is selected from meglumine antimoniate, stibogluconate, Amphotericin, Miltefosine and paromomycin. In another variation, for treating Human African Trypanosomiasis, the second agent is selected from pentamidine, suramin, melarsoprol, and eflornithine. In another particular variation of the method, for treating Chagas disease, the second agent is selected from benznidazole, nifurtimox or Amphotericin b.

In another aspect, the invention is directed to a compound, salt, stereoisomer, or pharmaceutical composition thereof, according to any one of the above embodiments or variation, for treating, preventing, inhibiting, ameliorating, or eradicating the pathology and/or symptomology of a disease caused by the parasiteLeishmania donovani, Leishmania infantum, Leishmania braziliensis, Leishmania panamensis, Leishmania guayanensis, Leishmania amazonensis, Leishmania mexicana, Leishmania tropica, Leishmania major, Trypanosoma cruzi, orTrypanosoma brucei. In one embodiment, the disease is visceral Leishmaniasis caused byLeishmania donovani. In another embodiment, the disease is Human African Trypanosomiasis caused byTrypanosoma brucei. In yet another embodiment, the disease is Chagas disease caused byTrypanosoma cruzi.

In still another aspect, the present invention is directed to the use of the compound, or a salt, a stereoisomer, or a pharmaceutical composition thereof, according to the any one of the above embodiments or variations in the manufacture of a medicament for treating, preventing, inhibiting, ameliorating, or eradicating the pathology and/or symptomology of a disease caused byLeishmania donovani, Leishmania infantum, Leishmania braziliensis, Leishmania panamensis, Leishmania guayanensis, Leishmania amazonensis, Leishmania mexicana, Leishmania tropica, Leishmania major, Trypanosoma cruzi, orTrypanosoma brucei. In one embodiment, the medicament is for treating visceral Leishmaniasis caused byLeishmania donovani. In another embodiment, the medicament is for treating Human African Trypanosomiasis caused byTrypanosoma brucei. In yet another embodiment, the medicament is for treating Chagas disease caused byTrypanosoma cruzi.

The medicament, in addition to the compound of the invention, may further include a second agent. The second agent may be other drugs that are known for treating Leishmaniasis, Human African Trypanosomiasis, or Chagas diseases. In one particular variation of the medicament, for treating Leishmaniasis, the second agent is selected from meglumine antimoniate, stibogluconate, Amphotericin, Miltefosine and paromomycin. In another particular variation of the medicament, for treating Human African Trypanosomiasis, the second agent is selected from pentamidine, suramin, melarsoprol, and eflornithine. In yet another particular variation of the medicament, for treating Chagas disease, the second agent is selected from benznidazole, nifurtimox or Amphotericin b.

In another aspect, the invention is related to a kit which comprises a compound of any one of the above embodiments and variations, and optionally a second therapeutic agent. In one particular variation, the kit comprises the compound in a multiple dose form.

Enumerated Embodiments

Various enumerated embodiments of the invention are described herein. It will be recognized that features specified in each embodiment may be combined with other specified features to provide further embodiments of the present invention.

In a first embodiment, the invention provides a compound of the formula (I), or a pharmaceutical acceptable salt, tautomer or stereoisomer thereof,

X is O or NR4, wherein R4is selected from hydrogen, C1-4alkyl, haloC1-4alkyl, and —C(O)R10, wherein R10is hydroxy, C1-4alkyl, C1-4alkoxy, amino, C1-4alkylamino, C3-6cycloalkyl and C4-6heterocycloalkyl, each of which is independently optionally substituted by 1-2 substituents independently selected from hydroxyl, halo and C1-4alkyl;L1is —C(O)— or —S(O)2—;R1is selected from nitro, C1-4alkyl, C1-6alkoxy, amino, C5-9heteroaryl, C3-6cycloalkyl and C4-6heterocycloalkyl, each of which is optionally substituted by 1-2 substituent independently selected from halo, cyano, amino, C1-4alkyl, haloC1-4alkyl, C1-6alkoxy, and C1-4alkylcarbonyl; or —NHL1R1is nitro;R3is selected from hydrogen, halo, cyano, C1-4alkyl and haloC1-4alkyl;L2is selected from a bond, —C(O)— and —S(O)2—;R2is selected from hydrogen, C1-6alkyl, C1-4alkoxy, amino, C3-6cycloalkyl, C4-6heterocycloalkyl, and C5-6heteroaryl; whereinthe C1-6alkyl, C1-4alkoxy, C3-6cycloalkyl, and amino of R2are each optionally substituted by 1-2 substituents independently selected from halo, hydroxy, C1-4alkyl, C1-4alkoxy, —NR9aR9b, C3-6cycloalkyl, C5-6heterocycloalkyl, phenyl and C5-6heteroaryl, wherein R9ais hydrogen or C1-4alkyl and R9bis selected from hydrogen, C1-4alkyl, C1-4alkylcarbonyl and C1-4alkoxycarbonyl, and the C5-6heterocycloalkyl, phenyl or C5-6heteroaryl is further optionally substituted by 1-2 substituents independently selected from hydroxyl, C1-4alkyl and C1-4alkoxycarbonyl;the C5-6heteroaryl of R2is optionally substituted with 1-2 substituents selected from hydroxy, C1-4alkyl, and C1-4alkoxycarbonyl;the C3-6cycloalkyl or C4-6heterocycloalkyl of R2are each independently optionally substituted by 1-2 substituents independently selected from halo, cyano, hydroxy, C1-4alkyl, haloC1-4alkyl, C1-4alkoxylC1-4alkyl, aminocarbonyl, C1-4alkoxycarbonyl, and C1-4alkoxycarbonylaminoC1-4alkyl;R5is hydrogen or C1-4alkyl;or R2and R5together with L2and N to which R2and R5, respectively, attached are taken together to form a heteroC5-6cycloalkyl or a heteroC5-6cycloalkenyl, each of which is optionally substituted by 1 to 3 substituents independently selected from oxo, C1-4alkyl, —(CH2)1-4OH, —(CH2)1-4NRaRb, wherein Raand Rbare each independently hydrogen, C1-4alkyl or C3-6cycloalkyl;or —N(R5)L2R2is nitro or —N═CHN(CH3)2.

A compound, or a salt, tautomer or stereoisomer thereof, according to Embodiment 1, wherein X is O.

A compound, or a salt, tautomer or stereoisomer thereof, according to Embodiment 1, wherein X is NR4and R4is C1-4alkyl.

A compound, or a salt, tautomer or stereoisomer thereof, according to Embodiment 1, wherein X is NH.

A compound, or a salt, tautomer or stereoisomer thereof, according to Embodiments 1 to 6, wherein L1is *—C(O)—.

A compound, or a salt, tautomer or stereoisomer thereof, according to Embodiments 1 to 6, wherein L1is —S(O)2—.

A compound, or a salt, tautomer or stereoisomer thereof, according to Embodiments 1 to 8, wherein R1is selected from C1-6alkoxy and C1-6alkylamino, wherein the C1-6alkoxy and C1-6alkylamino are each optionally substituted by 1-2 substituents independently selected from C1-4alkyl and C1-4alkoxy.

A compound, or a salt, tautomer or stereoisomer thereof, according to Embodiments 1 to 8, wherein R1is selected from C5-9heteroaryl, C4-6heterocycloalkyl, and C3-6cycloalkyl, each of which is independently optionally substituted by 1-2 substituents independently selected from halo, cyano, C1-4alkyl and C1-4alkoxy.

A compound, or a salt, tautomer or stereoisomer thereof, according to Embodiments 1 to 6, wherein -L1-R1is selected from

A compound, or a salt, tautomer or stereoisomer thereof, according to Embodiments 1 to 6, wherein L1-R1is selected from —C(O)OCH2CH3, —C(O)O(CH2)2OCH3,

A compound, or a salt, tautomer or stereoisomer thereof, according to Embodiments 1 to 19, wherein R3is selected from hydrogen, halo, methyl, or trifluoromethyl.

A compound, or a salt, tautomer or stereoisomer thereof, according to Embodiments 1 to 19, wherein R3is chloro or fluoro.

A compound, or a salt, tautomer or stereoisomer thereof, according to Embodiments 1 to 19, R3is methyl or trifluoromethyl.

A compound, or a salt, tautomer or stereoisomer thereof, according to Embodiments 1 to 19, wherein R3is hydrogen

A compound, or a salt, tautomer or stereoisomer thereof, according to Embodiments 1 to 23, wherein R5is hydrogen.

A compound, or a salt, tautomer or stereoisomer thereof, according to Embodiments 1 to 23, wherein R5is C1-4alkyl.

A compound, or a salt, tautomer or stereoisomer thereof, according to Embodiments 1 to 24, wherein L2is a bond.

A compound, or a salt, tautomer or stereoisomer thereof, according to Embodiments 1 to 24, wherein L2is —C(O)—.

A compound, or a salt, tautomer or stereoisomer thereof, according to Embodiments 1 to 24, wherein L2is —S(O)2—.

A compound, or a salt, tautomer or stereoisomer thereof, according to Embodiments 1 to 28, R2is C5-6heteroaryl optionally substituted with 1-2 substituents independently selected from hydroxyl and C1-4alkyl.

A compound, or a salt, tautomer or stereoisomer thereof, according to Embodiments 1 to 28, R2is selected from

each of which is optionally substituted with 1-2 substituents independently selected from methyl and hydroxyl.

A compound, or a salt, tautomer or stereoisomer thereof, according to Embodiments 1 to 28, R2is C3-6cycloalkyl or C4-6heterocycloalkyl, each of which is independently optionally substituted by 1-2 substituents independently selected from halo, cyano, hydroxy, C1-4alkyl, haloC1-4alkyl, C1-4alkoxy, aminocarbonyl, C1-4alkoxycarbonylaminoC1-4alkyl, and C1-4alkoxycarbonyl.

A compound, or a salt, tautomer or stereoisomer thereof, according to Embodiments 1 to 28, wherein R2is phenylC1-4alkyl or C5-6heteroarylC1-4alkyl, wherein the phenyl or C5-6heteroaryl is optionally substituted by 1-2 substituents selected from halo and C1-4alkyl.

A compound, or a salt, tautomer or stereoisomer thereof, according to Embodiments 1 to 28, wherein R2is —(CH2)1-2-4-fluorophenyl.

A compound, or a salt, tautomer or stereoisomer thereof, according to Embodiments 1 to 28, wherein R2is C1-4alkyl or C1-4alkylamino.

A compound, or a salt, tautomer or stereoisomer thereof, according to Embodiments 1 to 25, wherein -L2-R2is selected from —C(O)CH(CH3)2, —C(O)-cyclopropyl, —C(O)OCH(CH3)2, —C(O)OCH3, —C(O)N(CH3)2, —C(O)O-cyclopropyl, —C(O)-cyclobutyl, wherein the cyclopropyl and cyclobutyl are each independently optionally substituted by a substituent independently selected from cyano, halo and C1-4alkyl.

A compound, or a salt, tautomer or stereoisomer thereof, according to

A compound, or a salt, tautomer or stereoisomer thereof, according to Embodiments 1 to 25, wherein -L2-R2is —C(O)OCH(CH3)2.

A compound, or a salt, tautomer or stereoisomer thereof, according to

Embodiments 1 to 23, wherein R5and R2with N and L2to which they attached are taken to form the C5-6heterocycloalkyl or C5-6heterocycloalkenyl selected from

A pharmaceutical composition comprising a compound of any one of Embodiments 1 to 45 as an active ingredient and at least one excipient.

A compound, or a salt, tautomer or stereoisomer thereof, according to any one of Embodiments 1 to 45 or a pharmaceutical composition according to Embodiment 46 for use as a medicament.

A compound, or a salt, tautomer or stereoisomer thereof, according to any one of Embodiments 1 to 45 or a pharmaceutical composition according to Embodiment 46 for treating, preventing, inhibiting, ameliorating, or eradicating the pathology and/or symptomology of a parasitic disease, wherein the disease is selected from Leishmaniasis, Human African Trypanosomiasis and Chagas disease, and wherein the compound is optionally used in combination with a second agent.

A compound for treating, preventing, inhibiting, ameliorating, or eradicating the pathology and/or symptomology of a parasitic disease according to Embodiment 48, wherein the disease is Leishmaniasis.

A compound for treating, preventing, inhibiting, ameliorating, or eradicating the pathology and/or symptomology of a parasitic disease according to Embodiment 48, wherein the disease is visceral Leishmaniasis

A compound for treating, preventing, inhibiting, ameliorating, or eradicating the pathology and/or symptomology of a parasitic disease according to Embodiment 48, wherein the disease is Human African Trypanosomiasis.

A compound for treating, preventing, inhibiting, ameliorating, or eradicating the pathology and/or symptomology of a parasitic disease according to Embodiment 48, wherein the disease is Chagas disease.

A compound, or a salt, tautomer or stereoisomer thereof, according to Embodiment 48 for treating, preventing, inhibiting, ameliorating, or eradicating the pathology and/or symptomology of Leishmaniasis, wherein the second agent is selected from stibogluconate, meglumine antimoniate, Amphotericin, Miltefosine and paromomycin.

A compound, or a salt, tautomer or stereoisomer thereof, according to Embodiment 48 for treating, preventing, inhibiting, ameliorating, or eradicating Human African Trypanosomiasis, wherein the second agent is selected from pentamidine, suramin, melarsoprol, eflornithine, and nifurtimox.

A compound, or a salt, tautomer or stereoisomer thereof, according to any one of Embodiment 48 for treating, preventing, inhibiting, ameliorating, or eradicating the pathology and/or symptomology of Chagas disease, wherein the second agent is selected from benznidazole, nifurtimox and Amphotericin.

A method for treating, preventing, inhibiting, ameliorating, or eradicating the pathology and/or symptomology of a disease caused by a parasite, comprising administering to a subject a therapeutically effective amount of a compound according to any one of Embodiments 1 to 45 or a composition according to Embodiment 46, wherein the disease is selected from Leishmaniasis, Human African Trypanosomiasis, and Chagas disease, and wherein the administering is optionally in combination with a second agent.

A method for treating, preventing, inhibiting, ameliorating, or eradicating the pathology and/or symptomology of a parasitic disease according to Embodiment 56, wherein the disease is Leishmaniasis.

A method for treating, preventing, inhibiting, ameliorating, or eradicating the pathology and/or symptomology of a parasitic disease according to Embodiment 56, wherein the disease is visceral Leishmaniasis

A method for treating, preventing, inhibiting, ameliorating, or eradicating the pathology and/or symptomology of a parasitic disease according to Embodiment 56, wherein the disease is Human African Trypanosomiasis.

A method for treating, preventing, inhibiting, ameliorating, or eradicating the pathology and/or symptomology of a parasitic disease according to Embodiment 56, wherein the disease is Chagas disease.

A method for treating, preventing, inhibiting, ameliorating, or eradicating the pathology and/or symptomology of Leishmaniasis according to Embodiment 56, wherein the second agent selected from stibogluconate, meglumine antimoniate, Amphotericin, Miltefosine and paromomycin.

A method for treating, preventing, inhibiting, ameliorating, or eradicating the pathology and/or symptomology of Human African Trypanosomiasis according to Embodiment 56, wherein the second agent selected from pentamidine, suramin, melarsoprol, eflornithine, and nifurtimox.

A method for treating, preventing, inhibiting, ameliorating, or eradicating the pathology and/or symptomology of Chagas disease according to Embodiment 56, wherein the second agent selected from benznidazole, nifurtimox and Amphotericin.

Use of a compound according to any one of Embodiments1to45, for the manufacture of a medicament for treating, preventing, inhibiting, ameliorating, or eradicating the pathology and/or symptomology of a parasitic disease, wherein the disease is selected from Leishmaniasis, Human African Trypanosomiasis and Chagas disease.

A use of a compound according to Embodiment 64 for the manufacture of a medicament for treating, preventing, inhibiting, ameliorating, or eradicating the pathology and/or symptomology of a parasitic disease, wherein the parasitic disease is Leishmaniasis.

A use of a compound according to Embodiment 65 for the manufacture of a medicament for treating, preventing, inhibiting, ameliorating, or eradicating the pathology and/or symptomology of a parasitic disease, wherein the parasitic disease is visceral Leishmaniasis.

A use of a compound according to Embodiment 65 for the manufacture of a medicament for treating, preventing, inhibiting, ameliorating, or eradicating the pathology and/or symptomology of a parasitic disease, wherein the parasitic disease is Human African Trypanosomiasis.

A use of a compound according to Embodiment 65 for the manufacture of a medicament for treating, preventing, inhibiting, ameliorating, or eradicating the pathology and/or symptomology of a parasitic disease, wherein the parasitic disease is Chagas disease.

As used herein, the term “an optical isomer” or “a stereoisomer” refers to any of the various stereo isomeric configurations which may exist for a given compound of the present invention and includes geometric isomers. It is understood that a substituent may be attached at a chiral center of a carbon atom. The term “chiral” refers to molecules which have the property of non-superimposability on their mirror image partner, while the term “achiral” refers to molecules which are superimposable on their mirror image partner. Therefore, the invention includes enantiomers, diastereomers or racemates of the compound. “Enantiomers” are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a “racemic” mixture. The term is used to designate a racemic mixture where appropriate. “Diastereoisomers” are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other. The absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R-S system. When a compound is a pure enantiomer the stereochemistry at each chiral carbon may be specified by either R or S. Resolved compounds whose absolute configuration is unknown can be designated (+) or (−) depending on the direction (dextro- or levorotatory) which they rotate plane polarized light at the wavelength of the sodium D line. Certain compounds described herein contain one or more asymmetric centers or axes and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)-.

Depending on the choice of the starting materials and procedures, the compounds can be present in the form of one of the possible isomers or as mixtures thereof, for example as pure optical isomers, or as isomer mixtures, such as racemates and diastereoisomer mixtures, depending on the number of asymmetric carbon atoms. The present invention is meant to include all such possible isomers, including racemic mixtures, diasteriomeric mixtures and optically pure forms. Optically active (R)- and (S)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be E or Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis- or trans-configuration. All tautomeric forms are also intended to be included.

As used herein, the terms “salt” or “salts” refers to an acid addition or base addition salt of a compound of the invention. “Salts” include in particular “pharmaceutical acceptable salts”. The term “pharmaceutically acceptable salts” refers to salts that retain the biological effectiveness and properties of the compounds of this invention and, which typically are not biologically or otherwise undesirable. In many cases, the compounds of the present invention are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto.

The pharmaceutically acceptable salts of the present invention can be synthesized from a basic or acidic moiety, by conventional chemical methods. Generally, such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate or the like), or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two. Generally, use of non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is desirable, where practicable. Lists of additional suitable salts can be found, e.g., in “Remington's Pharmaceutical Sciences”, 20th ed., Mack Publishing Company, Easton, Pa., (1985); and in “Handbook of Pharmaceutical Salts Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

Any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine, such as2H,3H,11C,13C,14C,15N,18F31F,32F,35S,36Cl,125I respectively. The invention includes various isotopically labeled compounds as defined herein, for example those into which radioactive isotopes, such as3H and14C, or those into which non-radioactive isotopes, such as2H and13C are present. Such isotopically labelled compounds are useful in metabolic studies (with14C), reaction kinetic studies (with, for example2H or3H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients. In particular, an18F or labeled compound may be particularly desirable for PET or SPECT studies. Isotopically-labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labeled reagents in place of the non-labeled reagent previously employed.

Compounds of the invention, i.e. compounds of formula (I) that contain groups capable of acting as donors and/or acceptors for hydrogen bonds may be capable of forming co-crystals with suitable co-crystal formers. These co-crystals may be prepared from compounds of formula (I) by known co-crystal forming procedures. Such procedures include grinding, heating, co-subliming, co-melting, or contacting in solution compounds of formula (I) with the co-crystal former under crystallization conditions and isolating co-crystals thereby formed. Suitable co-crystal formers include those described in WO 2004/078163. Hence the invention further provides co-crystals comprising a compound of formula (I).

The term “a therapeutically effective amount” of a compound of the present invention refers to an amount of the compound of the present invention that will elicit the biological or medical response of a subject, for example, reduction or inhibition of an enzyme or a protein activity, or ameliorate symptoms, alleviate conditions, slow or delay disease progression, or prevent a disease, etc. In one non-limiting embodiment, the term “a therapeutically effective amount” refers to the amount of the compound of the present invention that, when administered to a subject, is effective to (1) at least partially alleviate, inhibit, prevent and/or ameliorate a condition, or a disorder or a disease (i) mediated by Plasdmodium or (ii) associated with Plasdmodium activity, or (iii) characterized by activity (normal or abnormal) of Plasdmodium or (2) reduce or inhibit the activity of Plasdmodium; or (3) reduce or inhibit the growth of Plasdmodium. In another non-limiting embodiment, the term “a therapeutically effective amount” refers to the amount of the compound of the present invention that, when administered to a cell, or a tissue, or a non-cellular biological material, or a medium, is effective to at least partially reducing or inhibiting the activity of Plasdmodium; or at least partially reducing or inhibiting the growth of Plasdmodium.

Any asymmetric atom (e.g., carbon or the like) of the compound(s) of the present invention can be present in racemic or enantiomerically enriched, for example the (R)-, (S)- or (R,S)-configuration. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the (R)- or (S)-configuration. Substituents at atoms with unsaturated double bonds may, if possible, be present in cis-(Z)- or trans-(E)-form.

Accordingly, as used herein a compound of the present invention can be in the form of one of the possible isomers, rotamers, atropisomers, tautomers or mixtures thereof, for example, as substantially pure geometric (cis or trans) isomers, diastereomers, optical isomers (antipodes), racemates or mixtures thereof.

Furthermore, the compounds of the present invention, including their salts, can also be obtained in the form of their hydrates, or include other solvents used for their crystallization. The compounds of the present invention may inherently or by design form solvates with pharmaceutically acceptable solvents (including water); therefore, it is intended that the invention embrace both solvated and unsolvated forms. The term “solvate” refers to a molecular complex of a compound of the present invention (including pharmaceutically acceptable salts thereof) with one or more solvent molecules. Such solvent molecules are those commonly used in the pharmaceutical art, which are known to be innocuous to the recipient, e.g., water, ethanol, and the like. The term “hydrate” refers to the complex where the solvent molecule is water.

The compounds of the present invention, including salts, hydrates and solvates thereof, may inherently or by design form polymorphs.

General Processes for Preparing Compounds of the Invention

The present invention also includes processes for the preparation of compounds of the invention. In the reactions described, it can be necessary to protect reactive functional groups, for example hydroxy, amino, imino, thio or carboxy groups, where these are desired in the final product, to avoid their unwanted participation in the reactions. Conventional protecting groups can be used in accordance with standard practice, for example, see T. W. Greene and P. G. M. Wuts in “Protective Groups in Organic Synthesis”, John Wiley and Sons, 1991.

Typically, the compounds of formula (I) can be prepared according to Schemes 1A. 1B, 2 and 3 provided infra., where the variables: R1, R2, R3, and R5and others are as defined in the Summary of the Invention. The following reaction schemes are given to be illustrative, not limiting, descriptions of the synthesis of compounds of the invention. Detailed descriptions of the synthesis of compounds of the Invention are given in the Examples, infra.

The Azabenzimidazole analog having a *—NH(CO)R1— (1g) can be synthesized according to Scheme 1A.a. Condensation of the acid (1a) with amino acid (1b) to form an amide either by acid chloride formation or direct coupling using a suitable peptide coupling agent such as HATU in presence of amine base such as Et3N, DIEA (Hunig's base) at room temperature gives (1c);b. Condensation of 1c with 5-nitro-pyridine-2,3-diamine with PPA leads to formation of azabenzimidazole 1e.c. Reduction of nitro reduction to the corresponding amine using tin chloride and ethanol as solvent. This reduction can also be achieved by other metals such as Fe, HCl o zinc. Alternatively, this reduction can be carried out by catalytic hydrogentation using Pd, Pt, or raney-Ni using hydrogen gas as atmosphere.d. Coupling of the amine to form a amide either by using an acid chloride in pyridine as solvent or direct coupling of carboxylic acid using a suitable peptide coupling agent such as HATU in presence of amine base such as Et3N, DIEA (Hunig's base). Carbamates can be formed either by reaction with R2OCOCl or activated carbonates such as 4-nitrophenyl activated carbonates in the presence of base such as pyridine or DIEA. Sulfonamides are formed by the reaction of sulfonyl chloride with aniline in the presence of base such as pyridine. Urea's are formed by reaction of amine with isocyanate or carbamoyl chloride in DMF with or without base.

A. Condensation of 1b with 5-nitro-pyridine-2,3-diamine with PPA leads to formation of azabenzimidazole 1g.B. Coupling of the amine to form a amide either by using an acid chloride in pyridine as solvent or direct coupling of carboxylic acid using a suitable peptide coupling agent such as HATU in presence of amine base such as Et3N, DIEA (Hunig's base). Carbamates can be formed either by reaction with R2OCOCl or activated carbonates such as 4-nitrophenyl activated carbonates in the presence of base such as pyridine or DIEA. Sulfonamides are formed by the reaction of sulfonyl chloride with aniline in the presence of base such as pyridine. Urea's are formed by reaction of amine with isocyanate or carbamoyl chloride in DMF with or without base.C. Reduction of nitro reduction to the corresponding amine using tin chloride and ethanol as solvent. This reduction can also be achieved by other metals such as Fe, HCl or zinc. Alternatively, this reduction can be carried out by catalytic hydrogentation using Pd, Pt, or Raney-Ni using hydrogen gas as atmosphere.D. Coupling of the amine to form an amide either by using an acid chloride in pyridine as solvent or direct coupling of carboxylic acid using a suitable peptide coupling agent such as HATU in presence of amine base such as Et3N, DIEA (Hunig's base). Carbamates can be formed either by reaction with R2OCOCl or activated carbonates such as 4-nitrophenyl activated carbonates in the presence of base such as pyridine or DIEA. Sulfonamides are formed by the reaction of sulfonyl chloride with aniline in the presence of base such as pyridine. Urea's are formed by reaction of amine with isocyanate or carbamoyl chloride in DMF with or without base.

A. Condensation of 2a with 1b with polyphosphoric acid (PPA) leads to formation of azabenzoxazole 2-b.B. Coupling of the amine to form a amide either by using an acid chloride in pyridine as solvent or direct coupling of carboxylic acid using a suitable peptide coupling agent such as HATU in presence of amine base such as Et3N, DIEA (Hunig's base). Carbamates can be formed either by reaction with RyOCOCl or activated carbonates such as 4-nitrophenyl activated carbonates in the presence of base such as pyridine or DIEA. Sulfonamides are formed by the reaction of sulfonyl chloride with aniline in the presence of base such as pyridine. Urea's are formed by reaction of amine with isocyanate or carbamoyl chloride in DMF with or without base.C. Reduction of nitro reduction to the corresponding amine using tin chloride and ethanol as solvent. This reduction can also be achieved by other metals such as Fe, HCl or zinc. Alternatively, this reduction can be carried out by catalytic hydrogentation using Pd, Pt, or raney-Ni using hydrogen gas as atmosphere.D. Coupling of the amine to form a amide either by using an acid chloride in pyridine as solvent or direct coupling of carboxylic acid using a suitable peptide coupling agent such as HATU in presence of amine base such as Et3N, DIEA (Hunig's base). Carbamates can be formed either by reaction with RxOCOCl or activated carbonates such as 4-nitrophenyl activated carbonates in the presence of base such as pyridine or DIEA. Sulfonamides are formed by the reaction of sulfonyl chloride with aniline in the presence of base such as pyridine. Urea's are formed by reaction of amine with isocyanate or carbamoyl chloride in DMF with or without base.

A. Reductive amination of aniline with aldehyde with sodium triacetoxy borohydride and acetic acid lead to the formation of secondary amines 3-a. Alternatively, sodium cyano borohydride can be used to achieve the same transformation.

The invention further includes any variant of the present processes, in which an intermediate product obtainable at any stage thereof is used as starting material and the remaining steps are carried out, or in which the starting materials are formed in situ under the reaction conditions, or in which the reaction components are used in the form of their salts or optically pure material.

Compounds of the invention and intermediates can also be converted into each other according to methods generally known to those skilled in the art.

Compounds of the invention are useful in the treatment and/or prevention of infections such as Leishmaniasis, Human African Trypanosomiasis, or Chagas disease.

Leishmaniasis is a disease caused by protozoan parasites that belong to the genusLeishmania, typically caused byLeishmania donovani. Leishmania infantum, Leishmania braziliensis, Leishmania panamensis, Leishmania guayanensis, Leishmania amazonensis, Leishmania mexicana, Leishmania tropica, orLeishmania major, and more typically caused byLeishmania donovani. These parasites are typically transmitted by the bite of an infected female sandfly fromPhlebotomusorLutzomyiagenus.

Leishmaniasis is mostly a disease of the developing world, and is rarely known in the developed world outside a small number of cases, mostly in instances where troops are stationed away from their home countries. Leishmaniasis can be transmitted in many tropical and subtropical countries, and is found in parts of about 88 countries. Approximately 350 million people live in these areas. The settings in which leishmaniasis is found range from rainforests in Central and South America to deserts in West Asia and the Middle East. It affects as many as 12 million people worldwide, with 1.5-2 million new cases each year. The visceral form of leishmaniasis has an estimated incidence of 500,000 new cases and 60,000 deaths each year. More than 90 percent of the world's cases of visceral leishmaniasis are in India, Bangladesh, Nepal, Sudan, and Brazil. Kabul is estimated as the largest center of cutaneous leishmaniasis in the world, with approximately 67,500 cases as of 2004.

There are four main forms of Leishmaniasis. Cutaneous leishmaniasis is the most common form of leishmaniasis. Visceral leishmaniasis, also called kala-azar, is the most serious form in which the parasites migrate to the vital organs. Visceral leishmaniasis is caused by the parasiteLeishmania donovani, and is potentially fatal if untreated.

Currently, no vaccines are in routine use. The two main therapies for visceral leishmaniasis are the antimony derivatives sodium stibogluconate (Pentostam®) and meglumine antimoniate (Glucantim®). Sodium stibogluconate has been used for about 70 years and resistance to this drug is a growing problem. In addition, the treatment is relatively long and painful, and can cause undesirable side effects. Amphotericin (AmBisome) is now the treatment of choice. Miltefosine (Impavido), and paromomycin are the other treatment alternatives. These drugs are known to produce a definitive cure in >90% of patients. Amphotericin (AmBisome) is expansive and has to be given intravenously; it is not affordable to most patients affected. Paromomycin, although affordable, requires intramuscular injections for 3 weeks; compliance is a major issue. Miltefosine is an oral drug and has shown to be more effective and better tolerated than other drugs. However, there are problems associated with the use of miltefosine that arise from its teratogenicity and pharmacokinetics. Miltefosine was shown to be much slower eliminated from the body and was still detectable five months after the end of treatment. The presence of subtherapeutic miltefosine concentrations in the blood beyond five months after treatment might contribute to the selection of resistant parasites and, moreover, the measures for preventing the teratogenic risks of miltefosine must be reconsidered. This led to some reluctance to taking Miltefosine by affected populations.

The Drugs for Neglected Diseases Initiative is actively facilitating the search for novel therapeutics. Our invention meets that need.

Human African trypanosomiasis (HAT), also known as African sleeping sickness, is a vector-borne parasitic disease caused by the protozoaTrypanosoma brucei. There are two subspecies that infect humans,T.b. gambienseandT.b. rhodesiense, with the former accounting for over 95% of reported cases and the latter accounting for the remaining reported cases. The parasites are transmitted to humans by tsetse fly (Glossinagenus) bites which have acquired their infection from human beings or from animals harboring the human pathogenic parasites.

The disease has been recorded as occurring in 36 countries, all in subtropical and equatorial Africa. It is endemic in southeast Uganda and western Kenya. In 1995, the WHO estimated that 300,000 people were afflicted with the disease. In its 2001 report, the WHO set the figure of people at risk of infection at 60 million, of which only 4 to 5 million had access to any kind of medical monitoring. In 2006, the WHO estimated that about 70,000 people could have the disease, and many cases are believed to go unreported. About 48,000 people died of sleeping sickness in 2008. Public health efforts in prevention and the eradication of the tsetse fly population have proven to be successful in controlling the spread of the disease; under 10,000 new cases were reported in 2009 according to WHO figures, which represents a huge decrease from the estimated 300,000 new cases in 1998.

African trypanosomiasis symptoms occur in two stages. In the first stage, known as the haemolymphatic phase, the trypanosomes multiply in subcutaneous tissues, blood and lymph. The haemolymphatic phase is characterized by bouts of fever, headaches, joint pains and itching. In the second stage, the neurological phase, the parasites cross the blood-brain barrier to infect the central nervous system. It is in this stage when more obvious signs and symptoms of the disease appear: changes of behaviour, confusion, sensory disturbances and poor coordination. Disturbance of the sleep cycle, which gives the disease its name, is an important feature of the second stage of the disease. Without treatment, the disease is invariably fatal, with progressive mental deterioration leading to coma, systemic organ failure, and death.

Four drugs are registered for the treatment of sleeping sickness. The protocol depends on the stage of the disease. The current standard treatment for first-stage disease is intravenous or intramuscular pentamidine (forT.b. gambiense), or intravenous suramin (forT.b. rhodesiense). The current standard treatment for second-stage disease is: Intravenous melarsoprol, or interavenous melarsoprol in combination with oral nifurtimox, intravenous eflornithine only or eflornithine in combination with nifurtimox. All of the drugs have undesirable or sometime serious side effects. For example, 3-10% of patients those injected with Melarsoprol (Arsobal), an organoarsenical, developed reactive encephalopathy (convulsions, progressive coma, or psychotic reactions), and 10-70% of such cases result in death. There remains a need for new therapy.

Chagas disease, also called American trypanosomiasis, is a tropical parasitic disease caused by the flagellate protozoanTrypanosoma cruzi. T. cruziis commonly transmitted to humans and other mammals by the blood-sucking “kissing bugs” of the subfamily Triatominae (family Reduviidae).

Chagas disease is contracted primarily in the Americas. It is endemic in twenty one Central and Latin American countries; particularly in poor, rural areas of Mexico, Central America, and South America. Large-scale population movements from rural to urban areas of Latin America and to other regions of the world have increased the geographic distribution of Chagas disease, and cases have been noted in many countries, particularly in Europe. Rarely, the disease has been found in the Southern part of the United States.

Each year, an estimated 10 to 15 million people across the world are infected with Chagas disease, most of whom do not know they are infected. Every year, 14,000 people die as a consequence of the disease. In Central and South America, Chagas kills more people than any other parasite-borne disease, including malaria. By applying published seroprevalence figures to immigrant populations, CDC estimates that more than 300,000 persons withTrypanosoma cruziinfection live in the United States. Most people with Chagas disease in the United States acquired their infections in endemic countries.

Chagas disease has an acute and a chronic phase. If untreated, infection is lifelong. Acute Chagas disease occurs immediately after infection, may last up to a few weeks or months, and parasites may be found in the circulating blood. Infection may be mild or asymptomatic. There may be fever or swelling around the site of inoculation (where the parasite entered into the skin or mucous membrane). Rarely, acute infection may result in severe inflammation of the heart muscle or the brain and lining around the brain. The initial acute phase is responsive to antiparasitic treatments, with 60-90% cure rates. Following the acute phase, most infected people enter into a prolonged asymptomatic form of disease (called “chronic indeterminate”) during which few or no parasites are found in the blood. During this time, most people are unaware of their infection. Many people may remain asymptomatic for life and never develop Chagas-related symptoms. However, an estimated 20-30% of infected people will develop debilitating and sometimes life-threatening medical problems over the course of their lives.

The symptoms of Chagas disease vary over the course of an infection. In the early, acute stage, symptoms are mild and usually produce no more than local swelling at the site of infection. The initial acute phase is responsive to antiparasitic treatments, with 60-90% cure rates. After 4-8 weeks, individuals with active infections enter the chronic phase of Chagas disease that is asymptomatic for 60-80% of chronically infected individuals through their lifetime.

There is no vaccine against Chagas disease. Treatment for Chagas disease focuses on killing the parasite and managing signs and symptoms.

During the acute phase of Chagas disease, the drugs currently available for treatment are benznidazole and nifurtimox. Once Chagas disease reaches the chronic phase, medications aren't effective for curing the disease. Instead, treatment depends on the specific signs and symptoms. However, problems with these current therapies include their diverse side effects, the length of treatment, and the requirement for medical supervision during treatment. Resistance to the two frontline drugs has already occurred. The antifungal agent Amphotericin b has been proposed as a second-line drug, but this drug is costly and relatively toxic.

In accordance with the foregoing, the present invention further provides a method for preventing or treating Leishmaniasis, Chagas disease or Human African Trypanosomiasis in a subject in need of such treatment, which method comprises administering to said subject a therapeutically effective amount of a compound selected from Formula I or a pharmaceutically acceptable salt thereof. The required dosage will vary depending on the mode of administration, the particular condition to be treated and the effect desired.

In one embodiment of the method of the invention, the disease being treated is Leishmaniasis caused by the parasitesLeishmania donovani, Leishmania infantum, Leishmania braziliensis, Leishmania panamensis, Leishmania guayanensis, Leishmania amazonensis, Leishmania mexicana, Leishmania tropica, Leishmania major. In one variation of the above embodiment, the disease being treated is Visceral leishmaniasis, caused by the parasiteLeishmania donovani.

In another embodiment of the method of the invention, the disease being treated is Human African Trypanosomiasis caused by a protozoa belonging to the speciesTrypanosoma brucei. In one embodiment, the protozoa isTrypanosoma brucei gambiense. In another embodiment, the protozoa isTrypanosoma brucei rhodesiense.

In yet another embodiment of the method of the invention, the disease being treated is Chagas disease (also call American Trypanosomiasis) caused by protozoaTrypanosoma cruzi.

In general, compounds of the invention will be administered in therapeutically effective amounts via any of the usual and acceptable modes known in the art, either singly or in combination with one or more therapeutic agents. A therapeutically effective amount may vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors. In general, satisfactory results are indicated to be obtained systemically at daily dosages of from about 0.03 to 2.5 mg/kg per body weight. An indicated daily dosage in the larger mammal, e.g. humans, is in the range from about 0.5 mg to about 100 mg, conveniently administered, e.g. in divided doses up to four times a day or in retard form. Suitable unit dosage forms for oral administration comprise from ca. 1 to 50 mg active ingredient.

Compounds of the invention can be administered as pharmaceutical compositions by any conventional route, in particular enterally, e.g., orally, e.g., in the form of tablets or capsules, or parenterally, e.g., in the form of injectable solutions or suspensions, topically, e.g., in the form of lotions, gels, ointments or creams, or in a nasal or suppository form. Pharmaceutical compositions comprising a compound of the present invention in free form or in a pharmaceutically acceptable salt form in association with at least one pharmaceutically acceptable carrier or diluent can be manufactured in a conventional manner by mixing, granulating or coating methods. For example, oral compositions can be tablets or gelatin capsules comprising the active ingredient together with a) diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; b) lubricants, e.g., silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol; for tablets also c) binders, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and or polyvinylpyrrolidone; if desired d) disintegrants, e.g., starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and/or e) absorbents, colorants, flavors and sweeteners. Injectable compositions can be aqueous isotonic solutions or suspensions, and suppositories can be prepared from fatty emulsions or suspensions. The compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In addition, they may also contain other therapeutically valuable substances. Suitable formulations for transdermal applications include an effective amount of a compound of the present invention with a carrier. A carrier can include absorbable pharmacologically acceptable solvents to assist passage through the skin of the host. For example, transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound to the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin. Matrix transdermal formulations may also be used. Suitable formulations for topical application, e.g., to the skin and eyes, are preferably aqueous solutions, ointments, creams or gels well-known in the art. Such may contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.

Compounds of the invention can be administered in therapeutically effective amounts in combination with one or more therapeutic agents (pharmaceutical combinations). In one embodiment, the compound of the invention is administered with the known treatment drugs. For example, for the treatment of Leishmaniasis, compound of the invention may be used in combination with stibogluconate, meglumine antimoniate, Amphotericin, Miltefosine and paromomycin. For the treatment of Human African Trypanosomiasis, the compound of the invention may be used in combination with pentamidine, suramin, melarsoprol, eflornithine, and nifurtimox. For the treatment of Chagas disease, the compound of the invention may be used in combination with benznidazole, nifurtimox and Amphotericin.

Where the compounds of the invention are administered in conjunction with other therapies, dosages of the co-administered compounds will of course vary depending on the type of co-drug employed, on the specific drug employed, on the condition being treated and so forth.

The invention also provides for a pharmaceutical combinations, e.g. a kit, comprising a) a first agent which is a compound of the invention as disclosed herein, in free form or in pharmaceutically acceptable salt form, and b) optionally co-agent. The kit can comprise instructions for its administration.

The terms “co-administration” or “combined administration” or the like as utilized herein are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time.

The term “pharmaceutical combination” as used herein means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients. The term “fixed combination” means that the active ingredients, e.g. a compound of Formula I and a co-agent, are both administered to a patient simultaneously in the form of a single entity or dosage. The term “non-fixed combination” means that the active ingredients, e.g. a compound of Formula I and a co-agent, are both administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the 2 compounds in the body of the patient. The latter also applies to cocktail therapy, e.g. the administration of 3 or more active ingredients.

Biological Assays

Assay forLeishmaniaProliferation In Vitro

Leishmania donovaniaxenic amastigote parasites are grown at 37° C., 5% CO2in media made of RPMI 1640, 4 mM L-glutamine, 20% heat inactivated FBS, 100 units/ml of penicillin and 100 μg/ml of streptomycin, 23 μM Folic Acid, 100 μM Adenosine, 22 mM D-glucose, 25 mM MES. The pH of media is adjusted to 5.5 at 37° C. using HCl. 20 μL of media is first dispensed into 384 well plates and 100 mL of the compounds of invention in DMSO are added to the plate wells. At the same time control compounds and DMSO are added to plates to serve as the positive and negative controls, respectively. 40 μL of parasite culture (9600 parasites) are then added to the plate wells. The plates are then placed into incubators. After 2 day incubation, 20 μL of Cell TiterGlo (Promega) is added to the plate wells. The luminescence signal of each well is measured using the Envision reader (Perkin Elmer). The percentage inhibition of 50%, EC50, is calculated for each of the compounds.

Compounds of the invention have an EC50range between >25 μM to 0.13 μM; typically between 20 μM or less, typically less than 5 μm, and about half of the compounds have an EC50below 1 μM. Selected compounds of the invention can significantly delay the proliferation ofL. donovani. The inhibitory efficacy of the compounds of the invention againstL. donovaniaxenic amastigotes in vitro is provided in Table I.

Assay for Proliferation ofLeishmaniaParasites

The activity of a compound according to the present invention for inhibition of parasitemai can be assessed by the parasite proliferation assay. The assay measures the increase in the parasite number in the assayed plate well using a DNA intercalating dye, SYBR Green I® dye (INVITROGEN) to stainLeishmaniacell nuclei. It is understood that the assays illustrate the invention without in any way limiting the scope of the invention.

L. donovaniHU3 strain is propagated by infecting BALBc mice through tail vein injection with 107Leishmaniaparasites. Infected mice are allowed to develop infection during 9-11 weeks post-infection. During this time, the parasites accumulate in the infected mouse spleens to large numbers, and the infected mice serve as the source of parasites for the in vitro measurement of compound efficacies. To assay a compound for anti-leishmanial activity, peritoneal macrophages isolated from non-infected BALBc mice are seeded into 384-well plates at density 2×104macrophages per well in 25 mL of medium (RPMI1640, 10% fetal serum albumin, 10 mM HEPES, 1 mM sodium pyruvate, 1% Pen/Strep). Subsequently, the seeded plates are placed into an incubator set to maintain 37° C. temperature and atmosphere with 5% CO2. The next day,Leishmaniaparasites are isolated from the spleens of mice infected for 9-11 weeks and 4×105isolated parasites in 10 mL of the above media are added to each plate well. Plates are then returned into incubators and infection is allowed to proceed for 24 hours. After the infection of macrophages is completed, 5 mL of compounds of the invention in the above medium, which also contains 5% DMSO, are added to plate wells containing infected macrophages. At the same time control compounds (miltefosine and amphotericin B) and DMSO are added to plates to serve as the positive and negative controls, respectively. After the compound addition, the plates are returned into incubator and cells infected with parasites are cultured for 5 days. At the end of cultivation, 40 mL of 8% paraformaldehyde is added to plate wells and incubated for 15 min at room temperature. Following the incubation, the paraformaldehyde from plate wells is aspirated, and 40 mL of PBS containing 0.2% Triton X-100 is added to wells. After 15 min incubation, the solution is aspirated from wells again, and replaced with SybrGreen Dye solution in PBS (1:125,000 dilution). Infected cells are imaged with Evotec Opera high-content microscope, and the number of parasites in well is determined by counting parasite nuclei visualized by staining with SybrGreen dye. The percentage inhibition of 50%, EC50, is calculated for each compound.

Compounds of the invention have EC50in a range between >50 μM to 0.315 μM, typically below 10 μM. Selected compounds have EC50less than 1 μM. The inhibitory efficacy of the compounds of the invention against proliferation ofL. donovaniin mouse peritoneal macrophages is provided in Table I.

Assay for Proliferation of Kinetoplastid ParasiteTrypanosoma brucei.

The proliferation is quantified by the addition of Cell Titer Glo (Promega®) a luminescent cell viability assay that measures the number of viable cells in culture based on the quantification of cellular ATP amount, which is an indicator of metabolically active cells. The following assay illustrates the invention without in any way limiting the scope of the invention. This parasite proliferation assay measures the increase in parasite growth using an assay that measures ATP activity, Cell Titer Glo®.

Trypanosoma bruceiLister 427 strain is grown in HMI-9 Trypanosome media forT. bruceibloodstream form. 30 μl of HMI-9 media is dispensed into 384 well assay plates. 200 nL of compounds of the invention (in DMSO), including anti-trypanosome controls (Pentamidine and suramin), are then transferred into the assay plates, as well as DMSO alone to serve as a negative control for inhibition. Then 25 μl of a suspension ofT. bruceiculture in HMI-9 media is dispensed into the assay plates. The final concentration of parasites in culture corresponds to 1.7% of 0.5 uM ATP activity with Cell Titer Glo® in HMI-9 media. The plates are placed in a 37° C. incubator for 48 hours in an atmospheric environment containing 5% CO2. 40 μl of Cell Titer Glo® is dispensed into the plates. The plates are then read for luminescence. The percentage inhibition of 50%, EC50, is calculated for each compound.

Compounds of the invention have EC50in a range between >20 μM to 0.142 μM, typically below 10 μM. Selected compounds have EC50less than 1 μM. The inhibitory efficacy of the compounds of the invention against proliferation ofT. bruceiis provided in Table I.

Assay for Proliferation of Kinetoplastid ParasiteTrypanosoma cruzi.

Compounds of the invention can be assayed to measure their capacity to inhibit proliferation of kinetoplastid parasiteTrypanosoma cruzi. The screening procedure is for identifying compounds with inhibitor activity againstTrypanosoma cruziamastigotes cultured in 3T3 fibroblast cells. The assay is done using the mammalian stage (amastigotes) ofT. cruzithat replicates in the intracellular space of host cells. The host cells are initially infected with the culture-derived trypomastigotes that rapidly invade and then divide as amastigotes. The protocol uses the Tulahuen strain ofT. cruzithat has been engineered to express theE. colibeta-galactosidase gene (Lac-Z) (Antimicr. Agents Chemoth. 40:2592, 1996). This allows for a colorimetric readout by using the substrate CPRG and an absorbance plate reader.

3T3 fibroblast cells are re-suspended in RPMI-1640 medium without phenol red medium supplemented with 10% FBS (heat inactivated), 100 μg/ml penicillin, and 100 μg/ml streptomycin. Forty μL of suspension (1,000 cells) is dispensed into 384-well plates and incubated overnight at 37° C. temperature and in atmosphere containing 5% CO2. The following day, 100 nL of compounds of the invention in DMSO are added to plate wells containing 3T3 cells. At the same time control compounds (benznidazole and nifurtimox) and DMSO are added to plates to serve as the positive and negative controls, respectively. After that, 10 μL of media containing 10,000T. cruzitrypomastigotes are added to each plate well and plates are placed back into incubators. After 6 day incubation, 10 μL of reagent solution (0.6 mM CPRG, 0.6% NP-40 in PBS) is added to plates and incubated at room temperature for 2 hours. Absorbance is then measured on SpectraMax Gemini fluorimeter to determine relative number ofT. cruzicells present in each plate well. The percentage inhibition of 50%, EC50, is calculated for each compound.

Compounds of the invention have an EC50of 15 μM or less, typically less than 2 μM. Selected compounds have EC50of 100 nM or less. Compounds of the invention can significantly delay the proliferation ofT. cruzi.

The inhibitory efficacy of the compounds of the invention in delaying the proliferation ofT. cruziis provided in Table I.

EXAMPLES

The present invention is further exemplified, but not to be limited, by the following examples and intermediates that illustrate the preparation of compounds of the invention. It is understood that if there appears to be a discrepancy between the name and structure of a particular compound, the structure is to be considered correct as the compound names were generated from the structures.

Temperatures are given in degrees Celsius. If not mentioned otherwise, all evaporations are performed under reduced pressure, typically between about 15 mm Hg and 100 mm Hg (=20-133 mbar). The structure of final products, intermediates and starting materials is confirmed by standard analytical methods, e.g., microanalysis and spectroscopic characteristics, e.g., MS, IR, NMR. Abbreviations used are those conventional in the art.

All starting materials, building blocks, reagents, acids, bases, dehydrating agents, solvents, and catalysts utilized to synthesis the compounds of the present invention are either commercially available or can be produced by organic synthesis methods known to one of ordinary skill in the art (Houben-Weyl 4th Ed. 1952, Methods of Organic Synthesis, Thieme, Volume 21). Further, the compounds of the present invention can be produced by organic synthesis methods known to one of ordinary skill in the art as shown in the following examples.

Method for Analysis:

Synthesis of Intermediates

Synthesis of I-4

A solution of furan-2-carboxylic acid (10 g, 89.22 mmol, 1.00 equiv) in thionyl chloride (100 mL) was heated to reflux overnight and concentrated under vacuum to give 12 g (crude) of furan-2-carbonyl chloride as brown oil.

Synthesis of I-5

To a suspension of 5-amino-2-chlorobenzoic acid (13.7 g, 79.85 mmol, 1.00 equiv) in tetrahydrofuran (100 mL) was added furan-2-carbonyl chloride (11.5 g, 88.10 mmol, 1.10 equiv) in a bath of ice and stirred overnight at room temperature. The resulting mixture was concentrated under vacuum and diluted with DCM. The solid was collected by filtration to give 17 g (80%) of 2-chloro-5-(furan-2-amido)benzoic acid as a gray solid.

Synthesis of (I-3)

A mixture of 5-nitropyridine-2,3-diamine (1-2) (6 g, 38.93 mmol, 1.00 equiv) and 2-chloro-5-(furan-2-amido)benzoic acid (I-3) (10.4 g, 39.15 mmol, 1.00 equiv) in PPA (100 mL) was stirred overnight at 130° C. The reaction was then poured into water/ice and the pH value of the mixture was adjusted to 9 with sodium carbonate. The solids were collected by filtration and applied onto a silica gel column with ethyl acetate/petroleum ether (31) to give 3.9 g (26%) of N-(4-chloro-3-[6-nitro-1H-imidazo[4,5-b]pyridin-2-yl]phenyl)furan-2-carboxamide (I-3) as a light yellow solid.

Synthesis of (I-1)

Synthesis of I-6

Into a 1-L round-bottom flask, was placed 5-nitropyridine-2,3-diamine (30 g, 194.65 mmol, 1.00 equiv), 5-amino-2-chlorobenzoic acid (33.4 g, 194.66 mmol, 1.00 equiv), PPA (400 mL). The resulting solution was stirred for 2 days at 130° C. The reaction mixture was cooled with a water/ice bath. The resulting solution was diluted with 400 mL of ice water. The pH value of the solution was adjusted to 7 with sodium hydroxide (5%). The solids were collected by filtration and washed with 3×50 mL water. The solid was dried in an oven under reduced pressure. This resulted in 40 g (71%) of 4-chloro-3-[6-nitro-1H-imidazo[4,5-b]pyridin-2-yl]aniline (I-6) as a yellow solid.

Synthesis of I-8

Into a 500-mL round-bottom flask, was placed a solution of 4-chloro-3-[6-nitro-1H-imidazo[4,5-b]pyridin-2-yl]aniline (I-6) (8 g, 27.62 mmol, 1.00 equiv) in N,N-dimethylformamide (50 mL), 1-7 (3.6 g, 28.10 mmol, 1.02 equiv), HATU (12.6 g, 33.14 mmol, 1.20 equiv), DIEA (7.14 g, 55.25 mmol, 2.00 equiv). The resulting solution was stirred overnight at 100° C. The resulting solution was diluted with 100 mL of EA. The resulting mixture was washed with 3×100 mL of H2O. The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:1). The collected fractions were combined and concentrated under vacuum. This resulted in 6.5 g (59%) of N-(4-chloro-3-[6-nitro-1H-imidazo[4,5-b]pyridin-2-yl]phenyl)-5-fluorofuran-2-carboxamide (I-8) as a gray solid

Synthesis of I-9

Into a 250-mL round-bottom flask, was placed a solution of N-(4-chloro-3-[6-nitro-1H-imidazo[4,5-b]pyridin-2-yl]phenyl)-5-fluorofuran-2-carboxamide(1-8) (3.5 g, 8.71 mmol, 1.00 equiv), SnCl2.2H2O (9.89 g, 43.83 mmol, 5.03 equiv) in ethanol (100 mL). The resulting solution was stirred for 3 h at 80° C. The resulting mixture was concentrated under vacuum. The residue was dissolved in 100 mL of H2O. The resulting solution was diluted with 100 mL of EA. The resulting solution was extracted with 3×200 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate. This resulted in 1.55 g (48%) of N-(3-[6-amino-1H-imidazo[4,5-b]pyridin-2-yl]-4-chlorophenyl)-5-fluorofuran-2-carboxamide (1-9) as a yellow solid.1H NMR (400 MHz, CD3OD): δ 8.15 (s, 1H), 8.03 (s, 1H), 7.91-7.94 (m, 1H), 7.57-7.59 (m, 1H), 7.31-7.34 (m, 2H), 5.89-5.92 (m, 1H). (ES, m/z): [M+H]+=372 (M+1)

Synthesis of I-10

Into a 3-L 3-necked round-bottom flask, was placed a solution of 2-aminopyridin-3-ol (100 g, 908.15 mmol, 1.00 equiv), 1-[(1H-imidazol-1-yl)carbonyl]-1H-imidazole (221.3 g, 1.36 mol, 1.50 equiv) in THF (1000 mL). The resulting solution was heated to reflux overnight. After cooling, the reaction was concentrated under vacuum. The residue was dissolved in 1000 mL of DCM and extracted with 1M NaOH (3×800 mL). The combined liquids were cooled with a water/ice bath and adjusted to pH 5-6 by adding 3M HCl. The solids were collected by filtration. The solid was dried in an oven under reduced pressure. This resulted in 90 g (73%) of 2H,3H-[1,3]oxazolo[4,5-b]pyridin-2-one (1-10) as a gray solid.

Synthesis of I-11

Into a 3-L 3-necked round-bottom flask, was placed a solution of 2H,3H-[1,3]oxazolo[4,5-b]pyridin-2-one (90 g, 661.24 mmol, 1.00 equiv) in sulfuric acid (400 mL). This was followed by the addition of HNO3(200 mL) dropwise with stirring at −5° C. The resulting solution was stirred for 2 days at 50° C. The resulting solution was diluted with 1000 mL of ice water. The solids were collected by filtration and dried in an oven under reduced pressure. This resulted in 30 g (25%) of 6-nitro-2H,3H-[1,3]oxazolo[4,5-b]pyridin-2-one (I-11) as a light yellow solid.

Synthesis of I-12

Into a 500-mL round-bottom flask, was placed a solution of 6-nitro-2H,3H-[1,3]oxazolo[4,5-b]pyridin-2-one (30 g, 165.65 mmol, 1.00 equiv) in ethanol (130 mL). Then a solution of sodium hydroxide (24 g, 600.00 mmol, 3.62 equiv) in water (225 mL) was added. The resulting solution was stirred for 3 h at 80° C. The reaction was then quenched by the addition of 48 mL of concentrated hydrochloric. The pH value of the solution was adjusted to 8 with 2M sodium carbonate. The solids were collected by filtration. This resulted in 10 g (39%) of 2-amino-5-nitropyridin-3-ol (I-12) as a yellow solid.

Synthesis of I-13

Into a 1000-mL round-bottom flask, was placed 2-amino-5-nitropyridin-3-ol (9.5 g, 61.25 mmol, 1.00 equiv), 5-amino-2-chlorobenzoic acid (10.5 g, 61.20 mmol, 1.00 equiv), PPA (300 mL). The resulting solution was stirred for 2 days at 150° C. The reaction was then quenched by the addition of 1000 mL of water/ice. The pH value of the solution was adjusted to 7 with sodium hydroxide (aq.). The solids were collected by filtration. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:1). This resulted in 2 g (11%) of 4-chloro-3-[6-nitro-[1,3]oxazolo[4,5-b]pyridin-2-yl]aniline (I-13) as a red solid.

Synthesis of I-14

Synthesis of I-15

Synthesis of I-16

Into a 250-mL round-bottom flask, was placed 4-chloro-3-[6-nitro-1H-imidazo[4,5-b]pyridin-2-yl]aniline (6 g, 20.71 mmol, 1.00 equiv), triphosgene (4.93 g), dichloromethane (100 mL). This was followed by the addition of triethylamine (17.3 mL) dropwise with stirring at 0° C. To this was added pyrrolidine (1.7 mL) dropwise with stirring at 0° C. The resulting solution was stirred for 1 h at room temperature. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (20:1). The crude product was purified by re-crystallization from methanol. This resulted in 3.76 g (47%) of N-(4-chloro-3-[6-nitro-1H-imidazo[4,5-b]pyridin-2-yl]phenyl)pyrrolidine-1-carboxamide (I-16) as a yellow solid.

Synthesis of I-17

Into a 250-mL round-bottom flask, was placed N-(4-chloro-3-[6-nitro-1H-imidazo[4,5-b]pyridin-2-yl]phenyl)pyrrolidine-1-carboxamide (3 g, 7.76 mmol, 1.00 equiv), SnCl22H2O (8.78 g), ethanol (100 mL). The resulting solution was refluxed for 1 h in an oid bath. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 100 mL of water. The pH value of the solution was adjusted to 8 with sodium hydroxide (5%). The solids were filtered out, then washed with 5×30 mL EA. The water phase was extracted with 3×100 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (20:1). This resulted in 2.2 g (79%) of N-(3-[6-amino-1H-imidazo[4,5-b]pyridin-2-yl]-4-chlorophenyl)pyrrolidine-1-carboxamide as a yellow solid.1H-NMR-: (d6-DMSO, 400 MHz): 9.84-9.85 (m, 1H), 8.46 (s, 1H), 8.09 (brs, 1H), 7.87 (s, 1H), 7.74-7.77 (m, 1H), 7.45 (d, J=8.8 Hz, 1H), 7.07 (brs, 1H), 5.22 (brs, 2H), 4.09-4.12 (m, 4H), 1.86-1.87 (m, 4H) EI, m/z): MS (M+H)+=357 (M+1).

Synthesis of I-18

Into a 100-mL round-bottom flask, was placed a solution of 4-chloro-3-[6-nitro-[1,3]oxazolo[4,5-b]pyridin-2-yl]aniline (I-13) (300 mg, 1.03 mmol, 1.00 equiv), triphosgene (246 mg, 0.83 mmol, 0.80 equiv), triethylamine (627 mg, 6.20 mmol, 6.00 equiv), pyrrolidine (73.5 mg, 1.03 mmol, 1.00 equiv) in dichloromethane (15 mL). The resulting solution was stirred for 10 min at room temperature. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/ethyl acetate (1:1). The collected fractions were combined and concentrated under vacuum. This resulted in 300 mg (75%) of N-(4-chloro-3-[6-nitro-[1,3]oxazolo[4,5-b]pyridin-2-yl]phenyl)pyrrolidine-1-carboxamide (1-18) as a yellow solid

Synthesis of I-19

Into a 100-mL round-bottom flask, was placed a solution of N-(4-chloro-3-[6-nitro-[1,3]oxazolo[4,5-b]pyridin-2-yl]phenyl)pyrrolidine-1-carboxamide (1-18) (300 mg, 0.77 mmol, 1.00 equiv), SnCl22H2O (877 mg, 3.89 mmol, 5.02 equiv) in ethanol (15 mL). The resulting solution was stirred for 30 min at 80° C. The resulting mixture was concentrated under vacuum. The residue was dissolved in 50 mL of H2O. The solids were collected by filtration. The solid was dried in an oven under reduced pressure. This resulted in 200 mg (72%) of N-(3-[6-amino-[1,3]oxazolo[4,5-b]pyridin-2-yl]-4-chlorophenyl)pyrrolidine-1-carboxamide (I-19) as a yellow solid.

In a 20 mL vial was transferred the amine starting material 1-6 (100 mg, 0.345 mmol) in EtOAC (Volume: 6 mL) to give a yellow solution. To the reaction mixture was added the Tin Chloride dihydrate (195 mg, 0.863 mmols, 2.5 eq). The reaction mixture was heated at 70° C. for 1 hr. The reaction mixture was checked via LCMS the next day, looked for the desired mass, found 260, M+H). The reaction mixture was quenched with ice-cold sodium bicarbonate and extracted with ethyl acetate (3×50 mL).

The crude was at this point injected into the silica gel column and eluted with MeOH/DCM (0-10 to obtain desired product I-20.

Synthesis of Final Compounds

Compound 29 was synthesized using the protocol described in Example 1 for the synthesis of Intermediate 1-1 using 5-methylfuran-2-carbonyl chloride instead.

The synthesis of compound 8 is described in the synthesis of I-3.

In a 20 mL vial was transferred the amine starting material Mishrpr3-001-exp-015 (50 mg, 0.193 mmol) (50 mg, 0.193 mmol) in Pyridine (Volume: 5 mL) to give a yellow solution. The reaction mixture was cooled down to 0° C. and was added the 1 molar solution of Isopropyl chloroformate (47.2 mg, 0.385 mmol) exactly 2 equivalent and stirred for 1 hr. The reaction mixture was checked via LCMS, looked for the desired mass (M+H, 432), found the right peak. Quenched with water and was then removed all solvents under vacuo. Checked again via LCMS and found the desired mass of M+H (432). The reaction mixture was then injected into silica gel column and purified via ISCO (0-100%) (Ethyl acetate Hexane), the compound comes out at 60-80% EtOACHex.

Procedure: The 6-amino imidazopyridine (50 mg) was placed in DMF with EDCI.HCl (1.5 eq), HOBT (1.5 eq), DIEA (2 eq) and ispropylcarboxylic acid (1.5 eq). The resulting mixture was stirred overnight at room temperature. AcOEt was added and the mixture washed with water. The organic phase were dried over MgSO4, filtered and concentrated. Isco purification (Hexane/AcOEt) gave 24 mg of the desired product.

Compounds 18, 35 to 46, 55 to 57, 62 to 67, and 70 to 72 were synthesized, using the appropriate carboxylic acids, by the above procedure for the synthesis of Compound 10.

In a 20 mL vial was transferred N-(3-(6-amino-1H-imidazo[4,5-b]pyridin-2-yl)-4-chlorophenyl)furan-2-carboxamide (1-1) (20 mg, 0.056 mmol) in DMF (2 mL), and pyridine (2 drops) was added. The reaction mixture was stirred at 0° C. for ten minutes and then pyrrolidine-1-carbonyl chloride (250 μL, 3 mmols, 54 eq) was added. The brown reaction mixture was stirred at room temperature for 12 hrs. Checked via LCMS for the desired peak and found M+H (451). The reaction mixture was then quenched with solid sodium carbonate to neutralize the excess acid chloride and to make the solution basic (pH 8-9). Extracted with ethyl acetate (3×5 mL), combined all organics and dried over sodium sulfate, combined and dried under vacuo. Purified via mass triggered preparative HPLC, combined the pure fractions, removed solvents and treated carbonate resin, to get a free base of compound 12.

In a 20 mL vial was transferred N-(3-(6-amino-1H-imidazo[4,5-b]pyridin-2-yl)-4-chlorophenyl)furan-2-carboxamide I-1 (15 mg, 0.042 mmols) in DMF (2 mL), and the 2-isocyanatopropane (7 mg, 0.0.084 mmols, 2 eq) was added. The yellow reaction mixture was stirred at room temperature for 12 hrs. Checked via LCMS for the desired peak and found M+H (439). The reaction mixture was purified via preparative HPLC to isolate desired product (Compound 24). Yielded 7.2 mg, 0.016 mmols, 39%) of the desired compound.

Synthesis of Compound 21

Compound 21 was synthesized using the protocol as described for the synthesis of Compound 24 using the appropriate isocyanate.

Synthesis of Compound 68

In a 40 mL vial N-(3-(6-amino-1H-imidazo[4,5-b]pyridin-2-yl)-4-chlorophenyl)-5-fluorofuran-2-carboxamide (1-9) (20 mg, 0.054 mmol) was dissolved in DMF (Volume: 3 mL) to give a tan solution. The N-Boc-propanoic acid (10.18 mg, 0.054 mmol) was then added to the reaction mixture followed by HATU (20.46 mg, 0.054 mmol) and (iPr)2NEt (0.023 mL, 0.134 mmol). The reaction was stirred at rt for 4 hrs. The reaction was monitored by LCMS which indicated the reaction was complete with a new peak of desired mass was observed (M+H=543). The reaction mixture was quenched with water and extracted with ethyl acetate (3×5 mL). Combined all organics, dried over sodium sulfate and concentrated under reduce pressure. The crude reaction purified by reverse phase HPLC yield the desired product. The TFA salt was neutralized to a free base by a HCO3 column.

Following the above protocol for the synthesis of Compound 68, the cited compounds were synthesized using the appropriate carboxylic acid with Boc protection if required.

Synthesis of Compound 73

In a 40 mL vial was added Compound 68 (16 mg, 0.029 mmol) and added TFA/DCM (1:1) 4 mL). The reaction was stirred at room temperature for 0.5 hrs. The reaction was monitored by LCMS which indicated the reaction was complete with a new peak after the desired mass was observed (M+H=443). Removed all solvents and the reaction mixture was redissolved in MeOH (2 mL). The reaction mixture was then purified by reverse phase HPLC and purified compound was then made a free base by treating with MP-bicarbonate resin (100 mg).

The Boc protecting group on the nitrogen was removed according to protocol for the synthesis of Compound 73 for the above cited compounds to yield the desired product.

Procedure: In a 20 mL vial was transferred N-(3-(6-amino-1H-imidazo[4,5-b]pyridin-2-yl)-4-chlorophenyl)furan-2-carboxamide I-1 (80 mg, 0.225 mmol) in DMF (4 mL) followed by addition of pyridine (2 drops), and the reaction mixture was stirred at 0° C. for 10 minutes. At this point was added isopropyl carbonochloridate (1 M solution in toluene, 1.45 mmols, 6.4 eq). The reaction mixture was stirred overnight while slowly warming up to room temperature. Checked via LCMS for the desired peak. Found M+H (440). The reaction mixture was then quenched with saturated sodium carbonate solution to neutralize the extra acid chloride and to make the solution basic (pH 8-9). Extracted with ethyl acetate (3×10 mL), combined all organics and dried over sodium sulfate. Filtered and dried under vacuo. Purified via ISCO column chromatography using (0-100 EtOAC/Hex). Isolated 53 mg, 0.119 mmols, 53% of the desired compound.

Following the above protocol for the synthesis of Compound 2, the cited compounds were synthesized using the appropriate carbonochloridates.

In a 20 mL vial was transferred N-(3-(6-amino-1H-imidazo[4,5-b]pyridin-2-yl)-4-chlorophenyl)furan-2-carboxamide I-1 (10 mg, 0.028 mmol) in dry DMF (3 mL), and the tert-butyl (2-methyl-1-(((4-nitrophenoxy)carbonyl)oxy)propan-2-yl)carbamate (15 mg, 0.042 mmols, 1.5 eq) was added. To this was then added at 0° C. DIEA (9 mg, 0.07 mmols, 2.5 eq). The bright yellow reaction mixture was stirred at room temperature overnight. Checked via LCMS for the desired peak and found M+H (569). The solvents were removed under vacuo and extracted the organics from water with ethyl acetate (3×5 mL). The organics were combined, dried over sodium sulfate, removed solvents and was then re-dissolved with 2 mL of TFA/DCM (1:1) and stirred at room temperature fort hr. Checked for the desired peak and fund M+H=469. The solvents were removed once again under vacuo and the dark brown reaction mixture was then purified via preparative HPLC (Acetonitrile/water). The desired fractions were collected, solvents were removed, by treated with carbonate based resins to make a free base. Isolated 1 mg of the desired compound (23) as a white solid.

Synthesis of Compound 15 and 16

Compound 15 and 16 were similarly synthesized using the protocol described above for the synthesis of 23 using the appropriate nitrophenylcarbonate.

In a 20 mL vial was transferred N-(3-(6-amino-1H-imidazo[4,5-b]pyridin-2-yl)-4-chlorophenyl)-5-fluorofuran-2-carboxamide (1-9) (60 mg, 0.161 mmol) in pyridine (2 mL), and the isopropyl carbonochloridate (1M solution, 0.241 mmols, 1.5 eq) was added. The brown reaction mixture was stirred at room temperature for 12 hrs. Checked via LCMS for the desired peak and found M+H (544) which seemed to be isopropyl 2-(2-chloro-5-(5-fluorofuran-2-carboxamido)phenyl)-6-((isopropoxycarbonyl)amino)-1H-imidazo[4,5-b]pyridine-1-carboxylate. Removed all solvents under vacuo and the reaction mixture was redissolved in MeOH (2 mL), and added potassium carbonate (55 mg, 0.402 mmols, 2.5 eq). The reaction mixture was heated at 60 C for 1 hr, checked via LCMS once more and found the M+H=470 as the only peak. The reaction mixture was filtered and the methanolic solution was then injected into the mass triggered HPLC to isolate the desired compound, treated with carbonate based resin and isolated the free base of Compound 39.

The 6-amino imidazopyridine 1-9 (900 mg) was placed in pyridine at 0° C. and isopropyl chloroformate (1M in toluene, 1 eq) was added dropwise. Batches of 100 μl of chloroformate were added until no starting material was detected by LC-MS. The pyridine was evaporated and the residue was purified by ISCO (gradient AcOEt/Hexane) to yield the desired product as an off white powder (360 mg).

Synthesis of Compounds 53 and 54

Compounds 53 and 54 were synthesized follow the procedure in the synthesis of Compound 47 using the appropriate chloroformate.

In a 4 ml vidal was added I-1 (40 mg, 0.113 mmol) and DIEA (0.030 ml, 0.170 mmol) in DMF (Volume: 1 ml). 1-methylcyclopropyl (4-nitrophenyl)carbonate (32.2 mg, 0.136 mmol) was added. The mixture was stirred overnight. The reaction monitored was LCMS which indicated the reaction was complete with a new peak was observed. The reaction mixture was diluted with AcOEt. washed with water. AcOEt was evaporated and treated with MeOH and K2CO3 (excess) and heated at 60° C. for 1 hr.

MeOH was evaporated Removed all solvents and the reaction mixture was redissolved in MeOH (2 mL).The reaction mixture was then purified by reverse phase HPLC and purified compound was then made a free base by treating with MP-bicarbonate resin (100 mg).

Synthesis of 69-1

In a 40 mL vial N-(3-(6-amino-1H-imidazo[4,5-b]pyridin-2-yl)-4-chlorophenyl)-5-fluorofuran-2-carboxamide (1-9) (30 mg, 0.081 mmol)) was dissolved in EtOH (volume: 3 mL) to give a tan solution. The aldehyde (20.97 mg, 0.121 mmol) was then added to the reaction mixture followed by sodium tri-acetoxyborohydride (42.8 mg, 0.202 mmol). The reaction was stirred at 60° C. for 2 hrs. The reaction was monitored was LCMS which indicated the reaction was complete with a new peak of desired mass was observed (M+H=529). The reaction mixture was quenched with water and extracted with ethyl acetate (3×5 mL). Combined all organics, dried over sodium sulfate and concentrated under reduce pressure. The crude reaction purified by reverse phase HPLC yield desired product.

Synthesis of Compound 69

In a 40 mL vial was added 69-1 (20 mg, 0.038 mmol) and added TFA/DCM (1:1) 4 mL). The reaction was stirred at room temperature for 0.5 hrs. The reaction was monitored was LCMS which indicated the reaction was complete with a new peak of desired mass was observed (M+H=429). Removed all solvents and the reaction mixture was redissolved in MeOH (2 mL). The reaction mixture was then purified by reverse phase HPLC and purified compound was then made a free base by treating with MP-bicarbonate resin (100 mg). M/Z=429.0 (M+1). RT=0.57 min

Compounds 11, 13, 27, 30 and 31 were synthesized following the protocol used in the synthesis of Compound 69 using the appropriate aldehydes.

In a 4 ml vidal was added I-1 (40 mg, 0.113 mmol) and DIEA (0.030 ml, 0.170 mmol) in DMF (Volume: 1 ml). Mesyl chloride (10.54 μl, 0.136 mmol was added. The mixture was stirred for one hour. The reaction was monitored was LCMS which indicated the reaction was complete with a new peak was observed. The reaction mixture was diluted with AcOEt and washed with water. AcOEt was evaporated and treated with MeOH and K2CO3(excess) and heated at 60° C. for 1 hr. MeOH was evaporated. Removed all solvents and the reaction mixture was redissolved in MeOH (2 mL). The reaction mixture was then purified by reverse phase HPLC. The main peak was collected (M+23=mass of the desired compound), corresponding to the imine of DMF. The purified compound was then made a free base by treating with MP-bicarbonate resin (100 mg).

Synthesis of Compound 58

Compound 58 was synthesized using 1-20 and methyl sulfonylchloride using a protocol described in the synthesis of Compound 77.

Synthesis of Compound 59

Compound 59 was synthesis following the method described in the synthesis of Compound 77 using isopropyl sulfonylchloride.

In a 10 ml vial, acetic anhydride (250 μL) and formic acid (100 μL) are stirred at 55° C. for 2 h. The mixture is cooled to room temperature before addition of 1-9 (2.5 mg, 5.63 μmol, in diethylether (10 mL). DMF was added to help solubilize the mixture and stirred overnight at room temperature. The pyridine was evaporated and the residue was purified by ISCO (gradient MeOH/CH2Cl2) to yield the desired product . M/Z=400 (M+1)

Into a 50-mL round-bottom flask, was placed a solution of N-(3-[6-amino-[1,3]oxazolo[4,5-b]pyridin-2-yl]-4-chlorophenyl)pyrrolidine-1-carboxamide (100 mg, 0.28 mmol, 1.00 equiv), propan-2-yl chloroformate (68.3 mg, 0.56 mmol, 1.99 equiv), pyridine (111 mg, 1.40 mmol, 5.02 equiv) in ethylene glycol dimethyl ether (15 mL). The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (10:1). The collected fractions were combined and concentrated under vacuum. This resulted in 60.8 mg (49%) of propan-2-yl N-[2-(2-chloro-5-[[(pyrrolidin-1-yl)carbonyl]amino]phenyl)-[1,3]oxazolo[4,5-b]pyridin-6-yl]carbamate (75) as a yellow solid.

Into a 50-mL round-bottom flask, was placed a solution of N-(3-[6-amino-[1,3]oxazolo[4,5-b]pyridin-2-yl]-4-chlorophenyl)furan-2-carboxamide (1-15) (100 mg, 0.28 mmol, 1.00 equiv), triethylamine (85 mg, 0.84 mmol, 2.98 equiv), chloro(propan-2-yloxy)methanone (70 mg, 0.57 mmol, 2.03 equiv) in dichloromethane (15 mL). The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (10:1). This resulted in 10 mg (8%) of propan-2-yl N-[2-[2-chloro-5-(furan-2-amido)phenyl]-[1,3]oxazolo[4,5-b]pyridin-6-yl]carbamate (76) as a yellow solid.

In a 20 mL vial in Pyridine (Volume: 2 mL), was transferred the amine starting material I-9 (20 mg, 0.059 mmol)) to give a yellow solution. The reaction mixture was cooled down to 0° C. and was added isopropyl-sulfonyl chloride (8.46 mg, 0.059 mmol) and stirred for an hour. The reaction mixture was checked via LCMS after an hr, and found the desired mass (M+H=444). The reaction mixture was quenched with a drop of water and then was diluted with methanol. The reaction mixture was then purified by reverse phase HPLC and purified compound was then made a free base by treating with MP-bicarbonate resin (100 mg).

Syntheses of Compounds 51 and 52

Compounds 51 and 52 were synthesized following the procedure for the synthesis of Compound 77 using the appropriate sulfonyl chloride.

The synthesis of Compound 79 is described in the synthesis of I-9.