WO2014078813A1 - Compounds and compositions for the treatment of parasitic diseases - Google Patents

Compounds and compositions for the treatment of parasitic diseases Download PDF

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Publication number
WO2014078813A1
WO2014078813A1 PCT/US2013/070623 US2013070623W WO2014078813A1 WO 2014078813 A1 WO2014078813 A1 WO 2014078813A1 US 2013070623 W US2013070623 W US 2013070623W WO 2014078813 A1 WO2014078813 A1 WO 2014078813A1
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Prior art keywords
pyrazine
carboxamide
methyl
imidazo
phenyl
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PCT/US2013/070623
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French (fr)
Inventor
Arnab Kumar CHATTERJEE
Advait Suresh NAGLE
Prasuna PARASELLI
Seh Yong Leong
Jason Thomas ROLAND
Pranab Kumar MISHRA
Bryan Ks Yeung
Bin Zou
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Irm Llc
Novartis Ag
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Priority to US14/443,604 priority Critical patent/US20150291598A1/en
Priority to EP13795980.5A priority patent/EP2920177A1/en
Priority to CN201380065714.4A priority patent/CN105189506A/en
Priority to JP2015543098A priority patent/JP2016500073A/en
Publication of WO2014078813A1 publication Critical patent/WO2014078813A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/541—Non-condensed thiazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
    • A61K31/635—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide having a heterocyclic ring, e.g. sulfadiazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A61P33/06—Antimalarials
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the invention provides a class of compounds, pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent malaria.
  • Malaria is an infectious disease caused by four protozoan parasites: Plasmodium falciparum; Plasmodium vivax; Plasmodium ovale; and Plasmodium malaria. These four parasites are typically transmitted by the bite of an infected female Anopheles mosquito. Malaria is a problem in many parts of the world and over the last few decades the malaria burden has steadily increased. An estimated 1 -3 million people die every year from malaria - mostly children under the age of 5. This increase in malaria mortality is due in part to the fact that Plasmodium falciparum, the deadliest malaria parasite, has acquired resistance against nearly all available antimalarial drugs, with the exception of the artemisinin derivatives.
  • liver stage development is crucial, because development of the proceeding infectious blood stage gametocytes would be block.
  • a single drug effective against hepatichypnozoites, primaquine, is available, but its deployment is curtailed by its potential side effects.
  • Leishmaniasis is caused by one or more than 20 varieties of parasitic protozoa that belong to the genus Leishmania, and is transmitted by the bite of female sand flies. Leishmaniasis is endemic in about 88 countries, including many tropical and sub-tropical areas. PAT054787-WO-PCT
  • Visceral leishmaniasis also called kala-azar
  • kala-azar is the most serious form and is caused by the parasite Leishmania donovani. Patients who develop visceral leishmaniasis can die within months unless they receive treatment.
  • the two main therapies for visceral leishmaniasis are the antimony derivatives sodium stibogluconate (Pentostam®) and meglumine antimoniate (Glucantim®).
  • Glucantim® sodium stibogluconate has been used for about 70 years and resistance to this drug is a growing problem.
  • the treatment is relatively long and painful, and can cause undesirable side effects.
  • Human African Trypanosomiasis also known as sleeping sickness, is a vector-borne parasitic disease.
  • the parasites concerned are protozoa belonging to the Trypanosoma Genus. They are transmitted to humans by tsetse fly (Glossina Genus) bites which have acquired their infection from human beings or from animals harboring the human pathogenic parasites.
  • Chagas disease also called American Trypanosomiasis
  • Chagas disease is another human parasitic disease that is endemic amongst poor populations on the American continent.
  • the disease is caused by the protozoan parasite Trypanosoma cruzi, which is transmitted to humans by blood-sucking insects.
  • the human disease occurs in two stages: the acute stage, which occurs shortly after infection and the chronic stage, which can develop over many years.
  • Chronic infections result in various neurological disorders, including dementia, damage to the heart muscle and sometimes dilation of the digestive tract, as well as weight loss. Untreated, the chronic disease is often fatal.
  • the drugs currently available for treating Chagas disease are Nifurtimox and benznidazole.
  • problems with these current therapies include their diverse side effects, the length of treatment, and the requirement for medical supervision during treatment.
  • treatment is really only effective when given during the acute stage of the disease. 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.
  • n 0, 1 or 2;
  • p 0, 1 , 2 or 3;
  • Ring A is selected from the group consisting of C 6 . 10 aryl, C 5 . 10 heteroaryl and fused bicyclyls comprising a C 5 . 6 heterocycloalkyl fused to a phenyl;
  • Ring B represents the imidazo[1 ,2-a]pyrazine fused ring depicted in Formula 1 ;
  • Ring C is selected from the group consisting of phenyl, C 5 -i 0 heteroaryl, C 5 - 6 cycloalkyl, C 5 - 6 heterocycloalkyl, and fused bicyclyl comprising a C 5 - 6 heterocycloalkyl fused to a phenyl;
  • L is selected from the group consisting of * -CH 2 N(R 2 )-, *-C(0)-, *-C(0)N(R 2 )-, *-C(0)N(R 2 )C(R 3 a)(R 3 bh *-N(R 2 )C(R 3a )(R 3 b)-, *-N(R 2 )C(0)-, *-N(R 2 )S0 2 -, and Ci -6 alkylene, wherein
  • R 2 is selected from the group consisting of hydrogen, d- 4 alkyl and R 0 -Ci- 4 alkylene, wherein R 0 is selected from the group consisting of Ci- 4 alkyl, Ci_ 4alkoxy, amino, Ci- 4 alkylamino, C 5 - 6 heteroaryl and Cs-eheterocycloalkyl, wherein the C 5 - 6 heteroaryl and C 5 - 6 heterocycloalkyl of R 0 are each unsubstituted or substituted with 1 to 2 substituents independently selected from the group consisting of Ci -4 alkyl, halo and amino;
  • R 3a and R 3b are each independently selected from the group consisting of hydrogen and C 1-4 alkyl, or R 3a and R 3b is taken together with the carbon to which both attached to form a cyclopropyl;
  • each R ⁇ is independently selected from the group consisting of halo, cyano, -OR 4 , - C(0)R 5 , -C(0)NR 6 R 7 , -NR 8 R 9 , -NHC(O)R 10 , -NHS0 2 Rn, -S0 2 R 12 , C 1-6 alkyl, phenyl, C 5 _ gheteroaryl, and C 4 .
  • PAT054787-WO-PCT R 4 is C -6 alkyl or phenyl, wherein the d_ 6 alkyl is unsubstituted or substituted by 1 to 3 substituents independently selected from the group consisting of halo, cyano, d- 4 alkyl, amino, di-Ci- 4 alkylamino, and -C(0)NH 2 );
  • R 5 is hydrogen, Ci -6 alkyl or Ci- 6 alkoxy
  • R 6 , R 8 and Rn are each independently hydrogen or d- 4 alkyl
  • R 7 and R g are each independently selected from the group consisting of hydrogen, Ci- 4 alkyl, Ci- 4 alkoxy, and C 3 - 6 cycloalkyl, wherein the Ci -4 alkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of amino, Ci. 4 alkyl, Ci- 4 alkylamino, di-Ci- 4 alkylamino, Ci.
  • Rio is Ci- 6 alkyl, d. 6 alkoxy or C 3-6 cycloalkyl, wherein the Ci -6 alkyl of Ri 0 is unsubstituted or substituted by 1 -2 substituents independently selected from amino and C 3 - 6 cycloalkyl, and the C 3 . 6 cycloalkyl of R 10 is unsubstituted or substituted by 1 to 2 substituents independently selected from the group consisting of amino and amino- C 1-4 alkyl,
  • R 12 is C 1-4 alkyl, amino or C ⁇ alkylamino
  • Ci_ 6 alkyl of is unsubstituted or substituted with 1 -3 substituents independently selected from the group consisting of halo, cyano, methoxy, amino, C ⁇ alkylamino, C 5 . 6 cycloalkyl, and phenyl; and
  • the phenyl, C 5 . 6 heteroaryl and C 3 . 6 heterocycoalkyl of are each independently unsubstituted or substituted with 1 to 2 substituents independently selected from the grounp consisting of Ci -4 alkyl, amino, Ci. 4 alkylamino, -C(0)CH 3 , and benzyl;
  • Ri5 and Ri 6 are each independently hydrogen, Ci -4 alkyl or haloCi_ 4 alkyl;
  • each R 17 is independently selected from the group consisting of cyano, halo, oxo, ORi 8 , -C(0)Ri 9 , -NR 20 R 2 i, -S0 2 R 22 , -S0 2 NHR 23 , Ci -4 alkyl, phenyl, C 5 - 9 heteroaryl, C 3 .
  • Ri 8 is selected from the group consisting of hydrogen, Ci -4 alkyl, haloCi -4 alkyl and phenyl;
  • Rig is selected from the group consisting of hydrogen, d_ 4 alkyl, amino, and d_ 4 alkylamino;
  • R 20 , R 2 i and R 22 are each independently hydrogen or d_ 4 alky; PAT054787-WO-PCT
  • R 23 is hydrogen, C ⁇ alkyl, or C 5 - 6 heteroaryl
  • the Ci -4 alkyl of R 17 is unsubstituted or substituted with 1 -3 substituents independently selected from the group consisting of halo, d- 4 alkoxy and amino; and the phenyl, C 5 -gheteroaryl, C 3 - 6 cycloalkyl and C 4 - 6 heterocycloalkyl of Ri 7 are each independently unsubstituted or substituted by 1 to 2 substituents independently selected from the group consisting of Ci- 4 alkyl, halo-Ci- 4 alkyl, Ci- 4 alkoxy-Ci- 4 alkyl, and Ci- 4 alkoxy.
  • the Ci- 4 alkyl of Ri 7 is unsubstituted or substituted with 1 -3 substituents independently selected from the group consisting of halo, Ci. 4 alkoxy and amino; and the phenyl, C 5 - 9 heteroaryl, C 3 - 6 cycloalkyl and C 4 . 6 heterocycloalkyl of Ri 7 are each independently unsubstituted or substituted with 1 to 2 substituents independently selected from the group consisting of C 1-4 alkyl, halo-C 1-4 alkyl, d. 4alkoxy-Ci -4 alkyl, and C ⁇ alkoxy.
  • the present invention provides a pharmaceutical composition which contains a compound selected from Formula I, 1 A or 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.
  • 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 disease caused by a parasite (such as, for example, Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, Plasmodium malaria, Trypanosoma cruzi or a parasite of the Leishmania genus such as, for example, Leishmania donovani) which method comprises administering to the animal a therapeutically effective amount of a compound selected from Formula 1, 1 A or a N-oxide derivative, individual isomers and mixture of isomers thereof, or a pharmaceutically acceptable salt thereof.
  • a parasite such as, for example, Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, Plasmodium malaria, Trypanosoma cruzi or a parasite of the Leishmania genus such as, for example, Leishmania donovani
  • the present invention provides a compound according to formula 1 , 1 A, 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 (such as, for example, Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, Plasmodium malaria, PAT054787-WO-PCT
  • a parasite such as, for example, Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, Plasmodium malaria, PAT054787-WO-PCT
  • the parasite is a Plasmodium which can be at the blood stages or at the hepatic stages, and the disease is malaria.
  • the present invention provides the use of a compound selected from Formula I or Formula 1 a in the manufacture of a medicament for treating a disease caused by a parasite in an animal.
  • the disease may be malaria, leishmaniasis and/or Chagas disease.
  • the present invention provides a process for preparing compounds selected from Formula I, Formula 1 a and the N-oxide derivatives, prodrug derivatives, individual isomers and mixture of isomers thereof, and the pharmaceutically acceptable salts thereof.
  • compounds of the present invention refers to compounds of Fomula (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.
  • Alkoxy refers the radical -O-alkyl, wherein the alkyl is as defined herein.
  • C x alkoxy and C X - Y alkoxy as used herein describe alkoxy groups where X and Y indicate the number of carbon atoms in the alkyl chain.
  • Representative examples of C ⁇ oalkoxy include, but PAT054787-WO-PCT 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 refers to a fully saturated branched or unbranched hydrocarbon chain having up to 10 carbon atoms.
  • C x alkyl and C X - Y alkyl as used herein describe alkyl groups where X and Y indicate the number of carbon atoms in the alkyl chain.
  • d-i 0 alkyl refers to an alkyl radical as defined above containing one to ten carbon atoms.
  • C M 0 alkyl includes, but are not limited to, methyl, ethyl, n-propyl, /so-propyl, n-butyl, sec-butyl, /so-butyl, te/t-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.
  • (C 6 -i o)aryl(C 1 . 3 )alkyl includes, benzyl, phenylethyl, 1 -phenylethyl,
  • an alkyl group may be unsubstituted or substituted by one or more substituents to the extent that such substitution makes sense chemically.
  • 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 refers to a straight or branched, hydrocarbon chain having up to 10 carbon atoms and at least one carbon-carbon double bond.
  • C x alkenyl and C X - Y alkenyl as used herein describe alkenyl groups where X and Y indicate the number of carbon atoms in the alkenyl chain.
  • Examples of C 2 - 7 alkenyl 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 refers to a straight or branched, hydrocarbon chain having up to 10 carbon atoms and at least one carbon-carbon triple bond.
  • Y alkenyl as used herein describe alkynyl groups, where X and Y indicate the number of carbon atoms in the PAT054787-WO-PCT alkynyl chain.
  • C 2 - 7 alkenyl 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 refers to a divalent alkyl group defined herein.
  • Ci-i 0 alkylene includes, but are not limited to, methylene, ethylene, n-propylene, /so-propylene, n-butylene, sec-butylene, /so-butylene, te/t-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 refers to a divalent alkenyl group defined herein.
  • Examples of Ci -3 alkenylene 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 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 refers to the radical -NH 2 .
  • the term includes NR'R" wherein each R' and R" is independently H, or is an alkyl, alkenyl, alkynyl, acyl, aryl, aryl, cycloalkyl, arylalkyi cycloalkylalkyl group or a heteroform of one of these groups, and each of the alkyl, alkenyl, alkynyl, acyl, aryl, arylalkyi 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.
  • 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, 0 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 PAT054787-WO-PCT aromatic group, it is optionally substituted with the substituents described as typical for heteroaryl groups.
  • 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 refers to the radical -NR a R b , where at least one of, or both, R a and R b are an alkyl group as described herein.
  • An d- 4 alkylamino group includes— NHCi -4 alkyl and - N(Ci. 4 alkyl) 2 ; e.g., -NHCH 3 , -N(CH 3 ) 2 , -NH(CH 2 CH 3 ), -N(CH 2 CH 3 ) 2 , and the like.
  • Aromatic refers to a moiety wherein the constituent atoms make up an unsaturated ring system, where all atoms in the ring system are sp 2 hybridized 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 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.
  • Y aryl as used herein describe an aryl group where X and Y indicate the number of carbon atoms in the ring system.
  • C 6 -i 4 aryls include, but are not limited to, phenyl, biphenyl, naphthyl, azulenyl, and anthracenyl.
  • An aryl may be unsubstituted or substituted by 1 -5 (such as one, or two, or three) substituents independently selected from the group consisting of hydroxy, thiol, cyano, nitro, Cr 4 alkyl, d- 4 alkenyl, Cr 4 alkynyl, Cr 4 alkoxy, thioCV 4 alkyl, Cr 4 alkenyloxy, Ci- 4 alkynyloxy, halogen, d- 4 alkylcarbonyl, carboxy, d- 4 alkoxycarbonyl, amino, Ci- 4 alkylamino, di-Ci- 4 alkylamino, d- 4 alkylaminocarbonyl, di-d- 4 alkylaminocarbonyl, Ci- 4 alkylcarbonylamino, d- 4 alkylcarbonyl(d- 4 alkyl)amino, sulfonyl, sulfamoyl, alkylsulfamoyl,
  • aryloxycarbonyl "aryloxy-carbonylalkyl”
  • aryl portion shall have the same meaning as described in the above-mentioned definition of "aryl”.
  • Aryloxy 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 refers to the radical -C(0)NR a - where R a is H, or is an alkyl, alkenyl, alkynyl, acyl, aryl, or arylalkyi group or a heteroform of one of these groups, and each of the alkyl, alkenyl, alkynyl, acyl, aryl, arylalkyi 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(0)NR a R b where R a and R b are each independently H, or is an alkyl, alkenyl, alkynyl, acyl, aryl, or arylalkyi group or a heteroform of one of these groups, and each of the alkyl, alkenyl, alkynyl, acyl, aryl, arylalkyi 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.
  • C x cycloalkyl and C x . Y cycloalkyl are typically used where X and Y indicate the number of carbon atoms in the ring assembly.
  • C 3 - 6 cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2,5-cyclohexadienyl.
  • Exemplary monocyclic cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl and cyclohexenyl and the like.
  • bicyclic cycloalkyls include bornyl, norbornanyl, indyl, hexahydroindyl,
  • Exemplary tricyclic cycloalkyl groups include, for example, adamantyl.
  • a cycloalkyl may be unsubstituted or substituted by one, or two, or three, or more substituents independently selected from the group consisting of hydroxyl, thiol, cyano, nitro, oxo, alkylimino, Cr 4 alkyl, Ci- 4 alkenyl, C r4 alkynyl, C r4 alkoxy, C r4 thioalkyl, C 4 alkenyloxy, d- 4 alkynyloxy, halogen, d- 4 alkylcarbonyl, carboxy, C r4 alkoxycarbonyl, amino, C ⁇ alkylamino, di-C r
  • Cycloalkylene refers to a divalent radical comprising a cycloalkyl ring assembly as defined herein.
  • Cycloalkoxy refers to -O-cycloalkyl, wherein the cycloalkyl is defined herein.
  • Representative examples of C 3 .i 2 cycloalklyoxy include, but are not limited to, monocyclic groups such as cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclopentenyloxy, cyclohexyloxy and cyclohexenyloxy and the like.
  • Exemplary bicyclic hydrocarbon groups include bornyloxy, indyloxy, hexahydroindyloxy, tetrahydronaphthyloxy, decahydronaphthyloxy,
  • Exemplary tricyclic hydrocarbon groups include, for example, adamantyloxy.
  • EC 50 refers to the molar concentration of an inhibitor or modulator that produces 50% efficacy.
  • fused ring 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 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.
  • Ci -4 perhaloalkyl group refers to a Ci -4 alkyl group having all hydrogen atoms replaced with halo atoms.
  • Heteroaryl refers to a 5-14 membered ring assembly (e.g., a 5-7 membered monocycle, an 8-10 membered bicycle, or a 13-14 membered tricyclic ring system) having 1 to 8 heteroatoms selected from N, 0 and S as ring atoms and the remaining ring atoms are carbon atoms.
  • the nitrogen atoms of such heteroaryl rings can be optionally quaternerized and the sulfur atoms of such heteroaryl rings can be optionally oxidized.
  • C x heteroaryl and C x .
  • Yheteroaryl as used herein describe heteroaryls where X and Y indicate the number of ring atoms in the heteroaryl ring.
  • Typical C 5 . 7 heteroaryl groups include thienyl, furanyl, imidazolyl, pyrazolyl, pyrrolyl, pyrrolinyl, thiazolyl, 1 ,3,4-thiadiazolyl, isothiazolyl, oxazolyl, oxadiazole isoxazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrazinyl, pyrazinyl, pyrimidinyl, and the like.
  • PAT054787-WO-PCT Bicyclic or tricyclic C 8 -i 4 heteroaryls include, but are not limited to, those derived from
  • a heteroaryl may be unsubstituted or substituted with one or more substituents independently selected from hydroxyl, thiol, cyano, nitro, C ⁇ alkyl, C ⁇ alkenyl, C ⁇ alkynyl, C ⁇ alkoxy, thioCr 4 alkyl, C 4 alkenyloxy, C ⁇ alkynyloxy, halogen, C ⁇ alkylcarbonyl, carboxy, C ⁇ alkoxycarbonyl, amino, C ⁇ alkylamino, di-C ⁇ alkylamino, C ⁇ alkylaminocarbonyl, di-C ⁇ alkylaminocarbonyl, C ⁇ alkylcarbonylamino, C ⁇ alkylcarbony ⁇ C ⁇ alky ⁇ amino, sulfonyl, sulfamoyl, alkylsulfamoyl, C ⁇ alkylaminosulfonyl where each of the afore-mentioned hydrocarbon groups (e.g.,
  • heteroaryl When a heteroaryl is represented along with another radical like “heteroaryloxy”,
  • heteroaryloxyalkyl "heteroaryloxycarbonyl"
  • heteroaryl portion shall have the same meaning as described in the above-mentioned definition of “heteroaryl”.
  • Heteroaryloxy refers to an -O-heteroaryl group, wherein the heteroaryl is as defined in this Application.
  • Heteroatom refers to an atom that is not a carbon atom. Particular examples of heteroatoms include, but are not limited to nitrogen, oxygen, and sulfur. PAT054787-WO-PCT
  • Heterocycloalkyl 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, 0, and S, preferably 0 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.
  • Y heterocycloalkyl are typically used where X and Y indicate the number of ring atoms in the ring.
  • 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.
  • Cxheterocycloalkyl examples include azetidinyl, tetrahydrofuran (THF), dihydrofuran, 1 , 4- dioxane, morpholine, 1 ,4-dithiane, piperazine, piperidine, 1 ,3-dioxolane, imidazoline, 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, C r 4 alkyl, C r4 alkenyl, C 1 - 4 alkynyl, Cr 4 alkoxy, C ⁇ thioalkyl, CV 4 alkenyloxy, C ⁇ alkynyloxy, halogen, C ⁇ alkylcarbonyl, carboxy, C ⁇ alkoxycarbonyl, amino, Cr 4 alkylamino, di- C ⁇ alkylamino, C r 4 alkylaminocarbonyl, di-Cr 4 alkylaminocarbonyl, Ci- 4 alkylcarbonylamino, Ci- 4 alkylcarbonylamino, Ci- 4 alkylcarbonylamino, Ci- 4 alkylcarbonyl(Ci- 4 alkyl)amin
  • heterocycloalkyl forms part of other groups like “heterocycloalkyl-alkyl”.
  • heterocycloalkoxy "heterocycloalkyl-aryl"
  • heteroaryl portion shall have the same meaning as described in the above-mentioned definition of “heteroaryl”
  • Heterocycloalkylene 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 refers to a bicyclic fused ring system that one of the ring is heterocycloalkyl as defined above and the other ring is a phenyl.
  • 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.
  • Y heterocyclyl 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 refers to the radical -OH.
  • Hydroxyalkyl or "hydroxyl-substituted alkyi” as used herein, refers to an alkyi as defined herein, having one or more of the available hydrogen of the alkyi replaced by a hydroxyl group.
  • a hydroxyC 1 _ 4 alkyl includes, but are not limited to, -CH 2 CH 2 OH, -CH(OH)CH 2 CH 2 OH, - CH(OH)CH 2 CH(OH)CH 3 .
  • Ni refers to the radical -N0 2 .
  • 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, ⁇ -methoxyethoxymethyl ether, p- methoxybenzyl, methylthiomethyl ether, pivaloyl, silyl ether, carbobenzyloxy, benzyl, tert- butoxycarbonyl, p-methoxyphenyl, 9-fluorenylmethyloxycarbonyl, acetals, ketals, acylals, dithianes, methylesters, benzyl esters, te/f-butyl esters, and silyl esters.
  • a comprehensive list of PAT054787-WO-PCT suitable protecting groups can be found in T.W. Greene,
  • 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.
  • C 1-4 alkyl substituted terminally by an amino means -C ⁇ alkylene-amino, which includes -(CH 2 )-NH 2 , -(CH 2 ) 2 -NH 2 , -(CH 2 ) 3 -NH 2 , - (CH 2 )CH 2 (CH 2 -NH 2 ), -(CH 2 ) 4 -NH 2 , -C(CH 2 )(CH 2 CH 2 -NH 2 ) -C(CH 3 ) 2 (CH 2 -NH 2 ), and the like.
  • substituents may include, but are not limited to, halo, nitro, cyano, thio, oxy, hydroxy, carbonyloxy, C ⁇ alkoxy, C 6 . 10 aryloxy, heteroC 5 .
  • Sulfamoyl refers to the radical -S(0) 2 NR a R b where R a and R b are
  • H independently H, or is an alkyl, alkenyl, alkynyl, acyl, aryl, aryl, cycloalkyl, arylalkyl
  • 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.
  • Sulfinyl as used herein, means the radical -S(0)-. It is noted that the term “sulfinyl” when referring to a monovalent substituent can alternatively refer to a substituted sulfinyl
  • any definition herein may be used in combination with any other definition to describe a composite structural group.
  • the trailing element of any such definition is that which attaches to the parent moiety.
  • the composite group alkoxyalkyl would represent an alkoxy group attached to the parent molecule through an alkyl group.
  • Cialkyl indicates that there is one carbon atom but does not indicate what are the substituents on the carbon atom.
  • a Cialkyl comprises methyl (i.e., -CH 3 ) as well as -CR a R b R c where R a , R b , and R c may each independently be hydrogen or any other substituent where the atom attached to the carbon is not a hydrogen atom.
  • - CF 3 , -CH 2 OH and -CH 2 CN are all Cialkyls.
  • 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.
  • the compounds can be used to treat malaria, leishmaniasis and/or Chagas disease.
  • the compounds of the invention are effective in inhibiting, ameliorating, or eradicating the pathology and/or symptomology of the parasite at both the blood stage and hepatic stage.
  • the compounds of the invention or a pharmaceutical acceptable salt, tautomer or stereoisomer thereof, are of Formula I:
  • n 0, 1 or 2;
  • p 0, 1 , 2 or 3;
  • Ring A is selected from the group consisting of C 6 -i 0 aryl, C 5 -i 0 heteroaryl and fused bicyclyls comprising a C 5 - 6 heterocycloalkyl fused to a phenyl;
  • Ring B represents the imidazo[1 ,2-a]pyrazine fused ring depicted in Formula 1 ;
  • Ring C is selected from the group consisting of phenyl, C 5 -ioheteroaryl, C 5 - 6 cycloalkyl, C 5 - 6 heterocycloalkyl, and fused bicyclyl comprising a C 5 - 6 heterocycloalkyl fused to a phenyl;
  • L is selected from the group consisting of * -CH 2 N(R 2 )-, * -C(0)-, * -C(0)N(R 2 )-, *-C(0)N(R 2 )C(R 3a )(R 3b )-, *-N(R 2 )C(R 3a )(R 3b )-, *-N(R 2 )C(0)-, *-N(R 2 )S0 2 -, and Ci. 6 alkylene, wherein
  • R 2 is selected from the group consisting of hydrogen, Ci_ 4 alkyl and
  • R 0 is selected from the group consisting of C 1 _ 4 alkyl, 4alkoxy, amino, C ⁇ alkylamino, C 5 . 6 heteroaryl and C 5 . 6 heterocycloalkyl, wherein the C 5 . 6 heteroaryl and C 5 . 6 heterocycloalkyl of R 0 are each unsubstituted or substituted with 1 to 2 substituents independently selected from the group consisting of C 1 4 alkyl, halo and amino;
  • R 3a and R 3b are each independently selected from the group consisting of hydrogen and C 1-4 alkyl. or R 3a and R 3b is taken together with the carbon to which both attached to form a cyclopropyl;
  • each is independently selected from the group consisting of halo, cyano, -OR 4 , - C(0)R 5 , -C(0)NR 6 R 7 , -NR 8 R 9 , -NHC(O)R 10 , -NHS0 2 R 11 ; -S0 2 R 12 , Ci -6 alkyl, phenyl, C 5 - gheteroaryl, and C 4 - 6 heterocycoalkyl, wherein
  • R 4 is Ci. 6 alkyl or phenyl, wherein the d- 6 alkyl is unsubstituted or substituted by 1 to 3 substituents independently selected from the group consisting of halo, cyano, Ci. 4 alkyl, amino, di-Ci -4 alkylamino, and -C(0)NH 2 );
  • R 5 is hydrogen, Ci. 6 alkyl or Ci- 6 alkoxy
  • R 6 , R 8 and Rn are each independently hydrogen or Ci -4 alkyl
  • R 7 and R g are each independently selected from the group consisting of hydrogen, C ⁇ alkyl, C 1-4 alkoxy, and C 3 . 6 cycloalkyl, wherein the C 1-4 alkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of amino, C 1 4 alkyl, C 1-4 alkylamino, di-C 1-4 alkylamino,
  • R 10 is C 1-6 alkyl, C 1-6 alkoxy or C 3 . 6 cycloalkyl, wherein the C 1-6 alkyl of R 10 is unsubstituted or substituted by 1 -2 substituents independently selected from amino and C 3-6 cycloalkyl, and the C 3 . 6 cycloalkyl of R 10 is unsubstituted or substituted by 1 to 2 substituents independently selected from the group consisting of amino and amino- Ci -4 alkyl,
  • Ri 2 is Ci -4 alkyl, amino or Ci- 4 alkylamino
  • Ci -6 alkyl of R is unsubstituted or substituted with 1 -3 substituents independently selected from the group consisting of halo, cyano, methoxy, amino, Ci -4 alkylamino, C 5 - 6 cycloalkyl, and phenyl; and
  • phenyl, C 5 - 6 heteroaryl and C 3 . 6 heterocycoalkyl of Ri are each independently unsubstituted or substituted with 1 to 2 substituents independently selected from the grounp consisting of Ci_ 4 alkyl, amino, Ci- 4 alkylamino, -C(0)CH 3 , and benzyl;
  • Ri5 and R 16 are each independently hydrogen, C 1-4 alkyl or haloC 1-4 alkyl; PAT054787-WO-PCT each R 17 is independently selected from the group consisting of cyano, 3 ⁇ 4 oxo,
  • R18 is selected from the group consisting of hydrogen, Ci -4 alkyl, haloCi -4 alkyl and phenyl;
  • Rig is selected from the group consisting of hydrogen, Ci -4 alkyl, amino, and Ci- 4 alkylamino;
  • R 20 , R 21 and R 22 are each independently hydrogen or C h alky
  • R 23 is hydrogen, Ci -4 alkyl, or C 5 - 6 heteroaryl
  • the Ci -4 alkyl of Ri 7 is unsubstituted or substituted with 1 -3 substituents independently selected from the group consisting of halo, d. 4 alkoxy and amino; and the phenyl, C 5 - 9 heteroaryl, C 3 - 6 cycloalkyl and C 4 . 6 heterocycloalkyl of R 17 are each independently unsubstituted or substituted by 1 to 2 substituents independently selected from the group consisting of C 1-4 alkyl, halo-C 1-4 alkyl, C 1-4 alkoxy-C 1-4 alkyl, and C 1-4 alkoxy.
  • the compound of the invention is where L is selected from the group consisting of *-CH 2 N(R 2 )-, *-C(0)-, *-C(0)N(R 2 )-,
  • R 2 is C 1 _ 4 alkyl
  • R 3a and R 3b are each independently selected from the group consisting of hydrogen and Ci -4 alkyl, or R 3a and R 3b is taken together with the carbon to which both attached to form a cyclopropyl.
  • L is selected from the group consisting of *-(CH 2 )-, *-CH 2 N(CH 3 )-, *- C(O)-, *-C(0)NH-, *-C(0)N(CH 3 )-, *-C(0)N(CH 2 CH 2 OCH 3 )-, *-C(0)N(CH 2 CH 2 NH 2 )-,
  • L is selected from the group consisting of * -CH 2 N(CH 3 )-, * -C(0)NH-, * - C(0)N(CH 3 )-, * -C(0)N(CH 2 CH 2 OCH 3 )-, * -C(0)N(CH 2 CH 2 N(CH 3 ) 2 )-, * -C(0)N(CH 2 CH 2 NH 2 )-, PAT054787-WO-PCT
  • L is * -C(0)N(CH 3 )-.
  • L is * -CH 2 N(CH 3 )-.
  • L is * -(CH 2 )-.
  • L is * -C(0)-.
  • Ring A is selected from the group consisting of C 6 -i 0 aryl and C 5 - 10 heteroaryl. In one variation, , Ring A is selected from the group consisting of
  • Ring A is selected from the group consisting of i eac h of which is unsubstituted or substituted with 1 to 2 Ri groups.
  • Ring A is selected from the group consisting of phenyl and pyridinyl, each of which is unsubstituted or substituted with 1 to 2 Ri groups.
  • PAT054787-WO-PCT PAT054787-WO-PCT
  • Ring A is of the formula: . In another particular variation, Ring A is of the formula: . In still another particular variation, Ring A is of the formula:
  • Ring C is selected from the group consisting of phenyl, C 5 .
  • Ring C is selected from the group consisting of
  • Ring C is selected from the group consisting of phenyl and pyridyl, each of which is unsubstituted or substituted with 1 to 2 R 17 groups. In one particular variation, Ring C
  • Ring C is of the formula: .
  • Ring C is of the formula: In still another particular variation, Ring C is of the formula: .
  • Ring C is CeheterocycloalkyI or fused bicyclyl comprising a C 5 - eheterocycloalkyl fused to a phenyl, wherein the CeheterocycloalkyI and fused bicyclyl are each unsubstituted or substituted with 1 to 3 (Ri 7 ) group.
  • Ring C is selected from the group consisting of CT
  • Ring C is In one particular variation, Ring C is In
  • Ring C is .
  • each ⁇ is independently selected from the group consisting of fluoro, chloro, cyano, methyl, isopropyl, t-butyl, cyanopropyl, -CH(CH 3 )(OCH 3 ), trifluoromethyl, difluoromethyl, -CF 2 CH 3 , -C(CH 3 ) 2 CN, -CH 2 NH 2 , -CH 2 N(CH 3 ) 2 , -CH 2 -morpholinyl, methoxy, proproxy, isoproproxy, difluoromethoxy, trifluoromethoxy, -OCH 2 CF 3 , cyanomethoxy, 2- aminoethoxy, -0(CH 2 ) 2 N(CH 3 ) 2 , -OC(CH 3 ) 2 CH 2 NH 2 , -OC(CH 3 ) 2 C(0)NH 2 , and phenoxy.
  • each R A is independently selected from the group consisting of -C(0)CH 3 , - C(0)OCH 3 , -C(0)NH 2 , -C(0)NHCH 3 , -C(0)N(CH 3 ) 2 , -C(0)N(CH 2 CH 3 ) 2 , -C(0)N(CH 3 )(OCH 3 ), - C(0)NH((CH 2 ) 2 N(CH 3 ) 2 ), -C(0)NH(cyclopropyl), and -C(0)NH(cyclohexyl).
  • each R ⁇ is independently selected from the group consisting of amino, methylamino, dimethylamino, -NH(OCH 3 ), -NH(CH 2 C(NH 2 )(CH 3 ) 2 ), - NH(C(CH 3 ) 2 CH 2 NH(C(0)OC(CH 3 ) 3 )), -NH(C(CH 3 ) 2 CH 2 NH 2 ), -NH((CH 2 ) 2 -morpholinyl), - NH(C(0)CH 3 ), -NH(C(0)CH 2 NH 2 ), -NH(C(0)CH(NH 2 )(CH 3 )), -NH(C(0)CH(NH 2 )CH(CH 3 ) 2 ), -NH(C(0)C(NH 2 )(CH 3 ) 2 ), -NH(C(0)C(NH 2 )(CH 3 ) 2 ), -NH(C(0)CH 2 CH(NH 2 )(CH 3 )), -NH(C(0)CH 2 CH(NH 2
  • each R ⁇ is independently selected from the group consisting of -S0 2 CH 3 , -S0 2 CH(CH 3 ) 2 , -S0 2 NH 2 , and -S0 2 N(CH 3 ) 2 .
  • each R is independently selected from the group consisting of
  • each R ⁇ is independently selected from the group consisting of
  • each R ⁇ is independently selected from the group consisting of
  • each Ri is independently selected from the group consisting of trifluoromethyl, -C(0)NH 2 , -C(0)NHCH 3 , -C(0)NH(CH 2 ) 2 N(CH 3 ) 2 , and -NHC(0)CH(NH 2 )- cycloalkyl. In one variation, is trifluoromethyl. In another variation, Ri is -C(0)NH 2 .. In still another variation, R is -C(0)NH 2 .. PAT054787-WO-PCT
  • n is 0. In one variation, n is 1. In yet another variation, n is 2.
  • Ri 5 is hydrogen
  • Ri 6 is hydrogen
  • each R 17 is independently selected from the group consisting of fluoro, chloro, bromo, cyano, methyl, ethyl, t-butyl, trifluoromethyl, methoxymethyl, aminomethyl, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, phenoxy, oxo, dimethylamino, methylsulfonyl, and aminocarbonyl.
  • each R 17 is independently selected from the group consisting of -C(0)CH 3 , -C(0)NH 2 , methylsulfonyl, --S0 2 NH-thiazol-2-yl, and - S0 2 NH 2 . In still other embodiments, each R 17 is independently selected from the group
  • each R 17 is independently selected from the group consisting of fluoro, chloro, bromo, cyano, methyl, methylsulfonyl, and aminocarbonyl.
  • R i7 is cyano.
  • Ri 7 is chloro.
  • Ri 7 is fluoro.
  • Ri 7 is methylsulfonyl.
  • p is 0. In some variations, p is 1 . In other variations, p is 2.
  • n 1 ;
  • p 1 ;
  • L is *-C(0)N(R 2 )- or *-CH 2 N(R 2 )-, wherein
  • R 2 is d- 4 alkyl or R 0 -Ci- 4 alkylene, wherein R 0 is selected from the group consisting of Ci- 4 alkoxy, amino, C ⁇ alkylamino, C 5 - 6 heteroaryl and C 5 - 6 heterocycloalkyl, wherein said C 5 - eheteroaryl and C 5 - 6 heterocycloalkyl are each independently unsubstituted or substituted by 1 -2 substituents independently selected from the group consisting of Ci -4 alkyl, halo, amino, and oxo;
  • Ring A is pheny or pyridyl
  • Ring C is pheny or pyridyl
  • each Ft ! is trifluoromethyl, * -C(0)NH 2 , or * -C(0)NHCH 3 ;
  • each R 17 is chloro, fluoro, or cyano.
  • L is *-C(0)N(CH 3 )-. In other variation, L is *-CH 2 N(CH 3 )-. is of the formula:
  • Particular examples of compounds or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, according to the present invention include, but are not limited to:
  • 6-carboxamide 6-chloro-1 -( ⁇ 3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl ⁇ carbonyl)-
  • a]pyrazine-6-carboxamide N,5-dimethyl-N-( ⁇ 3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin- 6-yl ⁇ methyl)pyridin-2-amine; N-(6-methoxy-5-methylpyridin-3-yl)-N-methyl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N,4-dimethyl-N- ⁇ 3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl ⁇ benzamide; N-(6-methoxypyridin-2-yl)-N- methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide;
  • Particular examples of compounds or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, according to the present invention include, but are not limited to:
  • 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 inventin may be a mixture of stereoisomers, or the compound may comprise a single stereoisomer.
  • 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.
  • the pharmaceutical composition further includes a second agent.
  • the second agent may be, but not limited to, a kinase inhibitor, an anti-malarial drug or an antiinflammatory agent.
  • the pharmaceutical composition includes an antimalarial drug as a second agent; the selections of the antimalarial includes, but are not limited to, artemisinin, artemether, artesunate, arteflene, dihydroartemisinin, chlorproguanil, trimethoprim, chloroquine, quinine, mefloquine, amodiaquine, atovaquone, proguanil, lumefantrine, piperaquine, pyronaridine, halofantrine, pyrimethamine-sulfadoxine, quinacrine, pyrimethamine-dapsone, quinidine, amopyroquine, sulphonamides, primaquine, ferroquine, tafenoquine, arterolane, and pyronaridine.
  • the selections of the antimalarial includes, but are not limited to, artemisinin, artemether, artesunate, arteflene, dihydroartemisinin, chlor
  • the pharmaceutical composition is a solid formulation adapted for oral administration.
  • the composition is a liquid formulation adapted for oral administration.
  • the composition is a tablet.
  • the composition is a liquid formulation adapted for parenteral administration.
  • the pharmaceutical composition is adapted for administration by a route selected from the group consisting of orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermal ⁇ , sublingually, intramuscularly, rectally, transbuccally, intranasally, Iiposomally, via inhalation, vaginally, intraoccularly, via local delivery (for example by catheter or stent), subcutaneously, intraadiposally, intraarticularly, and intrathecally.
  • 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.
  • 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.
  • 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 Plasmodium parasite.
  • the method involves administering to a subject a therapeutically effective amount of a compound or a pharmaceutical composition according to the above PAT054787-WO-PCT embodiments and variations.
  • the administering can be in combination with a second agent.
  • the disease being treated is malaria.
  • the malaria can be caused by the parasite Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, or Plasmodium malaria; in particular, the parasit Plasmodium falciparum.
  • the Plasmodium parasite can be at the blood stages; or the Plasmodium parasite can be at the hepatic stages.
  • the compounds or pharmaceutical compositions can be administered prior to, simultaneously with, or after a second agent.
  • the second agent can be a kinase inhibitor, an anti-malarial drug or an anti-inflammatory agent.
  • the second agent is an anti-malarial drug, which includes, but is not limited to, artemisinin, artemether, artesunate, arteflene, dihydroartemisinin, chlorproguanil, trimethoprim, chloroquine, quinine, mefloquine, amodiaquine, atovaquone, proguanil, lumefantrine, piperaquine, pyronaridine, halofantrine, pyrimethamine-sulfadoxine, quinacrine, pyrimethamine-dapsone, quinidine, amopyroquine, sulphonamides, primaquine, ferroquine, tafenoquine, arterolane, and pyronaridine.
  • artemisinin artemether
  • artesunate arteflene
  • dihydroartemisinin chlorproguanil
  • trimethoprim chloroquine
  • quinine quinine
  • the invention is directed to a compound, salt, stereoisomer, or
  • the disease caused by the Plasmodium parasite is malaria.
  • the Plasmodium parasite which causes the malaria can be Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, or Plasmodium malaria; in particular the parasite Plasmodium falciparum.
  • the Plasmodium parasite can be at the blood stages, or the Plasmodium parasite can be at the hepatic stages.
  • the above compound of invention may be administered prior to, simultaneously with, or after a second agent.
  • the second agent may be a kinase inhibitor, an anti-malarial drug or an antiinflammatory agent.
  • the second agent is an anti-malarial drug.
  • the antimalarial drug can be, but are not limited to, artemisinin, artemether, artesunate, arteflene, dihydroartemisinin, chlorproguanil, trimethoprim, chloroquine, quinine, mefloquine, amodiaquine, atovaquone, proguanil, lumefantrine, piperaquine, pyronaridine, halofantrine, pyrimethamine-sulfadoxine, quinacrine, pyrimethamine-dapsone, quinidine, amopyroquine, sulphonamides, primaquine, ferroquine, tafenoquine, arterolane, and pyronaridine.
  • the present invention is directed to the use of a compound, or a salt, a stereoisomer, or a pharmaceutical composition thereof, according to the above embodiments or variations in the manufacture of a medicament for treating, preventing, inhibiting, or ameliorating the pathology and/or symptomology of a disease caused by a Plasmodium parasite.
  • the disease is malaria
  • the parasite is Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, or Plasmodium malaria; in particular, the parasite is Plasmodium falciparum.
  • the Plasmodium parasite can be at the blood stages or the Plasmodium parasite can be at the hepatic stages.
  • the medicament may include, in addition to the compound of the invention, a second agent.
  • the second agent can be a kinase inhibitor, an anti-malarial drug or an anti-inflammatory agent.
  • the second agent is an anti-malarial drug, and the drug is selected from artemisinin, artemether, artesunate, arteflene, dihydroartemisinin, chlorproguanil, trimethoprim, chloroquine, quinine, mefloquine, amodiaquine, atovaquone, proguanil, lumefantrine, piperaquine, pyronaridine, halofantrine, pyrimethamine-sulfadoxine, quinacrine, pyrimethamine-dapsone, quinidine, amopyroquine, sulphonamides, primaquine, ferroquine, tafenoquine, arterolane, and pyronaridine.
  • 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.
  • the kit comprises the compound in a multiple dose form.
  • the invention provides a compound of formula (I), or a pharmaceutical acceptable salt, tautomer or stereoisomer thereof,
  • n 0, 1 or 2;
  • p 0, 1 , 2 or 3;
  • Ring A is selected from the group consisting of C 6 . 10 aryl, C 5 -i 0 heteroaryl and fused bicyclyls comprising a C 5 - 6 heterocycloalkyl fused to a phenyl;
  • Ring B represents the imidazo[1 ,2-a]pyrazine fused ring depicted in Formula 1 ;
  • Ring C is selected from the group consisting of phenyl, C 5 -i 0 heteroaryl, C 5 - 6 cycloalkyl, C 5 - 6 heterocycloalkyl, and fused bicyclyl comprising a C 5 - 6 heterocycloalkyl fused to a phenyl;
  • L is selected from the group consisting of * -CH 2 N(R 2 )-, * -C(0)-, * -C(0)N(R 2 )-,
  • R 2 is selected from the group consisting of hydrogen, d- 4 alkyl and R 0 -Ci- 4 alkylene, wherein R 0 is selected from the group consisting of Ci -4 alkyl, Ci- 4 alkoxy, amino, Ci- 4 alkylamino, C 5 - 6 heteroaryl and C ⁇ 6 heterocycloalkyl, wherein the C 5 - eheteroaryl and Cs-eheterocycloalkyl of R 0 are each unsubstituted or substituted with 1 to 2 substituents independently selected from the group consisting of Ci- 4 alkyl, halo and amino;
  • R 3a and R 3b are each independently selected from the group consisting of hydrogen and C 1-4 alkyl, or R 3a and R 3b is taken together with the carbon to which both attached to form a cyclopropyl;
  • each Ri is independently selected from the group consisting of halo, cyano, -OR 4 , - C(0)R 5 , -C(0)NR 6 R 7 , -NR 8 R 9 , -NHC(O)R 10 , -NHS0 2 Rn, -S0 2 R 12 , C 1-6 alkyl, phenyl, C 5 .
  • R 4 is Ci. 6 alkyl or phenyl, wherein the d_ 6 alkyl is unsubstituted or substituted by 1 to 3 substituents independently selected from the group consisting of halo, cyano, d_ 4alkyl, amino, di-Ci -4 alkylamino, and -C(0)NH 2 );
  • R 5 is hydrogen, d- 6 alkyl or d- 6 alkoxy
  • R 6 , R 8 and Rn are each independently hydrogen or d- 4 alkyl
  • R 7 and R 9 are each independently selected from the group consisting of hydrogen, d- 4 alkyl, d. 4 alkoxy, and C 3 - 6 cycloalkyl, wherein the d ⁇ alkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of amino, d -4 alkyl, Ci- 4 alkylamino, di-Ci -4 alkylamino, Ci- 4 alkoxycarbonylamino, and C 5 . eheterocycloalkyl;
  • Rio Ci- 6 alkyl, d. 6 alkoxy or C 3 - 6 cycloalkyl, wherein the d -6 alkyl of Ri 0 is unsubstituted or substituted by 1 -2 substituents independently selected from amino and d-ecycloalkyl, and the C 3 - 6 cycloalkyl of R 10 is unsubstituted or substituted by 1 to 2 substituents independently selected from the group consisting of amino and amino-d- 4alkyl,
  • R 12 is C 1-4 alkyl, amino or d- 4 alkylamino
  • the C 1-6 alkyl of is unsubstituted or substituted with 1 -3 substituents independently selected from the group consisting of halo, cyano, methoxy, amino, d- 4alkylamino, C 5 6 cycloalkyl, and phenyl; and
  • the phenyl, C 5 . 6 heteroaryl and C 3 . 6 heterocycoalkyl of are each independently unsubstituted or substituted with 1 to 2 substituents independently selected from the grounp consisting of d -4 alkyl, amino, Ci- 4 alkylamino, -C(0)CH 3 , and benzyl;
  • Ri5 and R 16 are each independently hydrogen, Ci -4 alkyl or haloCi -4 alkyl;
  • each R 17 is independently selected from the group consisting of cyano, halo, oxo, ORi 8 , - C(0)Ri 9 , -NR 20 R 21 , -S0 2 R 22 , -S0 2 NHR 23 , d- 4 alkyl, phenyl, C 5 - 9 heteroaryl, C 3 - 6 cycloalkyl and C 4 . eheterocycloalkyl, wherein
  • Ri 8 is selected from the group consisting of hydrogen, d -4 alkyl, haloCi- 4 alkyl and phenyl;
  • Rig is selected from the group consisting of hydrogen, d -4 alkyl, amino, and d- 4alkylamino;
  • R 20 , R 2 i and R 22 are each independently hydrogen or d_ 4 alky
  • R 23 is hydrogen, d. 4 alkyl, or C 5 - 6 heteroaryl
  • the C 1-4 alkyl of R 17 is unsubstituted or substituted with 1 -3 substituents independently selected from the group consisting of halo, Ci. 4 alkoxy and amino; and the phenyl, C 5 - 9 heteroaryl, C 3 - 6 cycloalkyl and C 4 - 6 heterocycloalkyl of R i7 are each independently unsubstituted or substituted by 1 to 2 substituents independently selected from the group consisting of d- 4 alkyl, halo-Ci -4 alkyl, C i _ 4 al koxy- C i_ 4 al ky I , and d- 4 alkoxy.
  • Embodiment 2 A compound, or a salt, tautomer or stereoisomer thereof, according to embodiment 1 , wherein L is selected from the group consisting of * -CH 2 N(R 2 )-, * -C(0)-, * -C(0)N(R 2 )-, * -C(0)N(R 2 )C(R 3a )(R 3b )-, * -N(R 2 )C(0)-, * -N(R 2 )S0 2 -, and C 1-6 alkylene, wherein
  • R 2 is Ci- 4 alkyl
  • R 3a and R 3b are each independently selected from the group consisting of hydrogen and Ci -4 alkyl, or R 3a and R 3b is taken together with the carbon to which both attached to form a cyclopropyl.
  • Embodiment 3 A compound, or a salt, tautomer or stereoisomer thereof, according to embodiment 1 , wherein L is selected from the group consisting of *-(CH 2 )-, *-CH 2 N(CH 3 )-, *- C(O)-, *-C(0)NH-, *-C(0)N(CH 3 )-, *-C(0)N(CH 2 CH 2 OCH 3 )-, *-C(0)N(CH 2 CH 2 NH 2 )-,
  • Embodiment 4 A compound, or a salt, tautomer or stereoisomer thereof, according to embodiment 1 , wherein L is selected from the group consisting of *-CH 2 N(CH 3 )-, *-C(0)NH-, *- C(0)N(CH 3 )-, *-C(0)N(CH 2 CH 2 OCH 3 )-, *-C(0)N(CH 2 CH 2 N(CH 3 ) 2 )-, *-C(0)N(CH 2 CH 2 NH 2 )-, *-C(0)N(CH 2 CH 2 -tetrahydropyran-4-yl)-, *-C(0)N(CH 2 CH 3 )-, *-C(0)N(CH(CH 3 ) 2 )-, *-NHCH 2 -, *-N(CH 3 )C(0)-, and *-N(CH 3 )S(0) 2 -.
  • L is selected from the group consisting of *-CH 2 N(CH 3 )-, *-C(0)NH-, *- C(0)N
  • Embodiment 5 A compound, or a salt, tautomer or stereoisomer thereof, according to embodiment 1 , wherein L is selected from the group consisting of *-CH 2 N(CH 3 )-, *-C(0)NH-, *- C(0)N(CH 3 )-, *-C(0)N(CH 2 CH 2 OCH 3 )-, *-C(0)N(CH 2 CH 2 NH 2 )-, *-C(0)N(CH 2 CH 3 )-,
  • Embodiment 6 A compound, or a salt, tautomer or stereoisomer thereof, according to embodiment 1 , wherein L is *-C(0)N(CH 3 )-..
  • Embodiment 7 A compound, or a salt, tautomer or stereoisomer thereof, according to embodiment 1 , wherein L is * -CH 2 N(CH 3 )-.
  • Embodiment 8 A compound, or a salt, tautomer or stereoisomer thereof, according to embodiment 1 , wherein L is * -(CH 2 )- or * -C(0)-.
  • Embodiment 9 A compound, or a salt, tautomer or stereoisomer thereof, according to any one of embodiments 1 to 8, wherein Ring A is C 6 -i 0 aryl or C 5 -i 0 heteroaryl.
  • Embodiment 10 A compound, or a salt, tautomer or stereoisomer thereof, according to any one of embodiments 1 to 8, wherein Ring A is selected from the group consisting of
  • Embodiment 1 A compound, or a salt, tautomer or stereoisomer thereof, according to any one of embodiments 1 to 8, wherein Ring A is selected from the group consisting of , each of which is unsubstituted or substituted with 1 to 2 R 1 groups PAT054787-WO-PCT
  • Embodiment 12 A compound, or a salt, tautomer or stereoisomer thereof, according to any one of embodiments 1 to 8, wherein Ring A is phenyl or pyridinyl, each of which is unsubstituted or substituted with 1 to 2 Ri groups.
  • Embodiment 13 A compound, or a salt, tautomer or stereoisomer thereof, according to any one
  • Ring A is of the formula Embodiment 14.
  • Ring A is of the formula Embodiment 15.
  • Ring A is of the formula
  • Embodiment 16 A compound, or a salt, tautomer or stereoisomer thereof, according to any one of embodiments 1 to 7 and 9 to 15, wherein Ring C is selected from the group consisting of phenyl, C &10 heteroaryl and C 5 -i 0 heterocycloalkyl.
  • Embodiment 17 A compound, or a salt, tautomer or stereoisomer thereof, according to any one of e
  • Embodiment 18 A compound, or a salt, tautomer or stereoisomer thereof, according to any one of embodiments 1 to 7 and 9 to 15, Ring C is selected from the group consisting of phenyl and pyridyl, each of which is unsubstituted or substituted with 1 to 2 R 17 groups.
  • Embodiment 19 A compound, or a salt, tautomer or stereoisomer thereof, according to any one
  • Ring C is of the formula:
  • Embodiment 20 A compound, or a salt, tautomer or stereoisomer thereof, according to any one
  • Ring C is of the formula: .
  • Embodiment 21 A compound, or a salt, tautomer or stereoisomer thereof, according to any one
  • Ring C is of the formula:
  • Embodiment 22 A compound, or a salt, tautomer or stereoisomer thereof, according to any one of embodiments 1 to 3 and 8 to 15, wherein Ring C is C 6 heterocycloalkyl or fused bicyclyl comprising a C 5 - 6 heterocycloalkyl fused to a phenyl, wherein the C 6 heterocycloalkyl and fused bicyclyl are each unsubstituted or substituted with 1 to 3 (R 17 ) group.
  • Embodiment 23 A compound, or a salt, tautomer or stereoisomer thereof, according to any one of embodiments 1 to 3 and 8 to 15, wherein Ring C is selected from the group consisting of
  • PAT054787-WO-PCT each of which is unsubstituted or substituted with 1 to 2 R 17 groups.
  • Embodiment 24 A compound, or a salt, tautomer or stereoisomer thereof, according to any one
  • Embodiment 25 A compound, or a salt, tautomer or stereoisomer thereof, according to any one of embodiments 1 to 24, wherein each R ⁇ is independently selected from the group consisting of fluoro, chloro, cyano, methyl, isopropyl, t-butyl, cyanopropyl, -CH(CH 3 )(OCH 3 ), trifluoromethyl, difluoromethyl, -CF 2 CH 3 , -C(CH 3 ) 2 CN, -CH 2 NH 2 , -CH 2 N(CH 3 ) 2 , -CH 2 -morpholinyl, methoxy, proproxy, isoproproxy, difluoromethoxy, trifluoromethoxy, -OCH 2 CF 3 , cyanomethoxy, 2- aminoethoxy, -0(CH 2 ) 2 N(CH 3 ) 2 , -OC(CH 3 ) 2 CH 2 NH 2 , -OC(CH 3 ) 2
  • Embodiment 26 A compound, or a salt, tautomer or stereoisomer thereof, according to any one of embodiments 1 to 24, wherein each R ⁇ is independently selected from the group consisting of -C(0)CH 3 , -C(0)OCH 3 , -C(0)NH 2 , -C(0)NHCH 3 , -C(0)N(CH 3 ) 2 , -C(0)N(CH 2 CH 3 ) 2 , - C(0)N(CH 3 )(OCH 3 ), -C(0)NH((CH 2 ) 2 N(CH 3 ) 2 ), -C(0)NH(cyclopropyl), and -C(0)NH(cyclohexyl).
  • Embodiment 27 A compound, or a salt, tautomer or stereoisomer thereof, according to any one of embodiments 1 to 24, wherein each R is independently selected from the group consisting of amino, methylamino, dimethylamino, -NH(OCH 3 ), -NH(CH 2 C(NH 2 )(CH 3 ) 2 ), - NH(C(CH 3 ) 2 CH 2 NH(C(0)OC(CH 3 ) 3 )), -NH(C(CH 3 ) 2 CH 2 NH 2 ), -NH((CH 2 ) 2 -morpholinyl), - PAT054787-WO-PCT
  • Embodiment 28 A compound, or a salt, tautomer or stereoisomer thereof, according to any one of embodiments 1 to 24, wherein each is independently selected from the group consisting of -S0 2 CH 3 , -S0 2 CH(CH 3 ) 2 , -S0 2 NH 2 , and -S0 2 N(CH 3 ) 2 .
  • Embodiment 29 A compound of the formula (I), or a salt, tautomer or stereoisomer thereof, according to any one of embodiments 1 to 24, wherein each is independently selected from the group consisting of
  • Embodiment 30 A compound, or a salt, tautomer or stereoisomer thereof, according to any one of embodiments 1 to 24, wherein each is independently selected from the group consisting of
  • Embodiment 31 A compound, or a salt, tautomer or stereoisomer thereof, according to any one of embodiments 1 to 24, wherein each is independently selected from the group consisting of
  • Embodiment 32 A compound, or a salt, tautomer or stereoisomer thereof, according to any one of embodiments 1 to 24, wherein each R ⁇ is independently selected from the group consisting of trifluoromethyl, -C(0)NH 2 , -C(0)NHCH 3 , -C(0)NH(CH 2 ) 2 N(CH 3 ) 2 , and -NHC(0)CH(NH 2 )- cycloalkyl.
  • Embodiment 33 A compound, or a salt, tautomer or stereoisomer thereof, according to any one of embodiments 1 to 24, wherein R ⁇ is trifluoromethyl.
  • Embodiment 34 A compound, or a salt, tautomer or stereoisomer thereof, according to any one of embodiments 1 to 24, wherein R ⁇ is -C(0)NH 2 .
  • Embodiment 35 A compound, or a salt, tautomer or stereoisomer thereof, according to any one of embodiments 1 to 24, wherein R ⁇ is -C(0)NHCH 3 .
  • Embodiment 36 A compound, or a salt, tautomer or stereoisomer thereof, according to any one of embodiments 1 to 35, wherein each R 17 is independently selected from the group consisting of fluoro, chloro, bromo, cyano, methyl, ethyl, t-butyl, trifluoromethyl, methoxymethyl, aminomethyl, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, phenoxy, oxo, dimethylamino, methylsulfonyl, and aminocarbonyl.
  • each R 17 is independently selected from the group consisting of fluoro, chloro, bromo, cyano, methyl, ethyl, t-butyl, trifluoromethyl, methoxymethyl, aminomethyl, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, phenoxy, oxo, dimethylamino,
  • Embodiment 37 A compound, or a salt, tautomer or stereoisomer thereof, according to any one of embodiments 1 to 35, wherein each R 17 is independently selected from the group consisting of -C(0)CH 3 , -C(0)NH 2 , methylsulfonyl, -S0 2 NH-thiazol-2-yl, and -S0 2 NH 2 .
  • Embodiment 38 A compound, or a salt, tautomer or stereoisomer thereof, according to any one of embodiments 1 to 35, wherein each R 17 is independently selected from the group consisting
  • Embodiment 39 A compound, or a salt, tautomer or stereoisomer thereof, according to any one of embodiments 1 to 35, wherein R 17 is cyano.
  • Embodiment 40 A compound, or a salt, tautomer or stereoisomer thereof, according to any one of embodiments 1 to 35, wherein R 17 is chloro.
  • Embodiment 41 A compound, or a salt, tautomer or stereoisomer thereof, according to any one of embodiments 1 to 35, wherein R 17 is fluoro.
  • Embodiment 42 A compound, or a salt, tautomer or stereoisomer thereof, according to any one of embodiments 1 to 35, wherein R 17 is methylsulfonyl.
  • Embodiment 43 A compound, or a salt, tautomer or stereoisomer thereof, according to any one of embodiments 1 -15 and 21 to 23, wherein each of the R i7 is independently selected from the group consisting of fluoro, chloro, bromo, cyano, methyl, methylsulfonyl, and aminocarbonyl.
  • R i7 is independently selected from the group consisting of fluoro, chloro, bromo, cyano, methyl, methylsulfonyl, and aminocarbonyl.
  • Embodiment 44 A compound, or a salt, tautomer or stereoisomer thereof, according to of embodiment 1 , wherein the compound is of Formula 1 A:
  • n 1 ;
  • p 1 ;
  • L is *-C(0)N(R 2 )- or *-CH 2 N(R 2 )-, wherein
  • R 2 is C 1 4 alkyl or Ro-C ⁇ alkylene, wherein R 0 is selected from the group consisting of C ⁇ alkoxy, amino, C ⁇ alkylamino, C 5 . 6 heteroaryl and C 5 . 6 heterocycloalkyl, wherein said C 5 . 6 heteroaryl and C 5 . 6 heterocycloalkyl are each independently
  • Ring A is pheny or pyridyl
  • Ring C is pheny or pyridyl
  • each R is trifluoromethyl, *-C(0)NH 2 , or *-C(0)NHCH 3 ;
  • each R 17 is chloro, fluoro, or cyano.
  • Embodiment 45 A compound, or a salt, tautomer or stereoisomer thereof, according to any one of embodiments 44, wherein L is *-C(0)N(CH 3 )-.
  • Embodiment 46 A compound, or a salt, tautomer or stereoisomer thereof, according to any one of embodiments 44, wherein L is * -CH 2 N(CH 3 )-.
  • Embodiment 47 A compound, or a salt, tautomer or stereoisomer thereof, according to any one
  • Ring A is of the formula:
  • Embodiment 48 A compound, or a salt, tautomer or stereoisomer thereof, according to any one
  • Ring A is of the formula:
  • Embodiment 49 A compound, or a salt, tautomer or stereoisomer thereof, according to any one
  • Ring A is of the formula:
  • Embodiment 50 A compound, or a salt, tautomer or stereoisomer thereof, according to any one
  • Ring C is of the formula:
  • Embodiment 51 A compound, or a salt, tautomer or stereoisomer thereof, according to any one
  • Ring C is of the formula:
  • Embodiment 52 A compound, or a salt, tautomer or stereoisomer thereof, according to any one
  • Ring C is of the formula:
  • Embodiment 53 A compound, or a salt, tautomer or stereoisomer thereof, according to embodiment 1 , wherein the compound is selected from the group consisting of:
  • 6-carboxamide N-(4-cyanophenyl)-N-methyl-3-[2-(propan-2-yl)-1 ,3-thiazol-4-yl]imidazo[1 ,2- a]pyrazine-6-carboxamide; N-(4-cyanophenyl)-N-methyl-3-(quinolin-6-yl)imidazo[1 ,2- a]pyrazine-6-carboxamide; N-(4-cyanophenyl)-3-[4-(cyclopropylcarbamoyl)phenyl]-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N-(3,4-difluorophenyl)-3-[4-[4-
  • 6-carboxamide 3-[4-(dimethylamino)phenyl]-N-(4-methanesulfonylphenyl)-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4-cyanophenyl)-3-[4-(2,5-dioxoimidazolidin-4- yl)phenyl]-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; methyl 4- ⁇ 6-[(4- cyanophenyl)(methyl)carbamoyl]imidazo[1 ,2-a]pyrazin-3-yl ⁇ benzoate; N-(4-cyanophenyl)-3-
  • 6-carboxamide 4-fluoro-N-methyl-N- ⁇ 3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6- yl ⁇ piperidine-1 -carboxamide; N-(4-cyanophenyl)-3-(6-methanesulfonamidopyridin-3-yl)-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide; 3- ⁇ 4-[(1 -amino-2-methylpropan-2- yl)amino]phenyl ⁇ -N-(4-cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; 3-(1 - benzofuran-5-yl)-N-(6-chloropyridin-3-yl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N- methyl-N-(pyridin-3
  • Embodiment 54 A compound, or a salt, tautomer or stereoisomer thereof, according to embodiment 1 , wherein the compound is selected from the group consisting of: 3-(4- carbamoylphenyl)-N-(4-fluorophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4- cyanophenyl)-N-methyl-3-[4-(methylcarbamoyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4-cyanophenyl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; 4-[methyl( ⁇ 3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl ⁇ methyl)amino]benzonitrile; 4- (6- ⁇ [(
  • Embodiment 55 A pharmaceutical composition comprising at least one compound of any one of embodiments 1 to 54, or a pharmaceutically acceptable salt, or stereoisomer, thereof, and a pharmaceutically acceptable carrier, diluent or excipient.
  • Embodiment 56 A pharmaceutical composition according to embodiment 55 further comprising a second agent.
  • Embodiment 57 A pharmaceutical composition according to embodiment 56, wherein the second agent is an antimalarial drug selected from artemisinin, artemether, artesunate, arteflene, dihydroartemisinin, chlorproguanil, trimethoprim, chloroquine, quinine, mefloquine, amodiaquine, atovaquone, proguanil, lumefantrine, piperaquine, pyronaridine, halofantrine, pyrimethamine-sulfadoxine, quinacrine, pyrimethamine-dapsone, quinidine, amopyroquine, sulphonamides, primaquine, ferroquine, tafenoquine, arterolane, and pyronaridine.
  • an antimalarial drug selected from artemisinin, artemether, artesunate, arteflene, dihydroartemisinin, chlorproguanil, trimethoprim, chloroqu
  • Embodiment 58 A compound according to any one of embodiments 1 to 54 or a
  • compositions according to any one of embodiments 55 to 57 for use as a medicament.
  • Embodiment 59 A method for treating, preventing, inhibiting, ameliorating, or eradicating the pathology and/or symptomology of a disease caused by a Plasmodium parasite, comprising administering to a subject a therapeutically effective amount of a compound according to any one of the embodiments 1 to 54 or a composition according to any one of the embodiments 55 to 57, wherein the administering may be in combination with a second agent.
  • Embodiment 60 A method for treating, preventing, inhibiting, ameliorating, or eradicating the pathology and/or symptomology of a disease caused by a Plasmodium parasite, according to embodiment 59, wherein the disease is malaria.
  • Embodiment 61 A method for treating, preventing, inhibiting, ameliorating, or eradicating the pathology and/or symptomology of a disease caused by a Plasmodium parasite according to any one of embodiments 59 to 60, wherein the Plasmodium parasite is at the blood stages.
  • Embodiment 62 A method for treating, preventing, inhibiting, ameliorating, or eradicating the pathology and/or symptomology of a Plasmodium related disease caused by a Plasmodium parasite according to any one of embodiments 59 to 60, wherein the Plasmodium parasite is at the hepatic stages.
  • Embodiment 63 A method for treating, preventing, inhibiting, ameliorating, or eradicating the pathology and/or symptomology of a Plasmodium related disease caused by a Plasmodium parasite according to any one of embodiments 59 to 62, wherein the Plasmodium parasite is selected from group consisting of Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, and Plasmodium malaria.
  • Embodiment 64 A method for treating, preventing, inhibiting, ameliorating, or eradicating the pathology and/or symptomology of a Plasmodium related disease caused by a Plasmodium parasite according to any one of embodiments 59 to 62, wherein the Plasmodium parasite is Plasmodium falciparum.
  • Embodiment 65 A method for treating, preventing, inhibiting, ameliorating, or eradicating the pathology and/or symptomology of a Plasmodium related disease caused by a Plasmodium parasite according to any one of embodiments 59 to 64, wherein the second agent is selected from a kinase inhibitor, an anti-malarial drug and an anti-inflammatory agent.
  • Embodiment 66 A method for treating, preventing, inhibiting, ameliorating, or eradicating the pathology and/or symptomology of a disease caused by Plasmodium parasite according to embodiment 65, wherein the anti-malarial drug is selected from artemisinin, artemether, artesunate, arteflene, dihydroartemisinin, chlorproguanil, trimethoprim, chloroquine, quinine, mefloquine, amodiaquine, atovaquone, proguanil, lumefantrine, piperaquine, pyronaridine, halofantrine, pyrimethamine-sulfadoxine, quinacrine, pyrimethamine-dapsone, quinidine,
  • the anti-malarial drug is selected from artemisinin, artemether, artesunate, arteflene, dihydroartemisinin, chlorproguanil, trimethoprim, chloroquine, quinine, me
  • 8i PAT054787-WO-PCT amopyroquine, sulphonamides, primaquine, ferroquine, tafenoquine, arterolane, and pyronaridine.
  • Embodiment 67 A method for treating, preventing, inhibiting, ameliorating, or eradicating the pathology and/or symptomology of a disease caused by Plasmodium parasite according to any one of embodiments 59 to 66, wherein the compound is administered prior to, simultaneously with, or after the second agent.
  • Embodiment 68 A compound according to any one of embodiments 1 to 54 or a composition according to any one of embodiemnts 55 to 57 for treating, preventing, inhibiting, ameliorating, or eradicating the pathology and/or symptomology of a disease caused by a Plasmodium parasite.
  • Embodiment 69 Use of a compound according to any one of embodiments 1 -54 or a pharmaceutical composition according to embodiments 55 to 57 in the manufacture of a medicament for treating, preventing, inhibiting, or ameliorating the pathology and/or
  • symptomology of a disease caused by a Plasmodium parasite wherein said use may be in combination with a second agent.
  • 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)-.
  • 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.
  • salt refers to an acid addition or base addition salt of a compound of the invention.
  • Salts include in particular “pharmaceutical acceptable salts”.
  • pharmaceutically acceptable salts refers to salts that retain the biological effectiveness and properties of the compounds of this invention and, which typically are not biologically or otherwise undesirable.
  • 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.
  • Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids, e.g., acetate, aspartate, benzoate, besylate, bromide/hydrobromide,
  • chlortheophyllonate citrate, ethandisulfonate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hydroiodide/iodide, isethionate, lactate, lactobionate, laurylsulfate, malate, maleate, malonate, mandelate, mesylate, methylsulphate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen PAT054787-WO-PCT phosphate, polygalacturonate, propionate, stearate, succinate, subsalicylate, tartrate, tosylate and trifluoroacetate salts.
  • Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,
  • compositions can be formed with inorganic and organic bases.
  • Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I to XII of the periodic table.
  • the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper;
  • particularly suitable salts include ammonium, potassium, sodium, calcium and magnesium salts.
  • Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like.
  • Certain organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine and tromethamine.
  • 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., PAT054787-WO-PCT
  • 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.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 F 31 P, 32 P, 35 S, 36 CI, 125 l respectively.
  • the invention includes various isotopically labeled compounds as defined herein, for example those into which radioactive isotopes, such as 3 H and 14 C, or those into which nonradioactive isotopes, such as 2 H and 13 C are present.
  • isotopically labelled compounds are useful in metabolic studies (with 14 C), reaction kinetic studies (with, for example 2 H or 3 H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients.
  • PET positron emission tomography
  • SPECT single-photon emission computed tomography
  • an 18 F or labeled compound may be particularly desirable for PET or SPECT studies.
  • 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.
  • isotopic enrichment factor means the ratio between the isotopic abundance and the natural abundance of a specified isotope.
  • a substituent in a compound of this invention is denoted deuterium, such compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium PAT054787-WO-PCT incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).
  • solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D 2 0, d 6 -acetone, d 6 -DMSO.
  • 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.
  • the invention further provides co-crystals comprising a compound of formula (I).
  • the term "pharmaceutically acceptable carrier” includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drug stabilizers, binders, excipients, disintegration agents, lubricants, sweetening agents, flavoring agents, dyes, and the like and combinations thereof, as would be known to those skilled in the art (see, for example, Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289- 1329). Except insofar as any conventional carrier is incompatible with the active ingredient, its use in the therapeutic or pharmaceutical compositions is contemplated.
  • 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.
  • a therapeutically effective amount PAT054787-WO-PCT 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
  • 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.
  • the term "subject" refers to an animal. Typically the animal is a mammal. A subject also refers to for example, primates ⁇ e.g., humans, male or female), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like. In certain embodiments, the subject is a primate. In yet other embodiments, the subject is a human.
  • the term “inhibit”, “inhibition” or “inhibiting” refers to the reduction or
  • the term “treat”, “treating” or “treatment” of any disease or disorder refers in one embodiment, to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof).
  • “treat”, “treating” or “treatment” refers to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient.
  • “treat”, “treating” or “treatment” refers to modulating the disease or disorder, either physically, ⁇ e.g., stabilization of a discernible symptom), physiologically, ⁇ e.g., stabilization of a physical parameter), or both.
  • “treat”, “treating” or “treatment” refers to preventing or delaying the onset or development or progression of the disease or disorder.
  • a subject is "in need of” a treatment if such subject would benefit biologically, medically or in quality of life from such treatment.
  • 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.
  • 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 c/ ' s- (Z)- or trans- (£)- form.
  • 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 (c/ ' s or trans) isomers, diastereomers, optical isomers (antipodes), racemates or mixtures thereof.
  • Any resulting mixtures of isomers can be separated on the basis of the physicochemical differences of the constituents, into the pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and/or fractional crystallization.
  • Any resulting racemates of final products or intermediates can be resolved into the optical antipodes by known methods, e.g., by separation of the diastereomeric salts thereof, obtained with an optically active acid or base, and liberating the optically active acidic or basic compound.
  • a basic moiety may thus be employed to resolve the compounds of the present invention into their optical antipodes, e.g., by fractional crystallization of a salt formed with an PAT054787-WO-PCT optically active acid, e.g., tartaric acid, dibenzoyl tartaric acid, diacetyl tartaric acid, d ⁇ -0,0'-p- toluoyl tartaric acid, mandelic acid, malic acid or camphor-10-sulfonic acid. Racemic products can also be resolved by chiral chromatography, e.g., high pressure liquid chromatography (HPLC) using a chiral adsorbent.
  • HPLC high pressure liquid chromatography
  • the compounds of the present invention 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
  • solvate refers to a molecular complex of a compound of the present invention (including pharmaceutically acceptable salts thereof) with one or more solvent molecules.
  • 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.
  • 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.
  • the present invention also includes processes for the preparation of compounds of the invention.
  • 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 .
  • the compounds of formula (I) can be prepared according to Schemes 1 -5 provided infra., where variables Ring A, Ring B, Ring C, L, R 1 ; R 15 , Ri 6 , R17, n, p and 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. PAT054787-WO-PCT
  • Ar A and Ar G represent rings A and C respectively in formula I PAT054787-WO-PCT
  • Ar A and Ar c represent rings A and C in formula I, respectively
  • Ar A and Ar c represent rings A and C in Formula I, respectively.
  • Ar A and Ar G represent rings A and C in Formula I, respectively.
  • Scheme 4. Direct arylation to introduce ring A.
  • Ar A and Ar c represent rings A and C in Formula I, respectively.
  • Ar A and Ar c represent rings A and C in Formula I, respectively.
  • 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 are useful in the treatment and/or prevention of infections such as those caused by Plasmodium falciparum; Plasmodium vivax; Plasmodium ovale; and PAT054787-WO-PCT
  • the parasite undergoes two main phases of development, the hepathocytic and erythrocytic phases, but it is the erythrocytic phase of its life cycle that causes severe pathology.
  • the erythrocytic phase the parasite goes through a complex but well synchronized series of stages, suggesting the existence of tightly regulated signaling pathways.
  • Plasmodium spp. genomes reveal many sequence identities with calcium binding/sensing protein motifs that include Pf39, calmodulin, and calcium dependent protein kinases (CDPKs).
  • Plasmodium CDPKs, Plasmodium CDPK3 and 4 have been shown to be involved in mosquito infection.
  • CDPK4 has been demonstrated to be essential for the sexual reproduction in the midgut of mosquito by translating the calcium signal into a cellular response and regulating cell cycle progression in the male gametocyte.
  • CDPK3 regulates ookinete gliding motility and penetration of the layer covering the midgut epithelium. P.
  • PfCDPKI falciparum CDPK1
  • PfCDPKI falciparum CDPK1
  • kinase activity is distributed in all the stages of P. falciparum parasite maturation and kinase inhibitors of the present invention can be used for treating Plasmodium related diseases.
  • the in vitro cellular assay, infra can be used to assess the activity of compounds of the invention against a variety of malarial parasite strains.
  • the present invention further provides a method for preventing or treating malaria in a subject in need of such treatment, which method comprises
  • a therapeutically effective amount of a compound selected from Formula I and la or a pharmaceutically acceptable salt thereof is administered to said subject a therapeutically effective amount of a compound selected from Formula I and la 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.
  • 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
  • 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 e
  • disintegrants e.g., starches, agar, alginic acid or its sodium salt, or e
  • 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.
  • 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).
  • therapeutic agents pharmaceutical agents
  • Non-limiting examples of compounds which can be used in combination with compounds of the invention are known anti-malarial drugs, for example, artemisinin, artemether, artesunate, arteflene, dihydroartemisinin, chlorproguanil, trimethoprim, chloroquine, quinine, mefloquine,
  • 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
  • the kit can comprise instructions for its administration.
  • 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.
  • pharmaceutical combination 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.
  • 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.
  • 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.
  • cocktail therapy e.g. the administration of 3 or more active ingredients.
  • the activity of a compound according to the present invention for inhibition of parasitemai in infected blood cells and liver cells can be assessed by the following assays. It is understood that the assays illustrate the invention without in any way limiting the scope of the invention.
  • Compounds of the invention can be assayed to measure their capacity to inhibit proliferation of P. falciparum parasitemia in infected red blood cells.
  • This parasite proliferation assay measures the increase in parasite DNA content using a DNA intercalating dye, SYBR Green ®
  • NF54 or 3D7 P falciparum strain is grown in complete culturing media until parasitemia reaches 3% to 8% with 0+ human erythrocytes. The selection of either strain is of convenience (3D7 is a clone of NF54) and does not make a difference to the assay. 20 ⁇ of screening media is dispensed into 384 well assay plates. 50 nl of compounds of the invention (in DMSO), including antimalarial controls (mefloquine, pyrimethamine and artemisinin), are then transferred into the assay plates, as well as DMSO alone to serve as a negative control for inhibition. Then 30 ⁇ of a suspension of a NF54 or 3D7 P.
  • falciparum infected erythrocytes in screening media is dispensed into the assay plates such that the final hematocrit is 2.5% with a final parasitemia of 0.3%.
  • the plates are placed in a 37 S C incubator for 72 hours in a low oxygen environment containing 93% N 2 , 4% C0 2 , and 3% 0 2 gas mixture.
  • 10 ⁇ of lysis buffer (saponin, triton-X, EDTA) containing a 10X solution of SYBR Green I ® in RPMI media is dispensed into the plates.
  • the plates are lidded and kept at room temperature overnight for the lysis of the infected red blood cells.
  • the fluorescence intensity is measured (excitation 425nm, emission 530nm) using the EnvisionTM system (Perkin Elmer).
  • the percentage inhibition of 50%, EC 50 is calculated for each compound.
  • compounds of the invention exhibit inhibitory efficacy (EC 50 ) of typically 10 ⁇ or less, more typically less than 2 ⁇ , most typically less than 200 nM.
  • inhibitory efficacy typically 10 ⁇ or less, more typically less than 2 ⁇ , most typically less than 200 nM.
  • Compounds of the invention can significantly delay the increase in P. falciparum parasitemia.
  • a]pyrazine-6-carboxamide (Example 483), and 3-(4-carbamoylphenyl)-N-(4-chlorophenyl)-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide (Example 486), all have EC50 values of less than 50 nM.
  • Compounds of the invention can be assayed to measure their capacity to inhibit proliferation of parasites in liver cells.
  • the proliferation is quantified by determine the number of infected cells by immunofluorescence.
  • HepG2-A16-CD81 EGFP A transgenic HepG2 cell line expressing the tetraspanin CD81 receptor (HepG2-A16-CD81 EGFP ) is used to increase the infectivity rate of rodent-malaria sporozoites into human cells.
  • HepG2- A16-CD81 EGFP cells are stably transformed to express a GFP-CD81 fusion protein.
  • CM complete media
  • HepG2-A16-CD81 EGFP cells are seeded into 384-well plates (Aurora 384 IQ-EB black plates with clear bottoms; 50 ⁇ of
  • Freshly dissected salivary glands from infected mosquitoes were homogenized in a glass tissue grinder, filtered twice through Nylon cell strainers (40 ⁇ pore size, BD Falcon) and counted using a hemocytometer.
  • the assay plate with HepG2-A16-CD81 EGFP cells and compound were then infected with 8x10 3 sporozoites per well and the plates are subjected to a centrifugal force of 650x0 to pellet the sporozoites onto the liver cell monolayer.
  • the assay plate is incubated at 37 °C for 2 hours to permit sporozoite invasion, then the media is aspirated from the media plate, and replaced with 50 ⁇ CM (containing a 5x concentration of penicillin/streptomycin; 500 units penicillin and 0.5 mg streptomycin per ml) per well. 50 nl of compound is re-introduced by PinTool and the assay plate incubated for 48 hours at 37 °C before quantification of infected PAT054787-WO-PCT cells by immunofluorescence. The increased antibiotic concentration does not interfere with the parasite or HepG2-A16-CD81 EGFP growth.
  • Atovaquone and uninfected wells were used as controls on each plate. Two replicate plates are tested for each assay.
  • EEFs were stained using a mouse polyclonal serum raised against the Plasmodium yoelii heal shock protein 70 (PyHSP70), a DyLight 649 goat anti-mouse IgG, Fc(gamma) fragment specific secondary antibody (Jackson Immuno Research, Cat# 1 15-495-071 ) and the Hoechst 33342 nucleic acid dye (Invitrogen, Carlsbad, USA). Stained EEFs were then quantified using the Opera Confocal High Content Screening System (PerkinElmer, Waltham, USA).
  • Images were collected using a 20x objective lens (20x/0.45 NA, LWD Plan Fluor, Olympus) at a binning of 2, using a 365 nm Xeon arc lamp illumination to detect the Hoechst-labeled nuclei and 635 nm laser line to excite Dyl_ight649- labeled parasites.
  • the image resolution yielded was approximately 0.66 ⁇ /pixel (- ⁇ .43 ⁇ 2/pixel). All images were analyzed using a custom AcapellaTM (PerkinElmer) script
  • compounds of the invention exhibit inhibitory efficacy (EC 50 ) of typically 1 ⁇ or less, more typically 200 nM less.
  • Selected compounds for io8 PAT054787-WO-PCT example, 4-[methyl( ⁇ 3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6- yl ⁇ methyl)amino]benzonitrile (Example 213); 4-(6- ⁇ [(4- fluorophenyl)(methyl)amino]methyl ⁇ imidazo[1 ,2-a]pyrazin-3-yl)benzamide (Example 222), 4-(6- ⁇ [(4-cyanophenyl)(methyl)amino]methyl ⁇ imidazo[1 ,2-a]pyrazin-3-yl)benzamide (Example 223); N-(4-chlorophenyl)-N-methyl-3-[4
  • 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.
  • MS Scan 100 to l OOOamu in 0.5 seconds per channel; Diode Array Detector: 190nm and 400nm; Drift tube temperature: 50 °C and N2 gas flow:40Psi for ELSD Detector.
  • Agilent 1 10Osl/ 1946 system UPLC Column: Waters atlantis; C18 1 .8um 50x2.0 mm ; Mobile Phase: (A) H 2 0 + 0.05%TFA and (B) Acetonitrile + 0.035%TFA. Gradient: 1 .0 mL/minute, initial 10% B ramp to 90 % B over 3.00 minutes, then return to 10% B at 3.5 minutes until end of run, MS Scan: 100 to 1000amu in 0.5 seconds per channel; Diode Array Detector: 190 nm and 400nm; Drift tube temperature: 50°C and N2 gas flow:40Psi for ELSD Detector.
  • Analytical method WATERS ZQ SHIMADZU LEAP CTC, ZORBAX SB-C8 30*4.6mm,3.5um, UV1 :220nm, UV2:254nm, A:H 2 O(0.03%TFA), B:CH 3 CN(0.05%TFA), Flow:2.000 (ml/min), Time/%B: 0/5, 1.90/95, 2.30/95, 2.31 /5, 2.50/5
  • the aqueous solution was extracted with ethyl acetate (3 x 3.0 mL). The organic extracts were combined and washed with Dl water (2 x 2.0 mL) and brine (2 x 2.0 mL). The organic solution was dried over MgS0 4 and purified by flash chromatography (silica, 20-100% ethyl
  • Pd-DPP Pallidium diphenylphosphine supported on silica, silicycle
  • 200 mg was added to a mixture of 3-bromoimidazo[1 ,2-a]pyrazine-6-carboxylate (500 mg, 1 .86 mmol), 4- trifluoromethylbenzene boronic acid (349 mg, 1 .86 mmol), Na 2 C0 3 (623 mg, 7.42 mmol), tetrahydrofuran (12 mL) and Dl water (3.0 mL).
  • the reaction was heated in a microwave reactor at 150 °C for 1 hour. After cooling to room temperature, the solvent was removed in vacuo.
  • the crude material was purified by flash chromatography to give I-5 as a white solid (silica, 25-100% ethyl acetate/hexanes).
  • Oxalyl chloride (0.050 mL, 0.59 mmol) was added dropwise to a solution of 3-(4- (trifluoromethyl)phenyl)imidazo[1 ,2-a]pyrazine-6-carboxylic acid (50 mg, 0.16 mmol), DMF (2 drops) and dichloromethane (2.0 mL). After 30 minutes at room temperature, the solvent was removed. The reaction remained on the high vacuum pump for 60 minutes. Fresh dichloromethane (2.0 mL) was added, followed by a solution of N-methylamine (0.30 mL, 0.587 mmol). Triethylamine (0.15 mL, 1.1 mmol) was added and the reaction stirred at room temperature for 1 hour. The reaction was purified by flash chromatography to give I-9 as a white solid (silica, 50-100% ethyl acetate/hexanes).
  • Oxalyl chloride (0.083 mL of a 2.0M solution in dichloromethane) was added drop wise to a solution of 3-bromoimidazo[1 ,2-a]pyrazine-6-carboxylic acid (200 mg, 0.833 mmol), DMF (2 drops) and dry dichloromethane (5.0 mL) at room temperature (gas evolution). After 30 minutes at room temperature, the solvent was removed in vacuo. The crude acid chloride was dissolved in dry dichloromethane (5.0 mL) and a solution of 4-(methylamino)chlorobenzene (235 mg, 1 .670 mmol in 2.0 mL of dichloromethane) was added drop wise at room temperature.
  • oxadiazole derivative 600 mg, 2.51 mmol, 1.0 eq.
  • bispinacolotodiboron 637.5 mg, 2.51 mmol, 1.0 eq.
  • Pd(dppf)CI 2 204.9 mg, 0.251 mmol, 0.1 eq.
  • potassium acetate 1 .47 gm, 15.06 mmol, 6.0 eq.
  • bromo derivative 250 mg, 1 .13 mmol, 1 .0 eq.
  • bispinacolotodiboron 288.6 mg, 1.13 mmol, 1 .0 eq.
  • Pd(dppf)CI 2 92.7 mg, 0.1 14 mmol, 0.1 eq.
  • potassium acetate 354.5 mg, 3.41 mmol, 3.0 eq.
  • bromo derivative 250 mg, 1 .1 1 mmol, 1 .0 eq.
  • bispinacolotodiboron (288.6 mg, 1.1 1 mmol, 1 .0 eq.)
  • Pd(dppf)CI 2 90.7 mg, 0.1 1 1 mmol, 0.1 eq.
  • potassium acetate 327.5 mg, 3.331 mmol, 3.0 eq.
  • bromo derivative (236 mg, 1 .06 mmol, 1 .0 eq.)
  • bispinacolotodiboron 253.6 mg, 1.06 mmol, 1 .0 eq.
  • Pd(dppf)CI 2 86.4 mg, 0.106 mmol, 0.1 eq.
  • potassium acetate 321 .8 mg, 3.17mmol, 3.0 eq.
  • the boronic ester was synthesized from the corresponding bromide using a protocol as described in the synthesis of I-24.
  • 2-methoxyethanamine 300 mg, 4.00 mmol was added to a mixture of 4-fluorobenzonitrile (250 mg, 2.07 mmol), cesium carbonate (750 mg, 2.30 mmol) and DMSO (4.0 mL). The reaction was heated to 60 °C for 4 hours. After cooling to room temperature, the reaction was diluted with water. The aqueous solution was extracted with ethyl acetate (3 x 15 mL). The combined extracts were dried over MgS0 4 and concentrated. The crude residue was purified by flash chromatography (silica, 0-10% methanol/dichloromethane) to give 4-((2- methoxyethyl)amino)benzonitrile (I-30) as a white solid.
  • a flask was charged with bromobenoxazine and CuCN. The flask was evacuated and refilled with nitrogen three times. The flask was evacuated once more, sealed, and heated to 150 °C for 6 hours. The reaction was cooled to room temperature. 1 mL of 10% FeCI 3 in water was added followed by 1 mL of ethyl acetate. The reaction mixture was stirred for 10 minutes and then filtered through celite. The filtrate was further diluted with water and extracted with EtOAc (3x). The combined organic extracts were again filtered through celite. The filtrate was dried over MgS0 4 and concentrated to a black oil. TLC analysis showed two major spots, with the top spot corresponding to the starting material and the lower spot corresponding to the product.
  • the compound was synthesized using a protocol described for the synthesis of 1-15.
  • Trifluorobenzenamine (3.2 g, 24.81 mmol, 3.00 equiv), triethylamine (10 g, 99.01 mmol, 1 1 .98 equiv) was added. The resulting solution was allowed to react, with stirring, overnight at room temperature. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1 :2-1 :1 ). This resulted in 1.6 g (55%) of 3-bromo-N- (3,4-difluorophenyl)imidazo[1 ,2-a]pyrazine-6-carboxamide as a white solid.
  • the compound was synthesized using a protocol as described for I-64.
  • the compound was synthesized using a protocol as described for I-58.
  • Step 1 3-Chloro-N-(4-fluorophenyl)prop
  • Step 2 6-Fluoro-3,4-dihvdroquinolin-2(1 H)-one PAT054787-WO-PCT
  • Step 3 6-Fluoro-1 ,2,3,4-tetrahvdroquinoline
  • the compound was synthesized using a protocol described for the synthesis of 1-71 using the intermediate I-69.
  • the compound was synthesized using a protocol described for the synthesis of 1-71 using the intermediate I-73.
  • the compound was synthesized using a protocol described for the synthesis of I-65 using the intermediate I-37.
  • the compound was synthesized using a protocol described for the synthesis of 1-15.
  • the compound was synthesized using a protocol described for the synthesis of 1-15.
  • the compound was synthesized using a protocol described for the synthesis of 1-15.
  • the compound was synthesized using 1-15 and an appropriate boronic acid/ester using ;

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Abstract

The present invention provides compounds of formula I: [INSERT FORMULA HERE] 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, such as malaria, caused by a Plasmodium parasite.

Description

PAT054787-WO-PCT
COMPOUNDS AND COMPOSITIONS FOR THE TREATMENT OF PARASITIC DISEASES
CROSS-REFERENCED TO RELATED APPLICATIONS
This application claims the benefit of priority to U.S. Provisional Patent Application Number 61 /728,024, filed 19 November 2012, the full disclosure of which is expressively incorporated herein by reference in its entirety and for all purposes.
BACKGROUND OF THE INVENTION
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 malaria.
Background
Malaria is an infectious disease caused by four protozoan parasites: Plasmodium falciparum; Plasmodium vivax; Plasmodium ovale; and Plasmodium malaria. These four parasites are typically transmitted by the bite of an infected female Anopheles mosquito. Malaria is a problem in many parts of the world and over the last few decades the malaria burden has steadily increased. An estimated 1 -3 million people die every year from malaria - mostly children under the age of 5. This increase in malaria mortality is due in part to the fact that Plasmodium falciparum, the deadliest malaria parasite, has acquired resistance against nearly all available antimalarial drugs, with the exception of the artemisinin derivatives. Further for true causal prophylaxis and interrupt transmission of the disease, prevention of liver stage development is crucial, because development of the proceeding infectious blood stage gametocytes would be block. A single drug effective against hepatichypnozoites, primaquine, is available, but its deployment is curtailed by its potential side effects.
Leishmaniasis is caused by one or more than 20 varieties of parasitic protozoa that belong to the genus Leishmania, and is transmitted by the bite of female sand flies. Leishmaniasis is endemic in about 88 countries, including many tropical and sub-tropical areas. PAT054787-WO-PCT
There are four main forms of Leishmaniasis. Visceral leishmaniasis, also called kala-azar, is the most serious form and is caused by the parasite Leishmania donovani. Patients who develop visceral leishmaniasis can die within months unless they receive treatment. 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.
Human African Trypanosomiasis, also known as sleeping sickness, is a vector-borne parasitic disease. The parasites concerned are protozoa belonging to the Trypanosoma Genus. They are transmitted to humans by tsetse fly (Glossina Genus) bites which have acquired their infection from human beings or from animals harboring the human pathogenic parasites.
Chagas disease (also called American Trypanosomiasis) is another human parasitic disease that is endemic amongst poor populations on the American continent. The disease is caused by the protozoan parasite Trypanosoma cruzi, which is transmitted to humans by blood-sucking insects. The human disease occurs in two stages: the acute stage, which occurs shortly after infection and the chronic stage, which can develop over many years. Chronic infections result in various neurological disorders, including dementia, damage to the heart muscle and sometimes dilation of the digestive tract, as well as weight loss. Untreated, the chronic disease is often fatal.
The drugs currently available for treating Chagas disease are Nifurtimox and benznidazole. However, problems with these current therapies include their diverse side effects, the length of treatment, and the requirement for medical supervision during treatment. Furthermore, treatment is really only effective when given during the acute stage of the disease. 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. PAT054787-WO-PCT
SUMMARY OF THE INVENTION
The invention therefore provides a compound of formula (I):
Figure imgf000004_0001
or a pharmaceutical acceptable salt, tautomer or stereoisomer thereof, wherein
n is 0, 1 or 2;
p is 0, 1 , 2 or 3;
Ring A is selected from the group consisting of C6.10aryl, C5.10heteroaryl and fused bicyclyls comprising a C5.6heterocycloalkyl fused to a phenyl;
Ring B represents the imidazo[1 ,2-a]pyrazine fused ring depicted in Formula 1 ;
Ring C is selected from the group consisting of phenyl, C5-i0heteroaryl, C5-6cycloalkyl, C5-6heterocycloalkyl, and fused bicyclyl comprising a C5-6heterocycloalkyl fused to a phenyl;
L is selected from the group consisting of *-CH2N(R2)-, *-C(0)-, *-C(0)N(R2)-, *-C(0)N(R2)C(R3a)(R3bh *-N(R2)C(R3a)(R3b)-, *-N(R2)C(0)-, *-N(R2)S02-, and Ci-6alkylene, wherein
* represents the point of attachment of L to Ring B;
R2 is selected from the group consisting of hydrogen, d-4alkyl and R0-Ci-4alkylene, wherein R0 is selected from the group consisting of Ci-4alkyl, Ci_ 4alkoxy, amino, Ci-4alkylamino, C5-6heteroaryl and Cs-eheterocycloalkyl, wherein the C5-6heteroaryl and C5-6heterocycloalkyl of R0 are each unsubstituted or substituted with 1 to 2 substituents independently selected from the group consisting of Ci-4alkyl, halo and amino;
R3a and R3b are each independently selected from the group consisting of hydrogen and C1-4alkyl, or R3a and R3b is taken together with the carbon to which both attached to form a cyclopropyl;
each R† is independently selected from the group consisting of halo, cyano, -OR4, - C(0)R5, -C(0)NR6R7, -NR8R9, -NHC(O)R10, -NHS02Rn, -S02R12, C1-6alkyl, phenyl, C5_ gheteroaryl, and C4.6heterocycoalkyl, wherein PAT054787-WO-PCT R4 is C -6alkyl or phenyl, wherein the d_6alkyl is unsubstituted or substituted by 1 to 3 substituents independently selected from the group consisting of halo, cyano, d-4alkyl, amino, di-Ci-4alkylamino, and -C(0)NH2);
R5 is hydrogen, Ci-6alkyl or Ci-6alkoxy;
R6, R8 and Rn are each independently hydrogen or d-4alkyl;
R7 and Rg are each independently selected from the group consisting of hydrogen, Ci-4alkyl, Ci-4alkoxy, and C3-6cycloalkyl, wherein the Ci-4alkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of amino, Ci.4alkyl, Ci-4alkylamino, di-Ci-4alkylamino, Ci.
4alkoxycarbonylamino, and C5-6heterocycloalkyl;
Rio is Ci-6alkyl, d.6alkoxy or C3-6cycloalkyl, wherein the Ci-6alkyl of Ri0 is unsubstituted or substituted by 1 -2 substituents independently selected from amino and C3-6cycloalkyl, and the C3.6cycloalkyl of R10 is unsubstituted or substituted by 1 to 2 substituents independently selected from the group consisting of amino and amino- C1-4alkyl,
R12 is C1-4alkyl, amino or C^alkylamino,
the Ci_6alkyl of is unsubstituted or substituted with 1 -3 substituents independently selected from the group consisting of halo, cyano, methoxy, amino, C^alkylamino, C5.6cycloalkyl, and phenyl; and
the phenyl, C5.6heteroaryl and C3.6heterocycoalkyl of are each independently unsubstituted or substituted with 1 to 2 substituents independently selected from the grounp consisting of Ci-4alkyl, amino, Ci.4alkylamino, -C(0)CH3, and benzyl;
Ri5 and Ri6 are each independently hydrogen, Ci-4alkyl or haloCi_4alkyl;
each R17 is independently selected from the group consisting of cyano, halo, oxo, ORi8, -C(0)Ri9, -NR20R2i, -S02R22, -S02NHR23, Ci-4alkyl, phenyl, C5-9heteroaryl, C3.
ecycloalkyl and C4-6heterocycloalkyl, wherein
Ri8 is selected from the group consisting of hydrogen, Ci-4alkyl, haloCi-4alkyl and phenyl;
Rig is selected from the group consisting of hydrogen, d_4alkyl, amino, and d_4alkylamino;
R20, R2i and R22 are each independently hydrogen or d_4alky; PAT054787-WO-PCT
R23 is hydrogen, C^alkyl, or C5-6heteroaryl
the Ci-4alkyl of R17 is unsubstituted or substituted with 1 -3 substituents independently selected from the group consisting of halo, d-4alkoxy and amino; and the phenyl, C5-gheteroaryl, C3-6cycloalkyl and C4-6heterocycloalkyl of Ri7 are each independently unsubstituted or substituted by 1 to 2 substituents independently selected from the group consisting of Ci-4alkyl, halo-Ci-4alkyl, Ci-4alkoxy-Ci-4alkyl, and Ci-4alkoxy.
the Ci-4alkyl of Ri7 is unsubstituted or substituted with 1 -3 substituents independently selected from the group consisting of halo, Ci.4alkoxy and amino; and the phenyl, C5-9heteroaryl, C3-6cycloalkyl and C4.6heterocycloalkyl of Ri7 are each independently unsubstituted or substituted with 1 to 2 substituents independently selected from the group consisting of C1-4alkyl, halo-C1-4alkyl, d. 4alkoxy-Ci-4alkyl, and C^alkoxy.
In a second aspect, the present invention provides a pharmaceutical composition which contains a compound selected from Formula I, 1 A or 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 disease caused by a parasite (such as, for example, Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, Plasmodium malaria, Trypanosoma cruzi or a parasite of the Leishmania genus such as, for example, Leishmania donovani) which method comprises administering to the animal a therapeutically effective amount of a compound selected from Formula 1, 1 A or a 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 according to formula 1 , 1 A, 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 (such as, for example, Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, Plasmodium malaria, PAT054787-WO-PCT
Trypanosoma cruzi or a parasite of the Leishmania genus such as, for example, Leishmania donovani). Particularly, the parasite is a Plasmodium which can be at the blood stages or at the hepatic stages, and the disease is malaria.
In a fifth aspect, the present invention provides the use of a compound selected from Formula I or Formula 1 a in the manufacture of a medicament for treating a disease caused by a parasite in an animal. The disease may be malaria, leishmaniasis and/or Chagas disease.
In a sixth aspect, the present invention provides a process for preparing compounds selected from Formula I, Formula 1 a and the N-oxide derivatives, prodrug derivatives, individual isomers and mixture of isomers thereof, and the pharmaceutically acceptable salts thereof.
Unless specified otherwise, the term "compounds of the present invention" refers to compounds of Fomula (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(=0)Ra, where Ra is 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 C^oalkoxy include, but PAT054787-WO-PCT 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. Cx alkyl and CX-Y alkyl as used herein describe alkyl groups where X and Y indicate the number of carbon atoms in the alkyl chain. For example, d-i 0 alkyl refers to an alkyl radical as defined above containing one to ten carbon atoms. CM 0 alkyl includes, but are not limited to, methyl, ethyl, n-propyl, /so-propyl, n-butyl, sec-butyl, /so-butyl, te/t-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-i o)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 PAT054787-WO-PCT 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
Ci-i0alkylene includes, but are not limited to, methylene, ethylene, n-propylene, /so-propylene, n-butylene, sec-butylene, /so-butylene, te/t-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 Ci-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, arylalkyi cycloalkylalkyl group or a heteroform of one of these groups, and each of the alkyl, alkenyl, alkynyl, acyl, aryl, arylalkyi 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, 0 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 PAT054787-WO-PCT 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, Ra and Rb are an alkyl group as described herein. An d-4alkylamino group includes— NHCi-4alkyl and - N(Ci.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 sp2 hybridized 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 Cx.Yaryl as used herein describe an aryl group where X and Y indicate the number of carbon atoms in the ring system. C6-i4aryls include, but are not limited to, phenyl, biphenyl, naphthyl, azulenyl, and anthracenyl.
An aryl may be unsubstituted or substituted by 1 -5 (such as one, or two, or three) substituents independently selected from the group consisting of hydroxy, thiol, cyano, nitro, Cr4alkyl, d- 4alkenyl, Cr4alkynyl, Cr4alkoxy, thioCV4alkyl, Cr4alkenyloxy, Ci-4alkynyloxy, halogen, d- 4alkylcarbonyl, carboxy, d-4alkoxycarbonyl, amino, Ci-4alkylamino, di-Ci-4alkylamino, d- 4alkylaminocarbonyl, di-d-4alkylaminocarbonyl, Ci-4alkylcarbonylamino, d-4alkylcarbonyl(d- 4alkyl)amino, sulfonyl, sulfamoyl, alkylsulfamoyl, d-4alkylaminosulfonyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl, wherein each of the afore-mentioned substitutents may be further substituted by one or more substituents independently selected from halogen, alkyl, hydroxyl or d-4alkoxy groups. PAT054787-WO-PCT
When an "aryl" is represented along with another radical like "arylalkyi", "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(0)NRa- where Ra is H, or is an alkyl, alkenyl, alkynyl, acyl, aryl, or arylalkyi group or a heteroform of one of these groups, and each of the alkyl, alkenyl, alkynyl, acyl, aryl, arylalkyi 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(0)NRaRb where Ra and Rb are each independently H, or is an alkyl, alkenyl, alkynyl, acyl, aryl, or arylalkyi group or a heteroform of one of these groups, and each of the alkyl, alkenyl, alkynyl, acyl, aryl, arylalkyi 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. PAT054787-WO-PCT
Exemplary monocyclic cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl and cyclohexenyl and the like.
Exemplary bicyclic cycloalkyls include bornyl, norbornanyl, indyl, hexahydroindyl,
tetrahydronaphthyl, decahydronaphthyl, bicyclo[2.1 .1 ]hexyl, bicyclo[2.2.1 ]heptyl,
bicyclo[2.2.1 ]heptenyl, 6,6-dimethylbicyclo[3.1 .1 ]heptyl, 2,6,6-trimethylbicyclo[3.1.1 ]heptyl, bicyclo[2.2.2]octyl. Exemplary tricyclic cycloalkyl groups include, for example, adamantyl.
A cycloalkyl may be unsubstituted or substituted by one, or two, or three, or more substituents independently selected from the group consisting of hydroxyl, thiol, cyano, nitro, oxo, alkylimino, Cr4alkyl, Ci-4alkenyl, Cr4alkynyl, Cr4alkoxy, Cr4thioalkyl, C 4alkenyloxy, d-4alkynyloxy, halogen, d-4alkylcarbonyl, carboxy, Cr4alkoxycarbonyl, amino, C^alkylamino, di-Cr
4alkylamino, C^alkylaminocarbonyl, di-C^alkylaminocarbonyl, Cr4alkylcarbonylamino, Cr 4alkylcarbonyl(C1-4alkyl)amino, sulfonyl, sulfamoyl, alkylsulfamoyl, d^alkylaminosulfonyl 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 C^alkoxy groups.
"Cycloalkylene", as used herein, refers to a divalent radical comprising a cycloalkyl ring assembly as defined herein.
"Cycloalkoxy", as used herein, refers to -O-cycloalkyl, wherein the cycloalkyl is defined herein. Representative examples of C3.i2cycloalklyoxy include, but are not limited to, monocyclic groups such as cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclopentenyloxy, cyclohexyloxy and cyclohexenyloxy and the like. Exemplary bicyclic hydrocarbon groups include bornyloxy, indyloxy, hexahydroindyloxy, tetrahydronaphthyloxy, decahydronaphthyloxy,
bicyclo[2.1.1 ]hexyloxy, bicyclo[2.2.1]heptyloxy, bicyclo[2.2.1 ]heptenyloxy, 6,6- dimethylbicyclo[3.1 .1 ]heptyloxy, 2,6,6-trimethylbicyclo[3.1 .1 ]heptyloxy, bicyclo[2.2.2]octyloxy and the like. Exemplary tricyclic hydrocarbon groups include, for example, adamantyloxy.
"Cyano", as used herein, refers to the radical -CN. PAT054787-WO-PCT
"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 d-4haloalkyl include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. A Ci-4perhaloalkyl group refers to a Ci-4alkyl group having all hydrogen atoms replaced with halo atoms.
"Heteroaryl", as used herein, refers to a 5-14 membered ring assembly (e.g., a 5-7 membered monocycle, an 8-10 membered bicycle, or a 13-14 membered tricyclic ring system) having 1 to 8 heteroatoms selected from N, 0 and S as ring atoms and the remaining ring atoms are carbon atoms. The nitrogen atoms of such heteroaryl rings can be optionally quaternerized and the sulfur atoms of such heteroaryl rings can be optionally oxidized. Cxheteroaryl and Cx.
Yheteroaryl as used herein describe heteroaryls where X and Y indicate the number of ring atoms in the heteroaryl ring. Typical C5.7heteroaryl groups include thienyl, furanyl, imidazolyl, pyrazolyl, pyrrolyl, pyrrolinyl, thiazolyl, 1 ,3,4-thiadiazolyl, isothiazolyl, oxazolyl, oxadiazole isoxazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrazinyl, pyrazinyl, pyrimidinyl, and the like. PAT054787-WO-PCT Bicyclic or tricyclic C8-i 4heteroaryls include, but are not limited to, those derived from
benzo[b]furan, benzo[b]thiophene, benzimidazole, imidazo[4,5-c]pyridine, quinazoline, thieno[2,3-c]pyridine, thieno[3,2-b]pyridine, thieno[2,3-b]pyridine, quinazolinyle, pteridinyl, indolizine, imidazo[1 ,2a]pyridine, quinoline, quinolinyl, isoquinoline, phthalazine, quinoxaline, naphthyridine, naphthyridinyl, quinolizine, indolyl, indole, isoindole, indazole, indoline, benzoxazole, benzopyrazole, benzothiazole, imidazo[1 ,5-a]pyridine, pyrazolo[1 ,5-a]pyridine, imidazo[1 ,2-a]pyrimidine, imidazo[1 ,2-c]pyrimidine, imidazo[1 ,5-a]pyrimidine, imidazo[1 ,5- c]pyrimidine, pyrrolo[2,3-b]pyridine, pyrrolo[2,3-c]pyridine, pyrrolo[3,2-c]pyridine, pyrrolo[3,2- b]pyridine, pyrrolo[2,3-d]pyrimidine, pyrrolo[3,2-d]pyrimidine, pyrrolo[2,3-b]pyrazine, pyrazolo[1 ,5-a]pyridine, pyrrolo[1 ,2-b]pyridazine, pyrrolo[1 ,2-c]pyrimidine, pyrrolo[1 ,2- a]pyrimidine, pyrrolo[1 ,2-a]pyrazine, triazo[1 ,5-a]pyridine, pteridine, purine, purinyl, carbazole, acridine, phenazine, phenothiazene, phenoxazine, 1 ,2-dihydropyrrolo[3,2,1 -/?/]indole, indolizine, pyrido[1 ,2-a]indole and 2(1 H)-pyridinone.
A heteroaryl may be unsubstituted or substituted with one or more substituents independently selected from hydroxyl, thiol, cyano, nitro, C^alkyl, C^alkenyl, C^alkynyl, C^alkoxy, thioCr 4alkyl, C 4alkenyloxy, C^alkynyloxy, halogen, C^alkylcarbonyl, carboxy, C^alkoxycarbonyl, amino, C^alkylamino, di-C^alkylamino, C^alkylaminocarbonyl, di-C^alkylaminocarbonyl, C^alkylcarbonylamino, C^alkylcarbony^C^alky^amino, sulfonyl, sulfamoyl, alkylsulfamoyl, C^alkylaminosulfonyl 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 d- alkoxy groups.
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. PAT054787-WO-PCT
"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, 0, and S, preferably 0 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 Cxheterocycloalkyl include azetidinyl, tetrahydrofuran (THF), dihydrofuran, 1 , 4- dioxane, morpholine, 1 ,4-dithiane, piperazine, piperidine, 1 ,3-dioxolane, imidazoline, 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, Cr 4alkyl, Cr4alkenyl, C1-4alkynyl, Cr4alkoxy, C^thioalkyl, CV4alkenyloxy, C^alkynyloxy, halogen, C^alkylcarbonyl, carboxy, C^alkoxycarbonyl, amino, Cr4alkylamino, di- C^alkylamino, Cr 4alkylaminocarbonyl, di-Cr4alkylaminocarbonyl, Ci-4alkylcarbonylamino, Ci-4alkylcarbonyl(Ci- 4alkyl)amino, sulfonyl, sulfamoyl, alkylsulfamoyl, Ci-4alkylaminosulfonyl where each of the aforementioned 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 Cr4alkoxy 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. PAT054787-WO-PCT
"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, 0, SO, S02, (C=0), and S, and preferably N, 0, S, optionally contaiing one to four additional heteroatoms in each ring. C heterocyclyl 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 alkyi" as used herein, refers to an alkyi as defined herein, having one or more of the available hydrogen of the alkyi 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 -N02.
"Oxo", as used herein, refers to the divalent radical =0
"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, te/f-butyl esters, and silyl esters. A comprehensive list of PAT054787-WO-PCT 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 -C^alkylene-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.
Unless otherwise specified, examples of substituents may include, but are not limited to, halo, nitro, cyano, thio, oxy, hydroxy, carbonyloxy, C^alkoxy, C6.10aryloxy, heteroC5.10aryloxy, carbonyl, oxycarbonyl, aminocarbonyl, amino, C1-6alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, C1-6alkyl, C1_6haloalkyl, hydroxyC1_6alkyl, carbonylC1_6alkyl, thiocarbonylC1-10alkyl, sulfonylC1 6alkyl, sulfinylC 6alkyl, C1-10azaalkyl, iminoC1-6alkyl, C3-12cycloalkylC1-6alkyl,
C4-15heterocycloalkylCi-6alkyl, C6-ioarylCi.6alkyl, C5-i 0heteroarylCi-6alkyl,
Ci o-i2bicycloarylCi-6alkyl, C9-i2heterobicycloarylCi-6alkyl, C3.i 2cycloalkyl, C4-12heterocycloalkyl, C9-12bicycloalkyl , C3-12heterobicycloalkyl, C4_ 2aryl, heteroCi-i 0aryl, C9- 2bicycloaryl and
C4-i2heterobicycloaryl.
"Sulfamoyl" as used herein refers to the radical -S(0)2NRaRb where Ra and Rb are
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-. PAT054787-WO-PCT
"Sulfinyl", as used herein, means the radical -S(0)-. It is noted that the term "sulfinyl" when referring to a monovalent substituent can alternatively refer to a substituted sulfinyl
group, -S(=0)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(0)2- It is noted that the term "sulfonyl" when referring to a monovalent substituent can alternatively refer to a substituted sulfonyl group, -S(=0)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.
*
" X " and " X" " 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 Cialkyl indicates that there is one carbon atom but does not indicate what are the substituents on the carbon atom. Hence, a Cialkyl comprises methyl (i.e., -CH3) as well as -CRaRbRc where Ra, Rb, and Rc may 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 Cialkyls. PAT054787-WO-PCT
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 malaria, leishmaniasis and/or Chagas disease. The compounds of the invention are effective in inhibiting, ameliorating, or eradicating the pathology and/or symptomology of the parasite at both the blood stage and hepatic stage.
In a first embodiment, the compounds of the invention, or a pharmaceutical acceptable salt, tautomer or stereoisomer thereof, are of Formula I:
Figure imgf000019_0001
or a pharmaceutical acceptable salt, tautomer or stereoisomer thereof, wherein
n is 0, 1 or 2;
p is 0, 1 , 2 or 3;
Ring A is selected from the group consisting of C6-i 0aryl, C5-i 0heteroaryl and fused bicyclyls comprising a C5-6heterocycloalkyl fused to a phenyl;
Ring B represents the imidazo[1 ,2-a]pyrazine fused ring depicted in Formula 1 ;
Ring C is selected from the group consisting of phenyl, C5-ioheteroaryl, C5-6cycloalkyl, C5-6heterocycloalkyl, and fused bicyclyl comprising a C5-6heterocycloalkyl fused to a phenyl;
L is selected from the group consisting of *-CH2N(R2)-, *-C(0)-, *-C(0)N(R2)-, *-C(0)N(R2)C(R3a)(R3b)-, *-N(R2)C(R3a)(R3b)-, *-N(R2)C(0)-, *-N(R2)S02-, and Ci.6alkylene, wherein
* represents the point of attachment of L to Ring B;
R2 is selected from the group consisting of hydrogen, Ci_4alkyl and
Ro-C^alkylene, wherein R0 is selected from the group consisting of C1_4alkyl, 4alkoxy, amino, C^alkylamino, C5.6heteroaryl and C5.6heterocycloalkyl, wherein the C5.6heteroaryl and C5.6heterocycloalkyl of R0 are each unsubstituted or substituted with 1 to 2 substituents independently selected from the group consisting of C1 4alkyl, halo and amino;
i8 PAT054787-WO-PCT R3a and R3b are each independently selected from the group consisting of hydrogen and C1-4alkyl. or R3a and R3b is taken together with the carbon to which both attached to form a cyclopropyl;
each is independently selected from the group consisting of halo, cyano, -OR4, - C(0)R5, -C(0)NR6R7, -NR8R9, -NHC(O)R10, -NHS02R11 ; -S02R12, Ci-6alkyl, phenyl, C5- gheteroaryl, and C4-6heterocycoalkyl, wherein
R4 is Ci.6alkyl or phenyl, wherein the d-6alkyl is unsubstituted or substituted by 1 to 3 substituents independently selected from the group consisting of halo, cyano, Ci.4alkyl, amino, di-Ci-4alkylamino, and -C(0)NH2);
R5 is hydrogen, Ci.6alkyl or Ci-6alkoxy;
R6, R8 and Rn are each independently hydrogen or Ci-4alkyl;
R7 and Rg are each independently selected from the group consisting of hydrogen, C^alkyl, C1-4alkoxy, and C3.6cycloalkyl, wherein the C1-4alkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of amino, C1 4alkyl, C1-4alkylamino, di-C1-4alkylamino,
4alkoxycarbonylamino, and C5-6heterocycloalkyl;
R10 is C1-6alkyl, C1-6alkoxy or C3.6cycloalkyl, wherein the C1-6alkyl of R10 is unsubstituted or substituted by 1 -2 substituents independently selected from amino and C3-6cycloalkyl, and the C3.6cycloalkyl of R10 is unsubstituted or substituted by 1 to 2 substituents independently selected from the group consisting of amino and amino- Ci-4alkyl,
Ri2 is Ci-4alkyl, amino or Ci-4alkylamino,
the Ci-6alkyl of R] is unsubstituted or substituted with 1 -3 substituents independently selected from the group consisting of halo, cyano, methoxy, amino, Ci-4alkylamino, C5-6cycloalkyl, and phenyl; and
the phenyl, C5-6heteroaryl and C3.6heterocycoalkyl of Ri are each independently unsubstituted or substituted with 1 to 2 substituents independently selected from the grounp consisting of Ci_4alkyl, amino, Ci-4alkylamino, -C(0)CH3, and benzyl;
Ri5 and R16 are each independently hydrogen, C1-4alkyl or haloC1-4alkyl; PAT054787-WO-PCT each R17 is independently selected from the group consisting of cyano, ¾ oxo,
OR18, -C(0)Ri9, -NR20R21 , -S02R22, -S02NHR23! Ci-4alkyl, phenyl, C5-9heteroaryl, C3_ ecycloalkyl and C4-6heterocycloalkyl, wherein
R18 is selected from the group consisting of hydrogen, Ci-4alkyl, haloCi-4alkyl and phenyl;
Rig is selected from the group consisting of hydrogen, Ci-4alkyl, amino, and Ci-4alkylamino;
R20, R21 and R22 are each independently hydrogen or Chalky;
R23 is hydrogen, Ci-4alkyl, or C5-6heteroaryl
the Ci-4alkyl of Ri7 is unsubstituted or substituted with 1 -3 substituents independently selected from the group consisting of halo, d.4alkoxy and amino; and the phenyl, C5-9heteroaryl, C3-6cycloalkyl and C4.6heterocycloalkyl of R17 are each independently unsubstituted or substituted by 1 to 2 substituents independently selected from the group consisting of C1-4alkyl, halo-C1-4alkyl, C1-4alkoxy-C1-4alkyl, and C1-4alkoxy.
In one embodiment, with reference to the embodiment above, the compound of the invention is where L is selected from the group consisting of *-CH2N(R2)-, *-C(0)-, *-C(0)N(R2)-,
*-C(0)N(R2)C(R3a)(R3b)-, *-N(R2)C(0)-, *-N(R2)S02-, and C1-6alkylene, wherein * represents the point of attachment of L to Ring B; R2 is C1_4alkyl; R3a and R3b are each independently selected from the group consisting of hydrogen and Ci-4alkyl, or R3a and R3b is taken together with the carbon to which both attached to form a cyclopropyl.
In one variation, the compounds of the invention according to any one of the above
embodiments is where L is selected from the group consisting of *-(CH2)-, *-CH2N(CH3)-, *- C(O)-, *-C(0)NH-, *-C(0)N(CH3)-, *-C(0)N(CH2CH2OCH3)-, *-C(0)N(CH2CH2NH2)-,
*-C(0)N(CH2CH2-tetrahydropyran-4-yl)-, *-C(0)N(CH2CH3)-, *-C(0)N(CH2CH2N(CH3)2)-, *- C(0)NHCH2-, *-C(0)N(CH3)CH2-, *-C(0)N(CH(CH3)2)-, *-C(0)N(CH3)CH(CH3)-, *- C(0)N(CH3)C(CH3)2-,*-NHCH2-, *-N(CH3)C(0)-, and *-N(CH3)S(0)2-.
In another variation, L is selected from the group consisting of *-CH2N(CH3)-, *-C(0)NH-, *- C(0)N(CH3)-, *-C(0)N(CH2CH2OCH3)-, *-C(0)N(CH2CH2N(CH3)2)-, *-C(0)N(CH2CH2NH2)-, PAT054787-WO-PCT
*-C(0)N(CH2CH2-tetrahydropyran-4-yl)-, *-C(0)N(CH2CH3)-, *-C(0)N(CH(CH3)2)-, *-NHCH2-, *-N(CH3)C(0)-, and *-N(CH3)S(0)2-. In still another variation, *-CH2N(CH3)-, *-C(0)NH-, *- C(0)N(CH3)-, *-C(0)N(CH2CH2OCH3)-, *-C(0)N(CH2CH2NH2)-, *-C(0)N(CH2CH3)-,
*-C(0)N(CH2CH2N(CH3)2)-, *-C(0)N(CH(CH3)2)-, and *-N(CH3)C(0)-.
In a particular variation of the compounds of the invention according the above embodiments, L is *-C(0)N(CH3)-. In another particular variation, L is *-CH2N(CH3)-. In still another particular variation, L is *-(CH2)-. In yet another particular variation, L is *-C(0)-.
In another embodiment of the compounds of the invention according to any one of the above embodiments and variations, Ring A is selected from the group consisting of C6-i0aryl and C5- 10heteroaryl. In one variation, , Ring A is selected from the group consisting of
Figure imgf000022_0001
each of which is unsubstituted or substituted with 1 to 2 Ri groups.
In another variation, Ring A is selected from the group consisting of
Figure imgf000022_0002
i each of which is unsubstituted or substituted with 1 to 2 Ri groups.
In still another variation, Ring A is selected from the group consisting of phenyl and pyridinyl, each of which is unsubstituted or substituted with 1 to 2 Ri groups. In a particular variation, PAT054787-WO-PCT
Ring A is of the formula:
Figure imgf000023_0001
. In another particular variation, Ring A is of the formula:
Figure imgf000023_0002
. In still another particular variation, Ring A is of the formula:
In another embodiment of the compounds of the invention according to any one of the above embodiments and variations, Ring C is selected from the group consisting of phenyl, C5.
loheteroaryl and C5-ioheterocycloalkyl. In one variation, Ring C is selected from the group consisting of
Figure imgf000023_0003
each of which is unsubstituted or substituted with 1 to 2 R17 groups,
In another variation, Ring C is selected from the group consisting of phenyl and pyridyl, each of which is unsubstituted or substituted with 1 to 2 R17 groups. In one particular variation, Ring C
is of the formula:
Figure imgf000023_0004
. In another particular variation, Ring C is of the formula:
Figure imgf000023_0005
In still another particular variation, Ring C is of the formula: .
In one special variation, Ring C is CeheterocycloalkyI or fused bicyclyl comprising a C5- eheterocycloalkyl fused to a phenyl, wherein the CeheterocycloalkyI and fused bicyclyl are each unsubstituted or substituted with 1 to 3 (Ri7) group. Specifically, Ring C is selected from the group consisting of CT
Figure imgf000024_0001
where each of the above group is either unsubstituted or substituted with 1 to 2 R17
M
Figure imgf000024_0002
each of which is unsubstituted or substituted with 1 to 2 R17 groups.
Figure imgf000024_0003
In one particular variation, Ring C is In
another particular variation, Ring C is .
In another embodiment of the compounds of the invention according to any one of the above embodiments and variations, each Χ\ is independently selected from the group consisting of fluoro, chloro, cyano, methyl, isopropyl, t-butyl, cyanopropyl, -CH(CH3)(OCH3), trifluoromethyl, difluoromethyl, -CF2CH3, -C(CH3)2CN, -CH2NH2, -CH2N(CH3)2, -CH2-morpholinyl, methoxy, proproxy, isoproproxy, difluoromethoxy, trifluoromethoxy, -OCH2CF3, cyanomethoxy, 2- aminoethoxy, -0(CH2)2N(CH3)2, -OC(CH3)2CH2NH2, -OC(CH3)2C(0)NH2, and phenoxy.
In one variation, each RA is independently selected from the group consisting of -C(0)CH3, - C(0)OCH3, -C(0)NH2, -C(0)NHCH3, -C(0)N(CH3)2, -C(0)N(CH2CH3)2, -C(0)N(CH3)(OCH3), - C(0)NH((CH2)2N(CH3)2), -C(0)NH(cyclopropyl), and -C(0)NH(cyclohexyl).
In another variation, each R^ is independently selected from the group consisting of amino, methylamino, dimethylamino, -NH(OCH3), -NH(CH2C(NH2)(CH3)2), - NH(C(CH3)2CH2NH(C(0)OC(CH3)3)), -NH(C(CH3)2CH2NH2), -NH((CH2)2-morpholinyl), - NH(C(0)CH3), -NH(C(0)CH2NH2), -NH(C(0)CH(NH2)(CH3)), -NH(C(0)CH(NH2)CH(CH3)2), - NH(C(0)C(NH2)(CH3)2), -NH(C(0)CH2CH(NH2)(CH3)), -NH(C(0)CH2CH(NH2)CH(CH3)2), - NH(C(0)CH(NH2)(cyclopropyl)), -NH(C(0)(1 -aminomethylcyclopropyl)), -NH(C(0)CH(NH2)- cyclobutyl), -NH(C(0)CH(NH2)-cyclohexyl), -NH(C(0)-2-aminocyclopentyl), -NH(C(0)OCH3), - NH(C(0)OCH2CH3), -NH(C(0)OCH(CH3)2), -NH(S02CH3), and -NH(S02CH(CH3)2).
In still another variation, each R^ is independently selected from the group consisting of -S02CH3, -S02CH(CH3)2, -S02NH2, and -S02N(CH3)2. In yet still another variation, wherein each R is independently selected from the group consisting of
Figure imgf000026_0001
eeaacchh ooff wwhhiicchh iiss uunnssuubbssttiittuutteedd oorr ssuubbssttiittuutteedd bbyy 11 ttoo 22 ssuubbssttiittuueennttss iinnddeeppeennddeennttllyy sseelleecctteedd ffrroomm tthhee ggrroouupp ccoonnssiissttiinngg ooff mmeetthhyyll,, eetthhyyll,, --NNHH22,, --NNHH((CCHH33)),, --CC((00))CCHH33,, aanndd bbeennzzyyll..
Particularly, each R^ is independently selected from the group consisting of
Figure imgf000026_0002
particularly, each R^ is independently selected from the group consisting of
Figure imgf000026_0003
In some particular embodiment, each Ri is independently selected from the group consisting of trifluoromethyl, -C(0)NH2, -C(0)NHCH3, -C(0)NH(CH2)2N(CH3)2, and -NHC(0)CH(NH2)- cycloalkyl. In one variation, is trifluoromethyl. In another variation, Ri is -C(0)NH2.. In still another variation, R is -C(0)NH2.. PAT054787-WO-PCT
In some embodiments of the compounds of the invention according to any one of the above embodiments and variations, n is 0. In one variation, n is 1. In yet another variation, n is 2.
In some embodiments of the compounds of the invention according to any one of the above embodiments and variations, Ri5 is hydrogen.
In some embodiments of the compounds of the invention according to any one of the above embodiments and variations, Ri6 is hydrogen.
In some embodiments of the compounds of the invention according to any one of the above embodiments and variations, each R17 is independently selected from the group consisting of fluoro, chloro, bromo, cyano, methyl, ethyl, t-butyl, trifluoromethyl, methoxymethyl, aminomethyl, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, phenoxy, oxo, dimethylamino, methylsulfonyl, and aminocarbonyl. In other embodiments, each R17 is independently selected from the group consisting of -C(0)CH3, -C(0)NH2, methylsulfonyl, --S02NH-thiazol-2-yl, and - S02NH2. In still other embodiments, each R17 is independently selected from the group
consisting of
Figure imgf000027_0001
In some particular embodiments, each R17 is independently selected from the group consisting of fluoro, chloro, bromo, cyano, methyl, methylsulfonyl, and aminocarbonyl. In other particular embodiments, Ri7 is cyano. In other particular embodiments, Ri7 is chloro. In still other particular embodiments, Ri7 is fluoro. In yet still other embodiments, Ri7 is methylsulfonyl.
In other embodiments of the compounds of the invention according to any one of the above embodiments and variations, p is 0. In some variations, p is 1 . In other variations, p is 2.
In a special embodiment, the compounds of the invention, in reference to the first embodiment above, wherein the compound is of formula 1 A: PAT054787-WO-PCT
Figure imgf000028_0001
wherein
n is 1 ;
p is 1 ;
L is *-C(0)N(R2)- or *-CH2N(R2)-, wherein
* denotes the point of attachment of L to Ring B,
R2 is d-4alkyl or R0-Ci-4alkylene, wherein R0 is selected from the group consisting of Ci-4alkoxy, amino, C^alkylamino, C5-6heteroaryl and C5-6heterocycloalkyl, wherein said C5- eheteroaryl and C5-6heterocycloalkyl are each independently unsubstituted or substituted by 1 -2 substituents independently selected from the group consisting of Ci-4alkyl, halo, amino, and oxo;
Ring A is pheny or pyridyl;
Ring C is pheny or pyridyl;
each Ft! is trifluoromethyl, *-C(0)NH2, or *-C(0)NHCH3; and
each R17 is chloro, fluoro, or cyano.
In some embodiments of the special embodiment above, L is *-C(0)N(CH3)-. In other variation, L is *-CH2N(CH3)-. is of the formula:
. In other variations
Figure imgf000028_0002
PAT054787-WO-PCT of the formula
. In other variations
Figure imgf000029_0001
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-(4-cyanophenyl)-3-(6-(3-(dimethylamino)propoxy)pyridin-3-yl)-N-methylimidazo[1 ,2- a]pyrazine-6-carboxamide; 4-(((3-(4-(1 H-pyrazol-5-yl)phenyl)imidazo[1 ,2-a]pyrazin-6- yl)methyl)(methyl)amino)benzonitrile; N-((3-(4-(1 H-pyrazol-5-yl)phenyl)imidazo[1 ,2-a]pyrazin-6- yl)methyl)-4-fluoro-N-methylaniline; 4-(((3-(4-chlorophenyl)imidazo[1 ,2-a]pyrazin-6- yl)methyl)(methyl)amino)benzonitrile; N-((3-(4-(1 H-pyrazol-5-yl)phenyl)imidazo[1 ,2-a]pyrazin-6- yl)methyl)-4-chloro-N-methylaniline; N-(5-chloro-3-fluoropyridin-2-yl)-N-methyl-3-(4- (trifluoromethyl)phenyl)imidazo[1 ,2-a]pyrazine-6-carboxamide; 5-methanesulfonyl-1 -({3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}carbonyl)-2,3-dihydro-1 H-indole; 4-fluoro-N- methyl-N-((3-(1 -methyl-1 H-indazol-5-yl)imidazo[1 ,2-a]pyrazin-6-yl)methyl)aniline; N-((3-(4-(1 H- pyrazol-1 -yl)phenyl)imidazo[1 ,2-a]pyrazin-6-yl)methyl)-4-chloro-N-methylaniline; N-((3-(4-(1 H- pyrazol-1 -yl)phenyl)imidazo[1 ,2-a]pyrazin-6-yl)methyl)-4-chloro-N-methylaniline; 3-(4- carbamoylphenyl)-N-(4-fluorophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N- methyl-N-(1 -methyl-1 H-benzo[d][1 ,2,3]triazol-5-yl)-3-(4-(trifluoromethyl)phenyl)imidazo[1 ,2- a]pyrazine-6-carboxamide; N-(4-chlorophenyl)-N-methyl-3-[4-(1 H-pyrazol-5- yl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(1 ,3-benzothiazol-2-yl)-N-methyl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; [4-(5-amino-1 ,3,4-oxadiazol-2- yl)phenyl]-N-(4-chlorophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N-(3- methoxypyridin-2-yl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6- carboxamide; 3-(4-chlorophenyl)-N-(4-methanesulfonylphenyl)-N-methylimidazo[1 ,2- a]pyrazine-6-carboxamide; N-{[3-(4-chlorophenyl)imidazo[1 ,2-a]pyrazin-6-yl]methyl}-4-fluoro-N- methylaniline; N-(4-cyanophenyl)-N-methyl-3-(5-methylpyridin-2-yl)imidazo[1 ,2-a]pyrazine-6- carboxamide; N-(4-cyanophenyl)-3-(2,4-dichlorophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide; N-({3-[4-(difluoromethoxy)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}methyl)-4-fluoro-N- PAT054787-WO-PCT methylaniline; 3-(4-carbamoylphenyl)-N-(3,4-difluorophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide; N-(2,4-difluorophenyl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2- a]pyrazine-6-carboxamide; N-methyl-4-(morpholin-4-yl)-N-{3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}benzamide; 4-[({3-[4-(5-amino-1 ,3,4- thiadiazol-2-yl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}methyl)(methyl)amino]benzonitri 3-(4- chloro-2-methylphenyl)-N-(4-cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; 3- (2-chloropyridin-4-yl)-N-(4-cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; ({3- [4-(5-amino-1 ,3,4-thiadiazol-2-yl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}met yl)-6-ch
methylpyridin-3-amine; N-(4-cyanophenyl)-3-(3,5-difluoropyridin-2-yl)-N-methylimidazo[1 ,2- a]pyrazine-6-carboxamide; N-(4-cyanophenyl)-3-(4-methoxy-3-methylphenyl)-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide; 3-[2-chloro-4-(trifluoromethyl)phenyl]-N-(4- cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N-(3-chloro-4-fluorophenyl)-N- methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; 3-acetyl-N-(6- chloropyridin-3-yl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; 4-chloro-N-methyl-N-{[3-(1 - methyl-1 H-indazol-5-yl)imidazo[1 ,2-a]pyrazin-6-yl]methyl}aniline; N-(3-chlorophenyl)-N-methyl- 3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; 4-(6-{[(4- fluorophenyl)(methyl)amino]methyl}imidazo[1 ,2-a]pyrazin-3-yl)-N,N-dime ^ 4-(6-{[(4- chlorophenyl)(methyl)amino]methyl}imidazo[1 ,2-a]pyrazin-3-yl)-N,N-dimethylaniline; N-(4- cyanophenyl)-N-methyl-3-[4-(methylcarbamoyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(5-ethylpyridin-2-yl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6- carboxamide; N-methyl-N-[2-(trifluoromethoxy)phenyl]-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2- a]pyrazine-6-carboxamide; N-(2,4-dichlorophenyl)-3-(4-methoxyphenyl)-N-methylimidazo[1 ,2- a]pyrazine-6-carboxamide; N-(3-chloro-4-methoxyphenyl)-N-(4-cyanophenyl)-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N-methyl-N-(4-phenoxyphenyl)-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; 4-chloro-N-{[3-(4- chlorophenyl)imidazo[1 ,2-a]pyrazin-6-yl]methyl}-N-methylaniline; N,5-dimethyl-N-{[3-(1 -methyl- 1 H-indazol-5-yl)imidazo[1 ,2-a]pyrazin-6-yl]methyl}pyridin-2-amine; N-(4-cyanophenyl)-N- methyl-3-[3-(1 H-pyrazol-4-yl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N,5-dimethyl-N-({3- [4-(1 H-pyrazol-5-yl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}methyl)pyridin-2-amine; N-(4- cyanophenyl)-3-(3-methoxyphenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N-(2,4- dichlorophenyl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxami^ N-[4-(difluoromethoxy)p enyl]-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6- PAT054787-WO-PCT carboxamide; N-methyl-N-[4-(1 -methyl- 1 H-pyrazol-4-yl)phenyl]-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(3-bromo-4-fluorophenyl)-N- methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(3,4- difluorophenyl)-N-methyl-3-(1 -methyl-1 H-indazol-5-yl)imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(2-fluoropyridin-3-yl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6- carboxamide; N-(3,4-dichlorophenyl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2- a]pyrazine-6-carboxamide; N-(4-chloro-3-methylphenyl)-N-methyl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4-cyanophenyl)-3-[4- (difluoromethyl)phenyl]-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N-(6-bromopyridin-3- yl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4-chloro-2- methoxyphenyl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; 3-[4-chloro-3-(trifluoromethyl)phenyl]-N-(4-cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide; N-(2,4-dichlorophenyl)-N-methyl-3-(4-methylphenyl)imidazo[1 ,2-a]pyrazine-6- carboxamide; 4-[methyl({[3-(1 -methyl-1 H-indazol-5-yl)imidazo[1 ,2-a]pyrazin-6- yl]methyl})amino]benzonitrile; N-(5-fluoropyridin-2-yl)-N-methyl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; 4-chloro-N-({3-[4- (difluoromethoxy)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}methyl)-N-methylaniline; N-(4- cyanophenyl)-3-(2-fluoro-4-methoxyphenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N- (5-fluoropyridin-3-yl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6- carboxamide; N-(4-cyanophenyl)-3-(4-methoxyphenyl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide; N-methyl-N-[4-(2-methyl-2H-1 ,2,3,4-tetrazol-5-yl)phenyl]-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4-fluorophenyl)-3-(4- methoxyphenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; 3-(4-chlorophenyl)-N-(2,4- dichlorophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; 3-(4-chloro-3-fluorophenyl)-N- (4-cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4-cyanophenyl)-N-[2- (dimethylamino)ethyl]-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(2- chlorophenyl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; 3- [4-(5-amino-1 ,3,4-thiadiazol-2-yl)phenyl]-N-(4-cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide; N-(4-cyanophenyl)-3-[4-(1 ,1 -difluoroethyl)phenyl]-N-methylimidazo[1 ,2- a]pyrazine-6-carboxamide; N-(4-cyanophenyl)-N-methyl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4-cyanophenyl)-3-[4- (dimethylamino)phenyl]-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N-(6-chloropyridin-3- PAT054787-WO-PCT yl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(6- fluoropyridin-3-yl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxam
N-(6-chloropyridin-3-yl)-N-methyl-3-(4-methylphenyl)imidazo[1 ,2-a]pyrazine-6-carboxamide; N-
(4-chlorophenyl)-N-(6-chloropyridin-3-yl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4- cyanophenyl)-N-methyl-3-[6-(pyrrolidin-1 -yl)pyridin-3-yl]imidazo[1 ,2-a]pyrazine-6-carboxam
N-(5-cyanopyridin-2-yl)-N-methyl-3-(1 -methyl-1 H-indazol-5-yl)imidazo[1 ,2-a]pyrazine-6- carboxamide; N-(6-chloropyridin-3-yl)-N-methyl-3-(1 -methyl-1 H-indol-5-yl)imidazo[1 ,2- a]pyrazine-6-carboxamide; N-(5-cyanopyridin-2-yl)-3-[4-(difluoromethoxy)phenyl]-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N-(6-fluoropyridin-2-yl)-N-methyl-3-[4-
(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4-cyanophenyl)-N-methyl-3-
[4-(1 H-pyrazol-1 -yl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(6-methoxypyridin-3-yl)-N- methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(5-cyanopyridin-2- yl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4- cyanophenyl)-3-(6-methoxypyridin-3-yl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N-(5- chloropyrazin-2-yl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide;
N-(4-cyanophenyl)-N-(propan-2-yl)-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6- carboxamide; N-(5-chloropyrimidin-2-yl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2- a]pyrazine-6-carboxamide; N-(6-chloropyridazin-3-yl)-N-methyl-3-[4-
(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(5-cyanopyridin-2-yl)-3-[4-
(difluoromethyl)phenyl]-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N-(6-bromopyridazin-
3-yl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(5- bromopyrazin-2-yl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide;
3-(4-carbamoylphenyl)-N-(5-cyanopyridin-2-yl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide;
N-methyl-N-(pyridin-2-yl)-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-
(6-chloropyridin-3-yl)-3-(4-methoxyphenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N-
(4-fluorophenyl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide;
N-(4-chlorophenyl)-3-[4-(difluoromethoxy)phenyl]-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide; 3-(4-chlorophenyl)-N-(4-fluorophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide; 3-(4-carbamoylphenyl)-N-(4-cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide; N-(3,4-difluorophenyl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2- a]pyrazine-6-carboxamide; N-(4-fluorophenyl)-N-methyl-3-(1 -methyl-1 H-indazol-5- yl)imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4-fluorophenyl)-N-methyl-3-(1 -methyl-1 H-indazol-
3i PAT054787-WO-PCT
5- yl)imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4-fluorophenyl)-N-methyl-3-(4- methylphenyl)imidazo[1 ,2-a]pyrazine-6-carboxamide; N,3-bis(4-chlorophenyl)-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N-(2-methoxyphenyl)-N-methyl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; 6-fluoro-1 -({3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}carbonyl)-1 ,2,3,4-tetrahydroquinoline; 3-(4- chlorophenyl)-N-(3,4-difluorophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4- cyanophenyl)-N-methyl-3-(4-methylphenyl)imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4- cyanophenyl)-N-ethyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4- cyanophenyl)-N-methyl-3-[4-(propan-2-yl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4- cyanophenyl)-N-methyl-3-[4-(trifluoromethoxy)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamid N-(4-cyanophenyl)-N-methyl-3-[4-(methylamino)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxam 3-(4-tert-butylphenyl)-N-(4-cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N-(2- fluorophenyl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N- [4-(1 -cyano-1 -methylethyl)phenyl]-N-(4-cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide; 3-[4-(dimethylamino)phenyl]-N-(4-fluorophenyl)-N-methylimidazo[1 ,2-a]pyrazine-
6- carboxamide; N-(4-chlorophenyl)-3-[4-(dimethylamino)phenyl]-N-methylimidazo[1 ,2- a]pyrazine-6-carboxamide; N-(4-cyanophenyl)-N-methyl-3-(1 -methyl-1 H-indol-5-yl)imidazo[1 ,2- a]pyrazine-6-carboxamide; 3-(4-aminophenyl)-N-(4-cyanophenyl)-N-methylimidazo[1 ,2- a]pyrazine-6-carboxamide; N-(4-cyanophenyl)-3-[4-(furan-2-yl)phenyl]-N-methylimidazo[1 ,2- a]pyrazine-6-carboxamide; N-(4-cyano-3-fluorophenyl)-N-methyl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(3,4-difluorophenyl)-N-methyl- 3-(1 -methyl-1 H-indol-5-yl)imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4-methanesulfonylphenyl)- 3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4-cyanophenyl)-3-(4- methanesulfonylphenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4-cyanophenyl)-3- [4-(1 -methoxyethyl)phenyl]-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4- methanesulfonylphenyl)-N-methyl-3-[4-(1 H-pyrazol-5-yl)phenyl]imidazo[1 ,2-a]pyrazine-6- carboxamide; 3-(4-chlorophenyl)-N-(4-cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide; N-(4-cyanophenyl)-N-[2-(oxan-4-yl)ethyl]-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2- a]pyrazine-6-carboxamide; 3-(4-acetylphenyl)-N-(4-cyanophenyl)-N-methylimidazo[1 ,2- a]pyrazine-6-carboxamide; N-(3,4-difluorophenyl)-N-methyl-3-(4-methylphenyl)imidazo[1 ,2- a]pyrazine-6-carboxamide; N-(4-fluorophenyl)-N-methyl-3-(1 -methyl-1 H-indol-5-yl)imidazo[1 ,2- a]pyrazine-6-carboxamide; N-(3-fluorophenyl)-N-methyl-3-[4- PAT054787-WO-PCT
(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4-cyanophenyl)-N-methyl-3- [4-(2,2,2-trifluoroethoxy)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4-methoxyphenyl)-N- methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4-cyanophenyl)- 3-[2-fluoro-4-(trifluoromethyl)phenyl]-N-methylimidazo[1 ,2-a]pyrazine-6-carboxami N-(4- chlorophenyl)-N-methyl-3-(1 -methyl- 1 H-indol-5-yl)imidazo[1 ,2-a]pyrazine-6-carboxamide; 3-[4- (difluoromethoxy)phenyl]-N-(3,4-difluorophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; 3-(1 H-1 ,3-benzodiazol-5-yl)-N-(4-cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N-(3,4-difluorophenyl)-N-methyl-3-[4-(1 H-pyrazol-1 -yl)phenyl]imidazo[1 ,2-a]pyrazine-6- carboxamide; N-(4-cyanophenyl)-3-(1 H-indazol-5-yl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide; N-(6-cyanopyridin-3-yl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2- a]pyrazine-6-carboxamide; N-(6-cyanopyridin-3-yl)-N-methyl-3-[4-
(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4-cyanophenyl)-N-methyl-3- (2-methyl-2H-indazol-5-yl)imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4-cyanophenyl)-N-methyl- 3-(2-methyl-2H-indazol-5-yl)imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4-cyanophenyl)-N- methyl-3-[2-methyl-4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4- fluorophenyl)-N-methyl-3-[4-(1 H-pyrazol-1 -yl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N- (4-cyanophenyl)-N-methyl-3-[4-(propane-2-sulfonyl)phenyl]imidazo[1 ,2-a]pyrazine-6- carboxamide; N-(4-cyanophenyl)-3-(4-fluorophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide; N-(4-cyanophenyl)-3-(1 H-indazol-6-yl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide; 3-(4-chloro-3-cyanophenyl)-N-(4-cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine- 6-carboxamide; N-(4-cyanophenyl)-N-methyl-3-[2-(propan-2-yl)-1 ,3-thiazol-4-yl]imidazo[1 ,2- a]pyrazine-6-carboxamide; N-(4-cyanophenyl)-N-methyl-3-(quinolin-6-yl)imidazo[1 ,2- a]pyrazine-6-carboxamide; N-(4-cyanophenyl)-3-[4-(cyclopropylcarbamoyl)phenyl]-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N-(3,4-difluorophenyl)-3-[4- (dimethylamino)phenyl]-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4-cyanophenyl)-3- [4-(3,5-dimethyl-1 H-pyrazol-1 -yl)phenyl]-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; 3-(4- carbamoylphenyl)-N-(6-chloropyridin-3-yl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N- (4-cyanophenyl)-N-methyl-3-[4-(propan-2-yloxy)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4-cyanophenyl)-N-methyl-3-[4-(5-methyl-1 ,3,4-oxadiazol-2-yl)phenyl]imidazo[1 ,2-a]pyrazine- 6-carboxamide; 3-[4-(dimethylamino)phenyl]-N-(4-methanesulfonylphenyl)-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4-cyanophenyl)-3-[4-(2,5-dioxoimidazolidin-4- yl)phenyl]-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; methyl 4-{6-[(4- PAT054787-WO-PCT cyanophenyl)(methyl)carbamoyl]imidazo[1 ,2-a]pyrazin-3-yl}benzoate; N-(4-cyanophenyl)-3- (isoquinolin-6-yl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4-cyanophenyl)-N-methyl- 3-(1 -oxo-1 ,2-dihydroisoquinolin-6-yl)imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4-cyanophenyl)- 3-[3-fluoro-4-(trifluoromethyl)phenyl]-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4- cyanophenyl)-N-methyl-3-(6-propoxypyridin-3-yl)imidazo[1 ,2-a]pyrazine-6-carboxamide;
N-methyl-N-[2-(trifluoromethyl)phenyl]-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6- carboxamide; 3-(4-carbamoylphenyl)-N-(4-methanesulfonylphenyl)-N-methylimidazo[1 ,2- a]pyrazine-6-carboxamide; N-methyl-N-[4-(trifluoromethoxy)phenyl]-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-methyl-N-(1 -methyl-1 H- imidazol-2-yl)-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4- cyanophenyl)-N-methyl-3-[3-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; 5- fluoro-1 -({3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}carbonyl)-2,3-dihydro-1 H-indole; N-(4-cyanophenyl)-N-methyl-3-(4-phenoxyphenyl)imidazo[1 ,2-a]pyrazine-6-carboxamide; 3-(1 - benzyl-1 H-pyrazol-4-yl)-N-(4-cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; 3- [4-chloro-2-(trifluoromethyl)phenyl]-N-(4-cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide; N-(4-cyanophenyl)-N-methyl-3-[4-(1 H-1 ,2,3,4-tetrazol-5-yl)phenyl]imidazo[1 ,2- a]pyrazine-6-carboxamide; N-(4-cyanophenyl)-N-methyl-3-[4-(pyrrolidin-1 - yl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(5-cyanopyridin-2-yl)-N-methyl-3-[4-(1 H- pyrazol-5-yl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(3-bromophenyl)-N-methyl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4-cyanophenyl)-N-methyl-3- (5-sulfamoylpyridin-3-yl)imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4-cyanophenyl)-3-{4- [methoxy(methyl)carbamoyl]phenyl}-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; 3-[4- (aminomethyl)phenyl]-N-(4-cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N- (4-cyanophenyl)-N-methyl-3-[6-(trifluoromethyl)pyridin-3-yl]imidazo[1 ,2-a]pyrazine-6- carboxamide; N-(4-cyanophenyl)-3-[4-(diethylcarbamoyl)phenyl]-N-methylimidazo[1 ,2- a]pyrazine-6-carboxamide; N-(4-cyanophenyl)-N-methyl-3-(1 -methyl-1 H-pyrazol-4- yl)imidazo[1 ,2-a]pyrazine-6-carboxamide; N-methyl-N-[(6-methylpyridin-2-yl)methyl]-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; 3-(3-cyanophenyl)-N-(4- cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N-[(4-fluorophenyl)methyl]-N- methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4-cyanophenyl)- N-methyl-3-[4-(pyrrolidin-2-yl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-methyl-N- (pyridin-3-ylmethyl)-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4- PAT054787-WO-PCT cyanophenyl)-N-methyl-3-(pyridin-3-yl)imidazo[1 ,2-a]pyrazine-6-carboxamide; 3-(5- chloropyridin-2-yl)-N-(4-cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4- cyanophenyl)-3-[4-(dimethylsulfamoyl)phenyl]-N-methylimidazo[1 ,2-a]pyrazine-6
N-(4-cyanophenyl)-N-methyl-3-[2-(4-methylpiperidin-1 -yl)-1 ,3-thiazol-4-yl]imidazo[1 ,2- a]pyrazine-6-carboxamide; N-(4-cyanophenyl)-N-methyl-3-(3-methylphenyl)imidazo[1 ,2- a]pyrazine-6-carboxamide; N-(4-cyanophenyl)-N-methyl-3-(1 H-pyrazol-4-yl)imidazo[1 ,2- a]pyrazine-6-carboxamide; N-(4-cyanophenyl)-N-methyl-3-(1 -methyl-2,3-dihydro-1 H-indol-5- yl)imidazo[1 ,2-a]pyrazine-6-carboxamide; 3-(2,1 ,3-benzoxadiazol-5-yl)-N-(4-cyanophenyl)-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4-cyanophenyl)-N-methyl-3-{3-met yl-3H- imidazo[4,5-b]pyridin-6-yl}imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4-cyanophenyl)-N-met yl-
3-(2-oxo-2,3-dihydro-1 H-indol-5-yl)imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4- methanesulfonylphenyl)-N-met yl-3-(1 -methyl-1 H-indazol-5-yl)imidazo[1 ,2-a]pyrazine-6- carboxamide; N-methyl-N-{4-[3-(trifluoromethyl)-1 H-pyrazol-1 -yl]phenyl}-3-[4-
(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4-cyanophenyl)-3-{4-
[(dimethylamino)methyl]phenyl}-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4- cyanophenyl)-N-methyl-3-[4-(1 -methyl-1 H-pyrazol-5-yl)phenyl]imidazo[1 ,2-a]pyrazine-6- carboxamide; 3-[4-(difluoromethoxy)phenyl]-N-(4-methanesulfonylphenyl)-N-methylimidazo[1 ,2- a]pyrazine-6-carboxamide; 4-[3-(4-carbamoylphenyl)imidazo[1 ,2-a]pyrazin-6-yl]benzamide; N-
(4-cyanophenyl)-N-methyl-3-[5-(2-oxopyrrolidin-1 -yl)pyrazin-2-yl]imidazo[1 ,2-a]pyrazine-6- carboxamide; 3-{4-[(2S)-2-amino-2-cyclohexylacetamido]phenyl}-N-(4-cyanophenyl)-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide; 4-[methyl({3-[4-
(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}methyl)amino]benzonitrile; N-(4- cyanophenyl)-3-[4-(difluoromethoxy)phenyl]-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N-
(4-bromophenyl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide;
N-(6-chloropyridin-3-yl)-N-methyl-3-[4-(piperidin-1 -yl)phenyl]imidazo[1 ,2-a]pyrazine-6- carboxamide; N-(4-chlorophenyl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-
6-carboxamide; 6-chloro-1 -({3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}carbonyl)-
1 ,2,3,4-tetrahydroquinoline; N-(4-chlorophenyl)-3-(4-methoxyphenyl)-N-methylimidazo[1 ,2- a]pyrazine-6-carboxamide; N-(2-chloro-5-methylpyridin-3-yl)-N-methyl-3-[4-
(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(3-fluoropyridin-2-yl)-N- methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; 4-(6-{[(4- fluorophenyl)(methyl)amino]methyl}imidazo[1 ,2-a]pyrazin-3-yl)benzamide; 4-(6-{[(4- PAT054787-WO-PCT cyanophenyl)(methyl)amino]methyl}imidazo[1 ,2-a]pyrazin-3-yl)benzamide; N-(6-chloropyridin-3- yl)-N-methyl-3-[4-(1 H-pyrazol-5-yl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; methyl N-[4- (6-{[(4-cyanophenyl)(methyl)amino]methyl}imidazo[1 ,2-a]pyrazin-3-yl)phenyl]carbamate
N-[5-(6-{[(4-cyanophenyl)(methyl)amino]methyl}imidazo[1 ,2-a]pyrazin-3-yl)pyridin-2- yl]acetamide; 3-[4-(5-amino-1 ,3,4-oxadiazol-2-yl)phenyl]-N-(4-fluorophenyl)-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4-chlorophenyl)-N-methyl-3-[4- (methylcarbamoyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; 4-{6-[(6-fluoro-2,2-dimethyl- 1 ,2,3,4-tetrahydroquinolin-1 -yl)carbonyl]imidazo[1 ,2-a]pyrazin-3-yl}benzamide; 6-fluoro-2,2- dimethyl-1 -({3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}carbon
tetrahydroquinoline; 6-chloro-N-methyl-N-({3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6- yl}methyl)pyridin-3-amine; 3-(4-cyanophenyl)-N-(4-methanesulfonylphenyl)-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide; 4-(6-{[methyl(5-methylpyridin-2- yl)amino]methyl}imidazo[1 ,2-a]pyrazin-3-yl)benzamide; 6-fluoro-1 -({3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}methyl)-1 ,2,3,4-tetrahydroquinoline; N,5- dimethyl-N-({3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}methyl)pyridin-3-amine; N- (4-cyanophenyl)-3-(6-acetamidopyridin-3-yl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N-(6-chloropyridin-3-yl)-3-[4-(1 ,1 -difluoroethyl)phenyl]-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide; N-(4-cyanophenyl)-N-(2-methoxyethyl)-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2- a]pyrazine-6-carboxamide; N-methyl-3-[4-(trifluoromethyl)phenyl]-N-[6-(trifluoromethyl)pyridin- 3-yl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4-cyanophenyl)-N-methyl-3-[4-(1 ,3,4-oxadiazol- 2-yl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-({3-[4-(difluoromethyl)phenyl]imidazo[1 ,2- a]pyrazin-6-yl}methyl)-N,5-dimethylpyridin-2-amine; N-[5-(6-{[methyl(5-methylpyridin-2- yl)amino]methyl}imidazo[1 ,2-a]pyrazin-3-yl)pyridin-2-yl]acetamide; N-(4-cyanophenyl)-N- methyl-3-{1 H-pyrrolo[2,3-b]pyridin-5-yl}imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4- fluorophenyl)-N-methyl-3-[4-(methylcarbamoyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; methyl N-(4-{6-[(6-chloropyridin-3-yl)(methyl)carbamoyl]imidazo[1 ,2-a]pyrazin-3- yl}phenyl)carbamate; N-(4-cyanophenyl)-N-methyl-3-[6-(methylamino)pyridin-3-yl]imidazo[1 ,2- a]pyrazine-6-carboxamide; 3-[4-(2-aminoacetamido)phenyl]-N-(4-cyanophenyl)-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide; 3-[4-(5-amino-1 ,3,4-oxadiazol-2-yl)phenyl]-N-(4- cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N-methyl-N-(pyridin-4-yl)-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(2-methoxy-5-methylpyridin-3- yl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-methyl-N-(5- PAT054787-WO-PCT methylpyridin-3-yl)-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(2- methoxy-5-methylpyridin-3-yl)-N-methyl-3-[4-(trifluoromethyl)phenyl]im
carboxamide; ethyl 6-[(6-chloropyridin-3-yl)(methyl)carbamoyl]imidazo[1 ,2-a]pyrazine-3- carboxylate; ethyl N-(4-{6-[(4-cyanophenyl)(methyl)carbamoyl]imidazo[1 ,2-a]pyrazin-3- yl}phenyl)carbamate; 3-(4-{[(1 S,2R)-2-aminocyclopentane]arriido}phenyl)-N-(4-cyanophenyl)-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide; 3-{4-[(3S)-3-amino-4- methylpentanamido]phenyl}-N-(4-cyanophe^
N-(4-fluorophenyl)-N-methyl-3-[4-(1 H-pyrazol-5-yl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxami^ N-(3,4-difluorophenyl)-N-methyl-3-[4-(1 H-pyrazol-5-yl)phenyl]imidazo[1 ,2-a]pyrazine-6- carboxamide; 4-chloro-N-methyl-N-{3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6- yljbenzamide; methyl N-(5-{6-[(4-cyanophenyl)(methyl)carbamoyl]imidazo[1 ,2-a]pyrazin-3- yl}pyridin-2-yl)carbamate; Propan-2-yl N-(4-{6-[(4-cyanophenyl)(methyl)carbamoyl]imidazo[1 ,2- a]pyrazin-3-yl}phenyl)carbamate; N-(6-chloropyridin-3-yl)-N-methyl-3-{4-[5-(methylamino)- 1 ,3,4-thiadiazol-2-yl]phenyl}imidazo[1 ,2-a]pyrazine-6-carboxamide; N,4-dimethyl-N-({3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}methyl)aniline; 5-chloro-N-methyl-N-{3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}pyridine-2-carboxamide; N-(6-chloropyridin-3- yl)-3-[4-(difluoromethyl)phenyl]-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; 3-{4-[(2S)-2- amino-3-methylbutanamido]phenyl}-N-(4-cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide; 6-chloro-N-methyl-N-{3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6- yl}pyridine-3-carboxamide; 4-fluoro-N-methyl-N-{3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2- a]pyrazin-6-yl}benzamide; 3-{4-[(3R)-3-aminobutanamido]phenyl}-N-(4-cyanophenyl)-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide; 3-[4-(2-amino-2-cyclobutylacetamido)phenyl]-N- (4-cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; 3-{4-[(2S)-2- aminopropanamido]phenyl}-N-(4-cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; 3-(6-aminopyridin-3-yl)-N-(4-cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; 3- [4-(cyanomethoxy)phenyl]-N-(4-cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; 1 -({3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}carbonyl)-1 ,2,3,4-tetrahydroquinoline- 6-carbonitrile; N-(6-chloropyridin-3-yl)-3-[2-fluoro-4-(trifluoromethyl)phenyl]-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N-methyl-4-(trifluoromethyl)-N-{3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}benzamide; N-methyl-N-(6-methylpyridin-3- yl)-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; 3-{4-[(2-amino-2- methylpropyl)amino]phenyl}-N-(4-cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; PAT054787-WO-PCT
N-(6-chloropyridin-3-yl)-3-(4-acetamidophenyl)-N-m^
N-(6-chloropyridin-3-yl)-3-(2-fluoro-4-methoxyphenyl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide; 7-fluoro-4-({3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}methyl)-3,4- dihydro-2H-1 ,4-benzoxazine; 3-{4-[(2R)-2-aminopropanamido]phenyl}-N-(4-cyanophenyl)-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide; 4-cyano-N-methyl-N-{3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}benzamide; N-(4-cyanophenyl)-3-{4-[2- (dimethylamino)ethoxy]phenyl}-N-methylimidazo[1 ,2-a]pyrazine-6-carboxami N-(4- cyanophenyl)-N,2-dimethyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin
3-{4-[(2R)-2-amino-3-methylbutanamido]p enyl}-N-(4-cyanophenyl)-N-methylimi
a]pyrazine-6-carboxamide; N,5-dimethyl-N-({3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin- 6-yl}methyl)pyridin-2-amine; N-(6-methoxy-5-methylpyridin-3-yl)-N-methyl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N,4-dimethyl-N-{3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}benzamide; N-(6-methoxypyridin-2-yl)-N- methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide;
N-(4-cyanophenyl)-3-(4-{[2-(dimethylamino)ethyl]carbamoyl}phenyl)-N-methylimi
a]pyrazine-6-carboxamide; 3-{4-[(2S)-2-amino-2-cyclopropylacetamido]phenyl}-N-(4- cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4-cyano-2-fluorophenyl)-N- methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N,4,4-trimethyl-N-{3- [4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}piperidine-1 -carboxamide; 3-[6-(2- aminoacetamido)pyridin-3-yl]-N-(4-cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide; N-(2-methoxypyridin-4-yl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2- a]pyrazine-6-carboxamide; N-(4-cyanophenyl)-N-methyl-3-(6-methylpyridin-3-yl)imidazo[1 ,2- a]pyrazine-6-carboxamide; N-(1 -ethyl-1 H-pyrazol-5-yl)-N-methyl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-methyl-N-(2-methylpyridin-4- yl)-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; tert-butyl N-{2-[(4-{6-[(4- cyanophenyl)(methyl)carbamoyl]imidazo[1 ,2-a]pyrazin-3-yl}phenyl)amino]-2- methylpropyljcarbamate; N-(6-chloropyridin-3-yl)-3-(1 H-indol-5-yl)-N-methylimidazo[1 ,2- a]pyrazine-6-carboxamide; 3-(4-methoxy-2-methylphenyl)-N-[6-(4-methoxy-2- methylphenyl)pyridin-3-yl]-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4- methoxypyridin-3-yl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6- carboxamide; N-(6-chloro-5-methylpyridin-3-yl)-N-methyl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; 7-fluoro-4-({3-[4- PAT054787-WO-PCT
(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}carbonyl)-3,4-dihydro-2H-1 ,4-ben - ({3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}carbonyl)-3,4-dihydro-2H-1 ,4- benzoxazine; 3-(4-{[1 -(aminomethyl)cyclopropane]amido}phenyl)-N-(4-cyanophenyl)-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N-methyl-6-(trifluoromethyl)-N-{3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}pyridine-3-carboxamide; N-methyl-N-(4- methylpyridin-3-yl)-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxam N-(4- ethoxypyridin-2-yl)-N-methyl-3-[4-(trifluorom
4-methoxy-N-methyl-N-{3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}benzamide; N- (6-chloropyridin-3-yl)-N-methyl-3-{1 H-pyrrolo[2,3-b]pyridin-5-yl}imidazo[1 ,2-a]pyrazine-6- carboxamide; N-methyl-N-[4-(1 H-1 ,2,4-triazol-1 -yl)phenyl]-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4-cyanophenyl)-3-(4- methanesulfonamidophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamid; 4-({3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}carbonyl)-3,4-dihydro-2H-1 ,4-benzoxazine-7- carbonitrile; 6-methanesulfonyl-1 -({3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6- yl}carbonyl)- ,2,3,4-tetrahydroquinoline; N-(5-methanesulfonylpyridin-2-yl)-N-methyl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; methyl N-[4-(6-{[methyl(5- methylpyridin-2-yl)amino]methyl}imidazo[1 ,2-a]pyrazin-3-yl)phenyl]carbamate; 3-(1 H-indol-2- yl)-N-[6-(1 H-indol-2-yl)pyridin-3-yl]-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N-(6- chloropyridin-3-yl)-N-methyl-3-(3-methyl-1 H-indazol-5-yl)imidazo[1 ,2-a]pyrazine-6-carboxamide; N-methyl-N-[5-(morpholin-4-yl)pyridin-2-yl]-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine 6-carboxamide; 4-fluoro-N-methyl-N-{3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6- yl}piperidine-1 -carboxamide; N-(4-cyanophenyl)-3-(6-methanesulfonamidopyridin-3-yl)-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide; 3-{4-[(1 -amino-2-methylpropan-2- yl)amino]phenyl}-N-(4-cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; 3-(1 - benzofuran-5-yl)-N-(6-chloropyridin-3-yl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N- methyl-N-(pyridin-3-yl)-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N- methyl-N-(5-methylpyrazin-2-yl)-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6- carboxamide; N-methyl-N-(5-methylpyrazin-2-yl)-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2- a]pyrazine-6-carboxamide; N-methyl-3-[4-(trifluoromethyl)phenyl]-N-[2-(trifluoromethyl)pyridin- 4-yl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(6-chloropyridin-3-yl)-N-methyl-3-[4-(1 H-pyrazol- 1 -yl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; 5-{6-[(4- cyanophenyl)(methyl)carbamoyl]imidazo[1 ,2-a]pyrazin-3-yl}-N-methylpyridine-2-carboxamide; PAT054787-WO-PCT
N-(6-chloropyridin-3-yl)-3-[3-fluoro-4-(trifluoromethyl)phenyl]-N-methylimidaz ,2-a]pyrazine-6- carboxamide; N-(4-cyanophenyl)-3-(2-methoxypyrimidin-5-yl)-N-methylimidazo[1 ,2-a]pyrazin 6-carboxamide; N-(4-ethylpyridin-2-yl)-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6- carboxamide; N-(4-cyanophenyl)-3-(6-methoxypyrazin-2-yl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide; N-(6-chloropyridin-3-yl)-3-(6-methoxypyridin-3-yl)-N-methylimidazo[1 ,2- a]pyrazine-6-carboxamide; N-methyl-3-[4-(trifluoromethyl)phenyl]-N-[5-(trifluoromethyl)pyridin- 2-yl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-methyl-3-[4-(trifluoromethyl)phenyl]-N-[5- (trifluoromethyl)pyridin-2-yl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4-cyanophenyl)-N- methyl-3-[4-(3-methyl-1 ,2,4-oxadiazol-5-yl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(6- chloropyridin-3-yl)-N-methyl-3-[4-(morpholin-4-yl)phenyl]imidazo[1 ,2-a]pyrazin
N,3-bis(4-cyanophenyl)-N-methyl-2-(trifluoromethyl)imidazo[1 ,2-a]pyrazine-6-carb N- (2,6-dichloropyridin-3-yl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]p
carboxamide; N-(6-chloropyridin-3-yl)-3-[4-(cyclopropylcarbamoyl)phenyl]-N-methylimidazo[1 ,2- a]pyrazine-6-carboxamide; N-(4-cyanophenyl)-3-[2-(dimethylamino)pyrimidin-5-yl]-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N-methyl-N-(6-methylpyridin-2-yl)-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-[2-(difluoromethoxy)phenyl]- N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; 4-cyano-N- methyl-N-{3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}benzene-1 -sulfonamide; N- methyl-3-[4-(trifluoromethyl)phenyl]-N-[4-(trifluoromethyl)pyridin-2-yl]imidazo[1 ,2-a]pyrazine-6- carboxamide; N-(6-chloropyridin-3-yl)-3-(1 H-indazol-5-yl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide; 2,2-dimethyl-4-({3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}carbonyl)- 3,4-dihydro-2H-1 ,4-benzoxazine-7-carbonitrile; N-(4-cyanophenyl)-3-(6-fluoropyridin-2-yl)-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide; 3-[4-(1 -carbamoyl-1 -methylethoxy)phenyl]-N-(4- cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N-(5-methoxypyridin-2-yl)-N- methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; 3-(3-chloropyridin-2- yl)-N-(4-cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N-(5-chloropyridin-3-yl)- N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-methyl-N-(1 ,3- thiazol-2-yl)-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(6- chloropyridin-3-yl)-3-[6-(dimethylamino)pyridin-3-yl]-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide; N-(4-methoxypyridin-2-yl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2- a]pyrazine-6-carboxamide; N-{6-[(2S)-2-(methoxymethyl)pyrrolidin-1 -yl]pyridin-3-yl}-N-methyl-3- [4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(6-chloropyridin-3-yl)-3- PAT054787-WO-PCT
(2,3-dihydro-1 ,4-benzodioxin-6-yl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; 3-(4- acetamidophenyl)-N-methyl-N-(5-methylpyridin-2-yl)imidazo[1 ,2-a]pyrazine-6-carbo N- [(4-cyanophenyl)methyl]-3-[4-(trifluoromethyl)p^ N- (4-cyanophenyl)-N-methyl-3-[4-(propane-2-sulfonamido)phenyl]imidazo[1 ,2-a]pyrazine-6- carboxamide; N-(6-chloropyridin-3-yl)-N-methyl-3-[2-(propan-2-yl)-1 ,3-thiazol-4-yl]imidazo[1 ,2- a]pyrazine-6-carboxamide; N-methyl-N-[6-(1 H-1 ,2,4-triazol-1 -yl)pyridin-3-yl]-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-methyl-4-(trifluoromethoxy)-N- {3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}benzamide; N-(6-chloropyridin-3-yl)-N- methyl-3-[6-(5-methyl-1 ,3,4-oxadiazol-2-yl)pyridin-3-yl]imidazo[1 ,2-a]pyrazine-6-carboxami N-(1 -ethyl-1 H-pyrazol-5-yl)-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide;
3- (4-cyanophenyl)-N-methyl-N-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carbox N-benzyl-N-methyl-3-[4-(trifluoromet yl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; 2-C-3- [4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-pyridine-2,5-dicarboxamide; 3-[4-(2- aminoethoxy)phenyl]-N-(4-cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxami 3-(6- acetamidopyridin-3-yl)-N-methyl-N-(5-met^
4- ({3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}carbonyl)morpholine; N-[4- (aminomethyl)phenyl]-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazi
carboxamide; N-(4-cyanophenyl)-2-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine- 6-carboxamide; N,3-bis(4-cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4- cyanophenyl)-N-methyl-3-(2-methylpyridin-4-yl)imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(6- chloropyridin-3-yl)-N-methyl-3-(2-oxo-2,3-dihydro-1 H-indol-5-yl)imidazo[1 ,2-a]pyrazine-6- carboxamide; 3-(2-aminopyrimidin-5-yl)-N-(4-cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide; N-(6-chloropyridin-3-yl)-3-ethenyl-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide; N-(5-cyclobutylpyridin-2-yl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2- a]pyrazine-6-carboxamide; N-{[4-(morpholin-4-yl)phenyl]methyl}-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(6-tert-butylpyridin-3-yl)-N- methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4-cyanophenyl)- N-methyl-3-(pyridin-4-yl)imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(2-aminoethyl)-N-(4- cyanophenyl)-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(6- chloropyridin-3-yl)-3-(1 H-indol-2-yl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N-(6- chloropyridin-3-yl)-3-{4-[(dimethylamino)methyl]phenyl}-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide; N-(4-cyano-1 H-imidazol-5-yl)-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine- PAT054787-WO-PCT
6-carboxamide; N-methyl-N-(3-methylpyridin-2-yl)-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2- a]pyrazine-6-carboxamide; N-(4-cyanophenyl)-N-methyl-3-{1 -methyl-1 H-pyrazolo[3,4-b]pyridin-
5- yl}imidazo[1 ,2-a]pyrazine-6-carboxamide; 4-({3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2- a]pyrazin-6-yl}methyl)morpholine; 5-{6-[(4-cyanophenyl)(methyl)carbamoyl]imidazo[1 ,2- a]pyrazin-3-yl}pyridine-2-carboxamide; N-[6-(dimethylamino)pyridin-3-yl]-N-methyl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(6-methoxypyridazin-3-yl)-N- methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; 3-(3-amino-1 H- indazol-5-yl)-N-(4-cyanop enyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; 1 -({3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}carbonyl)piperidine-3-carboxami N-(6- chloropyridin-3-yl)-N-methyl-3-[4-(methylamm^
N-(2-methoxypyrimidin-5-yl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[ ,2-a]pyrazine-6- carboxamide; N-(4-cyanophenyl)-N-methyl-3-(6-{[2-(morpholin-4-yl)ethyl]amino}pyridin-3- yl)imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4-cyanophenyl)-3-(6-cyanopyridin-3-yl)-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide; 3-{4-[(1 -amino-2-methylpropan-2-yl)oxy]p enyl}- N-(4-cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; 6-N-(6-chloropyridin-3-yl)-
6- N-methyl-3-N-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-3,6-dicarboxamide; 5-C-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-1 H-imidazole-4,5-dicarboxamide; N-[1 -(4- chlorophenyl)ethyl]-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-{4-[(1 ,3-thiazol-2-yl)sulfamoyl]phenyl}-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6- carboxamide; N-(6-chloropyridin-3-yl)-N-methyl-3-[6-(methylamino)pyridin-3-yl]imidazo[1 ,2- a]pyrazine-6-carboxamide; 3-[4-(2-amino-2-methylpropanamido)phenyl]-N-(4-cyanophenyl)-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide; 3-[4-(2-aminoethoxy)phenyl]-N-methyl-N-(5- methylpyridin-2-yl)imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(6-chloropyridin-3-yl)-N-methyl-3- [4-(1 ,3,4-oxadiazol-2-yl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; 6-fluoro-1 -({8-methyl-3- [4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}carbonyl)-1 ,2,3,4-tetrahydroquinoline; N- (5-cyclopentylpyridin-2-yl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazi carboxamide; N-(6-chloropyridin-3-yl)-N-methyl-3-[6-(trifluoromethyl)pyridin-3-yl]imidazo[1 ,2- a]pyrazine-6-carboxamide; N-[2-(4-fluorophenyl)propan-2-yl]-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; methyl N-(5-{6-[methyl(5- methylpyridin-2-yl)carbamoyl]imidazo[1 ,2-a]pyrazin-3-yl}pyridin-2-yl)carbamate; N-methyl-N- {[1 ,2,4]triazolo[4,3-a]pyridin-5-yl}-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6- carboxamide; 4-tert-butyl-N-methyl-N-{3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6- PAT054787-WO-PCT yljbenzamide; N-(6-chloropyridin-3-yl)-3-[3-(dimethylamino)phenyl]-N-methylimidazo[1 ,2- a]pyrazine-6-carboxamide; N-(6-chloropyridin-3-yl)-3-(4-methanesulfonamidophenyl)-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N-methyl-N-(2-methylpyridin-3-yl)-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-methyl-N-(5-methylpyrimidin-
2- yl)-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(6-chloropyridin-3- yl)-3-(4-fluorophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N-methyl-N-(4-phenyl- 1 ,3-thiazol-2-yl)-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide;
cyanophenyl)-N-methyl-3-(3-methyl-1 H-indazol-5-yl)imidazo[1 ,2-a]pyrazine-6-carboxamide; N- (4-acetylphenyl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide;
1 -({3-[4-(trifluoromet yl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}met yl)piperidin-2-one; N-(4- cyanophenyl)-3-[4-(dimethylcarbamoyl)phenyl]-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4-cyanophenyl)-3-(1 H-indol-5-yl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N-(6- chloropyridin-3-yl)-3-[4-(difluoromethoxy)phenyl]-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide; N-(4-fluoro-2-methoxyphenyl)-N-methyl-3-[4 (trifluoromethyl)phenyl]imidazo[1 ,2- a]pyrazine; N-(3,4-difluorophenyl)-3-(4-methoxyphenyl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide; N-(4-chlorophenyl)-N-methyl-3-(4-methylphenyl)imidazo[1 ,2-a]pyrazine-6- carboxamide; 3-[4-(difluoromethoxy)phenyl]-N-(4-fluorophenyl)-N-methylimidazo[1 ,2- a]pyrazine-6-carboxamide; N-(5-bromopyrimidin-2-yl)-N-methyl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(5-chloropyridin-2-yl)-N- methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-methyl-N-[4- (propan-2-yloxy)phenyl]-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; 4- [({3-[4-(dimethylamino)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}methyl)(methyl)amino]benzonitrile N- (4-cyanophenyl)-3-[3-(dimethylamino)phenyl]-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide;
3- (6-chloropyridin-3-yl)-N-(4-cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N- (3-methoxyphenyl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4-cyanophenyl)-3-(4-methoxy-2-methylphenyl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide; N-(7-chloro-1 ,3-benzothiazol-2-yl)-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2- a]pyrazine-6-carboxamide; 4-fluoro-N-methyl-N-(3-{4-[5-(methylamino)-1 ,3,4-thiadiazol-2- yl]phenyl}imidazo[1 ,2-a]pyrazin-6-yl)benzamide; 3-{6-[(6-fluoro-1 ,2,3,4-tetrahydroquinolin-1 - yl)carbonyl]imidazo[1 ,2-a]pyrazin-3-yl}-N,N-dimethylaniline; N,3-bis[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4-cyanophenyl)-N-methyl-3- {4-[5-(methylamino)-1 ,3,4-oxadiazol-2-yl]phenyl}imidazo[1 ,2-a]pyrazine-6-carboxamide; 4-{6- PAT054787-WO-PCT
[(7-fluoro-3,3-dimethyl-3,4-dihydro- yljbenzamide; 4-{6-[(6-fluoro-1 ,2,3,4-tetrahydroquinolin-1 -yl)carbonyl]imidazo[1 ,2-a]pyrazin-3- yljbenzamide; N-(4-fluorophenyl)-N-methyl-3-[4-(1 ,3,4-thiadiazol-2-yl)phenyl]imidazo[1 ,2- a]pyrazine-6-carboxamide; 4-{6-[(6-fluoro-1 ,2,3,4-tetrahydroquinolin-l -yl)carbonyl]imidazo[1 ,2- a]pyrazin-3-yl}-N-methylbenzamide; N-(4-{6-[(7-fluoro-3,3-dimethyl-3,4-dihydro-2H-1 ,4- benzoxazin-4-yl)carbonyl]imidazo[1 ,2-a]pyrazin-3-yl}phenyl)acetamide; N-methyl-4-{6-[N- methyl(4-fluorobenzene)amido]imidazo[1 ,2-a]pyrazin-3-yl}benzamide; N-methyl-N-(4- sulfamoylphenyl)-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; 4-{6-[(7- fluoro-3,4-dihydro-2H-1 ,4-benzoxazin-4-yl)carbonyl]imidazo[1 ,2-a]pyrazin-3-yl}benzamide; 4-{6- [N-methyl(4-fluorobenzene)amido]imidazo[1 ,2-a]pyrazin-3-yl}benzamide; 4-fluoro-N-methyl-N- (3-{1 H-pyrrolo[2,3-b]pyridin-5-yl}imidazo[1 ,2-a]pyrazin-6-yl)benzamide; 1 -{[3-(2,3-dihydro-1 - benzofuran-5-yl)imidazo[1 ,2-a]pyrazin-6-yl]carbonyl}-6-fluoro-1 ,2,3,4-tetrahydroquinoline; 3-(4- carbamoylphenyl)-N-methyl-N-(5-methylpyridin-2-yl)imidazo[1 ,2-a]pyrazine-6-carboxamide; 4- {6-[(7-fluoro-3,4-dihydro-2H-1 ,4-benzoxazin-4-yl)carbonyl]imidazo[1 ,2-a]pyrazin-3-yl}-N- methylbenzamide; 6-fluoro-1 -{[3-(3-methanesulfonylphenyl)imidazo[1 ,2-a]pyrazin-6- yl]carbonyl}-1 ,2,3,4-tetrahydroquinoline; 3-[6-(4-acetylpiperazin-1 -yl)pyridin-3-yl]-N-(4- cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; 6-fluoro-1 -{[3-(4- methanesulfonylphenyl)imidazo[1 ,2-a]pyrazin-6-yl]carbonyl}-1 ,2,3,4-tetrahydroquinoline; 1 -{[3- (1 -ethyl- 1 H-pyrazol-4-yl)imidazo[1 ,2-a]pyrazin-6-yl]carbonyl}-6-fluoro-1 ,2,3,4- tetrahydroquinoline; N-(4-cyanophenyl)-N-methyl-3-[6-(piperazin-1 -yl)pyridin-3-yl]imidazo[1 ,2- a]pyrazine-6-carboxamide; N-(4-cyanophenyl)-3-(furan-2-yl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide; N-(4-cyanophenyl)-3-(furan-2-yl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; 6-fluoro-1 -({3-[2-(piperazin-1 -yl)pyridin-4-yl]imidazo[1 ,2-a]pyrazin-6-yl}carbonyl)-1 ,2,3,4- tetrahydroquinoline; N-(4-chlorophenyl)-N-methyl-3-[4-(1 ,3,4-thiadiazol-2-yl)phenyl]imidazo[1 ,2- a]pyrazine-6-carboxamide; N-methyl-3-[4-(methylcarbamoyl)phenyl]-N-(5-methylpyridin-2- yl)imidazo[1 ,2-a]pyrazine-6-carboxamide; N-cyclohexyl-4-{6-[(6-fluoro-1 ,2,3,4- tetrahydroquinolin-l -yl)carbonyl]imidazo[1 ,2-a]pyrazin-3-yl}benzamide; 4-fluoro-N-methyl-N-[3- (1 -methyl-1 H-indazol-5-yl)imidazo[1 ,2-a]pyrazin-6-yl]benzamide; 1 -[4-(5-{6-[(6-fluoro-1 ,2,3,4- tetrahydroquinolin-l -yl)carbonyl]imidazo[1 ,2-a]pyrazin-3-yl}pyridin-2-yl)piperazin-1 -yl]ethan-1 - one; 6-fluoro-1 -({3-[3-(morpholin-4-ylmethyl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}carbonyl)- 1 ,2,3,4-tetrahydroquinoline; N-(5-methylpyridin-2-yl)-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2- a]pyrazine-6-carboxamide; N-(4-ethylpyridin-2-yl)-N-methyl-3-[4- PAT054787-WO-PCT
(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4-cyanophenyl)-N-methyl-3- {4-[5-(methylamino)-1 ,3,4-thiadiazol-2-yl]phenyl}imidazo[1 ,2-a]pyrazine-6-carboxamide; 4-(6- {[(4-chlorophenyl)(methyl)amino]methyl}imidazo[1 ,2-a]pyrazin-3-yl)benzam N-(4- fluorophenyl)-N-methyl-3-{4-[5-(methylamino)-1 ,3,4-oxadiazol-2-yl]phenyl}imidazo
a]pyrazine-6-carboxamide; 4-[({3-[4-(difluoromethoxy)phenyl]imidazo[1 ,2-a]pyrazin-6- yl}methyl)(methyl)amino]benzonitrile; N-(4-chlorophenyl)-N-methyl-3-(1 -methyl-1 H-indazol-5- yl)imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4-cyanophenyl)-N-methyl-3-[4-(1 H-pyrazol-5- yl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; methyl N-(4-{6-[(4- cyanophenyl)(methyl)carbamoyl]imidazo[1 ,2-a]pyrazin-3-yl}phenyl)carbamate; N-(4- chlorophenyl)-N-methyl-3-{4-[5-(methylamino)-1 ,3,4-oxadiazol-2-yl]phenyl}imidazo[1 ,2- a]pyrazine-6-carboxamide; N-(4-cyanophenyl)-N-methyl-3-[4-(1 H-pyrazol-3- yl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4-cyanophenyl)-3-(4-acetamidophenyl)-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide; 3-(4-carbamoylphenyl)-N-(4-chlorophenyl)-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4-cyanophenyl)-N-methyl-3-(1 -methyl-1 H- indazol-5-yl)imidazo[1 ,2-a]pyrazine-6-carboxamide; N-[3-(6-acetamidopyridin-3-yl)imidazo[1 ,2- a]pyrazin-6-yl]-4-fluoro-N-methylbenzamide; N-(6-chloropyridin-3-yl)-N-methyl-3-(1 -methyl-1 H- indazol-5-yl)imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4-fluoropyridin-2-yl)-N-methyl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-methyl-N-(5-methylpyridin-2- yl)-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(2-methoxypyridin-3- yl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4- cyanophenyl)-N-methyl-3-[4-(1 ,3,4-thiadiazol-2-yl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; (1 ,1 -dioxido-2H-benzo[b][1 ,4]thiazin-4(3H)-yl)(3-(4-(trifluoromethyl)phenyl)imidazo[1 ,2- a]pyrazin-6-yl)methanone; 4-{6-[N-methyl(4-cyanobenzene)amido]imidazo[1 ,2-a]pyrazin-3- yljbenzamide; N-(2-chloro-1 ,3-thiazol-5-yl)-N-methyl-3-[4 (trifluoromethyl)phenyl]imidazo[1 ,2- a]pyrazine-6-carboxamide; 4-({3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}carbonyl)- 1 ,2,3,4-tetrahydroquinoxalin-2-one; N-methyl-N-{3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2- a]pyrazin-6-yl}pyrimidine-5-carboxamide; N-methyl-N-(6-phenylpyridin-3-yl)-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-methyl-N,3-bis[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4-methanesulfonylphenyl)-N- methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(3-chloro-4- cyanophenyl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; and PAT054787-WO-PCT
N-(4-cyano-2-methoxyphenyl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imi
carboxamide.
Particular examples of compounds or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, according to the present invention include, but are not limited to:
3- (4-carbamoylphenyl)-N-(4-fluorophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N- (4-cyanophenyl)-N-methyl-3-[4-(methylcarbamoyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4-cyanophenyl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide;
4- [methyl({3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}methyl)amino]benzonitrile; 4- (6-{[(4-fluorophenyl)(methyl)amino]methyl}imidazo[1 ,2-a]pyrazin-3-yl)benzamide; 4-(6-{[(4- cyanophenyl)(methyl)amino]methyl}imidazo[1 ,2-a]pyrazin-3-yl)benzamide; N-(4-chlorophenyl)- N-methyl-3-[4-(methylcarbamoyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4- cyanophenyl)-3-(6-acetamidopyridin-3-yl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; 4-(6- {[(4-chlorophenyl)(methyl)amino]methyl}imidazo[1 ,2-a]pyrazin-3-yl)benzamide; methyl N-(4-{6- [(4-cyanophenyl)(methyl)carbamoyl]imidazo[1 ,2-a]pyrazin-3-yl}phenyl)carbamate; 3-(4- carbamoylphenyl)-N-(4-chlorophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; and N- (4-cyanophenyl)-N-methyl-3-(1 -methyl-1 H-indazol-5-yl)imidazo[1 ,2-a]pyrazine-6-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 inventin 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 one embodiment, the pharmaceutical composition further includes a second agent. The second agent may be, but not limited to, a kinase inhibitor, an anti-malarial drug or an antiinflammatory agent. PAT054787-WO-PCT
In another embodiment, the pharmaceutical composition includes an antimalarial drug as a second agent; the selections of the antimalarial includes, but are not limited to, artemisinin, artemether, artesunate, arteflene, dihydroartemisinin, chlorproguanil, trimethoprim, chloroquine, quinine, mefloquine, amodiaquine, atovaquone, proguanil, lumefantrine, piperaquine, pyronaridine, halofantrine, pyrimethamine-sulfadoxine, quinacrine, pyrimethamine-dapsone, quinidine, amopyroquine, sulphonamides, primaquine, ferroquine, tafenoquine, arterolane, and pyronaridine.
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, transdermal^, sublingually, intramuscularly, rectally, transbuccally, intranasally, Iiposomally, 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 Plasmodium parasite. The method involves administering to a subject a therapeutically effective amount of a compound or a pharmaceutical composition according to the above PAT054787-WO-PCT embodiments and variations. In addition, the administering can be in combination with a second agent.
In one embodiment of the method of the invention, the disease being treated is malaria. The malaria can be caused by the parasite Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, or Plasmodium malaria; in particular, the parasit Plasmodium falciparum. Further, the Plasmodium parasite can be at the blood stages; or the Plasmodium parasite can be at the hepatic stages.
In one embodiment of the method of the invention, the compounds or pharmaceutical compositions, according to the above embodiments and variations, can be administered prior to, simultaneously with, or after a second agent. The second agent can be a kinase inhibitor, an anti-malarial drug or an anti-inflammatory agent. In one particular variation of the method, the second agent is an anti-malarial drug, which includes, but is not limited to, artemisinin, artemether, artesunate, arteflene, dihydroartemisinin, chlorproguanil, trimethoprim, chloroquine, quinine, mefloquine, amodiaquine, atovaquone, proguanil, lumefantrine, piperaquine, pyronaridine, halofantrine, pyrimethamine-sulfadoxine, quinacrine, pyrimethamine-dapsone, quinidine, amopyroquine, sulphonamides, primaquine, ferroquine, tafenoquine, arterolane, and pyronaridine.
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 a Plasmodium parasite. In one embodiment, the disease caused by the Plasmodium parasite is malaria. The Plasmodium parasite which causes the malaria can be Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, or Plasmodium malaria; in particular the parasite Plasmodium falciparum. Further, the Plasmodium parasite can be at the blood stages, or the Plasmodium parasite can be at the hepatic stages.
The above compound of invention may be administered prior to, simultaneously with, or after a second agent. The second agent may be a kinase inhibitor, an anti-malarial drug or an antiinflammatory agent. In one particular embodiment, the second agent is an anti-malarial drug. PAT054787-WO-PCT
The antimalarial drug can be, but are not limited to, artemisinin, artemether, artesunate, arteflene, dihydroartemisinin, chlorproguanil, trimethoprim, chloroquine, quinine, mefloquine, amodiaquine, atovaquone, proguanil, lumefantrine, piperaquine, pyronaridine, halofantrine, pyrimethamine-sulfadoxine, quinacrine, pyrimethamine-dapsone, quinidine, amopyroquine, sulphonamides, primaquine, ferroquine, tafenoquine, arterolane, and pyronaridine.
In still another aspect, the present invention is directed to the use of a compound, or a salt, a stereoisomer, or a pharmaceutical composition thereof, according to the above embodiments or variations in the manufacture of a medicament for treating, preventing, inhibiting, or ameliorating the pathology and/or symptomology of a disease caused by a Plasmodium parasite. In one embodiment, the disease is malaria, and the parasite is Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, or Plasmodium malaria; in particular, the parasite is Plasmodium falciparum. Further, the Plasmodium parasite can be at the blood stages or the Plasmodium parasite can be at the hepatic stages.
The medicament may include, in addition to the compound of the invention, a second agent. The second agent can be a kinase inhibitor, an anti-malarial drug or an anti-inflammatory agent. In one particular embodiment, the second agent is an anti-malarial drug, and the drug is selected from artemisinin, artemether, artesunate, arteflene, dihydroartemisinin, chlorproguanil, trimethoprim, chloroquine, quinine, mefloquine, amodiaquine, atovaquone, proguanil, lumefantrine, piperaquine, pyronaridine, halofantrine, pyrimethamine-sulfadoxine, quinacrine, pyrimethamine-dapsone, quinidine, amopyroquine, sulphonamides, primaquine, ferroquine, tafenoquine, arterolane, and pyronaridine.
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. PAT054787-WO-PCT
In a first embodiment, the invention provides a compound of formula (I), or a pharmaceutical acceptable salt, tautomer or stereoisomer thereof,
Figure imgf000051_0001
or a pharmaceutical acceptable salt, tautomer or stereoisomer thereof, wherein
n is 0, 1 or 2;
p is 0, 1 , 2 or 3;
Ring A is selected from the group consisting of C6.10aryl, C5-i0heteroaryl and fused bicyclyls comprising a C5-6heterocycloalkyl fused to a phenyl;
Ring B represents the imidazo[1 ,2-a]pyrazine fused ring depicted in Formula 1 ;
Ring C is selected from the group consisting of phenyl, C5-i 0heteroaryl, C5-6cycloalkyl, C5-6heterocycloalkyl, and fused bicyclyl comprising a C5-6heterocycloalkyl fused to a phenyl;
L is selected from the group consisting of *-CH2N(R2)-, *-C(0)-, *-C(0)N(R2)-,
*-C(0)N(R2)C(R3a)(R3b)-, *-N(R2)C(R3a)(R3b)-, *-N(R2)C(0)-, *-N(R2)S02-, and Ci-6alkylene, wherein
* represents the point of attachment of L to Ring B;
R2 is selected from the group consisting of hydrogen, d-4alkyl and R0-Ci-4alkylene, wherein R0 is selected from the group consisting of Ci-4alkyl, Ci-4alkoxy, amino, Ci-4alkylamino, C5-6heteroaryl and C^6heterocycloalkyl, wherein the C5- eheteroaryl and Cs-eheterocycloalkyl of R0 are each unsubstituted or substituted with 1 to 2 substituents independently selected from the group consisting of Ci-4alkyl, halo and amino;
R3a and R3b are each independently selected from the group consisting of hydrogen and C1-4alkyl, or R3a and R3b is taken together with the carbon to which both attached to form a cyclopropyl;
each Ri is independently selected from the group consisting of halo, cyano, -OR4, - C(0)R5, -C(0)NR6R7, -NR8R9, -NHC(O)R10, -NHS02Rn, -S02R12, C1-6alkyl, phenyl, C5.
gheteroaryl, and C4.6heterocycoalkyl, wherein
5» PAT054787-WO-PCT
R4 is Ci.6alkyl or phenyl, wherein the d_6alkyl is unsubstituted or substituted by 1 to 3 substituents independently selected from the group consisting of halo, cyano, d_ 4alkyl, amino, di-Ci-4alkylamino, and -C(0)NH2);
R5 is hydrogen, d-6alkyl or d-6alkoxy;
R6, R8 and Rn are each independently hydrogen or d-4alkyl;
R7 and R9 are each independently selected from the group consisting of hydrogen, d-4alkyl, d.4alkoxy, and C3-6cycloalkyl, wherein the d^alkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of amino, d-4alkyl, Ci-4alkylamino, di-Ci-4alkylamino, Ci-4alkoxycarbonylamino, and C5. eheterocycloalkyl;
Rio is Ci-6alkyl, d.6alkoxy or C3-6cycloalkyl, wherein the d-6alkyl of Ri0 is unsubstituted or substituted by 1 -2 substituents independently selected from amino and d-ecycloalkyl, and the C3-6cycloalkyl of R10 is unsubstituted or substituted by 1 to 2 substituents independently selected from the group consisting of amino and amino-d- 4alkyl,
R12 is C1-4alkyl, amino or d-4alkylamino,
the C1-6alkyl of is unsubstituted or substituted with 1 -3 substituents independently selected from the group consisting of halo, cyano, methoxy, amino, d- 4alkylamino, C5 6cycloalkyl, and phenyl; and
the phenyl, C5.6heteroaryl and C3.6heterocycoalkyl of are each independently unsubstituted or substituted with 1 to 2 substituents independently selected from the grounp consisting of d-4alkyl, amino, Ci-4alkylamino, -C(0)CH3, and benzyl;
Ri5 and R16 are each independently hydrogen, Ci-4alkyl or haloCi-4alkyl;
each R17 is independently selected from the group consisting of cyano, halo, oxo, ORi8, - C(0)Ri9, -NR20R21 , -S02R22, -S02NHR23, d-4alkyl, phenyl, C5-9heteroaryl, C3-6cycloalkyl and C4. eheterocycloalkyl, wherein
Ri8 is selected from the group consisting of hydrogen, d-4alkyl, haloCi-4alkyl and phenyl;
Rig is selected from the group consisting of hydrogen, d-4alkyl, amino, and d- 4alkylamino;
R20, R2i and R22 are each independently hydrogen or d_4alky;
R23 is hydrogen, d.4alkyl, or C5-6heteroaryl
5i PAT054787-WO-PCT the C1-4alkyl of R17 is unsubstituted or substituted with 1 -3 substituents independently selected from the group consisting of halo, Ci.4alkoxy and amino; and the phenyl, C5-9heteroaryl, C3-6cycloalkyl and C4-6heterocycloalkyl of Ri7 are each independently unsubstituted or substituted by 1 to 2 substituents independently selected from the group consisting of d-4alkyl, halo-Ci-4alkyl, C i _4al koxy- C i_4al ky I , and d-4alkoxy.
Embodiment 2. A compound, or a salt, tautomer or stereoisomer thereof, according to embodiment 1 , wherein L is selected from the group consisting of *-CH2N(R2)-, *-C(0)-, *-C(0)N(R2)-, *-C(0)N(R2)C(R3a)(R3b)-, *-N(R2)C(0)-, *-N(R2)S02-, and C1-6alkylene, wherein
* represents the point of attachment of L to Ring B;
R2 is Ci-4alkyl;
R3a and R3b are each independently selected from the group consisting of hydrogen and Ci-4alkyl, or R3a and R3b is taken together with the carbon to which both attached to form a cyclopropyl.
Embodiment 3. A compound, or a salt, tautomer or stereoisomer thereof, according to embodiment 1 , wherein L is selected from the group consisting of *-(CH2)-, *-CH2N(CH3)-, *- C(O)-, *-C(0)NH-, *-C(0)N(CH3)-, *-C(0)N(CH2CH2OCH3)-, *-C(0)N(CH2CH2NH2)-,
*-C(0)N(CH2CH2-tetrahydropyran-4-yl)-, *-C(0)N(CH2CH3)-, *-C(0)N(CH2CH2N(CH3)2)-, *- C(0)NHCH2-, *-C(0)N(CH3)CH2-, *-C(0)N(CH(CH3)2)-, *-C(0)N(CH3)CH(CH3)-, *- C(0)N(CH3)C(CH3)2-,*-NHCH2-, *-N(CH3)C(0)-, and *-N(CH3)S(0)2-.
Embodiment 4. A compound, or a salt, tautomer or stereoisomer thereof, according to embodiment 1 , wherein L is selected from the group consisting of *-CH2N(CH3)-, *-C(0)NH-, *- C(0)N(CH3)-, *-C(0)N(CH2CH2OCH3)-, *-C(0)N(CH2CH2N(CH3)2)-, *-C(0)N(CH2CH2NH2)-, *-C(0)N(CH2CH2-tetrahydropyran-4-yl)-, *-C(0)N(CH2CH3)-, *-C(0)N(CH(CH3)2)-, *-NHCH2-, *-N(CH3)C(0)-, and *-N(CH3)S(0)2-.
Embodiment 5. A compound, or a salt, tautomer or stereoisomer thereof, according to embodiment 1 , wherein L is selected from the group consisting of *-CH2N(CH3)-, *-C(0)NH-, *- C(0)N(CH3)-, *-C(0)N(CH2CH2OCH3)-, *-C(0)N(CH2CH2NH2)-, *-C(0)N(CH2CH3)-,
*-C(0)N(CH2CH2N(CH3)2)-, *-C(0)N(CH(CH3)2)-, and *-N(CH3)C(0)-. PAT054787-WO-PCT
Embodiment 6. A compound, or a salt, tautomer or stereoisomer thereof, according to embodiment 1 , wherein L is *-C(0)N(CH3)-..
Embodiment 7. A compound, or a salt, tautomer or stereoisomer thereof, according to embodiment 1 , wherein L is *-CH2N(CH3)-.
Embodiment 8. A compound, or a salt, tautomer or stereoisomer thereof, according to embodiment 1 , wherein L is *-(CH2)- or *-C(0)-.
Embodiment 9. A compound, or a salt, tautomer or stereoisomer thereof, according to any one of embodiments 1 to 8, wherein Ring A is C6-i 0aryl or C5-i 0heteroaryl.
Embodiment 10. A compound, or a salt, tautomer or stereoisomer thereof, according to any one of embodiments 1 to 8, wherein Ring A is selected from the group consisting of
Figure imgf000054_0001
, each of which is unsubstituted or substituted with 1 to 2 Ri groups.
Embodiment 1 1. A compound, or a salt, tautomer or stereoisomer thereof, according to any one of embodiments 1 to 8, wherein Ring A is selected from the group consisting of
Figure imgf000054_0002
, each of which is unsubstituted or substituted with 1 to 2 R1 groups PAT054787-WO-PCT
Embodiment 12. A compound, or a salt, tautomer or stereoisomer thereof, according to any one of embodiments 1 to 8, wherein Ring A is phenyl or pyridinyl, each of which is unsubstituted or substituted with 1 to 2 Ri groups.
Embodiment 13. A compound, or a salt, tautomer or stereoisomer thereof, according to any one
of embodiments 1 to 8, wherein Ring A is of the formula
Figure imgf000055_0001
Embodiment 14. A compound, or a salt, tautomer or stereoisomer thereof, according to any one
of embodiments 1 to 8, wherein Ring A is of the formula
Figure imgf000055_0002
Embodiment 15. A compound, or a salt, tautomer or stereoisomer thereof, according to any one
of embodiments 1 to 8, wherein Ring A is of the formula
Figure imgf000055_0003
Embodiment 16. A compound, or a salt, tautomer or stereoisomer thereof, according to any one of embodiments 1 to 7 and 9 to 15, wherein Ring C is selected from the group consisting of phenyl, C&10heteroaryl and C5-i0heterocycloalkyl.
Embodiment 17. A compound, or a salt, tautomer or stereoisomer thereof, according to any one of e
Figure imgf000055_0004
each of which is unsubstituted or substituted with 1 to 2 R17 groups PAT054787-WO-PCT
Embodiment 18. A compound, or a salt, tautomer or stereoisomer thereof, according to any one of embodiments 1 to 7 and 9 to 15, Ring C is selected from the group consisting of phenyl and pyridyl, each of which is unsubstituted or substituted with 1 to 2 R17 groups.
Embodiment 19. A compound, or a salt, tautomer or stereoisomer thereof, according to any one
of embodiments 1 to 7 and 9 to 15, Ring C is of the formula:
Figure imgf000056_0001
Embodiment 20. A compound, or a salt, tautomer or stereoisomer thereof, according to any one
of embodiments 1 to 7 and 9 to 15, Ring C is of the formula:
Figure imgf000056_0002
.
Embodiment 21. A compound, or a salt, tautomer or stereoisomer thereof, according to any one
of embodiments 1 to 7 and 9 to 15, Ring C is of the formula:
Figure imgf000056_0003
Embodiment 22. A compound, or a salt, tautomer or stereoisomer thereof, according to any one of embodiments 1 to 3 and 8 to 15, wherein Ring C is C6heterocycloalkyl or fused bicyclyl comprising a C5-6heterocycloalkyl fused to a phenyl, wherein the C6heterocycloalkyl and fused bicyclyl are each unsubstituted or substituted with 1 to 3 (R17) group.
Embodiment 23. A compound, or a salt, tautomer or stereoisomer thereof, according to any one of embodiments 1 to 3 and 8 to 15, wherein Ring C is selected from the group consisting of
Figure imgf000056_0004
PAT054787-WO-PCT each of which is unsubstituted or substituted with 1 to 2 R17 groups.
Embodiment 24. A compound, or a salt, tautomer or stereoisomer thereof, according to any one
Figure imgf000057_0001
Embodiment 25. A compound, or a salt, tautomer or stereoisomer thereof, according to any one of embodiments 1 to 24, wherein each R^ is independently selected from the group consisting of fluoro, chloro, cyano, methyl, isopropyl, t-butyl, cyanopropyl, -CH(CH3)(OCH3), trifluoromethyl, difluoromethyl, -CF2CH3, -C(CH3)2CN, -CH2NH2, -CH2N(CH3)2, -CH2-morpholinyl, methoxy, proproxy, isoproproxy, difluoromethoxy, trifluoromethoxy, -OCH2CF3, cyanomethoxy, 2- aminoethoxy, -0(CH2)2N(CH3)2, -OC(CH3)2CH2NH2, -OC(CH3)2C(0)NH2, and phenoxy.
Embodiment 26. A compound, or a salt, tautomer or stereoisomer thereof, according to any one of embodiments 1 to 24, wherein each R^ is independently selected from the group consisting of -C(0)CH3, -C(0)OCH3, -C(0)NH2, -C(0)NHCH3, -C(0)N(CH3)2, -C(0)N(CH2CH3)2, - C(0)N(CH3)(OCH3), -C(0)NH((CH2)2N(CH3)2), -C(0)NH(cyclopropyl), and -C(0)NH(cyclohexyl).
Embodiment 27. A compound, or a salt, tautomer or stereoisomer thereof, according to any one of embodiments 1 to 24, wherein each R is independently selected from the group consisting of amino, methylamino, dimethylamino, -NH(OCH3), -NH(CH2C(NH2)(CH3)2), - NH(C(CH3)2CH2NH(C(0)OC(CH3)3)), -NH(C(CH3)2CH2NH2), -NH((CH2)2-morpholinyl), - PAT054787-WO-PCT
NH(C(0)CH3), -NH(C(0)CH2NH2), -NH(C(0)CH(NH2)(CH3)), -NH(C(0)CH(NH2)CH(CH3)2), - NH(C(0)C(NH2)(CH3)2), -NH(C(0)CH2CH(NH2)(CH3)), -NH(C(0)CH2CH(NH2)CH(CH3)2), - NH(C(0)CH(NH2)(cyclopropyl)), -NH(C(0)(1 -aminomethylcyclopropyl)), -NH(C(0)CH(NH2)- cyclobutyl), -NH(C(0)CH(NH2)-cyclohexyl), -NH(C(0)-2-aminocyclopentyl)s -NH(C(0)OCH3), - NH(C(0)OCH2CH3), -NH(C(0)OCH(CH3)2), -NH(S02CH3), and -NH(S02CH(CH3)2).
Embodiment 28. A compound, or a salt, tautomer or stereoisomer thereof, according to any one of embodiments 1 to 24, wherein each is independently selected from the group consisting of -S02CH3, -S02CH(CH3)2, -S02NH2, and -S02N(CH3)2.
Embodiment 29. A compound of the formula (I), or a salt, tautomer or stereoisomer thereof, according to any one of embodiments 1 to 24, wherein each is independently selected from the group consisting of
Figure imgf000058_0001
each of which is unsubstituted or substituted by 1 to 2 substituents independently selected from the group consisting of methyl, ethyl, -NH2, -NH(CH3), -C(0)CH3, and benzyl.
Embodiment 30. A compound, or a salt, tautomer or stereoisomer thereof, according to any one of embodiments 1 to 24, wherein each is independently selected from the group consisting of
Figure imgf000059_0001
Embodiment 31. A compound, or a salt, tautomer or stereoisomer thereof, according to any one of embodiments 1 to 24, wherein each is independently selected from the group consisting of
Figure imgf000059_0002
Embodiment 32. A compound, or a salt, tautomer or stereoisomer thereof, according to any one of embodiments 1 to 24, wherein each R^ is independently selected from the group consisting of trifluoromethyl, -C(0)NH2, -C(0)NHCH3, -C(0)NH(CH2)2N(CH3)2, and -NHC(0)CH(NH2)- cycloalkyl.
Embodiment 33. A compound, or a salt, tautomer or stereoisomer thereof, according to any one of embodiments 1 to 24, wherein R^ is trifluoromethyl.
Embodiment 34. A compound, or a salt, tautomer or stereoisomer thereof, according to any one of embodiments 1 to 24, wherein R^ is -C(0)NH2.
Embodiment 35. A compound, or a salt, tautomer or stereoisomer thereof, according to any one of embodiments 1 to 24, wherein R^ is -C(0)NHCH3. PAT054787-WO-PCT
Embodiment 36. A compound, or a salt, tautomer or stereoisomer thereof, according to any one of embodiments 1 to 35, wherein each R17 is independently selected from the group consisting of fluoro, chloro, bromo, cyano, methyl, ethyl, t-butyl, trifluoromethyl, methoxymethyl, aminomethyl, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, phenoxy, oxo, dimethylamino, methylsulfonyl, and aminocarbonyl.
Embodiment 37. A compound, or a salt, tautomer or stereoisomer thereof, according to any one of embodiments 1 to 35, wherein each R17 is independently selected from the group consisting of -C(0)CH3, -C(0)NH2, methylsulfonyl, -S02NH-thiazol-2-yl, and -S02NH2.
Embodiment 38. A compound, or a salt, tautomer or stereoisomer thereof, according to any one of embodiments 1 to 35, wherein each R17 is independently selected from the group consisting
Figure imgf000060_0001
Embodiment 39. A compound, or a salt, tautomer or stereoisomer thereof, according to any one of embodiments 1 to 35, wherein R17 is cyano.
Embodiment 40. A compound, or a salt, tautomer or stereoisomer thereof, according to any one of embodiments 1 to 35, wherein R17 is chloro.
Embodiment 41. A compound, or a salt, tautomer or stereoisomer thereof, according to any one of embodiments 1 to 35, wherein R17 is fluoro.
Embodiment 42. A compound, or a salt, tautomer or stereoisomer thereof, according to any one of embodiments 1 to 35, wherein R17 is methylsulfonyl.
Embodiment 43. A compound, or a salt, tautomer or stereoisomer thereof, according to any one of embodiments 1 -15 and 21 to 23, wherein each of the Ri7 is independently selected from the group consisting of fluoro, chloro, bromo, cyano, methyl, methylsulfonyl, and aminocarbonyl. PAT054787-WO-PCT
Embodiment 44. A compound, or a salt, tautomer or stereoisomer thereof, according to of embodiment 1 , wherein the compound is of Formula 1 A:
Figure imgf000061_0001
wherein
n is 1 ;
p is 1 ;
L is *-C(0)N(R2)- or *-CH2N(R2)-, wherein
* represents the point of attachment of L to Ring B,
R2 is C1 4alkyl or Ro-C^alkylene, wherein R0 is selected from the group consisting of C^alkoxy, amino, C^alkylamino, C5.6heteroaryl and C5.6heterocycloalkyl, wherein said C5.6heteroaryl and C5.6heterocycloalkyl are each independently
unsubstituted or substituted by 1 -2 substituents independently independently selected from the group consisting of C1 4alkyl: halo, amino, and oxo;
Ring A is pheny or pyridyl;
Ring C is pheny or pyridyl;
each R is trifluoromethyl, *-C(0)NH2, or *-C(0)NHCH3; and
each R17 is chloro, fluoro, or cyano.
Embodiment 45. A compound, or a salt, tautomer or stereoisomer thereof, according to any one of embodiments 44, wherein L is *-C(0)N(CH3)-.
Embodiment 46. A compound, or a salt, tautomer or stereoisomer thereof, according to any one of embodiments 44, wherein L is *-CH2N(CH3)-.
Embodiment 47. A compound, or a salt, tautomer or stereoisomer thereof, according to any one
of embodiments 44 to 46, Ring A is of the formula:
Figure imgf000061_0002
6o PAT054787-WO-PCT
Embodiment 48. A compound, or a salt, tautomer or stereoisomer thereof, according to any one
of embodiments 44 to 46, Ring A is of the formula:
Figure imgf000062_0001
Embodiment 49. A compound, or a salt, tautomer or stereoisomer thereof, according to any one
of embodiments 44 to 46, Ring A is of the formula:
Figure imgf000062_0002
Embodiment 50. A compound, or a salt, tautomer or stereoisomer thereof, according to any one
of embodiments 44 to 49, Ring C is of the formula:
Figure imgf000062_0003
Embodiment 51. A compound, or a salt, tautomer or stereoisomer thereof, according to any one
of embodiments 44 to 49, Ring C is of the formula:
Figure imgf000062_0004
Embodiment 52. A compound, or a salt, tautomer or stereoisomer thereof, according to any one
of embodiments 44 to 49, Ring C is of the formula:
Figure imgf000062_0005
Embodiment 53. A compound, or a salt, tautomer or stereoisomer thereof, according to embodiment 1 , wherein the compound is selected from the group consisting of:
N-(4-cyanophenyl)-3-(6-(3-(dimethylamino)propoxy)pyridin-3-yl)-N-methylimidazo[1 ,2- a]pyrazine-6-carboxamide; 4-(((3-(4-(1 H-pyrazol-5-yl)phenyl)imidazo[1 ,2-a]pyrazin-6- yl)methyl)(methyl)amino)benzonitrile; N-((3-(4-(1 H-pyrazol-5-yl)phenyl)imidazo[1 ,2-a]pyrazin-6- yl)methyl)-4-fluoro-N-methylaniline; 4-(((3-(4-chlorophenyl)imidazo[1 ,2-a]pyrazin-6- yl)methyl)(methyl)amino)benzonitrile; N-((3-(4-(1 H-pyrazol-5-yl)phenyl)imidazo[1 ,2-a]pyrazin-6- yl)methyl)-4-chloro-N-methylaniline; N-(5-chloro-3-fluoropyridin-2-yl)-N-methyl-3-(4- (trifluoromethyl)phenyl)imidazo[1 ,2-a]pyrazine-6-carboxamide; 5-methanesulfonyl-1 -({3-[4-
6i PAT054787-WO-PCT
(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}carbonyl)-2,3-dihydro-1 H-indole; 4-fluoro-N- methyl-N-((3-(1 -methyl-1 H-indazol-5-yl)imidazo[1 ,2-a]pyrazin-6-yl)methyl)aniline; N-((3-(4-(1 H- pyrazol-1 -yl)phenyl)imidazo[1 ,2-a]pyrazin-6-yl)methyl)-4-chloro-N-methylaniline; N-((3-(4-(1 H- pyrazol-1 -yl)phenyl)imidazo[1 ,2-a]pyrazin-6-yl)methyl)-4-chloro-N-methylaniline; 3-(4- carbamoylphenyl)-N-(4-fluorophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N- methyl-N-(1 -methyl-1 H-benzo[d][1 ,2,3]triazol-5-yl)-3-(4-(trifluoromethyl)phenyl)imidazo[1 ,2- a]pyrazine-6-carboxamide; N-(4-chlorophenyl)-N-methyl-3-[4-(1 H-pyrazol-5- yl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(1 ,3-benzothiazol-2-yl)-N-methyl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; [4-(5-amino-1 ,3,4-oxadiazol-2- yl)phenyl]-N-(4-chlorophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N-(3- methoxypyridin-2-yl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6- carboxamide; 3-(4-chlorophenyl)-N-(4-methanesulfonylphenyl)-N-methylimidazo[1 ,2- a]pyrazine-6-carboxamide; N-{[3-(4-chlorophenyl)imidazo[1 ,2-a]pyrazin-6-yl]methyl}-4-fluoro-N- methylaniline; N-(4-cyanophenyl)-N-methyl-3-(5-methylpyridin-2-yl)imidazo[1 ,2-a]pyrazine-6- carboxamide; N-(4-cyanophenyl)-3-(2,4-dichlorophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide; N-({3-[4-(difluoromethoxy)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}methyl)-4-fluoro-N- methylaniline; 3-(4-carbamoylphenyl)-N-(3,4-difluorophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide; N-(2,4-difluorophenyl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2- a]pyrazine-6-carboxamide; N-methyl-4-(morpholin-4-yl)-N-{3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}benzamide; 4-[({3-[4-(5-amino-1 ,3,4- thiadiazol-2-yl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}methyl)(methyl)amino]benzonitrile; 3-(4- chloro-2-methylphenyl)-N-(4-cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; 3- (2-chloropyridin-4-yl)-N-(4-cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; ({3- [4-(5-amino-1 ,3,4-thiadiazol-2-yl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}methyl)-6-chloro-N- methylpyridin-3-amine; N-(4-cyanophenyl)-3-(3,5-difluoropyridin-2-yl)-N-methylimidazo[1 ,2- a]pyrazine-6-carboxamide; N-(4-cyanophenyl)-3-(4-methoxy-3-methylphenyl)-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide; 3-[2-chloro-4-(trifluoromethyl)phenyl]-N-(4- cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N-(3-chloro-4-fluorophenyl)-N- methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; 3-acetyl-N-(6- chloropyridin-3-yl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; 4-chloro-N-methyl-N-{[3-(1 - methyl-1 H-indazol-5-yl)imidazo[1 ,2-a]pyrazin-6-yl]methyl}aniline; N-(3-chlorophenyl)-N-methyl- 3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; 4-(6-{[(4- PAT054787-WO-PCT fluorophenyl)(methyl)amino]methyl}imidazo[1 ,2-a]pyrazin-3-yl)-N,N-dim 4-(6-{[(4- chlorophenyl)(methyl)amino]methyl}imidazo[1 ,2-a]pyrazin-3-yl)-N,N-dimethylaniline; N-(4- cyanophenyl)-N-methyl-3-[4-(methylcarbamoyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(5-ethylpyridin-2-yl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6- carboxamide; N-methyl-N-[2-(trifluoromethoxy)phenyl]-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2- a]pyrazine-6-carboxamide; N-(2,4-dichlorophenyl)-3-(4-methoxyphenyl)-N-methylimidazo[1 ,2- a]pyrazine-6-carboxamide; N-(3-chloro-4-methoxyphenyl)-N-(4-cyanophenyl)-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N-methyl-N-(4-phenoxyphenyl)-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; 4-chloro-N-{[3-(4- chlorophenyl)imidazo[1 ,2-a]pyrazin-6-yl]methyl}-N-methylaniline; N,5-dimethyl-N-{[3-(1 -methyl- 1 H-indazol-5-yl)imidazo[1 ,2-a]pyrazin-6-yl]methyl}pyridin-2-amine; N-(4-cyanophenyl)-N- methyl-3-[3-(1 H-pyrazol-4-yl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N,5-dimethyl-N-({3- [4-(1 H-pyrazol-5-yl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}methyl)pyridin-2-amine; N-(4- cyanophenyl)-3-(3-methoxyphenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N-(2,4- dichlorophenyl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide N-[4-(difluoromethoxy)phenyl]-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6- carboxamide; N-methyl-N-[4-(1 -methyl- 1 H-pyrazol-4-yl)phenyl]-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(3-bromo-4-fluorophenyl)-N- methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(3,4- difluorophenyl)-N-methyl-3-(1 -methyl-1 H-indazol-5-yl)imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(2-fluoropyridin-3-yl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6- carboxamide; N-(3,4-dichlorophenyl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2- a]pyrazine-6-carboxamide; N-(4-chloro-3-methylphenyl)-N-methyl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4-cyanophenyl)-3-[4- (difluoromethyl)phenyl]-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N-(6-bromopyridin-3- yl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4-chloro-2- methoxyphenyl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxami 3-[4-chloro-3-(trifluoromethyl)phenyl]-N-(4-cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide; N-(2,4-dichlorophenyl)-N-methyl-3-(4-methylphenyl)imidazo[1 ,2-a]pyrazine-6- carboxamide; 4-[methyl({[3-(1 -methyl-1 H-indazol-5-yl)imidazo[1 ,2-a]pyrazin-6- yl]methyl})amino]benzonitrile; N-(5-fluoropyridin-2-yl)-N-methyl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; 4-chloro-N-({3-[4- PAT054787-WO-PCT (difluoromethoxy)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}methyl)-N-methylaniline; N-(4- cyanophenyl)-3-(2-fluoro-4-methoxyphenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N-
(5-fluoropyridin-3-yl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6- carboxamide; N-(4-cyanophenyl)-3-(4-methoxyphenyl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide; N-methyl-N-[4-(2-methyl-2H-1 ,2,3,4-tetrazol-5-yl)phenyl]-3-[4-
(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4-fluorophenyl)-3-(4- methoxyphenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; 3-(4-chlorophenyl)-N-(2,4- dichlorophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; 3-(4-chloro-3-fluorophenyl)-N-
(4-cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4-cyanophenyl)-N-[2-
(dimethylamino)ethyl]-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxam N-(2- chlorophenyl)-N-methyl-3-[4-(trifluoro^ 3-
[4-(5-amino-1 ,3,4-thiadiazol-2-yl)phenyl]-N-(4-cyanophenyl)-N-methylimidazo[1 ,2-a]py ^^ carboxamide; N-(4-cyanophenyl)-3-[4-(1 ,1 -difluoroethyl)phenyl]-N-methylimidazo[1 ,2- a]pyrazine-6-carboxamide; N-(4-cyanophenyl)-N-methyl-3-[4-
(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4-cyanophenyl)-3-[4-
(dimethylamino)phenyl]-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N-(6-chloropyridin-3- yl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(6- fluoropyridin-3-yl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-c^
N-(6-chloropyridin-3-yl)-N-rnethyl-3-(4-methylphenyl)imidazo[1 ,2-a]pyrazine-6-carboxamide; N-
(4-chlorophenyl)-N-(6-chloropyridin-3-yl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4- cyanophenyl)-N-methyl-3-[6-(pyrrolidin-1 -yl)pyridin-3-yl]imidazo[1 ,2-a]pyrazine-6-c^
N-(5-cyanopyridin-2-yl)-N-methyl-3-(1 -methyl-1 H-indazol-5-yl)imidazo[1 ,2-a]pyrazine-6- carboxamide; N-(6-chloropyridin-3-yl)-N-methyl-3-(1 -methyl-1 H-indol-5-yl)imidazo[1 ,2- a]pyrazine-6-carboxamide; N-(5-cyanopyridin-2-yl)-3-[4-(difluoromethoxy)phenyl]-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N-(6-fluoropyridin-2-yl)-N-methyl-3-[4-
(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4-cyanophenyl)-N-methyl-3-
[4-(1 H-pyrazol-1 -yl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(6-methoxypyridin-3-yl)-N- methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(5-cyanopyridin-2- yl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4- cyanophenyl)-3-(6-methoxypyridin-3-yl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N-(5- chloropyrazin-2-yl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide;
N-(4-cyanophenyl)-N-(propan-2-yl)-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6- PAT054787-WO-PCT carboxamide; N-(5-chloropyrimidin-2-yl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2- a]pyrazine-6-carboxamide; N-(6-chloropyridazin-3-yl)-N-methyl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(5-cyanopyridin-2-yl)-3-[4- (difluoromethyl)phenyl]-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N-(6-bromopyridazin- 3-yl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(5- bromopyrazin-2-yl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; 3-(4-carbamoylphenyl)-N-(5-cyanopyridin-2-yl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N-methyl-N-(pyridin-2-yl)-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N- (6-c loropyridin-3-yl)-3-(4-methoxyphenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N- (4-fluorophenyl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4-chlorophenyl)-3-[4-(difluoromethoxy)phenyl]-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide; 3-(4-chlorophenyl)-N-(4-fluorophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide; 3-(4-carbamoylphenyl)-N-(4-cyanop enyl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide; N-(3,4-difluorophenyl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2- a]pyrazine-6-carboxamide; N-(4-fluorophenyl)-N-methyl-3-(1 -methyl-1 H-indazol-5- yl)imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4-fluorophenyl)-N-methyl-3-(1 -methyl-1 H-indazol-
5- yl)imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4-fluorophenyl)-N-methyl-3-(4- methylphenyl)imidazo[1 ,2-a]pyrazine-6-carboxamide; N,3-bis(4-chlorophenyl)-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N-(2-methoxyphenyl)-N-methyl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; 6-fluoro-1 -({3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}carbonyl)-1 ,2,3,4-tetrahydroquinoline; 3-(4- chlorophenyl)-N-(3,4-difluorophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4- cyanophenyl)-N-methyl-3-(4-methylphenyl)imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4- cyanophenyl)-N-ethyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4- cyanophenyl)-N-methyl-3-[4-(propan-2-yl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4- cyanophenyl)-N-methyl-3-[4-(trifluoromethoxy)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4-cyanophenyl)-N-methyl-3-[4-(methylamino)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; 3-(4-tert-butylphenyl)-N-(4-cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N-(2- fluorophenyl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N- [4-(1 -cyano-1 -methylethyl)phenyl]-N-(4-cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide; 3-[4-(dimethylamino)phenyl]-N-(4-fluorophenyl)-N-methylimidazo[1 ,2-a]pyrazine-
6- carboxamide; N-(4-chlorophenyl)-3-[4-(dimethylamino)phenyl]-N-methylimidazo[1 ,2- PAT054787-WO-PCT a]pyrazine-6-carboxamide; N-(4-cyanophenyl)-N-methyl-3-(1 -methyl-1 H-indol-5-yl)imidazo[1 ,2- a]pyrazine-6-carboxamide; 3-(4-aminophenyl)-N-(4-cyanophenyl)-N-methylimidazo[1 ,2- a]pyrazine-6-carboxamide; N-(4-cyanophenyl)-3-[4-(furan-2-yl)phenyl]-N-methylimidazo[1 ,2- a]pyrazine-6-carboxamide; N-(4-cyano-3-fluorophenyl)-N-methyl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(3,4-difluorophenyl)-N-methyl- 3-(1 -methyl-1 H-indol-5-yl)imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4-methanesulfonylphenyl)- 3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4-cyanophenyl)-3-(4- methanesulfonylphenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4-cyanophenyl)-3- [4-(1 -methoxyethyl)phenyl]-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4- methanesulfonylphenyl)-N-methyl-3-[4-(1 H-pyrazol-5-yl)phenyl]imidazo[1 ,2-a]pyrazine-6- carboxamide; 3-(4-chlorophenyl)-N-(4-cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide; N-(4-cyanophenyl)-N-[2-(oxan-4-yl)ethyl]-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2- a]pyrazine-6-carboxamide; 3-(4-acetylphenyl)-N-(4-cyanophenyl)-N-methylimidazo[1 ,2- a]pyrazine-6-carboxamide; N-(3,4-difluorophenyl)-N-methyl-3-(4-methylphenyl)imidazo[1 ,2- a]pyrazine-6-carboxamide; N-(4-fluorophenyl)-N-methyl-3-(1 -methyl-1 H-indol-5-yl)imidazo[1 ,2- a]pyrazine-6-carboxamide; N-(3-fluorophenyl)-N-methyl-3-[4-
(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4-cyanophenyl)-N-methyl-3- [4-(2,2,2-trifluoroethoxy)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4-methoxyphenyl)-N- methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4-cyanophenyl)- 3-[2-fluoro-4-(trifluoromethyl)phenyl]-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4- chlorophenyl)-N-methyl-3-(1 -methyl-1 H-indol-5-yl)imidazo[1 ,2-a]pyrazine-6-carboxamide; 3-[4- (difluoromethoxy)phenyl]-N-(3,4-difluorophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; 3-(1 H-1 ,3-benzodiazol-5-yl)-N-(4-cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N-(3,4-difluorophenyl)-N-methyl-3-[4-(1 H-pyrazol-1 -yl)phenyl]imidazo[1 ,2-a]pyrazine-6- carboxamide; N-(4-cyanophenyl)-3-(1 H-indazol-5-yl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide; N-(6-cyanopyridin-3-yl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2- a]pyrazine-6-carboxamide; N-(6-cyanopyridin-3-yl)-N-methyl-3-[4-
(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4-cyanophenyl)-N-methyl-3- (2-methyl-2H-indazol-5-yl)imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4-cyanophenyl)-N-methyl- 3-(2-methyl-2H-indazol-5-yl)imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4-cyanophenyl)-N- methyl-3-[2-methyl-4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4- fluorophenyl)-N-methyl-3-[4-(1 H-pyrazol-1 -yl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N- PAT054787-WO-PCT (4-cyanophenyl)-N-methyl-3-[4-(propane-2-sulfonyl)phenyl]imidazo[1 ,2-a]pyrazine-6- carboxamide; N-(4-cyanophenyl)-3-(4-fluorophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide; N-(4-cyanophenyl)-3-(1 H-indazol-6-yl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide; 3-(4-chloro-3-cyanophenyl)-N-(4-cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine-
6-carboxamide; N-(4-cyanophenyl)-N-methyl-3-[2-(propan-2-yl)-1 ,3-thiazol-4-yl]imidazo[1 ,2- a]pyrazine-6-carboxamide; N-(4-cyanophenyl)-N-methyl-3-(quinolin-6-yl)imidazo[1 ,2- a]pyrazine-6-carboxamide; N-(4-cyanophenyl)-3-[4-(cyclopropylcarbamoyl)phenyl]-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N-(3,4-difluorophenyl)-3-[4-
(dimethylamino)phenyl]-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4-cyanophenyl)-3-
[4-(3,5-dimethyl-1 H-pyrazol-1 -yl)phenyl]-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; 3-(4- carbamoylphenyl)-N-(6-chloropyridin-3-yl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N-
(4-cyanophenyl)-N-methyl-3-[4-(propan-2-yloxy)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide;
N-(4-cyanophenyl)-N-methyl-3-[4-(5-methyl-1 ,3,4-oxadiazol-2-yl)phenyl]imidazo[1 ,2-a]pyrazine-
6-carboxamide; 3-[4-(dimethylamino)phenyl]-N-(4-methanesulfonylphenyl)-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4-cyanophenyl)-3-[4-(2,5-dioxoimidazolidin-4- yl)phenyl]-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; methyl 4-{6-[(4- cyanophenyl)(methyl)carbamoyl]imidazo[1 ,2-a]pyrazin-3-yl}benzoate; N-(4-cyanophenyl)-3-
(isoquinolin-6-yl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4-cyanophenyl)-N-methyl-
3-(1 -oxo-1 ,2-dihydroisoquinolin-6-yl)imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4-cyanophenyl)-
3-[3-fluoro-4-(trifluoromethyl)phenyl]-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4- cyanophenyl)-N-methyl-3-(6-propoxypyridin-3-yl)imidazo[1 ,2-a]pyrazine-6-carboxamide;
N-methyl-N-[2-(trifluoromethyl)phenyl]-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6- carboxamide; 3-(4-carbamoylphenyl)-N-(4-methanesulfonylphenyl)-N-methylimidazo[1 ,2- a]pyrazine-6-carboxamide; N-methyl-N-[4-(trifluoromethoxy)phenyl]-3-[4-
(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-methyl-N-(1 -methyl-1 H- imidazol-2-yl)-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4- cyanophenyl)-N-methyl-3-[3-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; 5- fluoro-1 -({3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}carbonyl)-2,3-dihydro-1 H-indole;
N-(4-cyanophenyl)-N-methyl-3-(4-phenoxyphenyl)imidazo[1 ,2-a]pyrazine-6-carboxamide; 3-(1 - benzyl-1 H-pyrazol-4-yl)-N-(4-cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; 3-
[4-chloro-2-(trifluoromethyl)phenyl]-N-(4-cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide; N-(4-cyanophenyl)-N-methyl-3-[4-(1 H-1 ,2,3,4-tetrazol-5-yl)phenyl]imidazo[1 ,2- PAT054787-WO-PCT a]pyrazine-6-carboxamide; N-(4-cyanophenyl)-N-methyl-3-[4-(pyrrolidin-1 - yl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(5-cyanopyridin-2-yl)-N-methyl-3-[4-(1 H- pyrazol-5-yl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(3-bromophenyl)-N-methyl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4-cyanophenyl)-N-methyl-3- (5-sulfamoylpyridin-3-yl)imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4-cyanophenyl)-3-{4- [methoxy(methyl)carbamoyl]phenyl}-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; 3-[4- (aminomethyl)phenyl]-N-(4-cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxami N- (4-cyanophenyl)-N-methyl-3-[6-(trifluoromethyl)pyridin-3-yl]imidazo[1 ,2-a]pyrazine-6- carboxamide; N-(4-cyanophenyl)-3-[4-(diethylcarbamoyl)phenyl]-N-methylimidazo[1 ,2- a]pyrazine-6-carboxamide; N-(4-cyanophenyl)-N-methyl-3-(1 -methyl-1 H-pyrazol-4- yl)imidazo[1 ,2-a]pyrazine-6-carboxamide; N-methyl-N-[(6-methylpyridin-2-yl)methyl]-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; 3-(3-cyanophenyl)-N-(4- cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N-[(4-fluorophenyl)methyl]-N- methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4-cyanophenyl)- N-methyl-3-[4-(pyrrolidin-2-yl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-methyl-N- (pyridin-3-ylmethyl)-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4- cyanophenyl)-N-methyl-3-(pyridin-3-yl)imidazo[1 ,2-a]pyrazine-6-carboxamide; 3-(5- chloropyridin-2-yl)-N-(4-cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4- cyanophenyl)-3-[4-(dimethylsulfamoyl)phenyl]-N-methylimidazo[1 ,2-a]pyrazine-6-carboxam N-(4-cyanophenyl)-N-methyl-3-[2-(4-methylpiperidin-1 -yl)-1 ,3-thiazol-4-yl]imidazo[1 ,2- a]pyrazine-6-carboxamide; N-(4-cyanophenyl)-N-methyl-3-(3-methylphenyl)imidazo[1 ,2- a]pyrazine-6-carboxamide; N-(4-cyanophenyl)-N-methyl-3-(1 H-pyrazol-4-yl)imidazo[1 ,2- a]pyrazine-6-carboxamide; N-(4-cyanophenyl)-N-methyl-3-(1 -methyl-2,3-dihydro-1 H-indol-5- yl)imidazo[1 ,2-a]pyrazine-6-carboxamide; 3-(2,1 ,3-benzoxadiazol-5-yl)-N-(4-cyanophenyl)-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4-cyanophenyl)-N-methyl-3-{3-methyl-3H- imidazo[4,5-b]pyridin-6-yl}imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4-cyanophenyl)-N-methyl- 3-(2-oxo-2,3-dihydro-1 H-indol-5-yl)imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4- methanesulfonylphenyl)-N-methyl-3-(1 -methyl-1 H-indazol-5-yl)imidazo[1 ,2-a]pyrazine-6- carboxamide; N-methyl-N-{4-[3-(trifluoromethyl)-1 H-pyrazol-1 -yl]phenyl}-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4-cyanophenyl)-3-{4- [(dimethylamino)methyl]phenyl}-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4- cyanophenyl)-N-methyl-3-[4-(1 -methyl-1 H-pyrazol-5-yl)phenyl]imidazo[1 ,2-a]pyrazine-6- PAT054787-WO-PCT carboxamide; 3-[4-(difluoromethoxy)phenyl]-N-(4-methanesulfonylphenyl)-N-methylimidazo[1 ,2- a]pyrazine-6-carboxamide; 4-[3-(4-carbamoylphenyl)imidazo[1 ,2-a]pyrazin-6-yl]benzamide; N- (4-cyanophenyl)-N-methyl-3-[5-(2-oxopyrrolidin-1 -yl)pyrazin-2-yl]imidazo[1 ,2-a]pyrazine-6- carboxamide; 3-{4-[(2S)-2-amino-2-cyclohexylacetamido]phenyl}-N-(4-cyanophenyl)-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide; 4-[methyl({3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}methyl)amino]benzonitrile; N-(4- cyanophenyl)-3-[4-(difluoromethoxy)phenyl]-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N- (4-bromophenyl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(6-chloropyridin-3-yl)-N-methyl-3-[4-(piperidin-1 -yl)phenyl]imidazo[1 ,2-a]pyrazine-6- carboxamide; N-(4-chlorophenyl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine- 6-carboxamide; 6-chloro-1 -({3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}carbonyl)- 1 ,2,3,4-tetrahydroquinoline; N-(4-chlorophenyl)-3-(4-methoxyphenyl)-N-methylimidazo[1 ,2- a]pyrazine-6-carboxamide; N-(2-chloro-5-methylpyridin-3-yl)-N-methyl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(3-fluoropyridin-2-yl)-N- methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; 4-(6-{[(4- fluorophenyl)(methyl)amino]methyl}imidazo[1 ,2-a]pyrazin-3-yl)benzamide; 4-(6-{[(4- cyanophenyl)(methyl)amino]methyl}imidazo[1 ,2-a]pyrazin-3-yl)benzamide; N-(6-chloropyridin-3- yl)-N-methyl-3-[4-(1 H-pyrazol-5-yl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; methyl N-[4- (6-{[(4-cyanophenyl)(methyl)amino]methyl}imidazo[1 ,2-a]pyrazin-3-yl)phenyl]carbamate
N-[5-(6-{[(4-cyanophenyl)(methyl)amino]methyl}imidazo[1 ,2-a]pyrazin-3-yl)pyridin-2- yl]acetamide; 3-[4-(5-amino-1 ,3,4-oxadiazol-2-yl)phenyl]-N-(4-fluorophenyl)-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4-chlorophenyl)-N-methyl-3-[4- (methylcarbamoyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; 4-{6-[(6-fluoro-2,2-dimethyl- 1 ,2,3,4-tetrahydroquinolin-1 -yl)carbonyl]imidazo[1 ,2-a]pyrazin-3-yl}benzamide; 6-fluoro-2,2- dimethyl-1 -({3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}carbonyl)-1 ,2,3,4- tetrahydroquinoline; 6-chloro-N-methyl-N-({3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6- yl}methyl)pyridin-3-amine; 3-(4-cyanophenyl)-N-(4-methanesulfonylphenyl)-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide; 4-(6-{[methyl(5-methylpyridin-2- yl)amino]methyl}imidazo[1 ,2-a]pyrazin-3-yl)benzamide; 6-fluoro-1 -({3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}methyl)-1 ,2,3,4-tetrahydroquinoline; N,5- dimethyl-N-({3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}methyl)pyridin-3-amine; N- (4-cyanophenyl)-3-(6-acetamidopyridin-3-yl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; PAT054787-WO-PCT
N-(6-chloropyridin-3-yl)-3-[4-(1 ,1 -difluoroethyl)phenyl]-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide; N-(4-cyanophenyl)-N-(2-methoxyethyl)-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2- a]pyrazine-6-carboxamide; N-methyl-3-[4-(trifluoromethyl)phenyl]-N-[6-(trifluoromethyl)pyridin- 3-yl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4-cyanophenyl)-N-methyl-3-[4-(1 ,3,4-oxadiazol- 2-yl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-({3-[4-(difluoromethyl)phenyl]imidazo[1 ,2- a]pyrazin-6-yl}methyl)-N,5-dimethylpyridin-2-amine; N-[5-(6-{[methyl(5-methylpyridin-2- yl)amino]methyl}imidazo[1 ,2-a]pyrazin-3-yl)pyridin-2-yl]acetamide; N-(4-cyanophenyl)-N- methyl-3-{1 H-pyrrolo[2,3-b]pyridin-5-yl}imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4- fluorophenyl)-N-methyl-3-[4-(methylcarbamoyl)ph
methyl N-(4-{6-[(6-chloropyridin-3-yl)(methyl)carbamoyl]imidazo[1 ,2-a]pyrazin-3- yl}phenyl)carbamate; N-(4-cyanophenyl)-N-methyl-3-[6-(methylamino)pyridin-3-yl]imidazo[1 ,2- a]pyrazine-6-carboxamide; 3-[4-(2-aminoacetamido)phenyl]-N-(4-cyanophenyl)-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide; 3-[4-(5-amino-1 ,3,4-oxadiazol-2-yl)phenyl]-N-(4- cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N-methyl-N-(pyridin-4-yl)-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(2-methoxy-5-methylpyridin-3- yl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-methyl-N-(5- methylpyridin-3-yl)-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(2- methoxy-5-methylpyridin-3-yl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6- carboxamide; ethyl 6-[(6-chloropyridin-3-yl)(methyl)carbamoyl]imidazo[1 ,2-a]pyrazine-3- carboxylate; ethyl N-(4-{6-[(4-cyanophenyl)(methyl)carbamoyl]imidazo[1 ,2-a]pyrazin-3- yl}phenyl)carbamate; 3-(4-{[(1 S,2R)-2-aminocyclopentane]amido}phenyl)-N-(4-cyanophenyl)-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide; 3-{4-[(3S)-3-amino-4- methylpentanamido]phenyl}-N-(4-cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4-fluorophenyl)-N-methyl-3-[4-(1 H-pyrazol-5-yl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(3,4-difluorophenyl)-N-methyl-3-[4-(1 H-pyrazol-5-yl)phenyl]imidazo[1 ,2-a]pyrazine-6- carboxamide; 4-chloro-N-methyl-N-{3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6- yljbenzamide; methyl N-(5-{6-[(4-cyanophenyl)(methyl)carbamoyl]imidazo[1 ,2-a]pyrazin-3- yl}pyridin-2-yl)carbamate; Propan-2-yl N-(4-{6-[(4-cyanophenyl)(methyl)carbamoyl]imidazo[1 ,2- a]pyrazin-3-yl}phenyl)carbamate; N-(6-chloropyridin-3-yl)-N-methyl-3-{4-[5-(methylamino)- 1 ,3,4-thiadiazol-2-yl]phenyl}imidazo[1 ,2-a]pyrazine-6-carboxamide; N,4-dimethyl-N-({3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}methyl)aniline; 5-chloro-N-methyl-N-{3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}pyridine-2-carboxamide; N-(6-chloropyridin-3- PAT054787-WO-PCT yl)-3-[4-(difluoromethyl)phenyl]-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; 3-{4-[(2S)-2- amino-3-methylbutanamido]phenyl}-N-(4-cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide; 6-chloro-N-methyl-N-{3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6- yl}pyridine-3-carboxamide; 4-fluoro-N-methyl-N-{3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2- a]pyrazin-6-yl}benzamide; 3-{4-[(3R)-3-aminobutanamido]phenyl}-N-(4-cyanophenyl)-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide; 3-[4-(2-amino-2-cyclobutylacetamido)phenyl]-N- (4-cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; 3-{4-[(2S)-2- aminopropanamido]phenyl}-N-(4-cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; 3-(6-aminopyridin-3-yl)-N-(4-cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; 3- [4-(cyanomethoxy)phenyl]-N-(4-cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; 1 -({3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}carbonyl)-1 ,2,3,4-tetrahydroquinoline- 6-carbonitrile; N-(6-chloropyridin-3-yl)-3-[2-fluoro-4-(trifluoromethyl)phenyl]-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N-methyl-4-(trifluoromethyl)-N-{3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}benzamide; N-methyl-N-(6-methylpyridin-3- yl)-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; 3-{4-[(2-amino-2- methylpropyl)amino]phenyl}-N-(4-cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N-(6-chloropyridin-3-yl)-3-(4-acetamidophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N-(6-chloropyridin-3-yl)-3-(2-fluoro-4-methoxyphenyl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide; 7-fluoro-4-({3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}methyl)-3,4- dihydro-2H-1 ,4-benzoxazine; 3-{4-[(2R)-2-aminopropanamido]phenyl}-N-(4-cyanophenyl)-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide; 4-cyano-N-methyl-N-{3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}benzamide; N-(4-cyanophenyl)-3-{4-[2- (dimethylamino)ethoxy]phenyl}-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4- cyanophenyl)-N,2-dimethyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; 3-{4-[(2R)-2-amino-3-methylbutanamido]phenyl}-N-(4-cyanophenyl)-N-methylimidazo[1 ,2- a]pyrazine-6-carboxamide; N,5-dimethyl-N-({3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin- 6-yl}methyl)pyridin-2-amine; N-(6-methoxy-5-methylpyridin-3-yl)-N-methyl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N,4-dimethyl-N-{3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}benzamide; N-(6-methoxypyridin-2-yl)-N- methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide;
N-(4-cyanophenyl)-3-(4-{[2-(dimethylamino)ethyl]carbamoyl}phenyl)-N-methylimidazo[1 ,2 a]pyrazine-6-carboxamide; 3-{4-[(2S)-2-amino-2-cyclopropylacetamido]phenyl}-N-(4-
7i PAT054787-WO-PCT cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4-cyano-2-fluorophenyl)-N- methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N,4,4-trimet yl-N-{3- [4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}piperidine-1 -carboxamide; 3-[6-(2- aminoacetamido)pyridin-3-yl]-N-(4-cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide; N-(2-methoxypyridin-4-yl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2- a]pyrazine-6-carboxamide; N-(4-cyanophenyl)-N-methyl-3-(6-methylpyridin-3-yl)imidazo[1 ,2- a]pyrazine-6-carboxamide; N-(1 -ethyl-1 H-pyrazol-5-yl)-N-methyl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-methyl-N-(2-methylpyridin-4- yl)-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; tert-butyl N-{2-[(4-{6-[(4- cyanophenyl)(methyl)carbamoyl]imidazo[1 ,2-a]pyrazin-3-yl}phenyl)amino]-2- methylpropyljcarbamate; N-(6-chloropyridin-3-yl)-3-(1 H-indol-5-yl)-N-methylimidazo[1 ,2- a]pyrazine-6-carboxamide; 3-(4-methoxy-2-methylphenyl)-N-[6-(4-methoxy-2- methylphenyl)pyridin-3-yl]-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4- methoxypyridin-3-yl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine
carboxamide; N-(6-chloro-5-methylpyridin-3-yl)-N-methyl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; 7-fluoro-4-({3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}carbonyl)-3,4-dihydro-2H-1 ,4-benzoxazine; - ({3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}carbonyl)-3,4-dihydro-2H-1 ,4- benzoxazine; 3-(4-{[1 -(aminomethyl)cyclopropane]amido}phenyl)-N-(4-cyanophenyl)-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N-methyl-6-(trifluoromethyl)-N-{3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}pyridine-3-carboxamide; N-methyl-N-(4- methylpyridin-3-yl)-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4- ethoxypyridin-2-yl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; 4-methoxy-N-methyl-N-{3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}benzamide; N- (6-chloropyridin-3-yl)-N-methyl-3-{1 H-pyrrolo[2,3-b]pyridin-5-yl}imidazo[1 ,2-a]pyrazine-6- carboxamide; N-methyl-N-[4-(1 H-1 ,2,4-triazol-1 -yl)phenyl]-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4-cyanophenyl)-3-(4- methanesulfonamidophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamid; 4-({3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}carbonyl)-3,4-dihydro-2H-1 ,4-benzoxazine-7- carbonitrile; 6-methanesulfonyl-1 -({3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6- yl}carbonyl)-1 ,2,3,4-tetrahydroquinoline; N-(5-methanesulfonylpyridin-2-yl)-N-methyl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; methyl N-[4-(6-{[methyl(5- PAT054787-WO-PCT methylpyridin-2-yl)amino]methyl}imidazo[1 ,2-a]pyrazin-3-yl)phenyl]carbamate; 3-(1 H-indol-2- yl)-N-[6-(1 H-indol-2-yl)pyridin-3-yl]-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N-(6- chloropyridin-3-yl)-N-methyl-3-(3-methyl-1 H-in^^
N-methyl-N-[5-(morpholin-4-yl)pyridin-2-yl]-3-[4-(trifluoromethyl)phenyl]imi
6-carboxamide; 4-fluoro-N-methyl-N-{3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6- yl}piperidine-1 -carboxamide; N-(4-cyanophenyl)-3-(6-methanesulfonamidopyridin-3-yl)-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide; 3-{4-[(1 -amino-2-methylpropan-2- yl)amino]phenyl}-N-(4-cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; 3-(1 - benzofuran-5-yl)-N-(6-chloropyridin-3-yl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N- methyl-N-(pyridin-3-yl)-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N- methyl-N-(5-methylpyrazin-2-yl)-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6- carboxamide; N-methyl-N-(5-methylpyrazin-2-yl)-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2- a]pyrazine-6-carboxamide; N-methyl-3-[4-(trifluoromethyl)phenyl]-N-[2-(trifluoromethyl)pyridin- 4-yl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(6-chloropyridin-3-yl)-N-methyl-3-[4-(1 H-pyrazol- 1 -yl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; 5-{6-[(4- cyanophenyl)(methyl)carbamoyl]imidazo[1 ,2-a]pyrazin-3-yl}-N-methylpyridine-2-carboxamide; N-(6-chloropyridin-3-yl)-3-[3-fluoro-4-(trifluoromethyl)phenyl]-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide; N-(4-cyanophenyl)-3-(2-methoxypyrimidin-5-yl)-N-methylimidazo[1 ,2-a]pyrazine- 6-carboxamide; N-(4-ethylpyridin-2-yl)-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6- carboxamide; N-(4-cyanophenyl)-3-(6-methoxypyrazin-2-yl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide; N-(6-chloropyridin-3-yl)-3-(6-methoxypyridin-3-yl)-N-methylimidazo[1 ,2- a]pyrazine-6-carboxamide; N-methyl-3-[4-(trifluoromethyl)phenyl]-N-[5-(trifluoromethyl)pyridin- 2-yl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-methyl-3-[4-(trifluoromethyl)phenyl]-N-[5- (trifluoromethyl)pyridin-2-yl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4-cyanophenyl)-N- methyl-3-[4-(3-methyl-1 ,2,4-oxadiazol-5-yl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(6- chloropyridin-3-yl)-N-methyl-3-[4-(morpholin-4-yl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N,3-bis(4-cyanophenyl)-N-methyl-2-(trifluoromethyl)imidazo[1 ,2-a]pyrazine-6-carboxamide; N- (2,6-dichloropyridin-3-yl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6- carboxamide; N-(6-chloropyridin-3-yl)-3-[4-(cyclopropylcarbamoyl)phenyl]-N-methylimidazo[1 ,2- a]pyrazine-6-carboxamide; N-(4-cyanophenyl)-3-[2-(dimethylamino)pyrimidin-5-yl]-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N-methyl-N-(6-methylpyridin-2-yl)-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-[2-(difluoromethoxy)phenyl]- PAT054787-WO-PCT
N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; 4-cyano-N- methyl-N-{3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}benzene-1 -sulfonamide; N- methyl-3-[4-(trifluoromethyl)phenyl]-N-[4-(trifluoromethyl)pyridin-2-yl]imidazo[1 ,2-a]pyrazine-6- carboxamide; N-(6-chloropyridin-3-yl)-3-(1 H-indazol-5-yl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide; 2,2-dimethyl-4-({3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}carbonyl)- 3,4-dihydro-2H-1 ,4-benzoxazine-7-carbonitrile; N-(4-cyanophenyl)-3-(6-fluoropyridin-2-yl)-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide; 3-[4-(1 -carbamoyl-1 -methylethoxy)phenyl]-N-(4- cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N-(5-methoxypyridin-2-yl)-N- methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; 3-(3-c loropyridin-2- yl)-N-(4-cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N-(5-chloropyridin-3-yl)- N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-methyl-N-(1 ,3- thiazol-2-yl)-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(6- chloropyridin-3-yl)-3-[6-(dimethylamino)pyridin-3-yl]-N-methylimidazo[1 ,2-a]pyrazine-6 carboxamide; N-(4-methoxypyridin-2-yl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2- a]pyrazine-6-carboxamide; N-{6-[(2S)-2-(methoxymethyl)pyrrolidin-1 -yl]pyridin-3-yl}-N-methyl-3- [4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(6-chloropyridin-3-yl)-3- (2,3-dihydro-1 ,4-benzodioxin-6-yl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; 3-(4- acetamidophenyl)-N-methyl-N-(5-methylpyridin-2-yl)imidazo[1 ,2-a]pyrazine-6-carboxamide; N- [(4-cyanophenyl)methyl]-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N- (4-cyanophenyl)-N-methyl-3-[4-(propane-2-sulfonamido)phenyl]imidazo[1 ,2-a]pyrazine-6- carboxamide; N-(6-chloropyridin-3-yl)-N-methyl-3-[2-(propan-2-yl)-1 ,3-thiazol-4-yl]imidazo[1 ,2- a]pyrazine-6-carboxamide; N-methyl-N-[6-(1 H-1 ,2,4-triazol-1 -yl)pyridin-3-yl]-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-methyl-4-(trifluoromethoxy)-N- {3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}benzamide; N-(6-chloropyridin-3-yl)-N- methyl-3-[6-(5-methyl-1 ,3,4-oxadiazol-2-yl)pyridin-3-yl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(1 -ethyl-1 H-pyrazol-5-yl)-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide;
3- (4-cyanophenyl)-N-methyl-N-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-benzyl-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; 2-C-3- [4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-pyridine-2,5-dicarboxamide; 3-[4-(2- aminoethoxy)phenyl]-N-(4-cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; 3-(6- acetamidopyridin-3-yl)-N-methyl-N-(5-methylpyridin-2-yl)imidazo[1 ,2-a]pyrazine-6-carboxamide;
4- ({3-[4-(trifluoromet yl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}carbonyl)morpholine; N-[4- PAT054787-WO-PCT
(aminomethyl)phenyl]-N-methyl-3-[4-(trifluorom
carboxamide; N-(4-cyanophenyl)-2-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine- 6-carboxamide; N,3-bis(4-cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4- cyanophenyl)-N-methyl-3-(2-methylpyridin-4-yl)imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(6- chloropyridin-3-yl)-N-methyl-3-(2-oxo-2,3-dihydro-1 H-indol-5-yl)imidazo[1 ,2-a]pyrazine-6- carboxamide; 3-(2-aminopyrimidin-5-yl)-N-(4-cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide; N-(6-chloropyridin-3-yl)-3-ethenyl-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide; N-(5-cyclobutylpyridin-2-yl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2- a]pyrazine-6-carboxamide; N-{[4-(morpholin-4-yl)phenyl]methyl}-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(6-tert-butylpyridin-3-yl)-N- methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4-cyanophenyl)- N-methyl-3-(pyridin-4-yl)imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(2-aminoethyl)-N-(4- cyanophenyl)-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(6- chloropyridin-3-yl)-3-(1 H-indol-2-yl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N-(6- chloropyridin-3-yl)-3-{4-[(dimethylamino)methyl]phenyl}-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide; N-(4-cyano-1 H-imidazol-5-yl)-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine- 6-carboxamide; N-methyl-N-(3-methylpyridin-2-yl)-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2- a]pyrazine-6-carboxamide; N-(4-cyanophenyl)-N-methyl-3-{1 -methyl-1 H-pyrazolo[3,4-b]pyridin-
5- yl}imidazo[1 ,2-a]pyrazine-6-carboxamide; 4-({3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2- a]pyrazin-6-yl}methyl)morpholine; 5-{6-[(4-cyanophenyl)(methyl)carbamoyl]imidazo[1 ,2- a]pyrazin-3-yl}pyridine-2-carboxamide; N-[6-(dimethylamino)pyridin-3-yl]-N-methyl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(6-methoxypyridazin-3-yl)-N- methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; 3-(3-amino-1 H- indazol-5-yl)-N-(4-cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; 1 -({3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}carbonyl)piperidine-3-carboxamide; N-(6- chloropyridin-3-yl)-N-methyl-3-[4-(methylamino)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(2-methoxypyrimidin-5-yl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6- carboxamide; N-(4-cyanophenyl)-N-methyl-3-(6-{[2-(morpholin-4-yl)ethyl]amino}pyridin-3- yl)imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4-cyanophenyl)-3-(6-cyanopyridin-3-yl)-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide; 3-{4-[(1 -amino-2-methylpropan-2-yl)oxy]phenyl}- N-(4-cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; 6-N-(6-chloropyridin-3-yl)-
6- N-methyl-3-N-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-3,6-dicarboxamide; 5-C-3-[4- PAT054787-WO-PCT
(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-1 H-imidazole-4,5-dicarboxamide; N-[1 -(4- chlorophenyl)ethyl]-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine
carboxamide; N-{4-[(1 ,3-thiazol-2-yl)sulfamoyl]phenyl}-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2- a]pyrazine-6-carboxamide; N-(6-chloropyridin-3-yl)-N-methyl-3-[6-(methylamino)pyridin-3- yl]imidazo[1 ,2-a]pyrazine-6-carboxamide; 3-[4-(2-amino-2-methylpropanamido)phenyl]-N-(4- cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; 3-[4-(2-aminoethoxy)phenyl]-N- methyl-N-(5-methylpyridin-2-yl)imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(6-chloropyridin-3-yl)- N-methyl-3-[4-(1 ,3,4-oxadiazol-2-yl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; 6-fluoro-1 - ({8-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}carbonyl)-1 ,2,3,4- tetrahydroquinoline; N-(5-cyclopentylpyridin-2-yl)-N-met yl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(6-chloropyridin-3-yl)-N- methyl-3-[6-(trifluoromethyl)pyridin-3-yl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-[2-(4- fluorophenyl)propan-2-yl]-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; methyl N-(5-{6-[methyl(5-methylpyridin-2-yl)carbamoyl]imidazo[1 ,2-a]pyrazin-3-yl}pyridin-2- yl)carbamate; N-methyl-N-{[1 ,2,4]triazolo[4,3-a]pyridin-5-yl}-3-[4-
(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; 4-tert-butyl-N-methyl-N-{3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}benzamide; N-(6-chloropyridin-3-yl)-3-[3- (dimethylamino)phenyl]-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N-(6-chloropyridin-3- yl)-3-(4-methanesulfonamidophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N- methyl-N-(2-methylpyridin-3-yl)-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6- carboxamide; N-methyl-N-(5-methylpyrimidin-2-yl)-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2- a]pyrazine-6-carboxamide; N-(6-chloropyridin-3-yl)-3-(4-fluorophenyl)-N-methylimidazo[1 ,2- a]pyrazine-6-carboxamide; N-methyl-N-(4-phenyl-1 ,3-thiazol-2-yl)-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; cyanophenyl)-N-methyl-3-(3- methyl-1 H-indazol-5-yl)imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4-acetylphenyl)-N-methyl-3- [4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; 1 -({3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}methyl)piperidin-2-one; N-(4-cyanophenyl)-3- [4-(dimethylcarbamoyl)phenyl]-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4- cyanophenyl)-3-(1 H-indol-5-yl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N-(6- chloropyridin-3-yl)-3-[4-(difluoromethoxy)phenyl]-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide; N-(4-fluoro-2-methoxyphenyl)-N-methyl-3-[4 (trifluoromethyl)phenyl]imidazo[1 ,2- a]pyrazine; N-(3,4-difluorophenyl)-3-(4-methoxyphenyl)-N-methylimidazo[1 ,2-a]pyrazine-6- PAT054787-WO-PCT carboxamide; N-(4-chlorophenyl)-N-methyl-3-(4-methylphenyl)imidazo[1 ,2-a]pyrazine-6- carboxamide; 3-[4-(difluoromethoxy)phenyl]-N-(4-fluorophenyl)-N-methylimidazo[1 ,2- a]pyrazine-6-carboxamide; N-(5-bromopyrimidin-2-yl)-N-methyl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(5-chloropyridin-2-yl)-N- methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-methyl-N-[4- (propan-2-yloxy)phenyl]-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxam 4- [({3-[4-(dimethylamino)phenyl]imidazo[1 ^^ N- (4-cyanophenyl)-3-[3-(dimet ylamino)phenyl]-N-methylimidazo[1 ,2-a]pyrazine-6-ca
3-(6-chloropyridin-3-yl)-N-(4-cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxami N- (3-methoxyphenyl)-N-met yl-3-[4-(trifluorom
N-(4-cyanophenyl)-3-(4-methoxy-2-methylphenyl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide; N-(7-chloro-1 ,3-benzothiazol-2-yl)-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2- a]pyrazine-6-carboxamide; 4-fluoro-N-methyl-N-(3-{4-[5-(methylamino)-1 ,3,4-thiadiazol-2- yl]phenyl}imidazo[1 ,2-a]pyrazin-6-yl)benzamide; 3-{6-[(6-fluoro-1 ,2,3,4-tetrahydroquinolin-1 - yl)carbonyl]imidazo[1 ,2-a]pyrazin-3-yl}-N,N-dimethylaniline; N,3-bis[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4-cyanophenyl)-N-methyl-3- {4-[5-(methylamino)-1 ,3,4-oxadiazol-2-yl]phenyl}imidazo[1 ,2-a]pyrazine-6-carboxamide; 4-{6- [(7-fluoro-3,3-dimethyl-3,4-dihydro-2H-1 ,4-benzoxazin-4-yl)carbonyl]imidazo[1 ,2-a]pyrazin-3- yljbenzamide; 4-{6-[(6-fluoro-1 ,2,3,4-tetrahydroquinolin-1 -yl)carbonyl]imidazo[1 ,2-a]pyrazin-3- yljbenzamide; N-(4-fluorophenyl)-N-methyl-3-[4-(1 ,3,4-thiadiazol-2-yl)phenyl]imidazo[1 ,2- a]pyrazine-6-carboxamide; 4-{6-[(6-fluoro-1 ,2,3,4-tetrahydroquinolin-l -yl)carbonyl]imidazo[1 ,2- a]pyrazin-3-yl}-N-methylbenzamide; N-(4-{6-[(7-fluoro-3,3-dimethyl-3,4-dihydro-2H-1 ,4- benzoxazin-4-yl)carbonyl]imidazo[1 ,2-a]pyrazin-3-yl}phenyl)acetamide; N-methyl-4-{6-[N- methyl(4-fluorobenzene)amido]imidazo[1 ,2-a]pyrazin-3-yl}benzamide; N-methyl-N-(4- sulfamoylphenyl)-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; 4-{6-[(7- fluoro-3,4-dihydro-2H-1 ,4-benzoxazin-4-yl)carbonyl]imidazo[1 ,2-a]pyrazin-3-yl}benzamide; 4-{6- [N-methyl(4-fluorobenzene)amido]imidazo[1 ,2-a]pyrazin-3-yl}benzamide; 4-fluoro-N-methyl-N- (3-{1 H^yrrolo[2,3-b]pyridin-5-yl}imidazo[1 ,2-a]pyrazin-6-yl)benzamide; 1 -{[3-(2,3-dihydro-1 - benzofuran-5-yl)imidazo[1 ,2-a]pyrazin-6-yl]carbonyl}-6-fluoro-1 ,2,3,4-tetrahydroquinoline; 3-(4- carbamoylphenyl)-N-methyl-N-(5-methylpyridin-2-yl)imidazo[1 ,2-a]pyrazine-6-carboxam 4- {6-[(7-fluoro-3,4-dihydro-2H-1 ,4-benzoxazin-4-yl)carbonyl]imidazo[1 ,2-a]pyrazin-3-yl}-N- methylbenzamide; 6-fluoro-1 -{[3-(3-met anesulfonylphenyl)imidazo[1 ,2-a]pyrazin-6- PAT054787-WO-PCT yl]carbonyl}-1 ,2,3,4-tetrahydroquinoline; 3-[6-(4-acetylpiperazin-1 -yl)pyridin-3-yl]-N-(4- cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; 6-fluoro-1 -{[3-(4- methanesulfonylphenyl)imidazo[1 ,2-a]pyrazin-6-yl]carbonyl}-1 ,2,3,4-tetrahydroquinoline; 1 -{[3- (1 -ethyl- 1 H-pyrazol-4-yl)imidazo[1 ,2-a]pyrazin-6-yl]carbonyl}-6-fluoro-1 ,2,3,4- tetrahydroquinoline; N-(4-cyanophenyl)-N-methyl-3-[6-(piperazin-1 -yl)pyridin-3-yl]imidazo[1 ,2- a]pyrazine-6-carboxamide; N-(4-cyanophenyl)-3-(furan-2-yl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide; N-(4-cyanophenyl)-3-(furan-2-yl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; 6-fluoro-1 -({3-[2-(piperazin-1 -yl)pyridin-4-yl]imidazo[1 ,2-a]pyrazin-6-yl}carbonyl)-1 ,2,3,4- tetrahydroquinoline; N-(4-chlorophenyl)-N-methyl-3-[4-(1 ,3,4-thiadiazol-2-yl)phenyl]imidazo[1 ,2- a]pyrazine-6-carboxamide; N-methyl-3-[4-(methylcarbamoyl)phenyl]-N-(5-methylpyridin-2- yl)imidazo[1 ,2-a]pyrazine-6-carboxamide; N-cyclohexyl-4-{6-[(6-fluoro-1 ,2,3,4- tetrahydroquinolin-1 -yl)carbonyl]imidazo[1 ,2-a]pyrazin-3-yl}benzamide; 4-fluoro-N-methyl-N-[3- (1 -methyl-1 H-indazol-5-yl)imidazo[1 ,2-a]pyrazin-6-yl]benzamide; 1 -[4-(5-{6-[(6-fluoro-1 ,2,3,4- tetrahydroquinolin-1 -yl)carbonyl]imidazo[1 ,2-a]pyrazin-3-yl}pyridin-2-yl)piperazin-1 -yl]ethan-1 - one; 6-fluoro-1 -({3-[3-(morpholin-4-ylmethyl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}carbonyl)- ,2,3,4-tetrahydroquinoline; N-(5-methylpyridin-2-yl)-3-[4-(trifluoromethyl)phenyl]imidazo[ ,2- a]pyrazine-6-carboxamide; N-(4-ethylpyridin-2-yl)-N-methyl-3-[4-
(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4-cyanophenyl)-N-methyl-3- {4-[5-(methylamino)-1 ,3,4-thiadiazol-2-yl]phenyl}imidazo[1 ,2-a]pyrazine-6-carboxamide; 4-(6- {[(4-chlorophenyl)(methyl)amino]methyl}imidazo[1 ,2-a]pyrazin-3-yl)benzamide; N-(4- fluorophenyl)-N-methyl-3-{4-[5-(methylamino)-1 ,3,4-oxadiazol-2-yl]phenyl}imidazo[1 ,2- a]pyrazine-6-carboxamide; 4-[({3-[4-(difluoromethoxy)phenyl]imidazo[1 ,2-a]pyrazin-6- yl}methyl)(methyl)amino]benzonitrile; N-(4-chlorophenyl)-N-methyl-3-(1 -methyl-1 H-indazol-5- yl)imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4-cyanophenyl)-N-methyl-3-[4-(1 H-pyrazol-5- yl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; methyl N-(4-{6-[(4- cyanophenyl)(methyl)carbamoyl]imidazo[1 ,2-a]pyrazin-3-yl}phenyl)carbamate; N-(4- chlorophenyl)-N-methyl-3-{4-[5-(methylamino)-1 ,3,4-oxadiazol-2-yl]phenyl}imidazo[1 ,2- a]pyrazine-6-carboxamide; N-(4-cyanophenyl)-N-methyl-3-[4-(1 H-pyrazol-3- yl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4-cyanophenyl)-3-(4-acetamidophenyl)-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide; 3-(4-carbamoylphenyl)-N-(4-chlorophenyl)-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4-cyanophenyl)-N-methyl-3-(1 -methyl-1 H- indazol-5-yl)imidazo[1 ,2-a]pyrazine-6-carboxamide; N-[3-(6-acetamidopyridin-3-yl)imidazo[1 ,2- PAT054787-WO-PCT a]pyrazin-6-yl]-4-fluoro-N-methylbenzamide; N-(6-chloropyridin-3-yl)-N-methyl-3-(1 -methyl-1 H- indazol-5-yl)imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4-fluoropyridin-2-yl)-N-methyl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-methyl-N-(5-methylpyridin-2- yl)-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(2-methoxypyridin-3- yl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4- cyanophenyl)-N-methyl-3-[4-(1 ,3,4-thiadiazol-2-yl)phenyl]imidazo[1 ,2-a]pyrazine-6- carboxamide; (1 ,1 -dioxido-2H-benzo[b][1 ,4]thiazin-4(3H)-yl)(3-(4- (trifluoromethyl)phenyl)imidazo[1 ,2-a]pyrazin-6-yl)methanone; 4-{6-[N-methyl(4- cyanobenzene)amido]imidazo[1 ,2-a]pyrazin-3-yl}benzamide; N-(2-chloro-1 ,3-thiazol-5-yl)-N- methyl-3-[4 (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; 4-({3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}carbonyl)-1 ,2,3,4-tetrahydroquinoxalin-2-one; N-methyl-N-{3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}pyrimidine-5-carboxamide; N-methyl-N-(6-phenylpyridin-3-yl)-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6- carboxamide; N-methyl-N,3-bis[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6- carboxamide; N-(4-methanesulfonylphenyl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2- a]pyrazine-6-carboxamide; N-(3-chloro-4-cyanophenyl)-N-methyl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; and N-(4-cyano-2- methoxyphenyl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide
Embodiment 54. A compound, or a salt, tautomer or stereoisomer thereof, according to embodiment 1 , wherein the compound is selected from the group consisting of: 3-(4- carbamoylphenyl)-N-(4-fluorophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4- cyanophenyl)-N-methyl-3-[4-(methylcarbamoyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4-cyanophenyl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; 4-[methyl({3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}methyl)amino]benzonitrile; 4- (6-{[(4-fluorophenyl)(methyl)amino]methyl}imidazo[1 ,2-a]pyrazin-3-yl)benzamide; 4-(6-{[(4- cyanophenyl)(methyl)amino]methyl}imidazo[1 ,2-a]pyrazin-3-yl)benzamide; N-(4-chlorophenyl)- N-methyl-3-[4-(methylcarbamoyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4- cyanophenyl)-3-(6-acetamidopyridin-3-yl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; 4-(6- {[(4-chlorophenyl)(methyl)amino]methyl}imidazo[1 ,2-a]pyrazin-3-yl)benzamide; methyl N-(4-{6- [(4-cyanophenyl)(methyl)carbamoyl]imidazo[1 ,2-a]pyrazin-3-yl}phenyl)carbamate; 3-(4- PAT054787-WO-PCT carbamoylphenyl)-N-(4-chlorophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; and N- (4-cyanophenyl)-N-methyl-3-(1 -methyl-1 H-indazol-5-yl)imidazo[1 ,2-a]pyrazine-6-carboxamide.
Embodiment 55. A pharmaceutical composition comprising at least one compound of any one of embodiments 1 to 54, or a pharmaceutically acceptable salt, or stereoisomer, thereof, and a pharmaceutically acceptable carrier, diluent or excipient.
Embodiment 56. A pharmaceutical composition according to embodiment 55 further comprising a second agent.
Embodiment 57. A pharmaceutical composition according to embodiment 56, wherein the second agent is an antimalarial drug selected from artemisinin, artemether, artesunate, arteflene, dihydroartemisinin, chlorproguanil, trimethoprim, chloroquine, quinine, mefloquine, amodiaquine, atovaquone, proguanil, lumefantrine, piperaquine, pyronaridine, halofantrine, pyrimethamine-sulfadoxine, quinacrine, pyrimethamine-dapsone, quinidine, amopyroquine, sulphonamides, primaquine, ferroquine, tafenoquine, arterolane, and pyronaridine.
Embodiment 58. A compound according to any one of embodiments 1 to 54 or a
pharmaceutical composition according to any one of embodiments 55 to 57 for use as a medicament.
Embodiment 59. A method for treating, preventing, inhibiting, ameliorating, or eradicating the pathology and/or symptomology of a disease caused by a Plasmodium parasite, comprising administering to a subject a therapeutically effective amount of a compound according to any one of the embodiments 1 to 54 or a composition according to any one of the embodiments 55 to 57, wherein the administering may be in combination with a second agent.
Embodiment 60. A method for treating, preventing, inhibiting, ameliorating, or eradicating the pathology and/or symptomology of a disease caused by a Plasmodium parasite, according to embodiment 59, wherein the disease is malaria.
8o PAT054787-WO-PCT
Embodiment 61. A method for treating, preventing, inhibiting, ameliorating, or eradicating the pathology and/or symptomology of a disease caused by a Plasmodium parasite according to any one of embodiments 59 to 60, wherein the Plasmodium parasite is at the blood stages.
Embodiment 62. A method for treating, preventing, inhibiting, ameliorating, or eradicating the pathology and/or symptomology of a Plasmodium related disease caused by a Plasmodium parasite according to any one of embodiments 59 to 60, wherein the Plasmodium parasite is at the hepatic stages.
Embodiment 63. A method for treating, preventing, inhibiting, ameliorating, or eradicating the pathology and/or symptomology of a Plasmodium related disease caused by a Plasmodium parasite according to any one of embodiments 59 to 62, wherein the Plasmodium parasite is selected from group consisting of Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, and Plasmodium malaria.
Embodiment 64. A method for treating, preventing, inhibiting, ameliorating, or eradicating the pathology and/or symptomology of a Plasmodium related disease caused by a Plasmodium parasite according to any one of embodiments 59 to 62, wherein the Plasmodium parasite is Plasmodium falciparum.
Embodiment 65. A method for treating, preventing, inhibiting, ameliorating, or eradicating the pathology and/or symptomology of a Plasmodium related disease caused by a Plasmodium parasite according to any one of embodiments 59 to 64, wherein the second agent is selected from a kinase inhibitor, an anti-malarial drug and an anti-inflammatory agent.
Embodiment 66. A method for treating, preventing, inhibiting, ameliorating, or eradicating the pathology and/or symptomology of a disease caused by Plasmodium parasite according to embodiment 65, wherein the anti-malarial drug is selected from artemisinin, artemether, artesunate, arteflene, dihydroartemisinin, chlorproguanil, trimethoprim, chloroquine, quinine, mefloquine, amodiaquine, atovaquone, proguanil, lumefantrine, piperaquine, pyronaridine, halofantrine, pyrimethamine-sulfadoxine, quinacrine, pyrimethamine-dapsone, quinidine,
8i PAT054787-WO-PCT amopyroquine, sulphonamides, primaquine, ferroquine, tafenoquine, arterolane, and pyronaridine.
Embodiment 67. A method for treating, preventing, inhibiting, ameliorating, or eradicating the pathology and/or symptomology of a disease caused by Plasmodium parasite according to any one of embodiments 59 to 66, wherein the compound is administered prior to, simultaneously with, or after the second agent.
Embodiment 68. A compound according to any one of embodiments 1 to 54 or a composition according to any one of embodiemnts 55 to 57 for treating, preventing, inhibiting, ameliorating, or eradicating the pathology and/or symptomology of a disease caused by a Plasmodium parasite.
Embodiment 69. Use of a compound according to any one of embodiments 1 -54 or a pharmaceutical composition according to embodiments 55 to 57 in the manufacture of a medicament for treating, preventing, inhibiting, or ameliorating the pathology and/or
symptomology of a disease caused by a Plasmodium parasite, wherein said use may be in combination with a second agent.
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. PAT054787-WO-PCT
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.
Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids, e.g., acetate, aspartate, benzoate, besylate, bromide/hydrobromide,
bicarbonate/carbonate, bisulfate/sulfate, camphorsulfonate, chloride/hydrochloride,
chlortheophyllonate, citrate, ethandisulfonate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hydroiodide/iodide, isethionate, lactate, lactobionate, laurylsulfate, malate, maleate, malonate, mandelate, mesylate, methylsulphate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen PAT054787-WO-PCT phosphate, polygalacturonate, propionate, stearate, succinate, subsalicylate, tartrate, tosylate and trifluoroacetate salts.
Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,
toluenesulfonic acid, sulfosalicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.
Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I to XII of the periodic table. In certain embodiments, the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper;
particularly suitable salts include ammonium, potassium, sodium, calcium and magnesium salts.
Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like. Certain organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine and tromethamine.
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., PAT054787-WO-PCT
(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 as 2H, 3H, 11C, 13C, 14C, 15N, 18F 31 P, 32P, 35S, 36CI, 125l respectively. The invention includes various isotopically labeled compounds as defined herein, for example those into which radioactive isotopes, such as 3H and 14C, or those into which nonradioactive isotopes, such as 2H and 13C are present. Such isotopically labelled compounds are useful in metabolic studies (with 14C), reaction kinetic studies (with, for example 2H or 3H), 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, an 18F 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.
Further, substitution with heavier isotopes, particularly deuterium (i.e., 2H or D) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements or an improvement in therapeutic index. It is understood that deuterium in this context is regarded as a substituent of a compound of the formula (I). The concentration of such a heavier isotope, specifically deuterium, may be defined by the isotopic enrichment factor. The term "isotopic enrichment factor" as used herein means the ratio between the isotopic abundance and the natural abundance of a specified isotope. If a substituent in a compound of this invention is denoted deuterium, such compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium PAT054787-WO-PCT incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).
Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D20, d6-acetone, d6-DMSO.
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).
As used herein, the term "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drug stabilizers, binders, excipients, disintegration agents, lubricants, sweetening agents, flavoring agents, dyes, and the like and combinations thereof, as would be known to those skilled in the art (see, for example, Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289- 1329). Except insofar as any conventional carrier is incompatible with the active ingredient, its use in the therapeutic or pharmaceutical compositions is contemplated.
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" PAT054787-WO-PCT 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.
As used herein, the term "subject" refers to an animal. Typically the animal is a mammal. A subject also refers to for example, primates {e.g., humans, male or female), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like. In certain embodiments, the subject is a primate. In yet other embodiments, the subject is a human.
As used herein, the term "inhibit", "inhibition" or "inhibiting" refers to the reduction or
suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.
As used herein, the term "treat", "treating" or "treatment" of any disease or disorder refers in one embodiment, to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof). In another embodiment "treat", "treating" or "treatment" refers to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient. In yet another embodiment, "treat", "treating" or "treatment" refers to modulating the disease or disorder, either physically, {e.g., stabilization of a discernible symptom), physiologically, {e.g., stabilization of a physical parameter), or both. In yet another embodiment, "treat", "treating" or "treatment" refers to preventing or delaying the onset or development or progression of the disease or disorder.
As used herein, a subject is "in need of" a treatment if such subject would benefit biologically, medically or in quality of life from such treatment. PAT054787-WO-PCT
As used herein, the term "a," "an," "the" and similar terms used in the context of the present invention (especially in the context of the claims) are to be construed to cover both the singular and plural unless otherwise indicated herein or clearly contradicted by the context.
All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language {e.g. "such as") provided herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed.
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 c/'s- (Z)- or trans- (£)- 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 (c/'s or trans) isomers, diastereomers, optical isomers (antipodes), racemates or mixtures thereof.
Any resulting mixtures of isomers can be separated on the basis of the physicochemical differences of the constituents, into the pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and/or fractional crystallization.
Any resulting racemates of final products or intermediates can be resolved into the optical antipodes by known methods, e.g., by separation of the diastereomeric salts thereof, obtained with an optically active acid or base, and liberating the optically active acidic or basic compound. In particular, a basic moiety may thus be employed to resolve the compounds of the present invention into their optical antipodes, e.g., by fractional crystallization of a salt formed with an PAT054787-WO-PCT optically active acid, e.g., tartaric acid, dibenzoyl tartaric acid, diacetyl tartaric acid, d\-0,0'-p- toluoyl tartaric acid, mandelic acid, malic acid or camphor-10-sulfonic acid. Racemic products can also be resolved by chiral chromatography, e.g., high pressure liquid chromatography (HPLC) using a chiral adsorbent.
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.
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 1 -5 provided infra., where variables Ring A, Ring B, Ring C, L, R1 ; R15, Ri6, R17, n, p and 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. PAT054787-WO-PCT
Scheme 1A. General synthesis route for amides of Formula I.
Figure imgf000091_0001
Figure imgf000091_0002
Figure imgf000091_0003
reagen s
Figure imgf000091_0004
ArA and ArG represent rings A and C respectively in formula I
Figure imgf000091_0005
Figure imgf000091_0006
PAT054787-WO-PCT
Scheme 2A. Alternative synthesis of amide compounds of Formula I.
Figure imgf000092_0001
aq. base (R17)p-Arc-NR2Me org. cosolvent amide coupling
Figure imgf000092_0002
reagents
ArA and Arc represent rings A and C in formula I, respectively
Scheme 2B.
Figure imgf000092_0003
Scheme 3A. General route for synthesis of aminoalkyl-linked compounds of Formula I.
Figure imgf000092_0004
Figure imgf000092_0005
ArA and Arc represent rings A and C in Formula I, respectively.
Scheme 3B. Alternative synthesis of aminoalkyl-linked compounds of Formula I.
9i PAT054787-WO-PCT
Figure imgf000093_0001
Bioorg. Med. Chem. Lett,
vol. 12, 1203-8 (2002)
Figure imgf000093_0002
EtOH / heat (Ri7) Arc
iPQ
Figure imgf000093_0003
ArA and ArG represent rings A and C in Formula I, respectively. Scheme 4. Direct arylation to introduce ring A.
Figure imgf000093_0004
microwaves
aq. base org. cosolvent
Figure imgf000093_0005
ArA and Arc represent rings A and C in Formula I, respectively.
Scheme 5A. General method for synthesis of sulfonylaminopyrazine derivatives. PAT054787-WO-PCT (R17)p-Arc-S02CI
base
Figure imgf000094_0001
Figure imgf000094_0002
Scheme 5B. General method for synthesis of acyl aminopyrazine derivatives.
Figure imgf000094_0003
ArA and Arc represent rings A and C in Formula I, respectively.
Figure imgf000094_0004
Boronic ester synthesis procedure A: PdCI2(dppf)■ CH2CI2;
A mixture of bromo compound (1 .0 eq.) and bis(pinacolato)diboron (1 .1 eq.) and potassium acetate (2.0 eq.) dissolved in 1 ,4-dioxane (10 vol) was degassed with argon gas for 15 min. Subsequently, PdCI2(dppf)■ CH2CI2 (0.05 eq.) was added and the reaction mixture was stirred at 85-100 °C for 16 h. The reaction mixture (generally black color) was filtered and concentrated under reduced pressure. The resulting black mixture was used further without any purification.
Boronic ester synthesis procedure B: Pd(PPh3)4; PAT054787-WO-PCT
A mixture of bromo compound (1 .0 eq.) and bis(pinacolato)diboron (1 .1 eq.), and potassium acetate (2.0 eq.) dissolved in 1 ,4-dioxane (10 vol) was degassed with argon gas for 15 min. Subsequently, Pd2(dba)3 (0.05 eq.) and tricyclohexyl phosphine (0.05 eq.) were added and the reaction mixture was stirred at 90 -1 10 °C for 16 h. The reaction mixture (generally black color) was filtered and concentrated under reduced pressure. The crude product was used further without any purification.
Figure imgf000095_0001
Suzuki Procedure A: SiliaCat® DPP-Pd and K2C03:
A mixture of bromo compound (0.2 mmol, 1 .0 equiv.), boronic acid (0.22 mmol, 1.1 equiv.), and SiliaCat® DPP-Pd (0.25 mmol/g loading, 0.01 mmol, 0.05 equiv.) was treated with 660 μΙ_ dioxane and 220 μΙ_ 1 M aq. K2C03 and the resulting mixture was allowed to heat overnight at 100 °C in a capped vial. The resulting black mixture was dry-loaded onto silica gel and was purified by silica gel chromatography, eluting with hexanes/EtOAc to give the desired product.
Suzuki Procedure B: Pd(dppf)CI2 and K2C03 in the microwave:
A mixture of aryl bromide (1 .0 equiv.), aryl boronic acid (1.5 equiv.), K2C03 (2.5 equiv.), and Pd(dppf)CI2 (0.05-0.15 equiv.) in THF/water was allowed to heat at 140 °C in a microwave reactor for 40 minutes. Purified by mass-triggered HPLC or silica gel chromatography to provide the desired product.
Suzuki Procedure C: SiliaCat® DPP-Pd/Pd(dppf)CI2 and K2HP04 in the microwave:
A mixture of aryl bromide (1 .0 equiv.), aryl boronic acid (1.5 equiv.), KH2P04 (3.5 equiv.), and SiliaCat® DPP-Pd or Pd(dppf)CI2 (0.05-0.15 equiv.) in THF/water was allowed to heat at 150 Ό in a microwave reactor for 40-60 minutes. Purified by mass-triggered HPLC or silica gel chromatography to provide the desired product.
Suzuki Procedure D: Pd(dppf)CI2, K2C03, DME-WATER: PAT054787-WO-PCT
A mixture of aryl bromide (1 .0 equiv.), aryl boronic acid (1.5 equiv.), K2C03 (3.0 equiv.), and Pd(dppf)CI2 (0.05-0.15 equiv.) in DME/water was allowed to heat at 1 10 °C for two hours.
Following extraction of the reaction mixture with CH2CI2, the combined organic extracts were concentrated and the residue was purified by silica gel chromatography, eluting with
hexanes/EtOAc to give the desired product.
Figure imgf000096_0001
Suzuki Procedure E: Pd2(dba)3, P(0-tolyl)3, 2M KF solution in toluene/ethanol :
A mixture of aryl bromide (1 .0 equiv.), aryl boronic acid (1.2-2.0 equiv.), 2 M aq KF (3 equiv.), and Pd2(dba)3 (0.1 equiv.), P(o-tolyl)3(0.1 equiv.) in toluene: ethanol (7:3) was degassed and heated to 100°C for 1 -5h. The crude products were purified by preparative TLC or silica gel chromatography to provide the desired product.
Suzuki Procedure F: Pd(PPh3)4, 1 N Na2C03, dioxane:
A mixture of aryl bromide (1 .0 equiv.), aryl boronic acid (1 .2-2.0 equiv.), 1 N Na2C03 (2.0 equiv.), and Pd(PPh3)4 (0.2 equiv.) in 1 ,4-dioxane was degassed and heated in a sealed tube to 100 °C (microwave or convential heating) for 2-6 h. The crude products were purified by preparative TLC or silica gel chromatography to provide the desired product.
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 those caused by Plasmodium falciparum; Plasmodium vivax; Plasmodium ovale; and PAT054787-WO-PCT
Plasmodium malaria, trypanosoma cruzi and parasites of the Leishmania genus, such as, for example, Leishmania donovani.
Plasmodia spp. which cause malaria belong to the phylum, Apicomplexa, which is a large and diverse group of protists that are human or animal parasites. These parasites are unicellular, spore-forming, and possess motile structures such as flaqella or pseudopods at certain gamete stages. Most of these parasites possess a unique organelle called apicoplast and an apical comples structure involved in penetrating a host's cell. The pathogenesis associated the diseases caused by these parasites is due to repeated cycles of host-cell invasion, intracellular replication and host-cell lysis. Therefore, understanding parasite proliferation is essential for development of novel drugs and vaccines, for example, to treat malaria.
In vertebrate hosts, the parasite undergoes two main phases of development, the hepathocytic and erythrocytic phases, but it is the erythrocytic phase of its life cycle that causes severe pathology. During the erythrocytic phase, the parasite goes through a complex but well synchronized series of stages, suggesting the existence of tightly regulated signaling pathways.
Calcium serves as an intracellular messenger to control synchronization and development in the erythrocytic life phase. The Plasmodium spp. genomes reveal many sequence identities with calcium binding/sensing protein motifs that include Pf39, calmodulin, and calcium dependent protein kinases (CDPKs). Plasmodium CDPKs, Plasmodium CDPK3 and 4, have been shown to be involved in mosquito infection. CDPK4 has been demonstrated to be essential for the sexual reproduction in the midgut of mosquito by translating the calcium signal into a cellular response and regulating cell cycle progression in the male gametocyte. CDPK3 regulates ookinete gliding motility and penetration of the layer covering the midgut epithelium. P.
falciparum CDPK1 (PfCDPKI ) is expressed during late schizogony of blood stage and in the infectious sporozoite stage and is secreted to the parasitophorous vacuole by an acylation- dependent mechanism. It can be myristoylated and is abundantly found in detergent-resistant membrane fractions isolated from schizogony-phase parasites. Ontology based pattern identification analysis reveals that PfCDPKI is clustered with genes associated with either parasite egress or erythrocyte invasion. Direct inhibition of PfCDPKI can arrest the parasite erythrocytic life cycle progression in the late schizogony phase. PAT054787-WO-PCT
Therefore, kinase activity is distributed in all the stages of P. falciparum parasite maturation and kinase inhibitors of the present invention can be used for treating Plasmodium related diseases.
The in vitro cellular assay, infra, can be used to assess the activity of compounds of the invention against a variety of malarial parasite strains.
In accordance with the foregoing, the present invention further provides a method for preventing or treating malaria 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 and la 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 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, PAT054787-WO-PCT 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). Non-limiting examples of compounds which can be used in combination with compounds of the invention are known anti-malarial drugs, for example, artemisinin, artemether, artesunate, arteflene, dihydroartemisinin, chlorproguanil, trimethoprim, chloroquine, quinine, mefloquine,
amodiaquine, atovaquone, proguanil, lumefantrine, piperaquine, pyronaridine, halofantrine, pyrimethamine-sulfadoxine, quinacrine, pyrimethamine-dapsone, quinidine, amopyroquine, sulphonamides, primaquine, ferroquine, tafenoquine, arterolane, and pyronaridine, etc. PAT054787-WO-PCT
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) at least one 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
The activity of a compound according to the present invention for inhibition of parasitemai in infected blood cells and liver cells can be assessed by the following assays. It is understood that the assays illustrate the invention without in any way limiting the scope of the invention.
Assay for P. falciparum Proliferation in Infected Human Blood Cells PAT054787-WO-PCT
Compounds of the invention can be assayed to measure their capacity to inhibit proliferation of P. falciparum parasitemia in infected red blood cells. This parasite proliferation assay measures the increase in parasite DNA content using a DNA intercalating dye, SYBR Green®
(INVITROGEN®) which has a high affinity for double stranded DNA.
NF54 or 3D7 P. falciparum strain is grown in complete culturing media until parasitemia reaches 3% to 8% with 0+ human erythrocytes. The selection of either strain is of convenience (3D7 is a clone of NF54) and does not make a difference to the assay. 20 μΙ of screening media is dispensed into 384 well assay plates. 50 nl of compounds of the invention (in DMSO), including antimalarial controls (mefloquine, pyrimethamine and artemisinin), are then transferred into the assay plates, as well as DMSO alone to serve as a negative control for inhibition. Then 30 μΙ of a suspension of a NF54 or 3D7 P. falciparum infected erythrocytes in screening media is dispensed into the assay plates such that the final hematocrit is 2.5% with a final parasitemia of 0.3%. The plates are placed in a 37 SC incubator for 72 hours in a low oxygen environment containing 93% N2, 4% C02, and 3% 02 gas mixture. 10 μΙ of lysis buffer (saponin, triton-X, EDTA) containing a 10X solution of SYBR Green I® in RPMI media is dispensed into the plates. The plates are lidded and kept at room temperature overnight for the lysis of the infected red blood cells. The fluorescence intensity is measured (excitation 425nm, emission 530nm) using the Envision™ system (Perkin Elmer). The percentage inhibition of 50%, EC50, is calculated for each compound.
Using the P. falciparum Proliferation Assay above, compounds of the invention exhibit inhibitory efficacy (EC50) of typically 10 μΜ or less, more typically less than 2 μΜ, most typically less than 200 nM. Compounds of the invention can significantly delay the increase in P. falciparum parasitemia. For example, 4-[({3-[4-(5-amino-1 ,3,4-thiadiazol-2-yl)phenyl]imidazo[1 ,2-a]pyrazin- 6-yl}methyl)(methyl)amino]benzonitrile (Example 25); N,5-dimethyl-N-({3-[4-(1 H-pyrazol-5- yl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}methyl)pyridin-2-amine (Example 47); N-(4-cyanophenyl)- N-[2-(dimethylamino)ethyl]-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide (Example 72); 4-(6-{[(4-fluorophenyl)(methyl)amino]methyl}imidazo[1 ,2-a]pyrazin-3- yl)benzamide (Example 222); 4-(6-{[(4-chlorophenyl)(methyl)amino]methyl}imidazo[1 ,2- a]pyrazin-3-yl)benzamide (Example 477), N-(4-fluorophenyl)-N-methyl-3-{4-[5-(methylamino)- 1 ,3,4-oxadiazol-2-yl]phenyl}imidazo[1 ,2-a]pyrazine-6-carboxamide (Example 478); N-(4- PAT054787-WO-PCT chlorophenyl)-N-methyl-3-{4-[5-(methylamino)-1 ,3,4-oxadiazol-2-yl]phen
a]pyrazine-6-carboxamide (Example 483), and 3-(4-carbamoylphenyl)-N-(4-chlorophenyl)-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide (Example 486), all have EC50 values of less than 50 nM.
The inhibitory efficacy of the compounds of the invention in delaying the increase in P.
falciparum parasitemia in infected human blood cells is provided in Table 1 .
Table 1. Inhibitory Efficacy of Compounds of the Invention in delaying P. falciparum Proliferation in Infected Human Blood Cells
Figure imgf000102_0001
Figure imgf000102_0003
PAT054787-WO-PCT
Figure imgf000103_0001
Figure imgf000103_0002
Figure imgf000103_0003
PAT054787-WO-PCT
Figure imgf000104_0001
Figure imgf000104_0002
Figure imgf000104_0003
PAT054787-WO-PCT
Figure imgf000105_0001
Figure imgf000105_0002
Figure imgf000105_0003
PAT054787-WO-PCT
Figure imgf000106_0001
Figure imgf000106_0002
Figure imgf000106_0003
PAT054787-WO-PCT
Figure imgf000107_0001
Figure imgf000107_0002
Figure imgf000107_0003
Assay for Profiferation of Parasite in Infected Liver Cells
Compounds of the invention can be assayed to measure their capacity to inhibit proliferation of parasites in liver cells. The proliferation is quantified by determine the number of infected cells by immunofluorescence.
Parasites io6 PAT054787-WO-PCT
Due to the difficulty of successfully infecting immortalized human liver cell lines with the human malaria sporozoites (liver-stage parasite), rodent malaria sporozoites from Plasmodium yoelii (17XNL) and P. berghei (ANKA) are the preferred surrogate. Sporozoites are obtained from Anopheles Stephens! mosquitoes supplied by the New York University Insectary, which ships the malaria-infected mosquitoes 10-13 days following the ingestion of an infective blood meal.
Cell Line
A transgenic HepG2 cell line expressing the tetraspanin CD81 receptor (HepG2-A16-CD81 EGFP) is used to increase the infectivity rate of rodent-malaria sporozoites into human cells. HepG2- A16-CD81 EGFP cells are stably transformed to express a GFP-CD81 fusion protein. A
continuous in vitro culture of this line was maintained at 37 °C in 4% C02 in complete media (CM) which contains: DMEM (Invitrogen, Carlsbad, USA) supplemented with 10% FCS, 0.29 mg/ml glutamine, 100 units penicillin and 100 μg/ml streptomycin (SigmaAldrich, USA).
P. yoelii Sporozoite Invasion Assay
Twenty to twenty-six hours prior to sporozoite infection, 7.5x103 HepG2-A16-CD81 EGFP cells are seeded into 384-well plates (Aurora 384 IQ-EB black plates with clear bottoms; 50 μΙ of
1.5x105cells/ml in CM). These plates are incubated at 37 °C with 4% C02 overnight. Two hours prior to infection, 50nl of compound dissolved in DMSO (0.1 % final DMSO concentration per well) were transferred with a PinTool (GNF Systems) into the assay plates (10 μΜ final concentration). A 1 :3 serial dilution of atovaquone (10 μΜ at the highest final concentration) and wells treated only with DMSO were used as positive and negative controls, respectively.
Freshly dissected salivary glands from infected mosquitoes were homogenized in a glass tissue grinder, filtered twice through Nylon cell strainers (40 μηι pore size, BD Falcon) and counted using a hemocytometer. The assay plate with HepG2-A16-CD81 EGFP cells and compound were then infected with 8x103 sporozoites per well and the plates are subjected to a centrifugal force of 650x0 to pellet the sporozoites onto the liver cell monolayer. The assay plate is incubated at 37 °C for 2 hours to permit sporozoite invasion, then the media is aspirated from the media plate, and replaced with 50 μΙ CM (containing a 5x concentration of penicillin/streptomycin; 500 units penicillin and 0.5 mg streptomycin per ml) per well. 50 nl of compound is re-introduced by PinTool and the assay plate incubated for 48 hours at 37 °C before quantification of infected PAT054787-WO-PCT cells by immunofluorescence. The increased antibiotic concentration does not interfere with the parasite or HepG2-A16-CD81 EGFP growth.
Atovaquone and uninfected wells were used as controls on each plate. Two replicate plates are tested for each assay.
Immunofluorescence quantification of exo-ervthrocvtic forms (EEFs)
After fixing the cells by addition of 12.5 μΙ of 20% solution of paraformaldehyde (EMS, Hatfield, USA) to each assay well (4% final formaldehyde concentration), membranes were
permeabilized with 0.5% Triton-X-100 (Thermo Fisher Scientific) and EEFs were stained using a mouse polyclonal serum raised against the Plasmodium yoelii heal shock protein 70 (PyHSP70), a DyLight 649 goat anti-mouse IgG, Fc(gamma) fragment specific secondary antibody (Jackson Immuno Research, Cat# 1 15-495-071 ) and the Hoechst 33342 nucleic acid dye (Invitrogen, Carlsbad, USA). Stained EEFs were then quantified using the Opera Confocal High Content Screening System (PerkinElmer, Waltham, USA). Images were collected using a 20x objective lens (20x/0.45 NA, LWD Plan Fluor, Olympus) at a binning of 2, using a 365 nm Xeon arc lamp illumination to detect the Hoechst-labeled nuclei and 635 nm laser line to excite Dyl_ight649- labeled parasites. The image resolution yielded was approximately 0.66 μηι/pixel (-Ό.43 μηι 2/pixel). All images were analyzed using a custom Acapella™ (PerkinElmer) script
parametrized for this assay. In brief, images from fields inside the well were first discarded as out-of focus when the intensity in the nuclear channel was too low. Then, HepG2-A16-CD81 EGFP cells were counted by detecting the nuclei labeled with Hoechst using the nuclei detection libraries available with Acapella™. Parasites were later segmented using the aPyHSP70 immuno-labeling signal, using a custom script library. Once the objects were segmented from the picture, morphological-based (e.g. size, roundness, etc) and intensity-based features were measured for each object detected in the image (i.e. nuclei and parasites). Infection ratio was set as the ratio between parasite number and number of nuclei counted in images considered as "in-focus". EC50 values were obtained using parasite area and a custom curve fitting model, and a standard logistic regression model was applied for curve fitting.
Using the P. yoe//7 Sporozoite Invasion Assay, compounds of the invention exhibit inhibitory efficacy (EC50) of typically 1 μΜ or less, more typically 200 nM less. Selected compounds, for io8 PAT054787-WO-PCT example, 4-[methyl({3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6- yl}methyl)amino]benzonitrile (Example 213); 4-(6-{[(4- fluorophenyl)(methyl)amino]methyl}imidazo[1 ,2-a]pyrazin-3-yl)benzamide (Example 222), 4-(6- {[(4-cyanophenyl)(methyl)amino]methyl}imidazo[1 ,2-a]pyrazin-3-yl)benzamide (Example 223); N-(4-chlorophenyl)-N-methyl-3-[4-(methylcarbamoyl)phenyl]imidazo[1 ,2-a]pyrazine-6- carboxamide (Example 228); and 4-(6-{[(4-chlorophenyl)(methyl)amino]methyl}imidazo[1 ,2- a]pyrazin-3-yl)benzamide (Example 477) all have EC50 values of less than 50 nM. Inhibitory efficacy of selected compounds in delaying the proliferation of P. yoelii Sporozoite in liver cells is listed in Table 2. Compounds of the invention hence show delay of the proliferation of P. yoelii in liver cells.
Table 2. Inhibitory Efficacy of Compounds of the Invention in delaying the Proliferation of P. yoelii Sporozoite in Infected Liver Cells
Figure imgf000110_0001
Figure imgf000110_0002
Figure imgf000110_0003
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- PAT054787-WO-PCT
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.
LC-MS Methods
Method 1 :
Waters Acquity Binary Gradient Pump; Waters Acquity PDA Detector. Waters Auto sampler; Waters Quattro micro API Mass Spectrometer with ESI and APCI ion source; UPLC Column: Waters Acquity;BEH;C18 1 .7um 50x2.1 mm ; Mobile Phase: (A) H20 + 0.025%TFA and (B) Acetonitrile + 0.025%TFA. Gradient: 0.4ml_/minute, initial 15% B ramp to 95% B over 3.0 minutes, then hold until 4.0 minutes, return to 15% B at 4.1 minutes until end of run , then equilibrated the column for 2.0 minutes; MS Scan: 100 to l OOOamu in 0.5 seconds per channel; Diode Array Detector: 200nm and 400nm.
Method 2:
Waters Acquity Binary Gradient Pump; Waters Acquity PDA Detector. Waters Auto sampler; Waters Quattro micro API Mass Spectrometer with ESI and APCI ion source; UPLC Column: Waters Acquity;BEH;C18 1 .7um 50x2.1 mm ; Mobile Phase: (A) H20 + 0.025%TFA and (B) Acetonitrile + 0.025%TFA. Gradient: 0.4ml_/minute, initial 20% B ramp to 90% B over 2.0 minutes, then hold until 4.0 minutes, return to 20% B at 4.1 minutes until end of run , then equilibrated the column for 2.0 minutes; MS Scan: 100 to l OOOamu in 0.5 seconds per channel; Diode Array Detector: 200nm and 400nm.
Method 3: no PAT054787-WO-PCT
Waters Acquity Binary Gradient Pump; Waters Acquity PDA Detector. Waters Auto sampler; Waters Acquity Evaporative Light Scattering Detector; Waters Quattro micro API Mass
Spectrometer with ESI and APCI ion source; UPLC Column: Waters Acquity;BEH;C18 1.7um 100x2.1 mm ; Mobile Phase: (A) H20 + 0.025%TFA and (B) Acetonitrile + 0.025%TFA.
Gradient: 0.3mL/minute, initial 10% B ramp to 80% B over 4.0 minutes, then hold until 6.0 minutes, return to 10% B at 6.1 minutes until end of run , then equilibrated the column for 2.5 minutes; MS Scan: 100 to 10OOamu in 0.5 seconds per channel; Diode Array Detector: 200nm and 400nm; Drift tube temperature: 50<€ and N2 gas flow:40Psi for ELSD Detector.
Method 4:
Agilent 1200sl/ 6140 system; UPLC Column: Waters Acquity;HSS T3;C18 1.8um 50x2.0 mm ; Mobile Phase: (A) H20 + 0.05%TFA and (B) Acetonitrile + 0.035%TFA. Gradient:
0.9mL/minute, initial 10% B ramp to 100 % B over 1.95 minutes, then return to 10% B at 2.00 minutes until end of run, MS Scan: 100 to l OOOamu in 0.5 seconds per channel; Diode Array Detector: 190nm and 400nm; Drift tube temperature: 50 °C and N2 gas flow:40Psi for ELSD Detector.
Method 5
Agilent 1 10Osl/ 1946 system; UPLC Column: Waters atlantis; C18 1 .8um 50x2.0 mm ; Mobile Phase: (A) H20 + 0.05%TFA and (B) Acetonitrile + 0.035%TFA. Gradient: 1 .0 mL/minute, initial 10% B ramp to 90 % B over 3.00 minutes, then return to 10% B at 3.5 minutes until end of run, MS Scan: 100 to 1000amu in 0.5 seconds per channel; Diode Array Detector: 190 nm and 400nm; Drift tube temperature: 50°C and N2 gas flow:40Psi for ELSD Detector.
Analytical method: WATERS ZQ SHIMADZU LEAP CTC, ZORBAX SB-C8 30*4.6mm,3.5um, UV1 :220nm, UV2:254nm, A:H2O(0.03%TFA), B:CH3CN(0.05%TFA), Flow:2.000 (ml/min), Time/%B: 0/5, 1.90/95, 2.30/95, 2.31 /5, 2.50/5
Synthesis of Intermediates Synthesis of Ethyl pyrrolo[1 ,2-a]pyrazine-3-carboxylate (1-1).
in PAT054787-WO-PCT
Figure imgf000113_0001
1-1
Chloroacetaldehyde (9.5 mL of a 50 wt% solution in water) was added to a mixture of aminopyrazine (2.00 g, 12.0 mmol), sodium bicarbonate (2.00 g, 23.8 mmol) and absolute ethanol (100 mL). The reaction was heated to 90 °C for 16 hours. After cooling to room temperature, the reaction was concentrated and purified by flash chromatography (silica, 0-10% methanol/chloroform) to give pure 1-1 as a tan colored solid. 1 H NMR (400 MHz, CDCI3) δ 9.18
(s, 1 H), 9.01 (d, J= 1.4, 1 H), 7.93 (d, J= 1 .1 , 1 H), 7.84 (s, 1 H), 4.51 (q, J= 7.1 , 3H), 1 .46 (t, J =
7.1 , 4H).
Synthesis of Ethyl 2-methylimidazo[1 ,2-a]pyrazine-6-carboxylate (I-2).
Figure imgf000113_0002
A mixture of aminopyrazine, 1 -chloropropan-2-one and ethanol was heated in a microwave synthesizer at 180 °C for 60 minutes. After cooling to room temperature, the solvent is removed and the dark brown residue is purified by flash chlromatography (silica, 30-60% ethyl acetate/hexanes) to give I-2 as a tan colored solid. 1 H NMR (400 MHz, CDCI3) δ 9.00 (s, 1 H), 8.89 (d, J= 1 .3, 1 H), 7.53 (d, J= 23.3, 1 H), 4.48 (q, J= 7.1 , 2H), 2.53 (s, 3H), 1 .44 (t, J= 7.1 , 3H).
Synthesis of Ethyl -(trifluoromethyl)imidazo[1 ,2-a]pyrazine-6-carboxylate (I-3)
Figure imgf000113_0003
A mixture of aminopyrazine, 3-bromo-1 ,1 ,1 -trifluoropropan-2-one and ethanol was heated in a microwave synthesizer at 180 °C for 60 minutes. After cooling to room temperature, the solvent is removed and the dark brown residue is purified by flash chlromatography (silica, 30-60% ethyl acetate/hexanes) to give I-3 as a tan colored solid. 1 H NMR (400 MHz, CDCI3) δ 9.24 (s, 1 H), 8.99 (d, J = 1 .4, 1 H), 8.10 (s, 1 H), 4.51 (q, J= 7.1 , 2H), 1.46 (t, J = 7.1 , 3H).
Synthesis of Ethyl 3-bromoimidazo[1 ,2-a]pyrazine-6-carboxylate (I-4) PAT054787-WO-PCT
Figure imgf000114_0001
NBS (139 mg, 0.785 mmol) was added in one portion to a solution of ethyl pyrrolo[1 ,2- a]pyrazine-3-carboxylate (100 mg, 0.523 mmol) and dichloromethane (2.0 mL) at room temperature. After three hours, the reaction was filtered and the filtrate was purified by flash chromatography (silica, 10-100% ethyl acetate/hexanes) to give pure I-4 as a white colored solid. 1H NMR (400 MHz, DMSO) 5 9.15 (s, 1 H), 8.83 (s, 1 H), 8.10 (s,1 H), 4.40 (q, J = 1.2 2H), 1.37 (t, J = 7.2, 3H).
Synthesis of Ethyl 3-(4-(trifluoromethyl)phenyl)imidazo[1 ,2-a]pyrazine-6-carboxylate and methyl 3-(4-(trifluoromethyl)phenyl)imidazo[1 ,2-a]pyrazine-6-carboxylate (I-5 & I-6)
Figure imgf000114_0002
Pd2(dba)3 (58 mg, 0.0629 mmol) was added to a degassed mixture of 3-bromoimidazo[1 ,2- a]pyrazine-6-carboxylate (170 mg, 0.629 mmol), 4-trifluoromethylphenyl boronic acid (237 mg, 1.25 mmol), P(o-tol)3 (23 mg, 0.075 mmol), KF (0.70 mL of a 2.0 M solution in water), toluene (8.4 mL), and methanol (5.6 mL). The reaction was heated in the microwave at 1 10 °C for 20 minutes. The reaction was cooled to room temperature, filtered and concentrated. The crude mixture was purified by flash chromatography (silica, 0-10% methanol/chloroform) to give a mixture of I-5 and I-6 as a white colored solid.
Synthesis of 3-(4-(trifluoromethyl)phenyl)imidazo[1 ,2-a]pyrazine-6-carboxylic acid (I-7)
Figure imgf000114_0003
NaOH (1.25 mL of a 1 .0 N solution in water) was added to a solution of ethyl 3-(4-
(trifluoromethyl)phenyl)imidazo[1 ,2-a]pyrazine-6-carboxylate and methyl 3-(4-
(trifluoromethyl)phenyl)imidazo[1 ,2-a]pyrazine-6-carboxylate (200 mg, 0.629 mmol) and tetrahydrofuran (1.25 mL). The reaction stirred at room temperature for three hours. The PAT054787-WO-PCT solvent was removed in vacuo. The crude reaction mixture was taken up in D I water and acidified to pH 3, resulting in a white precipitate that was collected by vacuum filtration to give I- 7 as a white colored solid. 1 H NMR (400 MHz, DMSO) δ 9.13 (s, 1 H), 9.01 (s, 1 H), 8.23 (s, 1 H), 8.05 - 7.95 (m, 4H).
Synthesis of N-(4-cyanophenyl)-3-(4-(trifluoromethyl)phenyl)imidazo[1 ,2-a]pyrazine-6- carboxamide -8)
Figure imgf000115_0001
EDC (19 mg, 0.098 mmol) was added to a solution of 3-(4-(trifluoromethyl)phenyl)imidazo[1 ,2- a]pyrazine-6-carboxylic acid (20 mg, 0.0653 mmol), 4-cyanoaniline (18 mg, 0.098 mmol), diisopropylethylamine (0.045 mL, 0.261 mmol), HOBt (14 mg, 0.098 mmol) and DMF (0.75 mL). The reaction stirred at room temperature for 6 hours and was then heated to 60 °C for 10 hours. After cooling to room temperature, the crude reaction mixture was diluted with Dl water (10 mL). The aqueous solution was extracted with ethyl acetate (3 x 3.0 mL). The organic extracts were combined and washed with Dl water (2 x 2.0 mL) and brine (2 x 2.0 mL). The organic solution was dried over MgS04 and purified by flash chromatography (silica, 20-100% ethyl
acetate/hexanes) to give pure I-8 as a white colored solid.
Synthesis of Ethyl -(4-(trifluoromethyl)phenyl)imidazo[1 ,2-a]pyrazine-6-carboxylate (I-5)
Figure imgf000115_0002
A solution of 4-trifluoromethylbenzene boronic acid (446 mg, 2.35 mmol) in degassed ethanol (4.2 mL) was added to a mixture of ethyl 3-bromoimidazo[1 ,2-a]pyrazine-6-carboxylate (200 mg, 1.18 mmol), P(o-tol)3 (44 mg, 0.142 mmol) and degassed toluene (6.3 mL). Pd2(dba)3 (108 mg, 0.1 18 mmol) was added followed by 1 .20 mL of an aqueous 2N KF solution. The reaction was heated in the microwave for 12 minutes at 1 10 °C. The solvent was removed and the crude PAT054787-WO-PCT reaction mixture was purified by flash chromatography (silica, 25-100% ethyl acetate/hexanes) to give pure I-5 as a tan colored solid.
Alternatively, it can also be synthesized using following protocol.
Figure imgf000116_0001
Pd-DPP (Pallidium diphenylphosphine supported on silica, silicycle) (200 mg) was added to a mixture of 3-bromoimidazo[1 ,2-a]pyrazine-6-carboxylate (500 mg, 1 .86 mmol), 4- trifluoromethylbenzene boronic acid (349 mg, 1 .86 mmol), Na2C03 (623 mg, 7.42 mmol), tetrahydrofuran (12 mL) and Dl water (3.0 mL). The reaction was heated in a microwave reactor at 150 °C for 1 hour. After cooling to room temperature, the solvent was removed in vacuo. The crude material was purified by flash chromatography to give I-5 as a white solid (silica, 25-100% ethyl acetate/hexanes).
Synthesis of N-methyl-3-(4-(trifluoromethyl)phenyl)imidazo[1 ,2-a]pyrazine-6-carboxamide
(I-9)
Figure imgf000116_0002
Oxalyl chloride (0.050 mL, 0.59 mmol) was added dropwise to a solution of 3-(4- (trifluoromethyl)phenyl)imidazo[1 ,2-a]pyrazine-6-carboxylic acid (50 mg, 0.16 mmol), DMF (2 drops) and dichloromethane (2.0 mL). After 30 minutes at room temperature, the solvent was removed. The reaction remained on the high vacuum pump for 60 minutes. Fresh dichloromethane (2.0 mL) was added, followed by a solution of N-methylamine (0.30 mL, 0.587 mmol). Triethylamine (0.15 mL, 1.1 mmol) was added and the reaction stirred at room temperature for 1 hour. The reaction was purified by flash chromatography to give I-9 as a white solid (silica, 50-100% ethyl acetate/hexanes).
Synthesis of 3-bromoimidazo[1 ,2-a]pyrazine-6-carboxylic acid (1-10) PAT054787-WO-PCT
Figure imgf000117_0001
1-4
NaOH (4.0 mL of a 1 .ON aqueous solution) was added to a mixture of ethyl 3-bromoimidazo[1 ,2- a]pyrazine-6-carboxylate (650 mg, 2.42 mmol) and tetrahydrofuran (4.0 mL). The reaction mixture was heated to 60 °C for 90 minutes. After cooling to room temperature, the solvent was removed in vacuo. The crude product was taken up in D I water and acidified to pH 3 with 1 .ON HCI resulting in the formation of 1-10 as a white precipitate that was collected by vacuum filtration. 1 H NMR (400 MHz, DMSO) δ 9.15 (d, J = 1 .4, 1 H), 8.83 (d, J = 1 .4, 1 H), 8.13 (s, 1 H).
Synthesis of 3-bromo-N-(4-chlorophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide
(1-11)
Figure imgf000117_0002
DCM/Et3N, r.t.
Oxalyl chloride (0.083 mL of a 2.0M solution in dichloromethane) was added drop wise to a solution of 3-bromoimidazo[1 ,2-a]pyrazine-6-carboxylic acid (200 mg, 0.833 mmol), DMF (2 drops) and dry dichloromethane (5.0 mL) at room temperature (gas evolution). After 30 minutes at room temperature, the solvent was removed in vacuo. The crude acid chloride was dissolved in dry dichloromethane (5.0 mL) and a solution of 4-(methylamino)chlorobenzene (235 mg, 1 .670 mmol in 2.0 mL of dichloromethane) was added drop wise at room temperature.
Triethylamine (0.25 mL, 2.44 mmol) was added and the reaction stirred at room temperature for 3 hours. The solvent was removed in vacuo and the crude material was purified by flash chromatography to give 1-11 as a tan solid (silica, 10-100% ethyl acetate/hexanes). 1 H NMR
(400 MHz, CDCI3) δ 8.62 (d, J = 1 .3, 1 H), 8.59 (s, 1 H), 7.78 (s, 1 H), 7.21 (d, J = 8.6, 2H), 7.04 (d, J = 7.7, 2H), 3.51 (s, 3H).
Synthesis of tert-butyl (5-(((4-cyanophenyl)(methyl)amino)methyl)pyrazin-2-yl)carbamate (1-12) PAT054787-WO-PCT
Figure imgf000118_0001
4-(N-methylamino)benzonitrile (574 mg, 4.35 mmol) was added to a mixture of tert-butyl (5- (bromomethyl)pyrazin-2-yl)carbamate (Prepared following the methods outlined in: Bioorganic & Medicinal Chemistry Letters, 2002, 12, 1203-1208.) (1 .0 g, 3.48 mmol), potassium carbonate (4.8 g, 34.8 mmol) and acetone (40.0 mL). The reaction was heated to reflux for two hours. LCMS analysis showed 80% conversion. Stir for an additional hour. The reaction was diluted with acetone (40.0 mL) and filtered to remove the solids. The filtrate was concentrated and purified by flash chromatography to give 1-12 as a white solid (silica 10-100% ethyl acetate/hexanes).
Synthesis of 4-(((5-aminopyrazin-2-yl)methyl)(methyl)amino)benzonitrile (1-13)
Figure imgf000118_0002
TFA (2.0 mL) was added to a solution of 1-12 (250 mg, 0.74 mmol) and dichloromethane (7.0 mL). The reaction stirred at room temperature for 12 hours. The solvent was removed and fresh dichloromethane (5 mL) was added. The organic layer was washed with NaHC03 (2 x 3 mL), dried over MgS04 and concentrated to give 1-13 as a colorless oil.
Synthesis of 4-((imidazo[1 ,2-a]pyrazin-6-ylmethyl)(methyl)amino)benzonitrile (1-14)
Figure imgf000118_0003
Chloroacetaldehyde was added to a solution of aminopyrazine and ethanol. The reaction was heated to reflux for 6 hours. After cooling to room temperature, the solvent was removed. The crude mixture was taken up in dichloromethane and washed with saturated sodium bicarbonate. The organic layer was dried over MgS04, concentrated and purified by flash chromatography to give 1-14 as a white solid (silica, 0-10% methanol/dichloromethane). 1 H NMR confirms the structure. 1 H NMR (400 MHz, CDCI3) δ 9.08 (s, 1 H), 7.78 (s, 2H), 7.60 (s, 1 H), 7.47 (d, J = 9.1 , 2H), 6.72 (d, J = 9.1 , 2H), 4.72 (s, 2H), 3.21 (s, 3H). PAT054787-WO-PCT
Synthesis of 4-(((3-bromoimidazo[1 ,2-a]pyrazin-6-yl)methyl)(methyl)amino)benzonitrile (1- 15)
Figure imgf000119_0001
NBS was added to a solution of imidazolopyrazine and dichloromethane at -78 °C. The reaction was allowed to slowly warm to room temperature. LCMS indicated that the reaction was complete. Mono-bromo and di-bromo and the starting material were present. The solvent was removed and the crude material was purified by flash chromatography to give 1-15 as a tan solid (silica, 50-100% ethyl acetae/hexanes).
Synthesis of (3-( -(trifluoromethyl)phenyl)imidazo[1 ,2-a]pyrazin-6-yl)methanol (1-16)
Figure imgf000119_0002
A mixture of imidazolopyridazine carboxylic acid (50 mg, 0.200 mmol) and THF (1 .0 mL) was cooled to -10 °C (ethylene glycol/C02). N-methyl morpholine (0.022 mL, 0.200 mmol) and ethyl chloroformate (0.019 mL, 0.200 mmol) were added. The reaction stirred at -10 °C for 10 minutes. Sodium borohydride (23 mg, 0.600 mmol) was added and the reaction was allowed to warm to 0 °C (ice/water). Methanol (2.0 mL) was then added dropwise over 10 minutes. The solvent was removed. The crude material was taken up in ethyl acetate and washed with 1 N HCI and 5% aqueous sodium bicarbonate, dried over MgS04 and purified by flash
chromatography to give 1-16 (silica, 0-25% MeOH/CH2CI2).
Synthesis of N-methyl-1 -(3-(4-(trif luoromethyl)phenyl)imidazo[1 ,2-a]pyrazin-6- yl)methanamine (1-17)
Figure imgf000119_0003
PAT054787-WO-PCT
Thionyl chloride (0.018 mL, 0.256 mmol) was added to a solution of alcohol (50 mg, 0.171 mmol) and dichloromethane (2.0 mL) at 0 °C. After 10 minutes at 0 °C, the reaction was allowed to warm to room temperature and stir for 1 hour. The solvent was removed to give the 6- chloromethylimidazolopyrazine, which was carried on without further purification. Methylamine (0.15 mL of a 40% solution in water) was added to a solution of the 6- chloromethylimidazolopyrazine (0.171 mmol) and acetonitrile (2 mL) at 0 °C. The reaction was warmed to 50 °C for 2 hours. The solvent was removed and the product was purified by flash chromatography (silica, 10% 7N NH3 in methanol/dichloromethane) to give 1-17 as a white foam.
Synthesis of 6-bromoimidazo[1 ,2-a]pyrazine (1-18)
» H2JN J N — MeOH, reflu -x,* 15 h ..^J
1-18
To a solution of 5-bromopyrazin-2-amine (1 1.3 g, 0.065 mol, 1 .0 equiv) in CH3OH (150 mL) was added 2-chloroacetaldehyde (40% in water, 65g, 0.33 mol, 5.1 equiv). The resulting solution was refluxed for 15 hrs then the resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate / petroleum ether (20:1 ). This resulted in 12 g of 6-bromoimidazo[1 ,2-a]pyrazine as a brown solid. (ES, m/z): [M + H+] 197.
Synthesis of 3,6-dibromoimidazo[1 ,2-a]pyrazine (1-19)
Figure imgf000120_0001
To a solution of 6-bromoimidazo [1 ,2-a]pyrazine (1 .43 g, 7.26 mmol, 1 .0 equiv) in DMF (50 mL) was added NBS (1 .39 g, 7.81 mmol, 1 .1 equiv) at -5~0 °C. The resulting solution was stirred at 0 °C for 1 hr. The resulting mixture was diluted with ethyl acetate (300 mL) then washed with brine. The organic layer was dried and concentrated to obtain 1 .8 g of the crude product as a white solid. (ES, m/z): [M + H+] 278; H-NMR (300 MHz, CDCI3): δ 8.92 (d, J = 1 .2 Hz, 1 H), 8.28 (s, 1 H), 7.84 (d, J = 1 .2 Hz, 1 H).
Synthesis of 3-bromo-N-methylimidazo[1 ,2-a]pyrazin-6-amine (I-20)
Figure imgf000120_0002
PAT054787-WO-PCT
A solution of 3,6-dibromoimidazo[1 ,2-a]pyrazine (1 .8 g, 6.49 mmol, 1 .0 equiv) in CH3NH2 (30% in water, 50 mL) was stirred at r.t. for 1 hr then concentrated. The residue was applied onto a silica gel column with ethyl acetate / petroleum ether (1 :1 ). This resulted in 1 .08 g of 3-bromo-N- methylimid-azo[1 ,2-a]pyrazin-6-amine as a white solid. (ES, m/z): [M + H+] 227; H-NMR (300 MHz, CDCI3): 58.70 (d, J = 1.5 Hz, 1 H), 7.64 (s, 1 H), 7.02 (d, J = 1.2 Hz, 1 H) , 4.41 (brs, 1 H), 2.94 (d, J = 5.4 Hz, 3 H)
Synthesis of N-methyl-3- -(trifluoromethyl)phenyl)imidazo[1 ,2-a]pyrazin-6-amine (1-21 )
Figure imgf000121_0001
To a solution of 3-bromo-N-methylimidazo[1 ,2-a]pyrazin-6-amine (1 .08 g, 4.76 mmol, 1 .0 equiv) in dioxane (50 mL) was added 4-(trifluoromethyl)phenylboronic acid (1 .80 g, 9.52 mmol, 2 equiv), PdCI2(dppf) (0.347g, 0.476 mmol) and K3P04 (3.026 g, 14.3 mmol, 3 equiv) under nitrogen atmosphere. The resulting solution was refluxed for 15 hr. The resulting solution was filtered. The filtrate was concentrated then applied onto a silica gel column with CH2CI2/CH3OH (100:1 ). This resulted in 1 .01 g of N-methyl-3-(4-(trifluoromethyl)phenyl)imidazo[1 ,2-a]pyrazin-6- amine as solid. (ES, m/z): [M + H]+ 293; H-NMR (300 MHz, CDCI3): 58.50 (d, J = 1 .5 Hz, 1 H), 7.87-7.95 (m, 5H), 7.47 (d, J = 1.5 Hz, 1 H), 2.84 (s, 3H).
Synthesis of 2-(4- romobenzylidene)hydrazinecarboxamide (I-22)
Figure imgf000121_0002
1-22
4-bromobenzaldehyde (3.7 gm, 20.0 mmol, 1 .0 eq.), semicarbazide (2.23 gm, 20.0 mmol, 1 .0 eq.) and sodium acetate (3.28 gm, 40.0 mmol, 2.0 eq.) were mixed in ethanol (50 ml) and stirred for 3 hours. The product was formed as a solid. The reaction was filtered and washed with ether to yield desired product (3.2 gm, 62%). The product was characterized by reverse phase HPLC using method 4. (ES, m/z): [M + H+] 242.1 . The product was carried to the next step without purification. PAT054787-WO-PCT
Synthesis of 5-(4-bromophenyl)-1 ,3,4-oxadiazol-2-amine (I-23)
Figure imgf000122_0001
Semicarbazone (2.58 gm, 0.0 mmol, 1 .0 eq.) and sodium acetate sodium acetate (3.28 gm, 40.0 mmol, 2.0 eq.) were dissolved in 30^ 0 ml of glacial acetic acid with continuous stirring. Bromine (0.7 ml in 5 ml of glacial acetic acid) was added slowly to it. Solution was stirred for 1 hour and then poured on crushed ice. The resulting solid was separated, dried to yield desired product (650 mg, 25%). 1 H NMR (400 MHz, MeOD) δ 7.86 - 7.77 (m, 1 H), 7.74 - 7.63 (m, 1 H)
Synthesis of 5-(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)-1 ,3,4-oxadiazol-2- amine (I-24).
Figure imgf000122_0002
In a 40 ml vial, oxadiazole derivative (600 mg, 2.51 mmol, 1.0 eq.), bispinacolotodiboron (637.5 mg, 2.51 mmol, 1.0 eq.), Pd(dppf)CI2 (204.9 mg, 0.251 mmol, 0.1 eq.) and potassium acetate (1 .47 gm, 15.06 mmol, 6.0 eq.) were mixed in dioxane (15 ml) and heated to 80 °C for 8 hours. LCMS indicated that the product was formed in major amount. . The crude reaction was purified in the presence of silica (10-15 gm) and purified using hexanes: ethyl acetate (0-100%) to yield desired boron ester (275 mg, 38%). The product was characterized by reverse phase HPLC using method 4. (ES, m/z): [M + H+] 297.9. Retention time = 1 .61 mins.
Synthesis of 2-(4-(1 ,1-difluoroeth l)phenyl)-4,4,5,5-tetrameth l-1 ,3,2-dioxaborolane (I-25)
Figure imgf000122_0003
I-25 PAT054787-WO-PCT
In a 40 ml vial, bromo derivative (250 mg, 1 .13 mmol, 1 .0 eq.), bispinacolotodiboron (288.6 mg, 1.13 mmol, 1 .0 eq.), Pd(dppf)CI2 (92.7 mg, 0.1 14 mmol, 0.1 eq.) and potassium acetate (354.5 mg, 3.41 mmol, 3.0 eq.) were mixed in dioxane (10 ml) and heated to 80 °C for 8 hours. LCMS indicated that the product was formed in major amount. . The crude reaction was purified in the presence of silica (10-15 gm) and purified using hexanes: ethyl acetate (0-100%) to yield desired boron ester. The product was characterized by reverse phase HPLC using method 4. (ES, m/∑): [M + H+] 269.0. Retention time = 1 .60 mins.
Synthesis of 6- 4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)isoquinolin-1 (2H)-one (I-26)
Figure imgf000123_0001
In a 40 ml vial, bromo derivative (250 mg, 1 .1 1 mmol, 1 .0 eq.), bispinacolotodiboron (288.6 mg, 1.1 1 mmol, 1 .0 eq.), Pd(dppf)CI2 (90.7 mg, 0.1 1 1 mmol, 0.1 eq.) and potassium acetate (327.5 mg, 3.331 mmol, 3.0 eq.) were mixed in dioxane (10 ml) and heated to 80 °C for 48 hours. LCMS indicated that the product was formed in major amount. . The crude reaction was purified in the presence of silica (10-15 gm) and purified using hexanes: ethyl acetate (0-100%) to yield desired boron ester. The product was characterized by reverse phase HPLC using method 4. (ES, m/z): [M + H+] 271 .9. Retention time = 1 .19 mins.
Synthesis of 1 -methyl-5-(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)-1 H- pyrazole (I-27)
Figure imgf000123_0002
In a 40 ml vial, bromo derivative (236 mg, 1 .06 mmol, 1 .0 eq.), bispinacolotodiboron (253.6 mg, 1.06 mmol, 1 .0 eq.), Pd(dppf)CI2 (86.4 mg, 0.106 mmol, 0.1 eq.) and potassium acetate (321 .8 mg, 3.17mmol, 3.0 eq.) were mixed in dioxane (10 ml) and heated to 80 °C for 48 hours. LCMS indicated that the product was formed in major amount. . The crude reaction was purified in the presence of silica (10-15 gm) and purified using hexanes: ethyl acetate (0-100%) to yield PAT054787-WO-PCT desired boron ester. The product was characterized by reverse phase HPLC using method 4. (ES, m/z): [M + H+] 284.9. Retention time = 1 .42 mins.
Synthesis of N-methyl-[1 ,2,4]triazolo[4,3-a]pyridin-5-amine (I-28)
Figure imgf000124_0001
I-28
To a solution of chloro derivative (300 mg, 1 .96 mmol, 1 .0 eq.) in 10 mL of dioxane were added, Pd2(dba)3 (90 mg, 0.098 mmol, 0.05 eq.), Xantphos (1 13 mg, , 0.196 mmol, 0.1 eq.) and Cs2C03 (1274 mg, 3.92 eq., 2.0 eq.) at room temperature. The reaction mixture was degassed for 5-10 mins and then methyl amine (121 .6 mg, 3.92 eq., 2.0 eq.) was added and stirred at 100 °C under N2 for 8 hours. HPLC/MS test showed that the starting material (I) was consumed and the desired product was one of the major peaks ([M+1 ]). The reaction mixture was cooled to room temperature and solid was filtered off. The resulting filtrate was concentrated and the product was purified by column chromatography using dichloromethane/methanol to yield the desired product (50 mg, 17 %). The product was characterized by reverse phase HPLC using method 4. (ES, m/z): [M + H+] 149.0. Retention time = 0.36 mins.
Synthesis of 3-methyl-5-(4,4,5,5-tetrameth l-1 ,3,2-dioxaborolan-2-yl)-1 H-indazole (I-29)
Figure imgf000124_0002
I-29
The boronic ester was synthesized from the corresponding bromide using a protocol as described in the synthesis of I-24. The product was characterized by reverse phase HPLC using method 4. (ES, m/z): [M + H+] 258.9. Retention time = 1.28 mins.
Synthesis of 4-((2-methoxyethyl)amino)benzonitrile (I-30)
Figure imgf000125_0001
1-30
2-methoxyethanamine (300 mg, 4.00 mmol) was added to a mixture of 4-fluorobenzonitrile (250 mg, 2.07 mmol), cesium carbonate (750 mg, 2.30 mmol) and DMSO (4.0 mL). The reaction was heated to 60 °C for 4 hours. After cooling to room temperature, the reaction was diluted with water. The aqueous solution was extracted with ethyl acetate (3 x 15 mL). The combined extracts were dried over MgS04 and concentrated. The crude residue was purified by flash chromatography (silica, 0-10% methanol/dichloromethane) to give 4-((2- methoxyethyl)amino)benzonitrile (I-30) as a white solid.
Synthesis of 4-((2-(tetrah dro-2H- ran-4- l)eth l)amino)benzonitrile (1-31)
Figure imgf000125_0002
(1-31 )
The above intermediate was prepared following the procedure outlined for the synthesis of 4- ((2-methoxyethyl)amino)benzonitrile (I-30).
Synthesis of 4-((2-(dimethylamino)ethyl)amino)benzonitrile (I-32)
Figure imgf000125_0003
I-32
The above intermediate was prepared following the procedure outlined for the synthesis of 4- ((2-methoxyethyl)amino)benzonitrile. 1 H NMR (400 MHz, DMSO) δ 7.44 (d, J= 8.8, 2H), 6.66 (d, J= 8.9, 2H), 3.15 (q, J = 6.6, 3H), 2.42 (t, J= 6.6, 2H), 2.18 (s, 6H).
Synthesis of tert-butyl (2-((4-cyanophenyl)amino)ethyl)carbamate (I-33) PAT054787-WO-PCT
Figure imgf000126_0001
1-33
The above intermediate was prepared following the procedure outlined for the synthesis of 4- ((2-methoxyethyl)amino)benzonitrile. 1 H NMR (400 MHz, DMSO) δ 7.45 (d, J= 8.8, 2H), 6.64 (d, J= 8.9, 2H), 3.18 - 2.95 (m, 4H), 1 .38 (s, 9H).
Preparation of N-methylanilines
Synthesis of N-methyl-4- -methyl-1 H-pyrazol-4-yl)aniline (I-34)
Figure imgf000126_0002
A solution of 4-(1 -methyl-1 H-pyrazol-4-yl)aniline (254 mg g, 1 .47 mmol) in THF (5 mL) was added to a suspension of NaH (60% dispersion in mineral oil, 60 mg, 1 .47 mmol) and THF (150 mL). The reaction stirred at room temperature for 3 hours, lodomethane (0.090 mL, 1 .47 mmol) was added and the reaction was heated to 40 °C for 9 hours. After cooling to room temperature, the solvent was removed. The crude material was tritrated in dichloromethane (100 mL) and filtered to remove any salts. The filtrate was purified by flash chromatography (silica, 10-80% ethyl acetate/hexanes). 1 H NMR (400 MHz, DMSO) δ 7.88 (s, 1 H), 7.65 (d, J = 0.8, 1 H), 7.27 (d, J= 8.6, 2H), 6.52 (d, J= 8.6, 2H), 5.59 (d, J= 5.1 , 1 H), 3.82 (s, 3H), 2.67 (d, J = 5.1 , 3H).
Preparation of N-methylaminopyridines
Synthesis of 6-chloro-N-methylpyridin-3-amine (I-35)
Figure imgf000126_0003
1-35
A solution of 3-amino-6-chloropyridine (2.46 g, 19.2 mmol) in THF (50 mL) was added to a suspension of NaH (60% dispersion in mineral oil, 768 mg, 19.2 mmol) and THF (150 mL). The reaction stirred at room temperature for 3 hours, lodomethane (1 .2 mL, 19.2 mmol) was added and the reaction was heated to 40 °C for 9 hours. After cooling to room temperature, the PAT054787-WO-PCT solvent was removed. The crude material was tritrated in dichloromethane (100 mL) and filtered to remove any salts. The filtrate was purified by flash chromatography (silica, 10-80% ethyl acetate/hexanes). 1H NMR (400 MHz, CDCI3) δ 7.72 (d, J= 3.1 , 1 H), 7.06 (d, J= 8.6, 1 H), 6.83 (dd, J = 3.1 , 8.6, 1 H), 3.78 (s, 1 H), 2.84 (d, J= 19.7, 3H).
Synthesis of 5-chloro-N-methylpyridin-2-amine (I-36)
Figure imgf000127_0001
1-36
The above intermediate was prepared following the procedure outlined for the synthesis of 6- chloro-N-methylpyridin-3-amine. 1H NMR (400 MHz, CDCI3) δ 8.00 (d, J= 2.5, 1 H), 7.35 (dd, J = 2.6, 8.9, 1 H), 6.31 (d, J= 8.9, 1 H), 4.58 (s, 1 H), 2.87 (d, J= 5.2, 3H).
Synthesis of 6-(methylamino)nicotinonitrile (I-37)
Figure imgf000127_0002
I-37
The above intermediate was prepared following the procedure outlined for the synthesis of 6- chloro-N-methylpyridin-3-amine. 1H NMR (400 MHz, CDCI3) δ 8.35 (d, J= 2.0, 1 H), 7.57 (dd, J = 2.0, 8.8, 1 H), 6.36 (dd, J = 0.5, 8.9, 1 H), 5.1 1 (s, 1 H), 2.96 (d, J= 5.2, 3H).
Synthesis of 5-fluoro-N-methylpyridin-2-amine (I-38)
Figure imgf000127_0003
I-38
The above intermediate was prepared following the procedure outlined for the synthesis of 6- chloro-N-methylpyridin-3-amine. 1H NMR (400 MHz, CDCI3) δ 7.93 (d, J= 3.0, 1 H), 7.19 (ddd, J = 3.0, 7.9, 9.0, 1 H), 6.31 (dd, J= 3.4, 8.9, 1 H), 4.48 (s, 1 H), 2.86 (s, 3H).
Synthesis of 6-fluoro-N-methylpyridin-2-amine (I-39) PAT054787-WO-PCT
Figure imgf000128_0001
The above intermediate was prepared following the procedure outlined for the synthesis of 6- chloro-N-methylpyridin-3-amine. 1H NMR (400 MHz, CDCI3) δ 7.46 (q, J= 8.0, 1 H), 6.16 (dd, J = 2.4, 8.0, 1 H), 6.1 1 (dd, J = 2.3, 7.7, 1 H), 5.25 - 4.30 (s, 1 H), 2.88 (s, 3H).
Synthesis of 4-fluoro-N-meth lpyridin-2-amine (I-40)
Figure imgf000128_0002
The above intermediate was prepared following the procedure outlined for the synthesis of 6- chloro-N-methylpyridin-3-amine.
N-methylpyridin-3-amine (1-41)
Figure imgf000128_0003
1-41
The above intermediate was prepared following the procedure outlined for the synthesis of 6- chloro-N-methylpyridin-3-amine. 1H NMR (400 MHz, CDCI3) δ 8.00 (d, J= 2.7, 1 H), 7.92 (d, J -- 4.6, 1 H), 7.07 (dd, J = 4.6, 8.3, 1 H), 6.84 (ddd, J = 1.3, 2.9, 8.3, 1 H), 2.83 (s, 3H).
N-methyl-6-(trifluoromethyl)pyridin-3-amine (I-42)
Figure imgf000128_0004
The above intermediate was prepared following the procedure outlined for the synthesis of 6- chloro-N-methylpyridin-3-amine. 1H NMR (400 MHz, CDCI3) δ 8.04 (d, J= 2.7, 1 H), 7.45 (d, J -- 8.6, 1 H), 6.85 (d, J= 8.6, 1 H), 4.34 - 3.88 (m, 1 H), 2.89 (s, 3H).
Synthesis of 2,6-dichloro-N-methylpyridin-3-amine (I-43) PAT054787-WO-PCT
Figure imgf000129_0001
1-43
The above intermediate was prepared following the procedure outlined for the synthesis of 6- chloro-N-methylpyridin-3-amine. 1H NMR (400 MHz, CDCI3) 5 7.1 1 (d, J= 8.1 , 1 H), 6.84 (d, J- 8.4, 1 H), 4.38 (s, 1 H), 2.88 (d, J= 5.2, 3H).
Synthesis of 6-bromo-N-methylpyridin-3-amine (I-44)
Figure imgf000129_0002
I-44
The above intermediate was prepared following the procedure outlined for the synthesis of 6- chloro-N-methylpyridin-3-amine. 1H NMR (400 MHz, CDCI3) δ 7.74 (d, J= 3.1 , 1 H), 7.20 (d, J-- 8.6, 1 H), 6.75 (dd, J= 3.1 , 8.6, 1 H), 2.82 (s, 3H).
Synthesis of 6-bromo-N-methylpyridin-3-amine (I-45)
Figure imgf000129_0003
1-45
The above intermediate was prepared following the procedure outlined for the synthesis of 6- chloro-N-methylpyridin-3-amine. 1H NMR (400 MHz, CDCI3) δ 8.97 (s, 1 H), 8.02 (s, 1 H), 7.80 (d, J= 2.8, 1 H), 7.68 (d, J = 8.5, 1 H), 7.03 (dd, J = 2.9, 8.8, 1 H), 2.90 (s, 3H).
Synthesis of 2-methoxy-N-methylpyridin-3-amine (I-4
Figure imgf000129_0004
The above intermediate was prepared following the procedure outlined for the synthesis of 6- chloro-N-methylpyridin-3-amine. 1H NMR (400 MHz, CDCI3) δ 7.46 (dd, J= 1.6, 5.1 , 1 H), 6.77 (dd, J= 5.1 , 7.6, 1 H), 6.67 (dd, J= 1 .5, 7.6, 1 H), 4.17 (s, 1 H), 3.95 (s, 3H), 2.82 (d, J= 4.2, 3H).
Synthesis of 2-fluoro-N-methylpyridin-3-amine (I-47) PAT054787-WO-PCT
Figure imgf000130_0001
1-47
The above intermediate was prepared following the procedure outlined for the synthesis of 6- chloro-N-methylpyridin-3-amine. 1H NMR (400 MHz, CDCI3) δ 7.47 - 7.35 (m, 1 H), 6.57 - 6.29 (m, 2H), 3.09 (s, 4H).
Synthesis of 6-chloro-N,5-dimethylpyridin-3-amine (I-48).
Figure imgf000130_0002
I-48
The above intermediate was prepared following the procedure outlined for the synthesis of 6- chloro-N-methylpyridin-3-amine. 1H NMR (400 MHz, CDCI3) δ 7.60 (d, J= 2.9, 1 H), 6.75 (d, J -- 2.6, 1 H), 2.81 (s, 3H), 2.28 (s, 3H).
Synthesis of 5-chloro-N-methylpyridin-3-amine (I-49)
Figure imgf000130_0003
I-49
The above intermediate was prepared following the procedure outlined for the synthesis of 6- chloro-N-methylpyridin-3-amine. 1H NMR (400 MHz, CDCI3) δ 7.94 (d, J= 5.5, 1 H), 6.55 (dd, J = 1.7, 5.5, 1 H), 6.35 (d, J = 1 .7, 1 H), 4.75 (s, 1 H), 2.88 (d, J = 5.2, 3H).
Synthesis of 2-chloro-N,5-dimethylpyridin-3-amine (I-50)
Figure imgf000130_0004
1-50
The above intermediate was prepared following the procedure outlined for the synthesis of 6- chloro-N-methylpyridin-3-amine. 1H NMR (400 MHz, CDCI3) δ 7.51 (s, 1 H), 6.66 (s, 1 H), 4.26 (s, 1 H), 2.86 (s, 3H), 2.25 (s, 3H). PAT054787-WO-PCT
Synthesis of 5-fluoro-N-methylpyridi -3-amine (1-51)
Figure imgf000131_0001
1-51
The above intermediate was prepared following the procedure outlined for the synthesis of 6- chloro-N-methylpyridin-3-amine.1H N R (400 MHz, CDCI3) δ 7.82 (s, 1 H), 7.78 (d, J= 2.3, 1H),6.54 (dt, J =2.4, 11.1, 1H), 3.99 (s, 1H), 2.83 (s, 3H).
Synthesis of 6-fluoro-N-methylpyridin-3-amine (I-52)
Figure imgf000131_0002
I-52
The above intermediate was prepared following the procedure outlined for the synthesis of 6- chloro-N-methylpyridin-3-amine.1H NMR (400 MHz, DMSO) δ 7.46 - 7.36 (m, 1 H), 7.11 (ddd, J = 3.1,7.1,8.8, 1H), 6.89 (dd, J =3.3, 8.8, 1H),5.81 (s, 1H), 2.68 (d, J= 5.2, 3H).
Synthesis of N-methyl-6-phenylpyridin-3-amine (I-53)
Figure imgf000131_0003
I-53
The above intermediate was prepared following the procedure outlined for the synthesis of 6- chloro-N-methylpyridin-3-amine.1H NMR (400 MHz, CDCI3) δ 8.10 (d, J= 2.9, 1 H), 7.91 - 7.85 (m, 2H), 7.56 (d, J= 8.6, 1H), 7.44 - 7.37 (m, 2H), 7.33 - 7.26 (m, 1 H), 6.93 (dd, J= 3.0, 8.6, 1H),3.85 (s, 1 H), 2.88 (s, 3H).
Synthesis of N-methyl-2-(trifluoromethyl)pyridin-4-amine (I-54)
Figure imgf000131_0004
I-54 PAT054787-WO-PCT
The above intermediate was prepared following the procedure outlined for the synthesis of 6- chloro-N-methylpyridin-3-amine. 1H NMR (400 MHz, DMSO) δ 8.16 (d, J= 5.7, 1 H), 7.10 (d, J =
4.3, 1 H), 6.86 (s, 1 H), 6.65 (dd, J- 2.2, 5.7, 1 H), 2.76 (d, J - 5.0, 3H).
Synthesis of 5-chloro-N-methylpyrazin-2-amine (I-55)
Figure imgf000132_0001
I-55
The above intermediate was prepared following the procedure outlined for the synthesis of 6- chloro-N-methylpyridin-3-amine. 1H NMR (400 MHz, DMSO) δ 8.05 (d, J= 1 .4, 1 H), 7.72 (d, J =
1.4, 1 H), 7.26 (s, 1 H), 2.77 (d, J= 4.7, 3H).
Synthesis of 2,2-dimethyl-3,4-dihydro- -benzo[b][1 ,4]oxazine-7-carbonitrile (I-56)
Figure imgf000132_0002
A flask was charged with bromobenoxazine and CuCN. The flask was evacuated and refilled with nitrogen three times. The flask was evacuated once more, sealed, and heated to 150 °C for 6 hours. The reaction was cooled to room temperature. 1 mL of 10% FeCI3 in water was added followed by 1 mL of ethyl acetate. The reaction mixture was stirred for 10 minutes and then filtered through celite. The filtrate was further diluted with water and extracted with EtOAc (3x). The combined organic extracts were again filtered through celite. The filtrate was dried over MgS04 and concentrated to a black oil. TLC analysis showed two major spots, with the top spot corresponding to the starting material and the lower spot corresponding to the product. The reaction was purified by flash chromatography (silica, 0-80% ethyl acetate/hexanes). 1 H NMR (400 MHz, DMSO) δ 7.08 (dd, J = 1 .9, 8.2, 1 H), 7.01 - 6.90 (m, 2H), 6.64 (d, J = 8.2, 1 H), 3.10 (d, J= 2.6, 2H), 2.51 (dd, J= 1.8, 3.6, 2H), 1 .24 (s, 6H).
Synthesis of 3-bromo-N-(6-chloropyridin-3-yl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide (I-57)
Figure imgf000133_0001
Into a 100-mL round-bottom flask, was placed a solution of 1-10 (1.84 g, 7.60 mmol, 1 .00 equiv) and 6-chloro-N-methylpyridin-3-amine (520 mg, 3.64 mmol, 1 .00 equiv) in DMF(dry) (20 mL). Then HATU (2.1 g, 5.50 mmol, 1 .50 equiv) and DIEA (470 mg, 3.64 mmol, 1 .00 equiv) was added. The resulting solution was stirred for 12 h at room temperature. The reaction was then quenched by the addition of water. The solids were collected by filtration and then washed with water. This resulted in 1 .2 g (42%) of I-57 as a grey solid. 1H-NMR-: (CDCI3, ppm): 68.79-8.73 ( d, J=1 .5 Hz ,1 H), 8.61 (s, 1 H), 8.15-8.14 (d, J=2.1 Hz ,1 H), 7.84 (s, 1 H) 7.58-7.54 ( m, 1 H ), 7.34-7.28 ( m, 1 H ), 3.57 (s, 3 H)
Synthesis of tert-butyl (2-methyl-2-(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenoxy)propyl)carbamate (I-58):
Figure imgf000133_0002
Synthesis of 2-bromo-2-methylpropanamide:
Figure imgf000133_0003
To a solution of 2-bromo-2-methylpropanoyl bromide (5 g, 21 .81 mmol, 1 eq) in Toluene (10 mL) NH3 gas was bubbled through for ½ hr. The reaction mixture was checked via LC/MS for the desired peak and full conversion and at this point the reaction mixture was neutralized with sodium bi-carbonate solution and extracted nice crystalline material (4 g, crude) which was used for the next step without further purification.
Synthesis of 2-(4-bromophenoxy)-2-methylpropanamide:
Figure imgf000133_0004
PAT054787-WO-PCT
To a solution of the Bromo-phenol (1 .30 g, 7.52 mmols 1 .0 eq) pre-dissolved in THF, NaH (9.03 mmol, 1 .5 eq,) was added. The reaction mixture was kept under reflux for 2 hrs. The 2-bromo- 2-methylpropanamide (1.0 g, 6.02 mmol) predissolved in THF (10 mL) was added drop by drop. The reaction mixture was kept under reflux for 2 hrs. Quenched with water and extracted with EtOAC (3 x 50 mL). The organics were combined and dried over Na2S04. The solvents were removed and the crude was further purified via column chromatography. Isolated 750 mg (2.9 mmol, 38%) of the desired product. M/Z = 258(M+1 ).
Synthesis of 2-(4-bromophenoxy)-2-methylpropan-1 -amine:
Figure imgf000134_0001
0.5 g (1 .93 mmol, 1 eq) of 2-(4-bromophenoxy)-2-methylpropanamide was dissolved in dry THF (6 mL) and Diborane-DMS complex (2.90 mmol, 1 .5 eq) was added slowly over ½ hr. The Reaction mixture was heated at reflux for 6 hrs. Checked via LC/MS and found the complete disappearance of the starting material and a nice product peak was found. The reaction mixture was diluted with EtOAc and sodium bicarbonate and the organics were extracted using EtOAc (3 x 15 mL). The desired compound was isolated by using column chromatography. M/Z = 243(M+1 )
Synthesis of tert-butyl (2-(4-bromophenoxy)-2-methylpropyl)carbamate:
Figure imgf000134_0002
To the solution of 2-(4-bromophenoxy)-2-methylpropan-1 -amine in DMF (0.37 g, 1 .51 mmol), added the (Boc)20 (0.49g, 2.26 mmols, 1.5 eq), followed by DIEA (1 mL). The reaction mixture was stirred for 12 hrs. The reaction was quenched with water, followed by extraction with EtOAc (3 x 10 mL). The desired compound was purified via ISCO to produce 300 mg (0.872 mmol, 58%) of the desired product.
Synthesis of tert-butyl (2-methyl-2-(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenoxy)propyl)carbamate:
Figure imgf000134_0003
PAT054787-WO-PCT
To a solution of tert-butyl (2-(4-bromophenoxy)-2-methylpropyl)carbamate (300 mg, 0.87 mmols, 1 eq), in THF/water (4:1 ) 6 mL was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1 ,3,2- dioxaborolane) (330 mg, 1 .30 mmol, 1 .5 eq), followed by DPPF (40 mg), and KOAc (127 mg, 1.30 mmols, 1.5 eq). The microwave vial was sealed and heated at 1 10 °C for 1 hr. The desired product was isolated via column chromatography to produce (1 16 mg34%, 0.296 mmol) of pure compound.
Synthesis of 3-bromo-N-(4-cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide (I-59)
Figure imgf000135_0001
1-10 I-59
To a solution of 3-bromoimidazo[1 ,2-a]pyrazine-6-carboxylic acid 1-10 (4 g, 16.53 mmol, 1.00 equiv) in toluene (100 mL) was added dropwise oxalyl chloride (4.2 g, 33.09 mmol, 2.00 equiv) and 2-3 drops of DMF at room temperature. The solution was stirred for 2 hours at 55 °C. Then the solvent was removed under vacuum, the residue was dissolved in dichloromethane (200 ml). To this was added triethylamine (8.3 g, 82.18 mmol, 5.00 equiv), 4-(methylamino)benzonitrile (2.4 g, 18.16 mmol, 1.10 equiv). The resulting solution was stirred for 1 hour at room
temperature. The resulting solution was diluted with dichloromethane (100 mL), washed, dried and cocentrated. The residue was applied onto a silica gel column with petroleum ether / dichloromethane / ethyl acetate (2/1/1 ). This resulted in 3.8 g (65%) of 3-bromo-N-(4- cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide as a light yellow solid. 1H-NMR (CDCIs, 300 MHz): 8.75 (d, J= 1 .5 Hz, 1 H), 8.59-8.57 (dd, J= 1.2, 5.4 Hz, 1 H), 7.83 (s, 1 H), 7.60-7.55 (m, 2 H), 7.25-7.21 (m, 2H), 3.58 (s, 3 H)
Synthesis of N-methyl-5-(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)-1 ,3,4- oxadiazol-2-amine (I-60)
Figure imgf000136_0001
Synthesis of 5-(4-bromophenyl)-N-methyl-1 ,3,4-oxadiazol-2-amine
Figure imgf000136_0002
To the solution of 4-bromobenzoic acid (10 g, 49.75 mmol, 1 eq) in dichloromethane (100 mL) was added N-methylhydrazine carbothioamide (5.22 g, 49.75 mmol, 1.02 eq) followed by EDCI (14.72g, 74.62 mmol, 1.5 eq). The reaction was stirred at room temperature for 12 hrs and checked via LC/MS for the desired amide intermediate peak. At this time another 1 .5 eq of EDCI (14.72 g, 74.62 mmol) was added to the reaction mixture and stirred for 24 hrs at room temperature. The reaction was quenched with saturated aqueous sodium bicarbonate (20 mL), and then extracted with ethyl acetate (3 x 25 mL). The resulting crude material was purified by flash column chromatography on silica gel using 60 % EtOAc / hexanes as eluant. IWZ= 254 (M+1 ) RT 1 .58 min using method 5.
Synthesis of N-methyl-5-(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)-1 ,3,4- oxadiazol-2-amine
Figure imgf000136_0003
To the solution of 5-(4-bromophenyl)-N-methyl-1 ,3,4-oxadiazol-2-amine (1 .8 g, 7.08 mmol, 1 eq) in THF/Water (4:1 ), was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1 ,3,2-dioxaborolane) (2.24 g , 8.85 mmols, 1 .25 eq.) followed by KOAc (1 .73 g, 17.70 mmol, 2.5eq), and DPPF (518 mg, 0.1 eq, 0.71 mmol) The microwave vial was sealed and heated at 100 °C for 2.5 hrs. Checked PAT054787-WO-PCT via LC/MS for the desired peak and then the desired product was isolated using column chromatography. The desired product was isolated off white solid (461 mg, 1 .51 mmol, 21 %) was used for the next step. 1H NMR (400 MHz, MeOD) δ 8.02 - 7.76 (m, 4H), 3.00 (s, 3H), 1 .37 (s, 12H).
Synthesis of 2-(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)-1 ,3,4-thiadiazole (I- 61 )
Figure imgf000137_0001
Synthesis of 4-Bromobenzhydrazide
Figure imgf000137_0002
4-bromobenzoic acid (500 mg, 2.48 mmol, 1 eq.) was added to hydrazine-hydrate (10 g, 50 mmol, 81 eq), and the reaction mixture was heated under microwave irradiation condition at 90 °C for 30 minutes. The solvents were removed and the crude was used for the next step. (M/Z) 214 (M+1 ). RT 1 .07 min using method 5.
Synthesis of 4-bromo-N'-formylbenzohydrazide
Figure imgf000137_0003
To a solution of 4-bromohydrazide (460mg, 2.15mmol, 1 eq) in toluene (12 mL) formic acid (1 .5 g, 32.6 mmol, 15 eq) was added drop-wise over 10 minute and the reaction mixture was heated under microwave irradiation condition at 120 °C for 90 minutes. The product was isolated and purified via ISCO column chromatography. Used for the next step. (M/Z) 244 (M+1 ). RT 1 .77
Figure imgf000137_0004
PAT054787-WO-PCT
To a solution of 4-bromo-N'-formylbenzohydrazide (400 mg, 1 .65mmols, 1 eq) dissolved in toluene (12 mL) Lawesson's reagent (1 g, 2.47 mmol, pre-dissolved in toluene (5 mL) was added. The reaction mixture was heated under microwave irradiation at 90 °C for 30 minutes. Isolated product was used for the next step. (M/Z) 241 (M+H). RT 1 .84 min using method 5.
Synthesis of 2-(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)-1 ,3,4-thiadiazole:
The compound was synthesized in using a procedure similar to one described for I-59. (M/Z) 289 (M+1 ). RT 1 .66 min using method
Figure imgf000138_0001
Synthesis of N-((3-bromoimidazo[1 ,2-a]pyrazin-6-yl)methyl)-4-fluoro-N-methylaniline (I-62)
Figure imgf000138_0002
I-62
The compound was synthesized using a protocol described for the synthesis of 1-15.
Synthesis of N-((3-bromoimidazo[1 ,2-a]pyrazin-6-yl)methyl)-4-chloro-N-methylaniline (I-63)
Figure imgf000138_0003
I-63
The compound was synthesized using a protocol described for the synthesis of 1-15. Synthesis 3-bromo-N-(4-fluorophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide (I-
64)
Figure imgf000138_0004
1-10 I-64 PAT054787-WO-PCT
To a solution of 3-bromoimidazo[1 ,2-a]pyrazine-6-carboxylic acid (4 g, 16.53 mmol, 1 .00 equiv) in toluene (100 mL) was added dropwise oxalyl dichloride (4.2 g, 33.09 mmol, 2.00 equiv) at room temperature. The solution was stirred for 2 hours at 55 °C. Then the solvent was removed under vacuum, the residue was dissolved dichloromethane (200 ml). To this was added triethylamine (8.3 g, 82.18 mmol, 5.00 equiv), 4-fluoro-N-methylbenzenamine (2.27 g, 18.16 mmol, 1 .10 equiv). The resulting solution was stirred for 1 hour at room temperature. The resulting solution was diluted with DCM (100 mL ), washed and dried. The residue was applied onto a silica gel column with petroleum ether / dichloromethane / ethyl acetate (2/1/1 ). This resulted in 3.8 g (67%) of 3-bromo-N-(4-fluorophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide as a light yellow solid. 1 H-NMR (CDCI3, 300 MHz): 8.62 (brs, 2H), 7.80 (s, 1 H), 7.1 1 (brs, 2H), 6.96 (t, J = 5.4 Hz, 2 H), 3.52 (s, 3H)
Synthesis 3-bromo-N-(3,4-difluorophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide (I-65)
Figure imgf000139_0001
1-10 I-65
Into a 250-mL round-bottom flask, was placed a solution of 3-bromoimidazo[1 ,2-a]pyrazine-6- carboxylic acid (2 g, 8.26 mmol, 1 .00 equiv) in dichloromethane (60 mL). Then oxalyl dichloride (5.3 g, 41 .73 mmol, 5.05 equiv) and several drops of DMF were added. The resulting solution was stirred for 60 min at room temperature. Concentrated under vacuum to remove excess oxalyl dichloride and freshed dichloromethane(60 mL) was added. Trifluorobenzenamine (3.2 g, 24.81 mmol, 3.00 equiv), triethylamine (10 g, 99.01 mmol, 1 1 .98 equiv) was added. The resulting solution was allowed to react, with stirring, overnight at room temperature. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1 :2-1 :1 ). This resulted in 1.6 g (55%) of 3-bromo-N- (3,4-difluorophenyl)imidazo[1 ,2-a]pyrazine-6-carboxamide as a white solid.
Into a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 3-bromo-N-(3,4-difluorophenyl)imidazo [1 ,2-a]pyrazine-6- carboxamide (1.6 g, 4.53 mmol, 1 .00 equiv) in N,N-dimethylformamide (30 mL). This was PAT054787-WO-PCT followed by the addition of sodium hydride (400 mg, 1 1 .67 mmol, 2.57 equiv, 70%) at room temperature. The resulting solution was stirred for 1 h at room temperature. To this was added iodomethane (4 g, 28.17 mmol, 6.21 equiv) at room temperature. The resulting solution was allowed to react, with stirring, for an additional 1 .5 h at room temperature. The reaction was then quenched by the addition of 50 mL of water. The resulting solution was extracted with 2x200 mL of ethyl acetate and the organic layers were combined, washed with 4x200 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with Petroleum Ether:EtOAc (2:1 -1 :1 ). This resulted in 1.2 g (70%) of I-65 as a yellow solid. 1 H NMR (300 MHz, CDCI3)68.70(s, 1 H), 8.65(s, 1 H), 7.82(s, 1 H), 7.06(m, 2H), 6.86(s, 1 H)..
Synthesis 3-bromo-N-(4-fluorophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide (I- 66)
Figure imgf000140_0001
1-10 I-66
The compound was synthesized using a protocol as described for I-64.
Synthesis of tert-butyl (2-methyl-2-(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenoxy)propanoyl)carbamate (I
Figure imgf000140_0002
The compound was synthesized using a protocol as described for I-58.
Synthesis of 5-cyclobutyl-N-methylpyridin-2-amine (I-68):
Figure imgf000140_0003
I-68 PAT054787-WO-PCT
General Procedure: To a solution of the 5-cyclobutylpyridin-2-amine (1 eq) in CH2CI2 was added the Boc-anhydride (1.25 eq) followed by DIEA. The reaction mixture was stirred at room temp, for 12 hours. The solvents were removed under vacuo, extracted the organics with ethyl acetate and the crude was used for the next step without further purifications. The crude yields are 50-90% in most cases (different substrates).
The solution of tert-butyl (5-cyclobutylpyridin-2-yl)carbamate was dissolved in dry THF and Mel, followed by NaH was added to the reaction mixture. The reaction mixture was stirred at room temp for 2 hrs and the checked via LC/MS for the desired peak. The crude was extracted and redissolved in TFA/DCM (1 :1 ) and stirred for ½ hr. The reaction mixture was quenched with sodium carbonate solution and comcentrated before using for the next step. Method B M/Z = 163(M+1 ), RT 1.18 min
Synthesis of 6-Fluoro-1 ,2,3,4-tetrahydroquinoline(l-69):
Figure imgf000141_0001
Step 1 : 3-Chloro-N-(4-fluorophenyl)prop
Figure imgf000141_0002
1
2-Chloropropionyl chloride (2.14 ml_, 22.45 mmol) was added to a solution of 4F-aniline (4.27 ml_, 45.05 mmol) in dichloromethane (200 mL) at 0 °C and stirred at ambient temperature for 1 hour. To the reaction mass was added water and the organic layer was washed with sat.
NaHC03, brine, dried over Na2S04 and concentrated under reduced pressure to afford 4.0 g (45% crude yield) of 3-chloro-N-(4-fluorophenyl)propanamide 1 as a light blue solid. 1 H-NMR (CDCI3): δ 7.44-7.48 (m, 3H), 7.01 (t, J = 8.35 Hz, 2H), 3.87 (t, J = 6.59 Hz, 2H), 2.80 (t, J = 6.15 Hz, 2H).
Step 2: 6-Fluoro-3,4-dihvdroquinolin-2(1 H)-one
Figure imgf000141_0003
PAT054787-WO-PCT
To a suspension of 3-chloro-N-(4-fluorophenyl)propanamide 1 (2.0 g, 9.95 mmol) and AICI3 (4.6 g, 34.82 mmol) was stirred at 120 °C for 3 h. Cold water was added to the reaction mass under vigorous stirring and neutralized with 6N HCI at 0°C. The solid was collected by filtration, washed with water and dried to afford 1.4 g (85%) of 6-fluoro-3,4-dihydroquinolin-2(1H)-one 2 as a brown solid. 1 H NMR (400 MHz, CDCI3): δ 6.85-6.90 (m, 2H), 6.72-6.75 (m, 1 H), 2.95 (t, J = 7.91 Hz, 2H), 2.62 (t, J = 7.03 Hz, 2H).
Step 3: 6-Fluoro-1 ,2,3,4-tetrahvdroquinoline
To a suspension of LiAIH4 (2.76 g, 72.73 mmol) THF (80 mL) was added a solution of 6-fluoro- 3,4-dihydroquinolin-2(1 H)-one 2 (6.0 g, 36.36 mmol) in THF at stirred at ambient temperature for 2 h. The reaction was quenched with brine and ethyl acetate and filtered through celite. The filtrate was diluted with ethyl acetate, washed with water, brine and dried over anhyd. Na2S04 and concentrated to gave 4.5 g (81 %) of 6-fluoro-1,2,3,4-tetrahydroquinoline as a brown color liquid. 1H NMR (400 MHz, CDCI3): δ 6.65-6.78 (m, 2H), 6.37-6.40 (m, 1 H), 3.26 (t, J = 5.3 Hz, 2H), 2.73 (t, J = 6.6 Hz, 2H), 1.88-1.94 (m, 2H).
Synthesis of 6-Fluoro-2,2-dimethyl-1 ,2,3 -tetrahydroquinoline (I-70):
Figure imgf000142_0001
Figure imgf000142_0002
To a cold solution (0°C) of compound quinolone derivative (5 g, 30.3 mmol) in DMF (100 mL) was added NaH (60%) (1 .98g, 45.4 mmol) and stirred at 0°C for 20 min. To the resulting solution benzyl chloride (4.2 mL, 36.3 mmol) was added and stirred at rt for 2 h. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (2 x 60 mL). The combined organic layer was washed with brine (20 mL), dried over Na2S04 and concentrated in vacuo to obtain 7.0 g (90%) of 1-benzyl-6-fluoro-3,4-dihydroquinolin-2(1H)-one 1 as a brown color PAT054787-WO-PCT liquid.1H NMR (400 MHz, CDCI3): δ 7.29-7.32 (m, 2H), 7.18-7.26 (m, 3H), 6.75-6.90 (m, 3H) 5.16 (s, 2H), 2.96 (t, J = 7.9 Hz, 2H), 2.76-2.80 (m, 2H). (2)
Figure imgf000143_0001
Brief procedure: To a cold solution (-78°C) of 1 -benzyl-6-fluoro-3,4-dihydroquinolin-2(1 H)-one 1 (3.8 g, 14.9 mmol) in dichloromethane (400 ml.) was added 2, 6-di-ter-butylpyridine (3.66 g, 17.88 mmol) followed by Tf20 (10.5 ml_, 37.25 mmol) and stirred at -78°C for 45 min. Then MeMgBr (3M in Et20, 29.7 mL, 89.4 mmol) was added at -78°C and stirred at ambient temperature for 3 h. The reaction was quenched with aq. NH4CI (100 mL) and extracted with dichloromethane (2 x 200 mL). The combined organic layer was washed with brine (100 mL), dried over Na2S04 and concentrated under reduced pressure. The crude compound was purified by column chromatography over silica gel (100-200 mesh) using a solvent gradient of 1 % EtOAc-pet ether as eluant to afford 985 mg (25%) of 1-benzyl-6-fluoro-2,2-dimethyl-1 ,2,3,4- tetrahydroquinoline 2 as a pale yellow liquid. LC-MS: m/z 270.14 ( +H) with a purity of 94.04%. 1 H NMR (400 MHz, CDCI3): δ 7.20-7.33 (m, 5H), 6.71 -74 (m, 1 H), 6.57-6.62 (m, 1 H), 6.15-6.19 (m, 1 H), 4.43 (s, 2H), 2.83 (t, J = 6.59 Hz, 2H), 1 .91 (t, J = 6.59 Hz, 2H), 1.24 (s, 6H).
Step 3: 6-Fluoro-2,2-dimethyl-1 -tetrahvdroquinoline
Figure imgf000143_0002
To a solution of 1 -benzyl-6-fluoro-2,2-dimethyl-1 ,2,3,4-tetrahydroquinoline 2 (1 .2 g, 4.46 mmol) in ethanol (100 mL) was added 10% Pd/C (300 mg) and hydrogenated under Paar hydrogenator at 40 psi for 6 h. The reaction mixture was filtered through celite and concentrated under reduced pressure. The crude compound was purified by column chromatography over silica gel (100-200 mesh) using a solvent gradient of 5% EtOAc-pet ether as eluent to afford 565 mg (70%) of 6-fluoro-2,2-dimethyl-1,2,3,4-tetrahydroquinoline I-70 as a pale yellow liquid. 1 H NMR PAT054787-WO-PCT
(400 MHz, CDCI3): δ 6.67-6.74 (m, 2H), 6.41 -6.44 (m, 1 H), 2.75 (t, J - 7.0 Hz, 2H), 1 .68 (t, J = 7.0 Hz, 2H), 1.20 (s, 6H).
Synthesis of (3-Bromoimidazo[1 ,2-a]pyrazin-6-yl)(6-f luoro-2,2-dimethyl-3,4- dihydroquinolin-1 (2H)-yl)methanone 1-71 :
Figure imgf000144_0001
70°C,16 , microwave
A mixture of 3-bromoimidazo[1,2-a]pyrazine-6-carboxylic acid 3 (200 mg, 0.829 mmol, 1 equiv) in SOCI2 (6 mL) was refluxed for 2 h. Excess of SOCI2 was distilled-off and the residue was dissolved in THF (20 mL). To the resulting solution were added a solution of 6-fluoro-2,2- dimethyl-1,2,3,4-tetrahydroquinoline I-70 (223 mg, 1 .24 mmol, 1 .5 equiv) and DIPEA (320 mg, 2.48 mmol, 3 equiv) in THF (2 mL) at 0°C and stirred at 70°C for 14 h under microwaves. The reaction mixture was concentrated and to the residue water (20 mL) was added and extracted with EtOAc (2 x 50 mL). The combined organic layer was washed with brine (20 mL), dried over Na2S04 and concentrated under reduced pressure. The crude compound was purified by column chromatography over silica gel (100-200 mesh) using a solvent gradient of 10% EtOAc- pet ether as eluant to afford 50 mg (15%) of (3-bromoimidazo[1,2-a]pyrazin-6-yl)(6-fluoro-2,2- dimethyl-3,4-dihydroquinolin-1(2H)-yl)methanone 1-71 as a Gummy solid.1 H NMR (400 MHz, DMSO-ds): δ 8.68 (s, 1 H), 8.62 (s, 1 H), 8.02 (s, 1 H), 7.02-7.08 (m, 1 H), 6.67-6.64 (m, 1 H), 6.58- 6.53 (m, 1 H), 2.69 (t, 2H), 1 .78 (br. s, 2H), 1 .65 (s, 6H).
Synthesis of (3-bromoimidazo[1 ,2-a]pyrazin-6-yl)(6-fluoro-3,4-dihydroquinolin-1 (2H)- yl)methanone I-72:
Figure imgf000144_0002
The compound was synthesized using a protocol described for the synthesis of 1-71 using the intermediate I-69.
Synthesis of Fluoro-3,4-dihydro-2H-benzo[b][1 ,4]oxazine I-73:
Figure imgf000145_0001
1-73
A suspension of 2-amino-5-fluorophenol (5.0 g, 39.37 mmol), 1 ,2-dibromoethane (21.9 g, 1 18.15 mmol), and potassium carbonate (27.16 g, 196.8 mmol) in DMF (50 mL) was stirred at 100°C for 6 h. The reaction was diluted with water and extracted the product into ethyl acetate. The combined organic layer was washed with water, brine, dried over anhyd. Na2S04 and concentrated in vacuo. The residue was purified by column chromatography over silica gel (100-200 mesh) with 10% ethyl acetate in pet-ether as eluant gave 2.6 g (43%) of 7-fluoro-3,4- dihydro-2H-benzo[b][1,4] xazine I-73 as a brown solid. 1 H NMR (400 MHz, CDCI3): 6.46-6.55 (m, 3H), 4.24 (t, J = 4.4 Hz, 2H), 3.61 (br. s, 1 H), 3.38 (t, J = 4.4 Hz, 2H).
Synthesis of (3-bromoimidazo[1 ,2-a]pyrazin-6-yl)(6-fluoro-3,4-dihydroquinolin-1 (2H)- yl)methanone I-74:
Figure imgf000145_0002
The compound was synthesized using a protocol described for the synthesis of 1-71 using the intermediate I-73.
Synthesis 3-bromo-N-(5-cyanopyridin-2-yl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide (I-75)
Figure imgf000145_0003
I-75
The compound was synthesized using a protocol described for the synthesis of I-65 using the intermediate I-37.
Synthesis of N-((3-bromoimidazo[1 ,2-a]pyrazin-6-yl)methyl)-6-chloro-N-methylpyridin-3- amine (I-76) PAT054787-WO-PCT
Figure imgf000146_0001
1-76
The compound was synthesized using a protocol described for the synthesis of 1-15.
Synthesis of N-((3-bromoimidazo[1 ,2-a]pyrazin-6-yl)methyl)-N,5-dimethylpyridin-2-amine (I-77)
Figure imgf000146_0002
1-77
The compound was synthesized using a protocol described for the synthesis of 1-15.
Synthesis of 3-bromo-N-methyl-N-(5-methylpyridin-2-yl)imidazo[1 ,2-a]pyrazine-6- carboxamide (I-78)
Figure imgf000146_0003
I-78
The compound was synthesized using a protocol described for the synthesis of 1-15.
Synthesis of Compounds
Synthesis of compound 1 : N-(4-cvanophenvl)-3-(6-(3-(dimethvlamino)propoxv)pyridin-3-vl)-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000146_0004
PAT054787-WO-PCT
The compound was synthesized using 1-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z = 456.20 (M+1 ), r.t = 1 .04 mins.
Synthesis of compound 2: 4-(((3-(4-(1 H-pyrazol-5-yl)phenyl)imidazo[1 ,2-a]pyrazin-6- yl)methyl)(methyl)amino)benzonitrile
Figure imgf000147_0001
The compound was synthesized using 1-15 and an appropriate boronic acid/ester using ;
procedure similar Suzuki coupling protocol described in 228. MS m/z 406.1 (M+H)+; r.t.
Synthesis of compound 3: N-((3-(4-(1 H-pyrazol-5-yl)phenyl)imidazo[1 ,2-a]pyrazin-6- yl)methyl)-4-fluoro-N-methylaniline
Figure imgf000147_0002
The compound was synthesized using I-62 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. MS m/z 399.2 (M+H)+; r.t. = 1.367
Synthesis of compound 4: 4-(((3-(4-chlorophenyl)imidazo[1 ,2-a]pyrazin-6- yl)methyl)(methyl)amino)benzonitrile
Figure imgf000147_0003
The compound was synthesized using I-63 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. MS m/z 374.0 (M+H)+; r.t. = 1.751 PAT054787-WO-PCT
Synthesis of compound 5: N-((3-(4-(1 H-pyrazol-5-yl)phenyl)imidazo[1 ,2-a]pyrazin-6- yl)methyl)-4-chloro-N-methylaniline
Figure imgf000148_0001
The compound was synthesized using I-63 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. MS m/z 415.1 (M+H)+; r.t. = 1 .654.
Synthesis of compound 6: N-(5-chloro-3-fluoropyridin-2-vl)-N-methvl-3-(4- (trifluoromethyl)phenyl)imidazo[1 ,2- e
Figure imgf000148_0002
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II). MS m/z 450.0 (M+H)+; r.t. = 1.908..
Synthesis of compound 7: 5-methanesulfonvl-1 -((3-[4-(trifluoromethvl)phenvl1imidazo[1.2- a]pyrazin-6-yl}carbonyl)-2,3-dihydro- -indole
Figure imgf000148_0003
The compound was synthesized using a procedure similar to one used for the synthesis of 128. MS m/z 487.1 (M+H)+; r.t. = 2.120.
Synthesis of compound 8: 4-fluoro-N-methyl-N-((3-(1 -methyl-1 H-indazol-5-yl)imidazoPI ,2- alpyrazin-6-yl)methyl)aniline
Figure imgf000149_0001
The compound was synthesized using 1-62 and an appropriate boronic acid/ester using < procedure similar Suzuki coupling protocol described in 228. MS m/z 387.1 (M+H)+; r.t.
Synthesis of compound 9: N-((3-(4-(1 H-pyrazol-1 -yl)phenyl)imidazo[1 ,2-a]pyrazin-6- yl)methyl)-4-chloro-N-methylaniline
Figure imgf000149_0002
The compound was synthesized using I-63 and an appropriate boronic acid/ester using < procedure similar Suzuki coupling protocol described in 228. MS m/z 415.1 (M+H)+; r.t.
Synthesis of compound 10: N-((3-(4-(1 H-pyrazol-1 -yl)phenyl)imidazo[1 ,2-a]pyrazin-6- yl)methyl)-4-chloro-N-methylaniline
Figure imgf000149_0003
The compound was synthesized using I-62 and an appropriate boronic acid/ester using < procedure similar Suzuki coupling protocol described in 228. MS m/z 399.1 (M+H)+; r.t.
Synthesis of compound 11 : 3-(4-carbamoylphenyl)-N-(4-fluorophenyl)-N-methylimidazo[1 ,2- a]pyrazine-6-carboxamide
Figure imgf000150_0001
The compound was synthesized using 1-64 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. 1H NMR (400 MHz, DMSO) δ 8.85 (s, 1 H), 8.79 (s, 1 H), 8.18 (s, 1 H), 8.16 (s, 1 H), 8.09 (d, J = 8.4, 2H), 7.78 (d, J = 8.3, 2H), 7.54 (s, 1 H), 7.40 - 7.26 (m, 2H), 7.12 (t, J = 8.6, 2H), 3.41 (s, 3H); MS m/z 390.1 (M+H)+; r.t. = 1.168.
Synthesis of compound 12: N-methvl-N-(1 -methvl-1 H-benzord1[1 ,2,3]triazol-5-yl)-3-(4- (trifluoromethyl)phenyl)imidazo[1 ,2- e
Figure imgf000150_0002
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II). MS m/z 452.1 (M+H)+; r.t. = 1.696
Synthesis of compound 13: N-(4-chlorophenvl)-N-methyl-3-[4-(1 H-pvrazol-5- yl)phenyl]imidazo[1 ,2-a]pyrazine-6-car
Figure imgf000150_0003
The compound was synthesized using 1-11 and an appropriate boronic acid/ester using < procedure similar Suzuki coupling protocol described in 228. MS m/z 429.0 (M+H)+; r.t.
Synthesis of compound 14: N-(1 ,3-benzothiazol-2-yl)-N-methyl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide PAT054787-WO-PCT
Figure imgf000151_0001
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method III). 1 H-NMR (400 MHz, CDCI3) ppm 9.17 (s, 1 H), 9.0 (s, 1 H), 8.06 (s, 1 H), 7.75- 7.91 (m, 6H), 7.47 (m, 1 H), 7.35 (m, 1 H), 4.04 (s, 3H); LC-MS: 98.84%; 454.03(M+H).
Synthesis of compound 15: -[4-(5-amino-1 1314-oxadiazol-2-vl)phenyl1-N-(4-chlorophenyl)-N- methylimidazo[1 ,2-a]pyrazine-6-carb
Figure imgf000151_0002
The compound was synthesized using 1-11 and I-24 using a procedure similar Suzuki coupling protocol described in 228. M/Z = 446.1 (M+1 ), r.t = 1 .27 mins.
Synthesis of compound 16: N-(3-methoxypyridin-2-vl)-N-methyl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000151_0003
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II) using intermediate I-46. MS m/z 428.1 (M+H)+; r.t. = 1.839.
Synthesis of compound 17: 3-(4-chlorophenvl)-N-(4-methanesulfonvlphenvl)-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000151_0004
PAT054787-WO-PCT
The compound was synthesized using 1-66 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. MS m/z 441 .0 (M+H)+; r.t. = 1 .454.
Synthesis of compound 18: N-{[3-(4-chlorophenvl)imidazo[112-alpyrazin-6-yl1methyl)-4-fluoro- N-methylaniline
Figure imgf000152_0001
The compound was synthesized using 1-62 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. MS m/z 367.1 (M+H)+; r.t. = 1 .741 .
Synthesis of compound 19: N-(4-cvanophenyl)-N-methvl-3-(5-methvlpyridin-2-vl)imidazo[1 12- a]pyrazine-6-carboxamide
Figure imgf000152_0002
The compound was synthesized using 1-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z = 369.13(M+1 ), r.t = 1 .31 mins.
Synthesis of compound 20: N-(4-cvanophenvl)-3-(2.4-dichlorophenvl)-N-methvlimidazo[1 ,2- a]pyrazine-6-carboxamide
Figure imgf000152_0003
The compound was synthesized using I-62 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z = 422.1 (M+1 ), r.t =2.06 mins.
Synthesis of compound 21 : N-((3-[4-(difluoromethoxv)phenvl1imidazo[1 ,2-alpvrazin-6- yl}methyl)-4-fluoro-N-methylaniline
Figure imgf000153_0001
The compound was synthesized using 1-62 and an appropriate boronic acid/ester using < procedure similar Suzuki coupling protocol described in 228. MS m/z 399.1 (M+H)+; r.t.
Synthesis of compound 22: 3-(4-carbamoylphenyl)-N-(314-difluorophenyl)-N- methylimidazo[1 ,2-a]pyrazine-6-carb
Figure imgf000153_0002
The compound was synthesized using I-65 and an appropriate boronic acid/ester using < procedure similar Suzuki coupling protocol described in 228. MS m/z 408.1 (M+H)+; r.t.
Synthesis of compound 23: N-(214-difluorophenyl)-N-methyl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2- e
Figure imgf000153_0003
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II). MS m/z 433.1 (M+H)+; r.t. = 1.929.
Synthesis of compound 24: N-methvl-4-(morpholin-4-vl)-N-l3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}benzamide
Figure imgf000154_0001
To a solution of acid in dichloromethane was added triethyl amine and a catalytic amount of DMF. The reaction mixture was cooled to 0 °C. Oxalyl chloride was added slowly dripwise and the reaction mixture was stirred for 15 minutes. The solvent was removed. A solution of imidazolopyrazine in dichloromethane containing triethylamine was added to the acid chloride at 0 °c and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water and extracted with dichloromethane. The organic extracts were washed with brine and dried over MgS04 and concentrated. The crude reaction mixture was purified by flash chromatography (silica. 0-100% ethyl acetate/hexanes). 1H NMR (400 MHz, CDCI3) δ 9.1 1 (s, 1 H), 7.91 (s, 1 H), 7.78 (s, 1 H), 7.66 (d, J= 8.1 , 2H), 7.37 (d, J= 8.8, 2H), 7.16 (d, J= 8.0, 2H), 6.82 (d, J= 8.8, 2H), 3.86 - 3.77 (m, 4H), 3.58 (s, 3H), 3.23 - 3.15 (m, 4H).
Synthesis of compound 25: 4-[(f3-[4-(5-amino-1 ,3,4-thiadiazol-2-yl)phenyl]imidazo[1 ,2- a]pyrazin-6-yl}methyl)(methyl)amino]benzonitrile
Figure imgf000154_0002
The compound was synthesized using 1-15 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z = 439.1 (M+1 ), r.t =1 .36 mins.
Synthesis of compound 26: 3-(4-chloro-2-methvlphenvl)-N-(4-cvanophenvl)-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000154_0003
The compound was synthesized using I-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z = 402.2 (M+1 ), r.t = 2.07 mins. PAT054787-WO-PCT
Synthesis of compound 27: 3-(2-chloropvridin-4-vl)-N-(4-cvanophenvl)-N-methvlimidazo[1 ,2- a]pyrazine-6-carboxamide
Figure imgf000155_0001
The compound was synthesized using I-59 and an appropriate boronic acid/ester using < procedure similar Suzuki coupling protocol described in 228. MS m/z 389.1 (M+H)+; r.t.
Synthesis of compound 28: -(f3-[4-(5-amino-1 ,3,4-thiadiazol-2-vl)phenyl1imidazo[1 ,2- a]pyrazin-6-yl}methyl)-6-chloro-N-methylpyridin-3-amine
Figure imgf000155_0002
The compound was synthesized using I-76 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. MS m/z 449.1 (M+H)+; r.t. = 1 .240.
Synthesis of compound 29: N-(4-cvanophenyl)-3-(3,5-difluoropyridin-2-vl)-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000155_0003
The compound was synthesized using I-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z = 391.10(M+1 ), r.t =
1 .35mins..
Synthesis of compound 30: N-(4-cyanophenvl)-3-(4-methoxv-3-methylphenvl)-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide PAT054787-WO-PCT
Figure imgf000156_0001
The compound was synthesized using 1-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z =398.2 (M+1 ), r.t = 2.01 mins.
Synthesis of compound 31 : 3-[2-chloro-4-(trifluoromethyl)phenvl1-N-(4-cvanophenvl)-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000156_0002
The compound was synthesized using I-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z = 456.1 (M+1 ), r.t = 2.23 mins.
Synthesis of compound 32: N-(3-chloro-4-fluorophenyl)-N-methyl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2- e
Figure imgf000156_0003
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II). MS m/z 449.1 (M+H)+; r.t. = 2.320.
Synthesis of compound 33: 3-acetyl-N-(6-chloropyridin-3-yl)-N-methylimidazo[1 ,2-a]pyrazine- 6-carboxamide
Figure imgf000156_0004
To the solution of 3-bromo-N-(4-chlorophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide (0,06g, 0.163mmols) in THF was added tributyl(1 -ethoxyvinyl)stannane (0.054g, 0.149 mmol, PAT054787-WO-PCT
0.9eq) followed by catalytic DPP-Pd. The reaction mixture was heated at 120 °C for 4 hours in a microwave. Subsequently, the reaction mixture was treated with 1 N HCI. The product was isolated via column chromatography. Yield = 10 mg (0.03mmol, 18%) of the desired product. M/Z = 330.1 ( +1 ), r.t = 1 .08 mins.
Synthesis of compound 34: 4-chloro-N-methvl-N-f[3-(1 -methyl-1 H-indazol-5-yl)imidazo[1 ,2- a]pyrazin-6-yl]methyl}aniline
Figure imgf000157_0001
The compound was synthesized using I-63 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228.
Synthesis of compound 35: N-(3-chlorophenvl)-N-methvl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2- e
Figure imgf000157_0002
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II). MS m/z 431 .1 (M+H)+; r.t. = 2.240
Synthesis of compound 36: 4-(6-|[(4-fluorophenvl)(methvl)amino1methyl)imidazo[1 ,2- a]pyrazin-3-yl)-N,N-dimethylaniline
Figure imgf000157_0003
The compound was synthesized using I-62 and an appropriate boronic acid/ester using < procedure similar Suzuki coupling protocol described in 228. MS m/z 376.2 (M+H)+; r.t. PAT054787-WO-PCT
Synthesis of compound 37: 4-(6-{[(4-chlorophenvl)(methvl)amino1rnethvl)imidazo[1 ,2- a]pyrazin-3-yl)-N,N-dimethylaniline
Figure imgf000158_0001
The compound was synthesized using I-63 and an appropriate boronic acid/ester using < procedure similar Suzuki coupling protocol described in 228. MS m/z 392.1 (M+H)+; r.t.
Synthesis of compound 38: N-(4-cvanophenyl)-N-methyl-3-[4- (methylcarbamoyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000158_0002
The compound was synthesized using I-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. 1 H NMR (400 MHz, DMSO) δ 8.90 (d, J = 1 .4 Hz, 1 H), 8.82 (d, J = 1 .3 Hz, 1 H), 8.63 (d, J = 4.6 Hz, 1 H), 8.22 (s, 1 H), 8.06 (d, J = 8.4 Hz, 2H), 7.85 (d, J = 8.4, 2H), 7.80 - 7.73 (m, 2H), 7.47 (d, J = 8.6 Hz, 2H), 3.48 (s, 3H), 2.85 (d, J = 4.5 Hz, 3H). M/Z = 41 1 .1 (M+1 ), r.t = 1 .1 1 mins.
Synthesis of compound 39: N-(5-ethvlpyridin-2-vn-N-methyl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000158_0003
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II). 1 H NMR (400 MHz, MeOD) δ 8.90 (s, 1 H), 8.67 (s, 1 H), 8.1 1 (s, 2H), 7.98 - 7.88 (m, 4H), 7.67 (d, J = 8.2 Hz, 1 H), 7.26 (d, J = 8.2Hz, 1 H), 3.56 (s, 3H), 2.65 (dd, J = 7.6Hz, 2H), 1 .22 (t, J = 7.6 Hz, 3H).ESI-MS m/z 426.14 [M+1 ]. RT: 1 .68min. PAT054787-WO-PCT
Synthesis of compound 40: N-methvl-N-[2-(trifluoromethoxv)ph
(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000159_0001
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II). MS m/z 481 .0 (M+H)+; r.t. = 2.380.
Synthesis of compound 41 : N-(214-dichlorophenvl)-3-(4-methoxvphenvl)-N-methylimidazo[1 ,2- a]pyrazine-6-carboxamide
Figure imgf000159_0002
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II). MS m/z 427.1 (M+H)+; r.t. = 2.220.
Synthesis of compound 42: -(3-chloro-4-methoxvphenvl)-N-(4-cvanophenvl)-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000159_0003
The compound was synthesized using I-59 and an appropriate boronic acid/ester using procedure similar Suzuki coupling protocol described in 228. M/Z =418.1 (M+1 ), r.t = 1 .
Synthesis of compound 43: N-methvl-N-(4-phenoxyphenyl)-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000160_0001
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II). MS m/z 489.1 (M+H)+; r.t. = 2.420.
Synthesis of compound 44: 4-chloro-N-|[3-(4-chlorophenyl)imidazo[1 ,2-a]pyrazin-6-yl]methyl}- N-methylaniline
Figure imgf000160_0002
The compound was synthesized using I-63 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. MS m/z 383.0 (M+H)+; r.t. = 2.014.
Synthesis of compound 45: N^-dimethyl-N-jfS-d -methyl-1 H-indazol-5-yl)imidazo[1 ,2- a]pyrazin-6-yl]methyl}pyridin-2-amin
Figure imgf000160_0003
The compound was synthesized using I-77 and an appropriate boronic acid/ester using ι procedure similar Suzuki coupling protocol described in 228. MS m/z 384.2 (M+H)+; r.t.
Synthesis of compound 46: N-(4-cvanophenvl)-N-methvl-3-[3-(1 H-pyrazol-4- yl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000160_0004
The compound was synthesized using I-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z =420.1 (M+1 ), r.t = 1 .83 mins. PAT054787-WO-PCT
Synthesis of compound 47: N,5-dimethvl-N-({3-[4-(1 H-pyrazol-5-yl)phenyl]imidazo[1 ,2- a]pyrazin-6-yl}methyl)pyridin-2-amin
Figure imgf000161_0001
The compound was synthesized using I-77 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. MS m/z 396.2 (M+H)+; r.t. = 1 .1 12.
Synthesis of compound 48: N-(4-cvanophenvl)-3-(3-methoxyphenvl)-N-methvlimidazo[112- a]pyrazine-6-carboxamide
Figure imgf000161_0002
The compound was synthesized using 1-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z = 384.1 (M+1 ), r.t = 1.59 mins.
Synthesis of compound 49: N-(2,4-dichlorophenvl)-N-methvl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2- e
Figure imgf000161_0003
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II). MS m/z 465.0 (M+H)+; r.t. = 2.500.
Synthesis of compound 50: N-[4-(difluoromethoxv)phenvH-N-methyl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000161_0004
i6o PAT054787-WO-PCT
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II). MS m/z 463.1 (M+H)+; r.t. = 1.771 .
Synthesis of compound 51 : N-methyl-N-[4-(1 -methyl-1 H-pyrazol-4-yl)phenyl]-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2- e
Figure imgf000162_0001
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II). using intermediate I-34. MS m/z 477.1 (M+H)+; r.t. = 1 .546.
Synthesis of compound 52: N-(3-bromo-4-fluorophenvn-N-methyl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2- e
Figure imgf000162_0002
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II). MS m/z 495.0 (M+H)+; r.t. = 2.320.
Synthesis of compound 53: N-(3,4-difluorophenyl)-N-methyl-3-(1 -methyl-1 H-indazol-5- yl)imidazo[1 ,2-a]pyrazine-6-carboxa
Figure imgf000162_0003
The compound was synthesized using I-65 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. 1H NMR (400 MHz, DMSO) δ 8.76 (s, 1 H), 8.75 (s, 1 H), 8.14 (s, 1 H), 8.07 (s, 1 H), 8.05 (s, 1 H), 7.84 (d, J = 8.7, 1 H), 7.65 (dd, J =
i6i PAT054787-WO-PCT
1.6, 8.7, 1 H), 7.48 (ddd, J = 2.5, 7.3, 1 1 .8, 1 H), 7.27 (dd, J - 9.1 , 19.4, 1 H), 7.05 (d, J = 15.3, 1 H), 4.07 (s, 3H), 3.34 (s, 3H); MS m/z 419.1 (M+H)+; r.t. = 1 .461.
Synthesis of compound 54: N-(2-fluoropyridin-3-vl)-N-methvl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2- e
Figure imgf000163_0001
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II), using intermediate I-47. MS m/z 396.1 (M+H)+; r.t. = 1.475.
Synthesis of compound 55: N-(3,4-dichlorophenvD-N-methyl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000163_0002
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II). MS m/z 465.0 (M+H)+; r.t. = 1.938.
Synthesis of compound 56: N-(4-chloro-3-methvlphenyl)-N-methyl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2- e
Figure imgf000163_0003
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II). MS m/z 445.1 (M+H)+; r.t. = 2.360. PAT054787-WO-PCT Synthesis of compound 57: N-(4-cvanophenyl)-3-[4-(difluoromethvl)phenyl1-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000164_0001
The compound was synthesized using I-59 and an appropriate boronic acid/ester using procedure similar Suzuki coupling protocol described in 228. M/Z = 404.1 ( +1 ), r.t = 1
Synthesis of compound 58: N-(6-bromopvridin-3-yl)-N-methvl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2- e
Figure imgf000164_0002
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II), using intermediate I-44. MS m/z 476.0 (M+H)+; r.t. = 1 .702.
Synthesis of compound 59: N-(4-chloro-2-methoxyphenvl)-N
(trifluoromethyl)phenyl]imidazo[1 ,2- e
Figure imgf000164_0003
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II). MS m/z 461 .0 (M+H)+; r.t. = 1.809.
Synthesis of compound 60: 3-[4-chloro-3-(trifluoromethyl)phenvl1-N-(4-cvanophe
methylimidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000164_0004
PAT054787-WO-PCT
The compound was synthesized using 1-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z = 456.1 (M+1 ), r.t = 2.18 mins.
Synthesis of compound 61 : N-(214-dichlorophenyl)-N-methvl-3-(4-methylphenvl)imidazo[1 12- a]pyrazine-6-carboxamide
Figure imgf000165_0001
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II). MS m/z 41 1 .1 (M+H)+; r.t. = 2.370.
Synthesis of compound 62: 4-[methvl({[3-(1 -methyl-1 H-indazol-5-yl)imidazo[1 ,2-a]pyrazin-6- yl]methyl})amino]benzonitrile
Figure imgf000165_0002
The compound was synthesized using I-63 and an appropriate boronic acid/ester using < procedure similar Suzuki coupling protocol described in 228. MS m/z 394.1 (M+H)+; r.t.
Synthesis of compound 63: N-(5-fluoropyridin-2-vl)-N-methvl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2- e
Figure imgf000165_0003
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II); using intermediate 1-38. MS m/z 416.0 (M+H)+; r.t. = 1 .910.
Synthesis of compound 64: 4-chloro-N-({3-[4-(difluoromethoxv)phenvl1imidazo[1 ,2-alpvrazin- 6-yl}methyl)-N-methylaniline
Figure imgf000166_0001
The compound was synthesized using 1-63 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. MS m/z 415.1 (M+H)+; r.t. = 1.929
Synthesis of compound 65: N-(4-cvanophenvl)-3-(2-fluoro-4-methoxyphenvl)-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000166_0002
The compound was synthesized using I-59 and an appropriate boronic acid/ester using procedure similar Suzuki coupling protocol described in 228. M/Z = 402.2 (M+1 ), r.t = 1
Synthesis of compound 66: N-(5-fluoropyridin-3-yl)-N-methvl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2- e
Figure imgf000166_0003
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II) using intermediate 1-51 . MS m/z 416.1 (M+H)+; r.t. = 1.564.
Synthesis of compound 67: N-(4-cvanophenvl)-3-(4-methoxvphenvl)-N-methvlimidazo[1 ,2- a]pyrazine-6-carboxamide
Figure imgf000166_0004
The compound was synthesized using I-59 and an appropriate boronic acid/ester using ;
procedure similar Suzuki coupling protocol described in 228. MS m/z 384.2 (M+H)+; r.t. PAT054787-WO-PCT
Synthesis of compound 68: N-methvl-N-[4-(2-methvl-2H-1 .2.3.4-tetrazol-5-vl)Dhenvll-3-r4- (trifluoromethyl)phenyl]imidazo[1 ,2- e
Figure imgf000167_0001
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II). MS m/z 479.1 (M+H)+; r.t. = 1.656.
Synthesis of compound 69: N-(4-fluorophenvl)-3-(4-methoxyphenvn-N-methvlimidazo[1 12- a]pyrazine-6-carboxamide
Figure imgf000167_0002
The compound was synthesized using 1-64 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. MS m/z 377.2 (M+H)+; r.t. = 1 .850.
Synthesis of compound 70: 3-(4-chlorophenyl)-N-(214-dichlorophenyn-N-methylimidazo[112- a]pyrazine-6-carboxamide
Figure imgf000167_0003
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II). MS m/z 432.9 (M+H)+; r.t. = 2.370.
Synthesis of compound 71 : 3-(4-chloro-3-fluorophenyl)-N-(4-cyanophenyl)-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide
i66
Figure imgf000168_0001
The compound was synthesized using 1-59 and an appropriate boronic acid/ester using procedure similar Suzuki coupling protocol described in 228. M/Z = 406.1 (M+1 ), r.t = 2
Synthesis of compound 72: N-(4-cyanophenvl)-N-[2-(dimethvlamino)ethyl1-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2- e
Figure imgf000168_0002
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II) using intermediate I-32. MS m/z 479.2 (M+H)+; r.t. = 1.450.
Synthesis of compound 73: N-(2-chlorophenvD-N-methyl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000168_0003
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II). MS m/z 431 .1 (M+H)+; r.t. = 2.270.
Synthesis of compound 74: 3-[4-(5-amino-1 1314-thiadiazol-2-vl)phenyl1-N-(4-cvanophenyl)-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000168_0004
PAT054787-WO-PCT
The compound was synthesized using 1-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. 1 H NMR (400 MHz, DMSO) δ 9.25 (s, 1 H), 8.91 (dd, J = 1 .3, 3.7, 1 H), 8.82 (d, J - 1.3, 1 H), 8.21 (d, J - 2.8 Hz, 1 H), 8.01 (m, 2H), 7.83 (m, 2H), 7.77 (d, J - 8.6 Hz, 2H), 7.48 (dd, J = 2.7, 8.6 Hz, 2H), 3.48 (s, 3H). M/Z = 453.1 (M+1 ), r.t = 1.03 mins.
Synthesis of compound 75: N-(4-cvanophenyl)-3-[4-(1 ,1 -difluoroethyl)phenyl]-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000169_0001
The compound was synthesized using I-59 and I-25 using a procedure similar Suzuki coupling protocol described in 228. M/Z = 418.1 (M+1 ), r.t = 1 .60 mins.
Synthesis of compound 76: N-(4-cvanophenyl)-N-methvl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000169_0002
Pd2(dba)3 (1 mg, 0.00078 mmol) was added to a mixture of N-methyl-3-(4- (trifluoromethyl)phenyl)imidazo[1 ,2-a]pyrazine-6-carboxamide (25 mg, 0.078 mmol), 4- bromobenzonitrile (12 mg, 0.065 mmol), cesium carbonate (36 mg, 0.1 1 mmol), XantPhos (1 .5 mg, 0.0023 mmol) and dioxane (0.25 ml_). The reaction vessel was evacuated to degas the mixture. The reaction vessel was left under vacuum, sealed, and heated to 1 10 °C for 6 hours. After cooling to room temperature, the solvent was removed. The crude material was taken up in dichloromethane and filtered to remove any salts. The crude reaction mixture was purified by preparatory TLC to give the desired product. 1 H NMR (400 MHz, MeOD) δ 8.92 (d, J = 1.4, 1 H), 8.75 (s, 1 H), 8.1 1 (s, 1 H), 7.93 (d, J = 8.5, 2H), 7.89 (d, J = 8.5, 2H), 7.71 - 7.63 (m, 2H), 7.45 - 7.38 (m, 2H), 3.55 (s, 3H). i68 PAT054787-WO-PCT
Method II :
Figure imgf000170_0001
Oxalyl chloride (0.47 mL, 5.40 mmol) was added drop wise to a solution of 3-(4- (trifluoromethyl)phenyl)imidazo[1 ,2-a]pyrazine-6-carboxylic acid (826 mg, 2.70 mmol), DMF (0.05 mL) and dry dichloromethane (20 mL) at room temperature (gas evolution). After 30 minutes at room temperature, the solvent was removed in vacuo. The crude acid chloride was dissolved in dry dichloromethane (15 mL) and a solution of 4-(methylamino)benzonitrile (533 mg, 4.04 mmol in 5.0 mL of dichloromethane) was added drop wise at room temperature.
Triethylamine (1 .13 mL, 8.10 mmol) was added and the reaction stirred at room temperature for 3 hours. The solvent was removed in vacuo and the crude material was purified by flash chromatography (silica, 10-100% ethyl acetate/hexanes). The product was further recrystallized from methanol to give pure N-(4-cyanophenyl)-N-methyl-3-(4-
(trifluoromethyl)phenyl)imidazo[1 ,2-a]pyrazine-6-carboxamide as white needles. 1 H NMR (400 MHz, DMSO) 5 9.72 (d, J = 1 .4, 1 H), 9.65 (d, J = 1 .3, 1 H), 9.06 (s, 1 H), 8.80 (s, 4H), 8.57 (d, J = 8.7, 2H), 8.27 (d, J = 8.6, 2H), 4.28 (s, 3H).
Method III :
Figure imgf000170_0002
I-8 72
Sodium hydride (4.0 mg, 0.0921 mmol) was added to a solution of N-(4-cyanophenyl)-3-(4-
(trifluoromethyl)phenyl)imidazo[1 ,2-a]pyrazine-6-carboxamide (25 mg, 0.0614 mmol) and DMF
(0.70 mL) at room temperature. After 30 minutes, methyl iodide (0.006 mL, 0.0921 mL) was added. The reaction stirred at room temperature for 12 hours. After quenching with water, the solvent was removed in vacuo. The crude reaction mixture was purified by preparative HPLC
(10-90% acetonitrile/water) to give the trifluoroacetamide salt of N-(4-cyanophenyl)-N-methyl-3-
(4-(trifluoromethyl)phenyl)imidazo[1 ,2-a]pyrazine-6-carboxamide as a white colored solid. 1 H
NMR (400 MHz, MeOD) δ 8.92 (d, J = 1 .4, 1 H), 8.75 (s, 1 H), 8.1 1 (s, 1 H), 7.93 (d, J = 8.5, 2H), PAT054787-WO-PCT
7.89 (d, J = 8.5, 2H), 7.71 - 7.63 (m, 2H), 7.45 - 7.38 (m, 2H), 3.55 (s, 3H); MS m/z 422.0
(M+H)+; r.t. = 1 .930.
Synthesis of compound 77: N-(4-cvanophenvl)-3-[4-(dimethylamino)phenvl1-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000171_0001
The compound was synthesized using I-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. 1 H NMR (400 MHz, DMSO) δ 8.67 (dd, J = 1 .4, 1 1 .4 Hz, 3H), 7.90 (s, 2H), 7.69 (m, 3H), 7.41 (dd, J = 8.7, 18.4 Hz, 5H), 6.85 (d, J= 8.9 Hz, 3H), 3.40 (s, 3H), 2.94 (s, 6H). M/Z = 397.2 (M+1 ), r.t = 1.21 mins.
Synthesis of compound 78: N-(6-chloropyridin-3-vl)-N-methvl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2- e
Figure imgf000171_0002
The compound was synthesized using I-57 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. 1H NMR (400 MHz, DMSO) δ 8.92 (d, J = 1 .4, 1 H), 8.85 (s, 1 H), 8.30 (s, 1 H), 8.26 (s, 1 H), 8.05 - 7.93 (m, 4H), 7.87 (dd, J = 2.8, 8.5, 1 H), 7.49 (d, J = 8.5, 1 H), 3.45 (s, 3H); MS m/z 432.1 (M+H)+; r.t. = 2.070.
Synthesis of compound 79: N-(6-fluoropyridin-3-yl)-N-methyl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000171_0003
PAT054787-WO-PCT
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II) using 1-52. MS m/z 416.1 (M+H)+; r.t. = 2.000.
Synthesis of compound 80: -(6-chloropvridin-3-vl)-N-methvl-3-(4-methylphenvl)imidazo[1 ,2- a]pyrazine-6-carboxamide
Figure imgf000172_0001
The compound was synthesized using I-57 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. MS m/z 378.1 (M+H)+; r.t. = 1 .940.
Synthesis of compound 81 : -(4-chlorophenvl)-N-(6-chloropvridin-3-vl)-N-methvlimidazo[1 ,2- a]pyrazine-6-carboxamide
Figure imgf000172_0002
The compound was synthesized using I-57 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. MS m/z 398.1 (M+H)+; r.t.
Synthesis of compound 82: N-(4-cvanophenvl)-N-methvl-3-[6-(pvrrolidin-1 -vl)pyridin-3- yl]imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000172_0003
The compound was synthesized using I-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z = 424.1 (M+1 ), r.t = 1.3 mins.
Synthesis of compound 83: N-(5-cyanopyridin-2-vl)-N-methyl-3-(1 -methyl-1 H-indazol-5- yl)imidazo[1 ,2-a]pyrazine-6-carboxamide PAT054787-WO-PCT
Figure imgf000173_0001
The compound was synthesized using 1-75 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z = 409.1 (M+1 ), r.t = 1.28 mins.
Synthesis of compound 84: N-(6-chloropvridin-3-vl)-N-methvl-3-(1 -methvl-1 H-indol-5- yl)imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000173_0002
The compound was synthesized using I-57 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. MS m/z 417.1 (M+H)+; r.t. = 1.94.
Synthesis of compound 85: N-(5-cvanopvridin-2-vl)-3-[4-(difluoromethoxy)phenyl1-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000173_0003
The compound was synthesized using I-75 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z =421 .1 (M+1 ), r.t = 1 .44 mins.
Synthesis of compound 86: N-(6-fluoropyridin-2-vl)-N-methvl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2- e
Figure imgf000173_0004
PAT054787-WO-PCT
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II) using 1-39. MS m/z 416.0 (M+H)+; r.t. - 1 .722.
Synthesis of compound 87: N-(4-cyanophenyl)-N-methyl-3-[4-(1 H-pyrazol-1 - yl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000174_0001
The compound was synthesized using I-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. 1 H NMR (400 MHz, DMSO) δ 8.82 (d, J = 1 .3 Hz, 1 H), 8.74 (d, J = 1 .3 Hz, 1 H), 8.10 (s, 1 H), 7.98 (d, J = 8.3 Hz, 2H), 7.78 - 7.67 (m, 5H), 7.40 (dd, J = 8.0, 9.9 Hz, 2H), 6.80 (d, J = 2.2, 1 H), 3.41 (s, 3H).M/Z =420.1 (M+1 ), r.t = 1.86 mins.
Synthesis of compound 88: N-(6-methoxvpyridin-3-yl)-N-methyl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000174_0002
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II). MS m/z 428.1 (M+H)+; r.t. = 2.050.
Synthesis of compound 89: N-(5-cvanopyridin-2-vl)-N-methvl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2- e
Figure imgf000174_0003
The compound was synthesized using I-75 and an appropriate boronic acid/ester using < procedure similar Suzuki coupling protocol described in 228. MS m/z 423.1 (M+H)+; r.t. PAT054787-WO-PCT
Synthesis of compound 90: N-(4-cvanophenvl)-3-(6-methoxvpyridin-3-vl)-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000175_0001
The compound was synthesized using I-59 and an appropriate boronic acid/ester using procedure similar Suzuki coupling protocol described in 228. M/Z =385.2 (M+1 ), r.t = 1 .
Synthesis of compound 91 : -(5-chloropyrazin-2-vl)-N-methvl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2- e
Figure imgf000175_0002
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II). MS m/z 433.1 (M+H)+; r.t. = 2.210.
Synthesis of compound 92: N-(4-cvanophenvl)-N-(propan-2-vl)-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000175_0003
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II). MS m/z 450.1 (M+H)+; r.t. = 2.230.
Synthesis of compound 93: N-(5-chloropyrimidin-2-vl)-N-methvl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000176_0001
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II). MS m/z 433.1 (M+H)+; r.t. = 2.270.
Synthesis of compound 94: N-(6-chloropyridazin-3-yl)-N-methvl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000176_0002
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II). MS m/z 433.1 (M+H)+; r.t. = 2.030.
Synthesis of compound 95: N-(5-cvanopyridin-2-vl)-3-[4-(difluoromethvl)phenvl1-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000176_0003
The compound was synthesized using I-75 and an appropriate boronic acid/ester using procedure similar Suzuki coupling protocol described in 228. M/Z =405.1 (M+1 ), r.t = 1 .
Synthesis of compound 96: N-(6-bromopyridazin-3-yl)-N-methyl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000176_0004
PAT054787-WO-PCT
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II). MS m/z 477.0 (M+H)+; r.t. = 2.090.
Synthesis of compound 97: N-(5-bromopyrazin-2-vl)-N-methvl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2- e
Figure imgf000177_0001
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II). MS m/z 477.0 (M+H)+; r.t. = 2.270.
Synthesis of compound 98: 3-(4-carbamovlphenyl)-N-(5-cvanopvridin-2-vl)-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000177_0002
The compound was synthesized using I-75 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z =398.1 (M+1 ), r.t = 1 .08 mins.
Synthesis of compound 99: N-methyl-N-ipyridin^-vD-S- -ftrifluoromethyDphenvllimidazofl ^- a]pyrazine-6-carboxamide
Figure imgf000177_0003
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II). MS m/z 398.1 (M+H)+; r.t. - 1.950.
I76 PAT054787-WO-PCT Synthesis of compound 100: N-(6-chloropvridin-3-vl)-3-(4-methoxyphenvl)-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000178_0001
The compound was synthesized using I-57 and an appropriate boronic acid/ester using < procedure similar Suzuki coupling protocol described in 228. MS m/z 394.1 (M+H)+; r.t.
Synthesis of compound 101 : N-(4-fluorophenvl)-N-methyl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2- e
Figure imgf000178_0002
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II). 1 H NMR (400 MHz, DMSO) δ 8.87 (s, 1 H), 8.82 (s, 1 H), 8.22 (s, 1 H), 7.95 (q, J = 8.4, 4H), 7.32 (s, 2H), 7.12 (t, J = 8.5, 2H), 3.40 (s, 3H); MS m/z 415.1 (M+H)+; r.t. = 2.100.
Synthesis of compound 102: N-(4-chlorophenvl)-3-[4-(difluoromethoxv)phenvl1-N- methylimidazo[1 ,2-a]pyrazine-6-carb
Figure imgf000178_0003
The compound was synthesized using I-64 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. MS m/z 429.0 (M+H)+; r.t. = 1 .773.
Synthesis of compound 103: 3-(4-chlorophenvl)-N-(4-fluorophenvl)-N-methylimidazo[1 ,2- a]pyrazine-6-carboxamide
Figure imgf000179_0001
The compound was synthesized using 1-64 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. 1H NMR (400 MHz, DMSO) δ 8.83 (s, 1 H), 8.73 (s, 1 H), 8.12 (s, 1 H), 7.76 - 7.66 (m, 4H), 7.37 - 7.24 (m, 2H), 7.12 (t, J = 8.6, 2H), 3.40 (s, 3H); MS m/z 381.1 (M+H)+; r.t. = 2.080.
Synthesis of compound 104: 3-(4-carbamovlphenvl)-N-(4-cvanophenvl)-N-methylimidazo[1 ,2- a]pyrazine-6-carboxamide
Figure imgf000179_0002
The compound was synthesized using I-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. 1 H NMR (400 MHz, DMSO) δ 8.82 (d, J = 1 .4 Hz, 1 H), 8.75 (d, J = 1 .3, 1 H), 8.15 (s, 1 H), 8.09 (s, 1 H), 8.03 (d, J = 8.4 Hz, 2H), 7.77 (d, J = 8.4 Hz, 2H), 7.73 - 7.65 (m, 2H), 7.48 (s, 1 H), 7.43 - 7.36 (m, 2H), 3.39 (s, 3H). M/Z =397.1 (M+1 ), r.t = 1 .14 mins.
Synthesis of compound 105: N-(3,4-difluorophenvl)-N-methyl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2- e
Figure imgf000179_0003
The compound was synthesized using I-65 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. 1H NMR (400 MHz, DMSO) δ 8.87 (s, 2H), 8.24 (s, 1 H), 8.04 - 7.90 (m, 4H), 7.54 (ddd, J = 2.5, 7.3, 1 1.7, 1 H), 7.33 (dd, J = 9.2, 19.3, 1 H), 7.13 (s, 1 H), 3.41 (s, 3H); MS m/z 433.0 (M+H)+; r.t. = 1 .837. PAT054787-WO-PCT Synthesis of compound 106: N-(4-fluorophenvl)-N-methvl-3-(1 -methyl-1 H-indazol-5- yl)imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000180_0001
The compound was synthesized using I-66 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z =401 .0(M+1 ), r.t = 1 .70 mins.
Synthesis of compound 107: N-(4-fluorophenvl)-N-methvl-3-(1 -methyl-1 H-indazol-5- yl)imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000180_0002
The compound was synthesized using I-64 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. MS m/z 41 1 .2 (M+H)+; r.t. = 2.230.
Synthesis of compound 108: N-(4-fluorophenvl)-N-methvl-3-(4-methvlphenvl)imidazo[1 ,2- a]pyrazine-6-carboxamide
Figure imgf000180_0003
The compound was synthesized using I-64 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. MS m/z 361 .2 (M+H)+; r.t. = 2.010.
Synthesis of compound 109: N13-bis(4-chlorophenvl)-N-methylimidazo[1 ,2-alpyrazine-6- carboxamide PAT054787-WO-PCT
Figure imgf000181_0001
The compound was synthesized using 1-11 and an appropriate boronic acid/ester using < procedure similar Suzuki coupling protocol described in 228. MS m/z 397.1 (M+H)+; r.t.
Synthesis of compound 110: N-(2-methoxvphenvD-N-methyl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000181_0002
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II). MS m/z 427.1 (M+H)+; r.t. = 2.120.
Synthesis of compound 111 : 6-fluoro-1 -((3-[4-(trifluoromethvl)phenvl1imidazo[1 ,2-a1pyrazin-6- yl}carbonyl)-1 ,2,3,4-tetrahydroquinoline
Figure imgf000181_0003
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II). MS m/z 441 .1 (M+H)+; r.t. - 2.300.
Synthesis of compound 112: 3-(4-chlorophenvl)-N-(3,4-difluorophenvl)-N-methvlimidazo[1 ,2- a]pyrazine-6-carboxamide
Figure imgf000181_0004
The compound was synthesized using I-65 and an appropriate boronic acid/ester using < procedure similar Suzuki coupling protocol described in 228. MS m/z 399.1 (M+H)+; r.t. i8o PAT054787-WO-PCT
Synthesis of compound 113: N-(4-cyanopheny0-N-methyl-3-(4-methvlphenyl)imidazo[1 ,2- a]pyrazine-6-carboxamide
Figure imgf000182_0001
The compound was synthesized using I-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z =368.2(M+1 ), r.t = 1 .94 mins.
Synthesis of compound 114: N-(4-cyanophenvl)-N-ethyl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000182_0002
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II). MS m/z 436.1 (M+H)+; r.t. = 2.250.
Synthesis of compound 115: N-(4-cvanophenvl)-N-methvl-3-[4-(propan-2- yl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000182_0003
The compound was synthesized using I-57 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. MS m/z 396.2 (M+H)+; r.t. = 2.300
Synthesis of compound 116: -(4-cvanophenvn-N-methvl-3-[4- (trifluoromethoxy)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide
i8i
Figure imgf000183_0001
The compound was synthesized using 1-59 and an appropriate boronic acid/ester using < procedure similar Suzuki coupling protocol described in 228. MS m/z 438.1 (M+H)+; r.t.
Synthesis of compound 117: N-(4-cvanophenvl)-N-methvl-3-[4- (methylamino)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000183_0002
The compound was synthesized using I-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z =383.1 (M+1 ), r.t = 1 .24 mins.
Synthesis of compound 118: 3 -(4-tert-butylphenyl)-N-(4-cyanophenyl)-N-methylimidazo[1 ,2- a]pyrazine-6-carboxamide
Figure imgf000183_0003
The compound was synthesized using I-59 and an appropriate boronic acid/ester using < procedure similar Suzuki coupling protocol described in 228. MS m/z 410.2 (M+H)+; r.t.
Synthesis of compound 119: N-(2-fluorophenvl)-N-methyl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000183_0004
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II). MS m/z 415.1 (M+H)+; r.t. = 2.160.. PAT054787-WO-PCT
Synthesis of compound 120: [4-(1 -cyano-1 -methylethyl)phenyl]-N-(4-cyanophenyl)-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000184_0001
The compound was synthesized using I-59 and an appropriate boronic acid/ester using ;
procedure similar Suzuki coupling protocol described in 228. MS m/z 421 .1 (M+H)+; r.t.
Synthesis of compound 121 : 3-[4-(dimethylamino)phenvH-N-(4-fluorophenyl)-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000184_0002
The compound was synthesized using I-64 and an appropriate boronic acid/ester using < procedure similar Suzuki coupling protocol described in 228. MS m/z 390.1 (M+H)+; r.t.
Synthesis of compound 122: N-(4-chlorophenvn-3-[4-(dimethvlamino)phenyl1-N- methylimidazo[1 ,2-a]pyrazine-6-carb
Figure imgf000184_0003
The compound was synthesized using 1-11 and an appropriate boronic acid/ester using ;
procedure similar Suzuki coupling protocol described in 228. MS m/z 406.0 (M+H)+; r.t.
Synthesis of compound 123: N-(4-cyanophenvl)-N-methvl-3-(1 -methyl-1 H-indol-5- yl)imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000185_0001
The compound was synthesized using 1-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z =407.2(M+1 ), r.t = 1 .95 mins.
Synthesis of compound 124: 3-(4-aminophenvl)-N-(4-cvanophenvl)-N-methvlimidazo[1 .2- a]pyrazine-6-carboxamide
Figure imgf000185_0002
To a solution of 3-bromo-N-(4-cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide I- 59 (1 gm, 2.8 mmol, 1 eq) in THF/water (5:1 ) 30 mL was added the 4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)aniline (766 mg, 3.5 mmols, 1 .25 eq) followed by DPP-Pd (cat) and K2HP04 (1 .21g, 7 mmol, 2.5 eq). The reaction mixture was heated under microwave condition at 150 °C for 45 mins. The reaction mixture was quenched with water, organics were extracted with ethyl acetate (3x10 mL), followed by drying over sodium sulfate. The crude was then purified using column chromatography to isolate the desired product (0.68g, 1 .84 mmol, 65%). M/Z
=369.1 (M+1 ), r.t = 1 .00 mins.
Synthesis of compound 125: N-(4-cvanophenvl)-3-[4-(furan-2-vl)phenvl1-N-methylimidazo[112- a]pyrazine-6-carboxamide
Figure imgf000185_0003
The compound was synthesized using 1-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z =420.1 (M+1 ), r.t = 1 .79 mins. PAT054787-WO-PCT
Synthesis of compound 126: N-(4-cvano-3-fluorophenvh-N-methvl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2- e
Figure imgf000186_0001
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II). MS m/z 440.1 (M+H)+; r.t. = 2.190.
Synthesis of compound 127: N-(3.4-difluorophenvl)-N-methvl-3-(1 -methyl-1 H-indol-5- yl)imidazo[1 ,2-a]pyrazine-6-carboxa
Figure imgf000186_0002
The compound was synthesized using I-65 and an appropriate boronic acid/ester using ;
procedure similar Suzuki coupling protocol described in 228. MS m/z 418.1 (M+H)+; r.t.
Synthesis of compound 128: N-(4-methanesulfonylphenyl)-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000186_0003
N-(4-(methylsulfonyl)phenyl)-3-(4-(trifluoromethyl)phenyl)imidazo[1 ,2-a]pyrazine-6-carboxamide was prepared according to the procedure described for the synthesis of N-(4-cyanophenyl)-N- methyl-3-(4-(trifluoromethyl)phenyl)imidazo[1 ,2-a]pyrazine-6-carboxamide by substituting 4- trifluoromethylaniline for 4-cyano-N-methyl aniline. LC/MS m/z 461 .1 (M+H)+; r.t. = 2.070.
Synthesis of compound 129: N-(4-cvanophenyl)-3-(4-methanesulfonvlphenvl)-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide PAT054787-WO-PCT
Figure imgf000187_0001
The compound was synthesized using 1-59 and an appropriate boronic acid/ester using procedure similar Suzuki coupling protocol described in 228. M/Z =432.0 (M+1 ), r.t = 1 .
Synthesis of compound 130: N-(4-cvanophenvl)-3-[4-(1 -methoxvethvQphenvl1-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000187_0002
The compound was synthesized using I-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. MS m/z 412.1 (M+H)+; r.t. = 1 .709.
Synthesis of compound 131 : N-(4-methanesulfonvlphenvl)-N-methyl-3-[4-(1 H-pyrazol-5- yl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000187_0003
The compound was synthesized using I-66 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. MS m/z 473.1 (M+H)+; r.t. = 1 .252.
Synthesis of compound 132: 3-(4-chlorophenvl)-N-(4-cvanophenvl)-N-methvlimidazo[1 ,2- a]pyrazine-6-carboxamide
Figure imgf000187_0004
i86 PAT054787-WO-PCT
The compound was synthesized using 1-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. MS m/z 388.1 (M+H)+; r.t. = 2.020.
Synthesis of compound 133: N-(4-cyanophenyl)-N-[2-(oxan-4-vl)ethyl1-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000188_0001
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II), using intermediate 1-31 . MS m/z 520.2 (M+H)+; r.t. = 2.240.
Synthesis of compound 134: 3-(4-acetylphenyl)-N-(4-cyanophenvl)-N-methylimidazo[1 ,2- a]pyrazine-6-carboxamide
Figure imgf000188_0002
The compound was synthesized using I-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z =396.1 (M+1 ), r.t = 1 .41 mins.
Synthesis of compound 135: N-(3,4-difluorophenvl)-N-methyl-3-(4-methylphenyl)imidazo[1 ,2- a]pyrazine-6-carboxamide
Figure imgf000188_0003
The compound was synthesized using I-65 and an appropriate boronic acid/ester using < procedure similar Suzuki coupling protocol described in 228. MS m/z 379.2 (M+H)+; r.t.
I87 PAT054787-WO-PCT Synthesis of compound 136: N-(4-fluorophenvl)-N-methvl-3-(1 -methyl-1 H-indol-5- yl)imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000189_0001
The compound was synthesized using I-64 and an appropriate boronic acid/ester using < procedure similar Suzuki coupling protocol described in 228. MS m/z 400.2 (M+H)+; r.t.
Synthesis of compound 137: N-(3-fluorophenvl)-N-methvl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2- e
Figure imgf000189_0002
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II). MS m/z 415.1 (M+H)+; r.t. = 2.1 10.
Synthesis of compound 138: N-(4-cyanophenyl)-N-methyl-3-[4-(2,2,2- trifluoroethoxy)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000189_0003
The compound was synthesized using I-59 and an appropriate boronic acid/ester using procedure similar Suzuki coupling protocol described in 228. M/Z =452.0 (M+1 ), r.t = 1 .
Synthesis of compound 139: N-(4-methoxyphenvl)-N-methyl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide
i88
Figure imgf000190_0001
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II). MS m/z 427.1 (M+H)+; r.t. - 2.1 10.
Synthesis of compound 140: N-(4-cvanophenvl)-3-[2-fluoro-4-(trifluoromethvl)phenvl1-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000190_0002
The compound was synthesized using I-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z =440.1 (M+1 ), r.t = 2.13
Synthesis of compound 141 : N-(4-chlorophenyl)-N-methyl-3-(1 -methyl-1 H-indol-5- yl)imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000190_0003
The compound was synthesized using 1-11 and an appropriate boronic acid/ester using ; procedure similar Suzuki coupling protocol described in 228. MS m/z 416.1 (M+H)+; r.t.
Synthesis of compound 142: 3-[4-(difluoromethoxy)phenyl]-N-(3,4-difluorophenyl)-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000190_0004
PAT054787-WO-PCT
The compound was synthesized using 1-65 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. MS m/z 431 .1 (M+H)+; r.t. = 1 .695.
Synthesis of compound 143: 3-(1 H-1 ,3-benzodiazol-5-yl)-N-(4-cyanophenyl)-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000191_0001
The compound was synthesized using I-59 and an appropriate boronic acid/ester using procedure similar Suzuki coupling protocol described in 228. M/Z =394.2 (M+1 ), r.t = 1 .
Synthesis of compound 144: N-(3,4-difluorophenvl)-N-methyl-3-[4-(1 H-pvrazol-1 - yl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000191_0002
The compound was synthesized using I-65 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. MS m/z 431 .1 (M+H)+; r.t. = 1 .815.
Synthesis of compound 145: N-(4-cyanophenyl)-3-(1 H-indazol-5-yl)-N-methylimidazo[1 ,2- a]pyrazine-6-carboxamide
Figure imgf000191_0003
The compound was synthesized using I-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z =394.1 (M+1 ), r.t = 1 .54 mins.
Synthesis of compound 146: N-(6-cyanopyridin-3-yl)-N-methyl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide PAT054787-WO-PCT
Figure imgf000192_0001
The compound was synthesized using 1-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z =420.1 (M+1 ), r.t = 1 .12 mins.
Synthesis of compound 147: N-(6-cyanopyridin-3-vl)-N-methyl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2- e
Figure imgf000192_0002
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II), using intermediate 1-37. MS m/z 423.1 (M+H)+; r.t. = 2.050.
Synthesis of compound 148: N-(4-cyanophenvl)-N-methvl-3-(2-methyl-2H-indazol-5- yl)imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000192_0003
The compound was synthesized using I-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z =433.0(M+1 ), r.t = 1 .21 mins.
Synthesis of compound 149: N-(4-cvanophenvl)-N-methvl-3-(2-methvl-2H-indazol-5- yl)imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000192_0004
PAT054787-WO-PCT
The compound was synthesized using 1-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z =408.1 (M+1 ), r.t = 1 .36 mins.
Synthesis of compound 150: N-(4-cyanophenyl)-N-methvl-3-[2-methyl-4- (trifluoromethyl)phenyl]imidazo[1 ,2- e
Figure imgf000193_0001
The compound was synthesized using I-59 and an appropriate boronic acid/ester using procedure similar Suzuki coupling protocol described in 228. M/Z =436.1 (M+1 ), r.t = 2.1
Synthesis of compound 151 : N-(4-fluorophenvl)-N-methyl-3-[4-(1 H-pyrazol-1 - yl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000193_0002
The compound was synthesized using I-64 and an appropriate boronic acid/ester using < procedure similar Suzuki coupling protocol described in 228. MS m/z 413.1 (M+H)+; r.t.
Synthesis of compound 152: N-(4-cyanophenyl)-N-methyl-3-[4-(propane-2- sulfonyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000193_0003
The compound was synthesized using 1-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z =460.1 (M+1 ), r.t = 1 .83 mins. PAT054787-WO-PCT
Synthesis of compound 153: N-(4-cvanophenvn-3-(4-fluorophenvl)-N-methvlimidazo[1 ,2- a]pyrazine-6-carboxamide
Figure imgf000194_0001
The compound was synthesized using I-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z =372.1 (M+1 ), r.t = 1 .89 mins.
Synthesis of compound 154: N-(4-cyanophenyl)-3-(1 H-indazol-6-yl)-N-methylimidazo[1 ,2- a]pyrazine-6-carboxamide
Figure imgf000194_0002
The compound was synthesized using I-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z =394.1 (M+1 ), r.t = 1 .62 mins.
Synthesis of compound 155: 3-(4-chloro-3-cvanophenvl)-N-(4-cvanophenvl)-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000194_0003
The compound was synthesized using 1-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z =413.1 (M+1 ), r.t = 1 .93 mins.
Synthesis of compound 156: N-(4-cyanophenyl)-N-methyl-3-[2-(propan-2-yl)-1 ,3-thiazol-4- yl]imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000194_0004
The compound was synthesized using i-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z =403.1 (M+1 ), r.t = 1 .94 mins. PAT054787-WO-PCT
Synthesis of compound 157: N-(4-cvanophenvl)-N-rnethvl-3-(auinolin-6-vl)imidazo[1 ,2- a]pyrazine-6-carboxamide
Figure imgf000195_0001
The The compound was synthesized using I-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z =405.1 (M+1 ), r.t = 1 .14 mins.
Synthesis of compound 158: N-(4-cvanopheny0-3-[4-(cvclopropvlcarbamovl)phenyl1-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000195_0002
The compound was synthesized using I-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z =437.1 (M+1 ), r.t = 1 .29 mins.
Synthesis of compound 159: N-(314-difluorophenvl)-3-[4-(dimethylamino)phenyl1-N- methylimidazo[1 ,2-a]pyrazine-6-carb
Figure imgf000195_0003
The compound was synthesized using I-65 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. MS m/z 408.1 (M+H)+; r.t. = 1 .357.
Synthesis of compound 160: N-(4-cvanophenvl)-3-[4-(3,5-dimethvl-1 H-pyrazol-1 -yl)phenvl1-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000196_0001
The compound was synthesized using 1-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z =448.1 (M+1 ), r.t = 1 .65 mins.
Synthesis of compound 161 : 3-(4-carbamovlphenyl)-N-(6-chloropyridin-3-yl)-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000196_0002
The compound was synthesized using I-57 and an appropriate boronic acid/ester using ;
procedure similar Suzuki coupling protocol described in 228. MS m/z 407.1 (M+H)+; r.t.
Synthesis of compound 162: N-(4-cyanophenvl)-N-methyl-3-[4-(propan-2- yloxy)phenyl]imidazo[1 ,2-a]pyrazine- -carboxamide
Figure imgf000196_0003
The compound was synthesized using I-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z =412.2(M+1 ), r.t = 2.1 1 mins.
Synthesis of compound 163: N-(4-cvanophenvl)-N-methvl-3-[4-(5-methvl-1 .3.4-oxadiazol-2- yl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000196_0004
PAT054787-WO-PCT
The compound was synthesized using 1-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z =436.1 (M+1 ), r.t = 1 .42 mins.
Synthesis of compound 164: 3-[4-(dimethylamino)phenvl1-N-(4-methanesulfonvlphenvl)-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000197_0001
The compound was synthesized using I-66 and an appropriate boronic acid/ester using < procedure similar Suzuki coupling protocol described in 228. MS m/z 450.1 (M+H)+; r.t.
Synthesis of compound 165: N-(4-cvanophenvl)-3-[4-(2.5-dioxoimidazolidin-4-vnphenv methylimidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000197_0002
The compound was synthesized using I-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z =452.1 (M+1 ), r.t = 1 .21 mins.
Synthesis of compound 166: methyl 4-{6-[(4-cyanophenyl)(methyl)carbamoyl]imidazo[1 ,2- a]pyrazin-3-yl}benzoate
Figure imgf000197_0003
The compound was synthesized using I-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z =412.1 (M+1 ), r.t = 1 .67 mins.
Synthesis of compound 167: N-(4-cyanophenyl)-3-(isoauinolin-6-vl)-N-methylimidazo[1 ,2- a]pyrazine-6-carboxamide
Figure imgf000198_0001
The compound was synthesized using 1-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z =405.1 (M+1 ), r.t = 1 .13 mins.
Synthesis of compound 168: N-(4-cvanophenvl)-N-methvl-3-(1 -oxo-1 ,2-dihvdroisoguinolin-6- yl)imidazo[1 ,2-a]pyrazine-6-carboxami
Figure imgf000198_0002
The compound was synthesized using I-59 and I-26 using a procedure similar Suzuki coupling protocol described in 228. M/Z =421 .1 (M+1 ), r.t = 1.17 mins.
Synthesis of compound 169: N-(4-cyanophenyl)-3-[3-fluoro-4-(trifluoromethyl)ph
methylimidazo[1 ,2-a]pyrazine-6-carbox
Figure imgf000198_0003
The compound was synthesized using I-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228... M/Z =413.2(M+1 ), r.t = 2.03 mins.
Synthesis of compound 170: N-(4-cyanophenyl)-N-methvl-3-(6-propoxvpyridin-3- yl)imidazo[1 ,2-a]pyrazine-6-carboxa
Figure imgf000198_0004
PAT054787-WO-PCT
The compound was synthesized using 1-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z =413.2(M+1 ), r.t = 2.03 mins.
Synthesis of compound 171 : N-methyl-N-[2-(trifluoromethyl)phenvl1-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000199_0001
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II). MS m/z 465.1 (M+H)+; r.t. = 2.390.
Synthesis of compound 172: 3-(4-carbamovlphenvl)-N-(4-methanesulfonvlphenvl)-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000199_0002
The compound was synthesized using I-66 and an appropriate boronic acid/ester using ;
procedure similar Suzuki coupling protocol described in 228. MS m/z 450.0 (M+H)+; r.t.
Synthesis of compound 173: N-methyl-N-[4-(trifluoromethoxy)phenvH-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2- e
Figure imgf000199_0003
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II). MS m/z 481 .1 (M+H)+; r.t. - 2.420.
Synthesis of compound 174: N-methyl-N-d -methyl-1 H-imidazol-2-yl)-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000200_0001
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II). MS m/z 401 .2 (M+H)+; r.t. = 1.390.
Synthesis of compound 175: N-(4-cyanophenyl)-N-methyl-3-[3- (trifluoromethyl)phenyl]imidazo[1 ,2- e
Figure imgf000200_0002
The compound was synthesized using I-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z =422.1 (M+1 ), r.t = 1 .76 mins.
Synthesis of compound 176: 5-fluoro-1 -((3-[4-(trifluoromethyl)phenvl1imidazo[1 .2-alpyrazin-6- yl}carbonyl)-2,3-dihydro-1 H-indole
Figure imgf000200_0003
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II). MS m/z 427.1 (M+H)+; r.t. = 2.430.
Synthesis of compound 177: N-(4-cvanophenvl)-N-methyl-3-(4-phenoxvphenvl)imidazo[1 ,2- a]pyrazine-6-carboxamide
Figure imgf000200_0004
The compound was synthesized using I-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z =446.1 (M+1 ), r.t = 2.24 mins. PAT054787-WO-PCT Synthesis of compound 178: 3-( 1 -benzyl- 1 H-pyrazol-4-yl)-N-(4-cyanoprienyn-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000201_0001
The compound was synthesized using I-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z 434.1 (M+1 ), r.t = 1 .59 mins.
Synthesis of compound 179: 3-[4-chloro-2-(trifluoromethyl)phenvll-N-(4-cvanophenvl)-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000201_0002
The compound was synthesized using I-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z =456.1.1 (M+1 ), r.t = 2.21 mins.
Synthesis of compound 180: N-(4-cvanophenvl)-N-methvl-3-[4-(1 H-1 ,2,3,4-tetrazol-5- yl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000201_0003
The compound was synthesized using i-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z =422.1 (M+1 ), r.t = 1 .35 mins.
Synthesis of compound 181 : N-(4-cyanophenvl)-N-methyl-3-[4-(pvrrolidin-1 - yl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000201_0004
PAT054787-WO-PCT
The compound was synthesized using 1-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z =423.1 (M+1 ), r.t = 1 .79 mins.
Synthesis of compound 182: N-(5-cyanopyridin-2-vl)-N-methvl-3-[4-(1 H-pyrazol-5- yl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000202_0001
The compound was synthesized using I-75 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z =421 .1 (M+1 ), r.t = 1 .49 mins.
Synthesis of compound 183: N-(3-bromophenyl)-N-methyl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2- e
Figure imgf000202_0002
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II). MS m/z 475.0 (M+H)+; r.t. = 1.814.
Synthesis of compound 184: N-(4-cvanophenvl)-N-methyl-3-(5-sulfamovlpvridin-3- yl)imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000202_0003
The compound was synthesized using I-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z =434.1 (M+1 ), r.t = 1 .43 mins.
Synthesis of compound 185: N-(4-cvanophenvl)-3-l4-[methoxv(methvl)carbamovllphenvl)-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000203_0001
The compound was synthesized using 1-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z =441 .1 (M+1 ), r.t = 1 .32 mins.
Synthesis of compound 186: 3-[4-(aminomethvl)phenvl1-N-(4-cvanophe
methylimidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000203_0002
The compound was synthesized using I-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z =382.1 (M+1 ), r.t = 1 .72 mins.
Synthesis of compound 187: N-(4-cyanophenyl)-N-methvl-3-[6-(trifluoromethyl)pyridin-3- yl]imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000203_0003
The compound was synthesized using I-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z =423.1 (M+1 ), r.t = 1 .49 mins.
Synthesis of compound 188: N-(4-cvanophenvl)-3-[4-(diethvlcarbamovl)phenvl1-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000203_0004
The compound was synthesized using I-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z =453.1 (M+1 ), r.t = 1 .43 mins. PAT054787-WO-PCT
Synthesis of compound 189: N-(4-cvanophenvl)-N-methvl-3-(1 -methvl-1 H-pvrazol-4- yl)imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000204_0001
The compound was synthesized using I-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z =358.2(M+1 ), r.t = 1 .43 mins.
Synthesis of compound 190: N-methyl-N-[(6-methvlpyridin-2-yl)methvH-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2- e
Figure imgf000204_0002
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II). MS m/z 426.1 (M+H)+; r.t. = 1.285.
Synthesis of compound 191 : 3-(3-cvanophenvl)-N-(4-cvanophenvl)-N-methylimidazo[1 12- a]pyrazine-6-carboxamide
Figure imgf000204_0003
The compound was synthesized using 1-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z =379.1 (M+1 ), r.t = 1 .50 mins.
Synthesis of compound 192: N-[(4-fluorophenvl)methvll-N-methvl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2- e
Figure imgf000204_0004
The compound was synthesized using I-62 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. MS m/z 429.1 (M+H)+; r.t. = 1 .867. PAT054787-WO-PCT
Synthesis of compound 193: N-(4-cvanophenvl)-N-methyl-3-[4-(pvrrolidin-2- yl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000205_0001
The compound was synthesized using I-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 212. MS m/z 423.1 (M+H)+; r.t. = 1 .350.
Synthesis of compound 194: N-methvl-N-(pvridin-3-vlmethvl)-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2- e
Figure imgf000205_0002
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II). MS m/z 412.1 (M+H)+; r.t. = 1.221 .
Synthesis of compound 195: N-(4-cyanophenyl)-N-methyl-3-(pyridin-3-yl)imidazo[1 ,2- a]pyrazine-6-carboxamide
Figure imgf000205_0003
The compound was synthesized using I-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z =355.2(M+1 ), r.t = 1 .31 mins.
Synthesis of compound 196: 3-(5-chloropvridin-2-vl)-N-(4-cvanophenvn-N-methylimidazo[1.2- a]pyrazine-6-carboxamide PAT054787-WO-PCT
Figure imgf000206_0001
The compound was synthesized using 1-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z =389.1 (M+1 ), r.t = 1 .92 mins.
Synthesis of compound 197: N-(4-cyanophenyl)-3-[4-(dimethylsulfamoyl)phenyl]-N- methylimidazo[1 ,2-a]pyrazine-6-carb
Figure imgf000206_0002
The compound was synthesized using 1-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z =461 .1 (M+1 ), r.t = 1 .84 mins.
Synthesis of compound 198: N-(4-cyanophenvl)-N-methyl-3-[2-(4-methylpiperidin-1 -vl)-1 13- thiazol-4-yl]imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000206_0003
The compound was synthesized using I-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z =458.1 (M+1 ), r.t = 2.38 mins.
Synthesis of compound 199: N-(4-cvanophenvl)-N-methvl-3-(3-methylphenvl)imidazo[1 ,2- a]pyrazine-6-carboxamide
Figure imgf000206_0004
The compound was synthesized using I-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z =368.1 (M+1 ), r.t = 1 .65 mins. PAT054787-WO-PCT
Synthesis of compound 200: N-(4-cyanophenyl)-N-methyl-3-(1 H-pyrazol-4-yl)imidazo[1 ,2- a]pyrazine-6-carboxamide
Figure imgf000207_0001
The compound was synthesized using I-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z =344.2(M+1 ), r.t = 1 .38 mins.
Synthesis of compound 201 : N-(4-cvanophenvl)-N-methvl-3-(1 -methyl-213-dihvdro-1 H-indol-5- yl)imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000207_0002
The compound was synthesized using I-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z =409.1 (M+1 ), r.t = 1 .90 mins.
Synthesis of compound 202: 3-(2, 1 ,3-benzoxadiazol-5-yl)-N-(4-cyanophenyl)-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000207_0003
The compound was synthesized using I-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z =396.1 (M+1 ), r.t = 1 .86 mins.
Synthesis of compound 203: N-(4-cvanophenvl)-N-methvl-3-l3-methyl-3H-imidazo[415- b]pyridin-6-yl}imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000208_0001
The compound was synthesized using 1-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. MS m/z 409.1 (M+H)+; r.t. = 1 .
Synthesis of compound 204: N-(4-cvanophenvl)-N-methvl-3-(2-oxo-2,3-dihydro-1 H-indol-5 yl)imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000208_0002
The compound was synthesized using I-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z =409.1 (M+1 ), r.t = 1 .50 mins.
Synthesis of compound 205: N-(4-methanesulfonylphenvD-N-methvl-3-(1 -methyl-1 H-indazol- 5-yl)imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000208_0003
The compound was synthesized using I-66 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. MS m/z 461 .1 (M+H)+; r.t. = 1 .254.
Synthesis of compound 206: -methvl-N-i4-[3-(trifluoromethyl)-1 H-pyrazol-1 -yllphenyl)-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2- e
Figure imgf000208_0004
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II). MS m/z 531 .1 (M+H)+; r.t. = 1.867. PAT054787-WO-PCT
Synthesis of compound 207: N-(4-cyanophenyl)-3-{4-[(dimethylamino)methyl]ph
methylimidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000209_0001
The compound was synthesized using I-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z =41 1 .2(M+1 ), r.t = 1 .18 mins.
Synthesis of compound 208: N-(4-cvanophenvl)-N-methvl-3-[4-(1 -methyl-1 H-pyrazol-5- yl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000209_0002
The compound was synthesized using I-59 and I-27 using a procedure similar Suzuki coupling protocol described in 228. M/Z =434.1 (M+1 ), r.t = 1.39 mins.
Synthesis of compound 209: 3-[4-(difluoromethoxv)phenvl1-N-(4-methanesulfonvlphenvl)-N- methylimidazo[1 ,2-a]pyrazine-6-car
Figure imgf000209_0003
The compound was synthesized using I-66 and an appropriate boronic acid/ester using < procedure similar Suzuki coupling protocol described in 228. MS m/z 473.0 (M+H)+; r.t.
Synthesis of compound 210: 4-[3-(4-carbamovlphenvl)imidazo[1 ,2-a1pyrazin-6-vl1benzamide Pd-DPP (on silica) (25 mg) was added to a solution of 3,6-dibromoimidazo[1 ,2-a]pyrazine (20 mg, 0.073 mmol), 4-carbamoylphenyl boronic acid (50 mg, 0.291 mmol), KH2P04 (60 mg, 0.44 mmol), THF (1 .0 mL) and water (0.5 ml_). The reaction was heated in a microwave reactor at 150 °C for 45 minutes. After cooling to room temperature, the reaction was filtered to remove the catalyst. The reaction was purified by mass-trigger HPLC. N R (400 MHz, ) δ 9.30 (s, 1 H), 9.04 (s, 1 H), 8.34 - 7.83 (m, 1 1 H), 7.49 (s, 1 H), 7.42 (s, 1 H). MS m/z 358.1 (M+H)+; r.t. =
1.049.
Synthesis of compound 211 : N-(4-cvanophenvl)-N-methvl-3-[5-(2-oxopyrrolidin-1 -vl)pvrazin-2- yl]imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000210_0001
The compound was synthesized using I-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z =439.1 (M+1 ), r.t = 1 .39 mins.
Synthesis of compound 212: 3-{4-[(2S)-2-amino-2-cyclohexvlacetamidolphenyl)-N-(4- cyanophenyl)-N-methylimidazo[1 ,2- e
Figure imgf000210_0002
To a solution of 3-(4-aminophenyl)-N-(4-cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide 124 (30 mg, 0.081 mmols, 1 eq) in DCM was added the (S)-tert-butyl (2-amino-1 - cyclohexyl-2-oxoethyl)carbamate (31 mg, 0.122 mmols, 1.5 eq), followed by HATU (46 mg, 0.121 mmols, 1 .5 eq), and DIEA (26 mg, 0.20 mmols, 2.5 eq). The reaction mixture was stirred PAT054787-WO-PCT for 12 hrs and then removed all solvents and extracted with ethyl acetate (3x10 mL). The solvent was removed under reduce pressure. The product was treated with TFA in
dichloromethane for 8 hours. The organics were concentrated and purified via preparative HPLC as a TFA salt. IWZ = 508.23(M+1 ), r.t = 1 .25 mins.
Synthesis of compound 213: 4-[methvl(|3-[4-(trifluoromethyl)phenyl1imidazo[1 12-alpvrazin-6- yl}methyl)amino]benzonitrile
Figure imgf000211_0001
MW, 150 °C, 45 min
Pd-DPP (on silica) (25 mg) was added to a solution of bromoimidazolopyrazine (45 mg, 0.131 mmol), 4-trifluoromethylphenyl boronic acid (50 mg, 0.263 mmol), KH2P04 (136 mg, 0.39 mmol), THF (3 mL) and water (1 mL). The reaction was heated in a microwave reactor at 150 °C for 45 minutes. After cooling to room temperature, the reaction was filtered to remove the catalyst. The reaction was purified by mass-trigger HPLC. 1 H NMR (400 MHz, DMSO) δ 9.14 (d, J = 1 .3, 1 H), 8.72 (d, J = 1 .1 , 1 H), 8.21 - 8.13 (m, 1 H), 7.98 - 7.90 (m, 4H), 7.53 (d, J = 9.0, 2H), 6.95 (d, J = 9.1 , 2H), 4.78 (s, 2H), 3.15 (s, 3H); MS m/z 408.1 (M+H)+; r.t. = 1 .826.
Synthesis of compound 214: N-(4-cvanophenvl)-3-[4-(difluoromethoxv)phe
methylimidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000211_0002
The compound was synthesized using I-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z =420.1 (M+1 ), r.t = 2.01 mins.
Synthesis of compound 215: N-(4-bromophenyl)-N-methvl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000212_0001
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II). MS m/z 477.0 (M+H)+; r.t. = 2.310.
Synthesis of compound 216: N-(6-chloropyridin-3-yl)-N-methvl-3-[4-(piperidin-1 - yl)phenyl]imidazo[1 ,2-a]pyrazine-6-c
Figure imgf000212_0002
The compound was synthesized using I-57 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z = 447.2(M+1 ), r.t = 1 .08mins.
Synthesis of compound 217: N-(4-chlorophenyl)-N-methyl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2- e
Figure imgf000212_0003
The compound was synthesized using 1-1 l and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. MS m/z 431 .0 (M+H)+; r.t. = 2.230.
Synthesis of compound 218: 6-chloro-1 -({3-[4-(trifluoromethvl)phenvl1imidazo[1 ,2-alpyrazin-6- yl}carbonyl)-1 ,2,3,4-tetrahydroquinoline
Figure imgf000212_0004
PAT054787-WO-PCT
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II). MS m/z 457.0 (M+H)+; r.t. = 2.210.
Synthesis of compound 219: N-(4-chlorophenyl)-3-(4-methoxyphenyn-N-methvlimidazo[1 12- a]pyrazine-6-carboxamide
Figure imgf000213_0001
The compound was synthesized using 1-11 and an appropriate boronic acid/ester using ;
procedure similar Suzuki coupling protocol described in 228. MS m/z 393.2 (M+H)+; r.t.
Synthesis of compound 220: N-(2-chloro-5-methylpyridin-3-yl)-N-methyl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2- e
Figure imgf000213_0002
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II) using I-50. MS m/z 446.1 (M+H)+; r.t. = 1 .707.
Synthesis of compound 221 : N-(3-fluoropyridin-2-vl)-N-methyl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000213_0003
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II). MS m z 416.1 (M+H)+; r.t. = 1.625.
Synthesis of compound 222: 4-(6-{[(4-fluorophenyl)(methvl)amino1methyl)imidazo[1 ,2- a]pyrazin-3-yl)benzamide PAT054787-WO-PCT
Figure imgf000214_0001
The compound was synthesized using 1-62 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. 1H NMR (400 MHz, DMSO) δ 9.14 (d, J = 1 .3, 1 H), 8.47 (s, 1 H), 8.12 (s, 2H), 8.04 (d, J = 8.4, 2H), 7.72 (d, J = 8.4, 2H), 7.51 (s, 1 H), 7.00 (t, J = 8.9, 2H), 6.84 (dd, J = 4.4, 9.2, 2H), 4.65 (s, 2H), 3.03 (s, 3H); MS m/z 376.1 (M+H)+; r.t. = 1.247.
Synthesis of compound 223: 4-(6-|[(4-cvanophenvn(methvl)amino1methvl)imidazo[1 .2- a]pyrazin-3-yl)benzamide
Figure imgf000214_0002
The compound was synthesized using 1-15 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. 1 H NMR (400 MHz, MeOD) δ 9.08 (d, J= 1 .3 Hz, 1 H), 8.31 (d, J = 1.0 Hz, 2H), 8.21 - 7.97 (m, 3H), 7.79 - 7.61 (m, 2H), 7.62 - 7.41 (m, 2H), 7.13 - 6.75 (m, 3H), 4.82 (s, 2H), 3.21 (s, 3H).
Synthesis of compound 224: N-(6-chloropvridin-3-vl)-N-methyl-3-[4-(1 H-pvrazol-5- yl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000214_0003
The compound was synthesized using I-57 and an appropriate boronic acid/ester using < procedure similar Suzuki coupling protocol described in 228. MS m/z 430.1 (M+H)+; r.t.
Synthesis of compound 225: methyl N-[4-(6-{[(4- cyanophenyl)(methyl)amino]methyl}imidazo[1 ,2-a]pyrazin-3-yl)phenyl]carbamat
Figure imgf000215_0001
The compound was synthesized using 1-15 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. MS m/z 413.2 (M+H)+; r.t. = 1 .510.
Synthesis of compound 226: N-[5-(6-([(4-cvanophenvl)(methvl)aminolmethvl)imidazo[1 .2- a]pyrazin-3-yl)pyridin-2-yl]acetamide
Figure imgf000215_0002
The compound was synthesized using 1-15 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. 1H NMR (400 MHz, DMSO) δ 10.76 (s, 1 H), 9.1 1 (s, 1 H), 8.64 (s, 2H), 8.28 (d, J = 8.7, 1 H), 8.12 (d, J = 8.7, 1 H), 8.09 (s, 1 H), 7.51 (d, J = 9.0, 2H), 6.95 (d, J = 9.0, 2H), 4.76 (s, 2H), 3.14 (s, 3H), 2.15 (s, 3H); MS m/z 398.2 (M+H)+; r.t. = 1.312.
Synthesis of compound 227: 3-[4-(5-amino-1 ,3,4-oxadiazol-2-yl)phenyl]-N-(4-fluorophenyl)-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000215_0003
The compound was synthesized using I-64 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. 1 H NMR (400 MHz, MeOD) δ 8.82 - 8.52 (m, 2H), 7.99 (m, 3H), 7.65 (m, 2H), 7.18 (m, 2H), 6.96 (m, 2H), 3.40 (s, 3H).M/Z
=430.2(M+1 ), r.t = 1 .21 mins.
Synthesis of compound 228: N-(4-chlorophenyl)-N-methyl-3-[4- (methylcarbamoyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide PAT054787-WO-PCT
Figure imgf000216_0001
Pd-DPP (palladium diphenylphosphine supported on silica, Silicycle) (25 mg) was added to a solution of 3-bromo-N-(4-chlorophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide (40 mg, 0.1 1 mmol), (4-(methylcarbamoyl)phenyl)boronic acid (50 mg, 0.28 mmol), K2HP04 (50 mg, 0.36 mmol), THF (2.0 mL) and water (1.0 mL). The reaction was heated in a microwave reactor at 150 °C for 45 minutes. After cooling to room temperature, the reaction was concentrated in vacuo. The crude material was purified by flash chromatography (silica, 0-15%
methanol/chloroform). 1 H NMR (400 MHz, DMSO) δ 8.86 (s, 1 H), 8.81 (d, J = 1 .3, 1 H), 8.62 (d, J - 4.6, 1 H), 8.19 (s, 1 H), 8.05 (d, J = 8.4, 2H), 7.79 (d, J= 8.4, 2H), 7.35 (d, J= 8.8, 2H), 7.30 (d, J= 8.8, 2H), 3.42 (s, 3H), 2.84 (d, J= 4.5, 3H). 1 H NMR (400 MHz, DMSO) δ 8.86 (s, 1 H), 8.81 (d, J = 1 .3, 1 H), 8.62 (d, J = 4.6, 1 H), 8.19 (s, 1 H), 8.05 (d, J = 8.4, 2H), 7.79 (d, J = 8.4, 2H), 7.35 (d, J = 8.8, 2H), 7.30 (d, J = 8.8, 2H), 3.42 (s, 3H), 2.84 (d, J = 4.5, 3H);; MS m/z 420.2 (M+H)+; r.t. = 0.98.
Synthesis of compound 229: 4-{6-[(6-fluoro-2,2-dimethvl-1 ,2,3,4-tetrahydroquinolin-1 - yl)carbonyl]imidazo[1 ,2-a]pyrazin-3-yl}benzamide
Figure imgf000216_0002
The compound was synthesized using 1-71 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. 1 H NMR (300 MHz, DMSO- /6) ppm 8.82 (d, J=9.67 Hz, 2 H) 8.20 (s, 1 H) 8.18 (br. s., 1 H) 8.13 (d, J=8.50 Hz, 2 H) 7.83 (d, J=8.50 Hz, 2 H) 7.54 (br. s., 1 H) 7.14 (dd, 1 H) 6.80 (dd, J=8.79, 4.98 Hz, 1 H) 6.65 (td, 1 H) 2.76 (br. s., 2 H) 1 .83 (br. s., 2 H) 1 .67 (s, 6 H) ; MS (ESI) for C25H22FN502 MS m/z: 444 (M + H+).
Synthesis of compound 230: 6-fluoro-2,2-dimethyl-1 -({3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}carbonyl)-1 ,2,3,4-tetrahydroquinoline PAT054787-WO-PCT
Figure imgf000217_0001
The compound was synthesized using 1-71 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. 1H NMR (400 MHz, CD3OD): δ 8.73 (s, 1 H), 8.71 (s, 1 H), 8.07(s, 1 H), 7.89 (d, J= 8.34 Hz, 2H), 7.80 (d, J= 8.34 Hz, 2H), 7.02- 6.99 (m, 1 H), 6.67-6.63 (m, 1 H), 6.56-6.51 (m, 1 H), 2.77 (t, J = 4.83 Hz, 2H), 1 .85 (bs, 2H), 1 .70 (s, 6H). MS m/z: 469.12 (M+H).
Synthesis of compound 231 : 6-chloro-N-methyl-N-((3-[4-(trifluoromethyl)phenvl1imidazo[1 ,2- a]pyrazin-6-yl}methyl)pyridin-3-amine
Figure imgf000217_0002
The compound was synthesized using I-64 and an appropriate boronic acid/ester using < procedure similar Suzuki coupling protocol described in 228. MS m/z 418.1 (M+H)+; r.t.
Synthesis of compound 232: 3-(4-cvanophenvl)-N-(4-methanesulfonvlphenvl)-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000217_0003
The compound was synthesized using I-66 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. MS m/z 432.1 (M+H)+; r.t. = 1 .560.
Synthesis of compound 233: 4-(6-|[methvl(5-methvlpvridin-2-vl)amino1methyl)imidazo[1 ,2- a]pyrazin-3-yl)benzamide
2l6
Figure imgf000218_0001
The compound was synthesized using 1-77 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. MS m/z 373.2 (M+H)+; r.t. = 0.91.
Synthesis of compound 234: S-fluoro-l -dS- -^rifluoromethyDphenyllimidazofl ^-alpyrazin-B- yl}methyl)-1 ,2,3,4-tetrahydroquinoline
Figure imgf000218_0002
The compound was synthesized using a procedure analogous to one use for synthesis of 5. H- NMR (400 MHz, CDCI3): 9.17 (d, J= 0.98 Hz, 1 H), 8.06 (d, J = 1 .45 Hz, 1 H) 7.91 (s, 1 H), 7.72 (d, J= 8.36 Hz, 2H), 7.52 (d, J = 8.3 Hz, 2H), 6.69-6.78 (m, 2H), 6.43-6.46 (m, 1 H), 4.62 (s, 2H), 3.42 (t, J = 5.85 Hz, 2H), 2.79 (t, J = 5.85 Hz, 2H), 1.71 -2.03 (m, 2H). MS m/z 427.2 (M+H).
Synthesis of compound 235: N,5-dimethvl-N-((3-[4-(trifluoromethyl)phenvl1imidazo[1 ,2- a]pyrazin-6-yl}methyl)pyridin-3-amine
Figure imgf000218_0003
A vial containing the N-methylamine 1-17 (17 mg, 0.057 mmol), bromopyridine (10 mg, 0.057 mmol), cesium carbonate (37 mg, 0.1 1 mmol), and dioxane (1 .0 mL) was degassed under vacuum. Pd2(dba)3 (3.0 mg, 0.0030 mmol) and XantPhos (4.0 mg, 0.0060 mmol) were added. The vial was evacuated until gas evolution ceased. The evacuated vial was heated to 100 °C for 4 hours. After cooling to room temperature, the reaction was diluted with dichloromethane (1 mL). The mixture was filtered, and the filtrate concentrated under reduced pressure. The mixture was purified by mass-trigger HPLC. MS m/z 398.2 (M+H)+; r.t. = 1 .373. PAT054787-WO-PCT Synthesis of compound 236: N-(4-cvanophenvl)-3-(6-acetamidopvridin-3-vl)-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000219_0001
The compound was synthesized using I-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z =412.1 (M+1 ), r.t = 1 .39 mins.
Synthesis of compound 237: N-(6-chloropyridin-3-vl)-3-[4-(1 ,1 -difluoroethyl)ph
methylimidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000219_0002
The compound was synthesized using I-57 and I-25 using a procedure similar Suzuki coupling protocol described in 228. M/Z = 428.1 (M+1 ), r.t = 1 .61 mins.
Synthesis of compound 238: N-(4-cyanophenyl)-N-(2-methoxyethyl)-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000219_0003
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II) using intermediate I-30. MS m/z 466.2 (M+H)+; r.t. = 1.847.
Synthesis of compound 239: N-methyl-3-[4-(trifluoromethyl)phenvH-N-[6- (trifluoromethyl)pyridin-3-yl]imidazo[1 ,2-a]pyrazine-6-carboxamide
2l8
Figure imgf000220_0001
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II), using 1-42. MS m/z 466.0 (M+H)+; r.t. = 1 .863.
Synthesis of compound 240: N-(4-cyanophenyl)-N-methyl-3-[4-(1 ,3,4-oxadiazol-2- yl)phenyl]imidazo[1 ,2-a]pyrazine-6-c
Figure imgf000220_0002
The compound was synthesized using I-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z =422.1 (M+1 ), r.t = 1 .26 mins.
Synthesis of compound 241 : N-({3-[4-(difluoromethvl)phenvllimidazo[1 .2-alpvrazin-6- yl}methyl)-N,5-dimethylpyridin-2-amin
Figure imgf000220_0003
The compound was synthesized using 1-77 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. MS m/z 380.2 (M+H)+; r.t. = 1 .280.
Synthesis of compound 242: N-[5-(6-|[methvl(5-methvlpvridin-2-vl)amino1methyl}imidazo[1 ,2- a]pyrazin-3-yl)pyridin-2-yl]acetamide
Figure imgf000220_0004
The compound was synthesized using I-77 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. MS m/z 388.2 (M+H)+; r.t. = 0.939. PAT054787-WO-PCT
Synthesis of compound 243: N-(4-cvanophenvl)-N-methvl-3-l1 H-pvrrolo[2,3-blpyridin-5- yl}imidazo[1 ,2-a]pyrazine-6-carboxa
Figure imgf000221_0001
The compound was synthesized using I-59 and an appropriate boronic acid/ester using < procedure similar Suzuki coupling protocol described in 228. MS m/z 394.1 (M+H)+; r.t.
Synthesis of compound 244: N-(4-fluorophenvl)-N-methvl-3-[4- (methylcarbamoyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000221_0002
The compound was synthesized using I-64 and an appropriate boronic acid/ester using < procedure similar Suzuki coupling protocol described in 228. MS m/z 404.1 (M+H)+; r.t.
Synthesis of compound 245: methyl N-(4-{6-[(6-chloropyridin-3- yl)(methyl)carbamoyl]imidazo[1 ,2-a]pyrazin-3-yl}phenyl)carbamate
Figure imgf000221_0003
The compound was synthesized using I-57 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. 1H NMR (400 MHz, MeOD) δ 8.93 (s, 1 H), 8.72 (s, 1 H), 8.27 (s, 1 H), 7.99 (s, 1 H), 7.78 (d, J - 8.2Hz, 1 H), 7.72 (d, J = 8.4Hz, 2H), 7.61 (d, J = 8.6Hz, 2H), 7.45 (d, J = 8.5Hz, 1 H), 3.79 (s, 3H), 3.54 (s, 3H), .ESI-MS m/z 437.1 [M+1]+. RT: 1.31 min.
Synthesis of compound 246: N-(4-cvanophenvl)-N-methvl-3-[6-(methvlamino)pyridin-3- yl]imidazo[1 ,2-a]pyrazine-6-carboxamide PAT054787-WO-PCT
Figure imgf000222_0001
The compound was synthesized using 1-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z =384.1 (M+1 ), r.t = 0.94 mins.
Synthesis of compound 247: 3-[4-(2-aminoacetamido)phenvl1-N-(4-cvanophenvl)-N- methylimidazo 1 ,2-a]pyrazine-6-carboxamide
Figure imgf000222_0002
To a stirred solution of 124 whose synthesis is previously described (100 mg, 0.27 mmol, 1 .0 eq.) and 2-(iert-butoxycarbonyl)amino)acetic acid (52.3 mg, 0.29 mmol, 1.1 eq.) in 6 mL of DMF were added HATU (124 mg, 0.32 mmol, 1 .2 eq.) and DIEA (162 μΙ_, 0.32 mmol, 1 .2 eq). The reaction mixture was stirred at room temperature for 8 hours. HPLC/MS test showed that desired product was formed. The product was partitioned in water/ Ethyl acetate and purified by column chromatography to yield the desired product (50 mg, 35 %). The Boc-derivative was carried to the next step. To a stirred solution of Boc- derivative (50 mg) in 2m L of
dichloromethane was added trifluoroacetic acid (2 ml) was stirred for 3 hours. LCMS indicated that the reaction was complete. The reaction was concentrated and purified by reverse phase HPLC to yield desired product. The product was characterized by reverse phase HPLC using method B. (ES, m/z): [M + H+] 426.2. Retention time = 0.83 mins. M/Z =426.2(M+1 ), r.t =0.83 mins.
Synthesis of compound 248: 3-[4-(5-amino-1 ,3,4-oxadiazol-2-vnphenvl1-N-(4-cvanophenvl)-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000222_0003
PAT054787-WO-PCT
The compound was synthesized using 1-59 and 1-24 using a procedure similar Suzuki coupling protocol described in 228. M/Z =437.1 (M+1 ), r.t = 1.19 mins.
Synthesis of compound 249: N-methyl-N-(pyridin-4-vl)-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000223_0001
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II). MS m/z 398.1 (M+H)+; r.t. = 1.278.
Synthesis of compound 250: N-(2-methoxv-5-methvlpvridin-3-vl)-N-methyl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000223_0002
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II). M/Z = 442.14(M+1 ), r.t = 1.48 mins.
Synthesis of compound 251 : N-methyl-N-(5-methylpvridin-3-vl)-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2- e
Figure imgf000223_0003
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II). 1 H NMR (400 MHz, CDCI3) δ 8.79 (s, J = 1 .3Hz, 1 H), 8.63 (s, 1 H), 8.22 (s, 1 H), 8.02 (s, 1 H), 7.88 (s, 1 H), 7.77 (d, J = 8.2Hz, 2H), 7.63 (d, J = 8.2Hz, 2H), 7.37 (s, 1 H), 3.47 (s, 3H), 2.30 (s, 3H). ESI-MS m/z 412 [M+1 ]. RT: 1 .36 min. PAT054787-WO-PCT Synthesis of compound 252: N-(2-methoxv-5-methvlpvridin-3-vn-N-methvl-3-[4-
(trifluoromethyl)phenyl]imidazo[1 ,2- e
Figure imgf000224_0001
The compound was synthesized using I-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z =418.1 (M+1 ), r.t = 1 .49 mins.
Synthesis of compound 253: ethyl 6-[(6-chloropyridin-3-yl)(methyl)carbamoyl]imidazo[1 ,2- a]pyrazine-3-carboxylate
Figure imgf000224_0002
1-57 253
To a solution of 3-bromo-N-(4-chlorophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide (I- 57) (0.09g, .245 mmol, 1 eq), in THF was added n-BuLi (0.245 mmol, 1 eq). The reaction mixture was stirred at -78 °C for ½ hr andat this point the ethyl chloroformate (0.026g, 0.245mmol) was added. The reaction mixture was stirred at - 78 °C for 4 more hours and then slowly warmed up to room temperature. Quenched with ice-water and extracted the organics with ethyl acetate (3 x10 ml_). The organics were combined and dried over sodium sulfate and then purified using column chromatography. Yield = 35 mg (0.1 Og mmols, 43%) of the desired product. 1 H NMR (400 MHz, MeOD) δ 9.69 - 9.54 (m, 1 H), 8.27 (s, 1 H), 7.82 - 7.66 (m, 1 H), 7.36 (d, J = 8.6Hz, 1 H), 4.08 (q, J = 7.1 Hz, 1 H), 3.45 (s, 3H), 2.60 (s, 3H), 1 .17 (t, J= 7.1 Hz, 3H), ESI-MS m/z 360 [M+H]+. RT: 1.28 min.
Synthesis of compound 254: ethyl N-(4-{6-[(4-cyanophenyl)(methyl)carbamoyl]imidazo[1 ,2- a]pyrazin-3-yl}phenyl)carbamate
Figure imgf000224_0003
PAT054787-WO-PCT
The compound was synthesized using 1-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z =441 .2(M+1 ), r.t = 1 .30 mins.
Synthesis of compound 255: 3-(4-|[(1 S,2R)-2-aminocyclopentane1amido)phenyl)-N-(4- cyanophenyl)-N-methylimidazo[1 ,2- e
Figure imgf000225_0001
The compound was synthesized using a procedure described in 212. M/Z = 480.2(M+1 ), r.t = 0.90mins.
Synthesis of compound 256: 3-(4-[(3S)-3-amino-4-methylpentanamido1prienyl)-N-(4- cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000225_0002
The compound was synthesized using a procedure described in 212. 1 H NMR (400 MHz, MeOD) δ 8.82 (s, 1 H), 8.71 (s, 1 H), 7.97 (s, 1 H), 7.88 (d, J = 8.5Hz, 2H), 7.67 (d, J = 8.4Hz, 2H), 7.62 (d, J = 8.6Hz, 2H), 7.41 (d, J = 8.5Hz, 2H), 3.56 (s, 4H), 2.92 (dd, J = 3.4Hz, 16.8Hz, 2H), 2.70 (dd, J = 9.3Hz, 16.8Hz, 2H), 2.06 (td, J = 6.8Hz, 13.4Hz, 3H), 1.10 (t, J = 6.6Hz, 6H). ESI- MS m/z 482 [M+1]. RT: 0.90 min.
Synthesis of compound 257: N-(4-fluorophenvl)-N-methyl-3-[4-(1 H-pvrazol-5- yl)phenyl]imidazo[1 ,2-a]pyrazine-6-car
Figure imgf000225_0003
The compound was synthesized using I-64 and an appropriate boronic acid/ester using < procedure similar Suzuki coupling protocol described in 228. MS m/z 413.1 (M+H)+; r.t. PAT054787-WO-PCT
Synthesis of compound 258: N-(3,4-difluorophenvl)-N-methyl-3-[4-(1 H-pvrazol-5- yl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000226_0001
The compound was synthesized using I-65 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. MS m/z 431 .1 (M+H)+; r.t. = 1 .477.
Synthesis of compound 259: 4-chloro-N-methyl-N-{3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2- a]pyrazin-6-yl}benzamide
Figure imgf000226_0002
The compound was synthesized using a procedure analogous to one use for synthesis of 24. 1 H NMR (400 MHz, CDCI3) δ 9.13 (d, J = 1 .2, 1 H), 7.92 (s, 1 H), 7.88 (s, 1 H), 7.72 (d, J = 8.2, 2H), 7.35 (q, J = 8.7, 4H), 7.23 (d, J = 8.0, 2H), 3.56 (s, 3H). HRMS calcd for C21H15CIF3N40 [M + H] + 431.08; found 431.1.
Synthesis of compound 260: methyl N-(5-{6-[(4-cyanophenyl)(methyl)carbamoyl]imidazo[1 ,2- a]pyrazin-3-yl}pyridin-2-yl)carbamat
Figure imgf000226_0003
The compound was synthesized using I-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z =428.1 (M+1 ), r.t = 1 .22 mins.
Synthesis of compound 261 : Propan-2-vl N-(4-{6-[(4- cyanophenyl)(methyl)carbamoyl]imidazo[1 ,2-a]pyrazin-3-yl}phenyl)carbamate
Figure imgf000227_0001
The compound was synthesized using 1-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z = 455.20(M+1 ), r.t = 1 .65 mins.
Synthesis of compound 262: N-(6-chloropyridin-3-vl)-N-methvl-3-|4-[5-(methylamino)-1 1314- thiadiazol-2-yl]phenyl}imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000227_0002
The compound was synthesized using I-57 and I-60 using a procedure similar Suzuki coupling protocol described in 228. M/Z = 477.2(M+1 ), r.t = 1 .26 mins.
Synthesis of compound 263: N,4-dimethvl-N-((3-[4-(trifluoromethvl)phenvl1imidazo[1 ,2- a]pyrazin-6-yl}methyl)aniline
Figure imgf000227_0003
A vial containing the amine (17 mg, 0.057 mmol), aryl bromide (10 mg, 0.057 mmol), cesium carbonate (27 mg, 0.1 1 mmol), and dioxane (1 .0 mL) was degassed under vacuum. Pd2(dba)3 (3 mg, 0.003 mmol) and XantPhos (4 mg, 0.006 mmol) were added. The vial was evacuated until gas evolution ceased. The evacuated vial was heated to 100 °C for 4 hours. After cooling to room temperature, the reaction was diluted with dichloromethane (1 mL). The mixture was filtered, and the filtrate concentrated under reduced pressure. The crude material was purified by preparatory TLC. LCMS analysis of the major band showed the same product mixture. The material was purified a second time using mass trigger HPLC (10 minute method, 20-70% water/acetonitrile). MS m/z 397.2 (M+H)+; r.t. = 1.771 . PAT054787-WO-PCT
Synthesis of compound 264: 5-chloro-N-methvl-N-{3-[4-(trifluoromethvl)phenvllimidazo[1 ,2- a]pyrazin-6-yl}pyridine-2-carboxamid
Figure imgf000228_0001
The compound was synthesized using a procedure analogous to one use for synthesis of 24. M/Z = 432.1 (M+1 ), r.t = 1 .78 mins.
Synthesis of compound 265: N-(6-chloropvridin-3-vl)-3-[4-(difluoromethvl)phenvl1-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000228_0002
The compound was synthesized using I-57 and an appropriate boronic acid/ester using procedure similar Suzuki coupling protocol described in 228. M/Z = 414.10(M+1 ), r.t = 1 mins.
Synthesis of compound 266: 3-{4-[(2S)-2-amino-3-methylbutanamido1ph
cyanophenyl)-N-methylimidazo[1 ,2- e
Figure imgf000228_0003
The compound was synthesized using a protocol described in 212. 1 H NMR (400 MHz, MeOD) δ 8.85 (d, J = 8.9Hz, 1 H), 8.71 (s, 1 H), 7.99 (s, 1 H), 7.89 (d, J = 8.6Hz, 2H), 7.73 - 7.61 (m, 4H), 7.42 (d, J = 8.6Hz, 2H), 3.84 (d, J = 5.8Hz, 1 H), 3.56 (s, 3H), 2.45 - 2.30 (m, 1 H), 1 .16 (dd, J = 6.9Hz, 13.9Hz, 6H), M/Z 468.1 [M+1 ], rt: 1 .12 min.
Synthesis of compound 267: 6-chloro-N-methvl-N-l3-[4-(trifluoromethvl)phenvl1imidazo[1 ,2- a]pyrazin-6-yl}pyridine-3-carboxamide
Figure imgf000229_0001
The compound was synthesized using a procedure analogous to one use for synthesis of 24. M/Z = 432.1 (M+1 ), r.t = 1 .76 mins.
Synthesis of compound 268: 4-fluoro-N-methvl-N-{3-[4-(trifluoromethyl)phenvl1imidazo[1 .2- a]pyrazin-6-yl}benzamide
Figure imgf000229_0002
The compound was synthesized using a procedure analogous to one use for synthesis of 24. M/Z = 415.1 (M+1 ), r.t = 1 .93 mins.
Synthesis of compound 269: 3-{4-[(3R)-3-aminobutanamido1phenvl}-N-(4-cvanophenyl)-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000229_0003
The compound was synthesized using a protocol described in 212. 1 H NMR (400 MHz, MeOD) δ 8.82 (s, 1 H), 8.71 (s, 1 H), 7.97 (s, 1 H), 7.87 (d, J = 8.6Hz, 2H), 7.65 (dd, J = 8.6Hz, 3H), 7.41 (d, J = 8.5Hz, 2H), 3.88 - 3.71 (m, 1 H), 3.56 (s, 3H), 2.99 - 2.64 (m, 3H), 1 .42 (d, J = 6.7Hz, 3H). M/Z 454.1 [M+1 ]. RT: 0.90 min.
Synthesis of compound 270: 3-[4-(2-amino-2-cvclobutvlacetamido)phenvl1-N-(4- cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000229_0004
PAT054787-WO-PCT
The compound was synthesized using a protocol described in 212. M/Z 480.20 [M+1 ]. RT: 0.93 min.
Synthesis of compound 271 : 3-{4-[(2S)-2-aminopropanamido]phenyl)-N-(4-cyanophenyl)-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000230_0001
The compound was synthesized using a protocol described in 212. M/Z 440.20 [M+1 ]. RT: 1 .08 min.
Synthesis of compound 272: 3-(6-aminopvridin-3-yl)-N-(4-cyanophenyl)-N-methylimidazo[112- a]pyrazine-6-carboxamide
Figure imgf000230_0002
The compound was synthesized using 1-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z =370.2(M+1 ), r.t =0.91 mins.
Synthesis of compound 273: 3-[4-(cvanomethoxv)phenvll-N-(4-cvanophenvl)-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000230_0003
The compound was synthesized using I-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z =409.2(M+1 ), r.t = 1 .52 mins.
Synthesis of compound 274: 1 -({3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6- yl}carbonyl)-1 ,2,3,4-tetrahydroquinoline-6-carbonitrile
Figure imgf000231_0001
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II). MS m/z 448.1 (M+H)+; r.t. = 1.699.
Synthesis of compound 275: N-(6-chloropyridin-3-vl)-3-[2-fluoro-4-(trifluoromethvl)phenvl1-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000231_0002
The compound was synthesized using I-57 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z =450.1 (M+1 ), r.t = 1 .64 mins.
Synthesis of compound 276: N-methvl-4-(trifluoromethvl)-N-{3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}benzamide
Figure imgf000231_0003
1-21 276
4-trifluoromethyl benzoyl chloride (1 equiv.) was added to a solution of N-methylamino imidazolopyrazine (1 equiv.), triethylamine (5 equiv.) and dichloromethane at room temperature. After 1 hour at room temperature, the solvent was removed and the crude reaction mixture was purified by mass-trigger HPLC. 1 H NMR (400 MHz, CDCI3) δ 9.17 (s, 1 H), 7.93 (s, 1 H), 7.72 (d, J = 8.1 , 2H), 7.64 (d, J = 8.1 , 1 H), 7.55 (d, J = 8.2, 2H), 7.28 (d, J = 6.8, 2H), 7.22 (d, J = 6.5, 2H), 3.56 (s, J = 9.0, 3H). HRMS calcd for C22H15F6N40 [M + H] + 465.1 1 ; found 465.2.
Synthesis of compound 277: N-methvl-N-(6-methvlpvridin-3-yl)-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000232_0001
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II). 1 H NMR (400 MHz, MeOD) δ 9.08 (d, J = 1 .3, 1 H), 8.72 (d, J = 29.4, 2H), 8.16 (s, 2H), 7.96 (s, 3H), 7.69 (d, J = 8.6, 2H), 3.59 (s, 3H), 2.69 (s, 3H).ESI-MS m/z 412 [M+1 ]. RT: 1 .25 min.
Synthesis of compound 278: 3-{4-[(2-amino-2-methvlpropv0aminolphenvl)-N-(4- cyanophenyl)-N-methylimidazo[1 ,2- e
Figure imgf000232_0002
To a solution of 124 in EtOH (0.03 g, 0.07 mmols), was added the aldehyde (0.175 mmols, 0.035g, 2.5 eq) followed by HOAc (2 drops), and the mixture was heated at 80 °C for 4 hrs. The reaction mixture was cooled down to 0 °C, added the NaBH(OAc)3 and stirred overnight.
Next day after checking via LC/MS for the desired mass, the solvents were removed under vacuo, the compound was re-dissolved in TFA DCM (1 :1 ) and stirred for ½ hr. Next solvents were removed once again and the desired compound was isolated via mass triggered HPLC. M/Z = 440.2(M+1 ), r.t = 1 .14 mins.
Synthesis of compound 279: N-(6-chloropyridin-3-vl)-3-(4-acetamidophenvl)-N- methylimidazo[1 ,2-a]pyrazine-6-car
Figure imgf000232_0003
The compound was synthesized using I-57 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z = 421.1 (M+1 ), r.t = 1 .16 mins. PAT054787-WO-PCT
Synthesis of compound 280: N-(6-chloropvridin-3-vl)-3-(2-fluoro-4-methoxvphenvl)-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000233_0001
The compound was synthesized using I-57 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z = 421.1 (M+1 ), r.t = 1 .16 mins.
Synthesis of compound 281 : 7-fluoro-4-((3-[4-(trifluoromethyl)phenvl1imidazo[1 12-a1pvrazin-6- yl}methyl)-3,4-dihydro-2H-1 ,4-benzoxazin
Figure imgf000233_0002
The compound was synthesized using 1-73 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. 1H NMR (400 MHz, CD3OD): δ 9.09 (s, 1 H), 8.42 (s, 1 H), 8.04 (s, 1 H), 7.77-7.84 (m, 4H), 6.75-6.79 (m, 1 H), 6.49-6.53 (m, 2H), 4.6 (s, 2H), 4.24 (t, J= 4.39 Hz, 2H), 3.45 (t, J= 4.39 Hz, 2H).LC-MS: 98.06%; 429.14 (M+H).
Synthesis of compound 282: 3-{4-[(2R)-2-aminopropanamido1phenvl)-N-(4-cvanophenyl)-N- methylimidazo[1 ,2-a]pyrazine-6-car
Figure imgf000233_0003
The compound was synthesized using a protocol described in 212. M/Z = 440.1 (M+1 ), r.t = 1.01 mins.
Synthesis of compound 283: 4-cvano-N-methvl-N-{3-[4-(trifluoromethyl)phenvl1imidazo[1 ,2- a]pyrazin-6-yl}benzamide
Figure imgf000234_0001
The compound was synthesized using a procedure analogous to one use for synthesis of 24 M/Z = 421 .1 (M+1 ), r.t = 1 .76 mins.
Synthesis of compound 284: N-(4-cvanophenyl)-3-{4-[2-(dimethylamino)ethoxv1phenvl)-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000234_0002
The compound was synthesized using I-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. 1H NMR (400 MHz, CDCI3) δ 8.83 (s, 1 H), 8.76 (s, 1 H), 7.90 (s, 1 H), 7.62 (d, J = 8.6Hz, 2H), 7.51 (d, J = 8.7Hz, 2H), 7.25 (d, J = 8.5Hz, 2H), 7.12 (d, J = 8.7Hz, 2H), 4.57 - 4.48 (m, 2H), 3.65 - 3.53 (m, 5H), 3.02 (s, 6H).ESI- MS m/z 441 [M+1]. RT: 1 .1 1 min.
Synthesis of compound 285: N-(4-cyanophenyl)-N,2-dimethvl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000234_0003
Ethyl 2-methylimidazo[1 ,2-a]pyrazine-6-carboxylate 285-I: To a solution of ethyl 5- aminopyrazine-2-carboxylate (668 mg, 4 mmol) in EtOH (25 mL) was added 1 -chloropropan-2- one (0.32 mL, 4 mmol) and triethylamine (0.83 mL, 6 mmol) and the mixture was heated in microwave synthesizer at 170 °C for 30 min. The reaction mixture was cooled to RT and PAT054787-WO-PCT solvent was removed. The residue was purified by flash chromatography (silica gel, EtOAc/ hexanes) to afford 230 mg (28%) of I as white solid. 1 H NMR (400 MHz, CDCI3) δ 9.03 (s, 1 H), 8.92 (d, J = 1 .3, 1 H), 7.59 (s, 1 H), 4.51 (q, J = 7.1 , 2H), 2.61 - 2.53 (m, 3H), 1 .47 (t, J - 7.1 , 3H). HRMS calcd for C10H12N3O2 [M + H] + 205.09; found 206.1 .
Ethyl 2-methyl-3-(4-(trifluoromethyl)phenyl)imidazo[1 ,2-a]pyrazine-6-carboxylate 285-II :
To a solution of Ethyl 2-methylimidazo[1 ,2-a]pyrazine-6-carboxylate I (102 mg, 0.5 mmol) in toluene was added 1 -bromo-4-(trifluoromethyl)benzene (135 mg, 0.6 mmol), Pd(OAc)2 (12mg, 0.3 mmol), PPh3 (26 mg, 0.1 mmol) and K2C03 (136 mg, 1 .0 mmol). The reaction jmixture was purged with N2 for 2 min and heated in microwave synthesizer at 140 °C for 2h. After cooling to rt, the reaction mixture was filtered through celite and washed with ethylacetate and solvent was removed. The dark brown residue was purified by flash chromatography (silica gel, EtOAc/ hexanes) to afford 104 mg (59%) of 285-II as off white solid. 1 H NMR (400 MHz, MeOD) δ 9.02 (s, 1 H), 8.92 (s, 1 H), 7.98 (d, J = 8.2, 2H), 7.86 (d, J = 8.1 , 2H), 4.10 (q, J = 7.1 , 2H), 4.10 (q, J = 7.1 , 1 H), 2.60 (s, 3H), 1 .25 (t, J = 7.1 , 3H) . HRMS calcd for C17H15F3N302 [M + H] + 349.10; found 350.10.
2-Methyl-3-(4-(trifluoromethyl)phenyl)imidazo[1 ,2-a]pyrazine-6-carboxylic acid 285-III : To a solution of ethyl 2-methyl-3-(4-(trifluoromethyl)phenyl)imidazo[1 ,2-a]pyrazine-6-carboxylate 285-II (102 mg, 0.2 mmol) in MeOH-THF (2:1 mixture, 2 mL) was added 1 N NaOH (0.5 mL, 0.5 mmol) and the reaction mixture was stirred at rt for 3h. THF was removed and the reaction mixture was acidified with 1 N HCI. The resulting precipitate was collected by filtration and dried to afford 58 mg (82%) of III as white solid. HRMS calcd for 0^^302 [M + H] 321 .07; found 322.10.
N-(4-cyanophenyl)-N, 2-dimethyl-3-(4-(trifluoromethyl) phenyl) imidazole [1 , 2-a] pyrazine- 6-carboxamide (285): To a solution of 2-Methyl-3-(4-(trifluoromethyl) phenyl) imidazole [1 , 2-a] pyrazine-6-carboxylic acid 285-III (25 mg, 0.08 mmol) in CH2CI2 (2 mL) was added a drop of DMF and the reaction mixture was cooled to 0 °C. Oxallylchloride (10 μί, 0.1 mmol) was added and stirred it for 30 min. Solvents removed in vaccuo and the residue was again dissolved in CH2CI2 (2 mL) and 4-(methylamino)benzonitrile (12 mg, 0.1 mmol) was added and the reaction mixture left it at RT overnight. Solvent was removed and purified by Prep LCMS (TFA- H20, CH3CN). 1 H NMR (400 MHz, MeOD) δ 8.69 (s, 1 H), 8.65 (s, 1 H), 7.96 (d, J = 8.2, 2H), 7.78 (d, J = 8.1 , 2H), 7.72 (d, J = 8.4, 2H), 7.40 (d, J = 8.6, 2H), 3.54 (s, 3H), 2.54 (s, 3H). HRMS calcd for C23H17F3N50 [M + H] 435.14; found 435.10. PAT054787-WO-PCT
Synthesis of compound 286: 3-{4-[(2R)-2-amino-3-methvlbutanamidolphe
cyanophenyl)-N-methylimidazo[1 ,2- e
Figure imgf000236_0001
The compound was synthesized using a protocol described in 212. 1 H NMR (400 MHz, CDCI3) 5 8.83 (s, 1 H), 8.76 (s, 1 H), 7.90 (s, 1 H), 7.62 (d, J = 8.6Hz, 2H), 7.51 (d, J= 8.7Hz, 2H), 7.25 (d, J = 8.5Hz, 2H), 7.12 (d, J = 8.7Hz, 2H), 4.57 - 4.48 (m, 2H), 3.65 - 3.53 (m, 5H), 3.02 (s, 6H).ESI-MS m/z 441 [M+1 ]. RT: 1.1 1 min.
Synthesis of compound 287 : N,5-dimethyl-N-({3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2- a]pyrazin-6-yl}methyl)pyridin-2-amin
Figure imgf000236_0002
The compound was synthesized using a procedure analogous to one use for synthesis of 1-15. MS m/z 398.2 (M+H)+; r.t. = 1 .395.
Synthesis of compound 288: N-(6-methoxv-5-methvlpvridin-3-vl)-N-methyl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2- e
Figure imgf000236_0003
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II). M/Z =442.2(M+1 ), r.t = 1 .83 mins.
Synthesis of compound 289: N^-dimethyl-N-IS- -ftrifluoromethyDphenyllimidazofl ^- a]pyrazin-6-yl}benzamide
Figure imgf000237_0001
The compound was synthesized using a procedure analogous to one use for synthesis of 24. 1 H N R (400 MHz, CDCI3) δ 9.05 (d, J = 1 .2, 1 H), 7.82 (s, 1 H), 7.70 (s, 1 H), 7.59 (d, J = 8.2, 2H), 7.25 (d, J = 8.1 , 2H), 7.10 (d, J = 8.0, 2H), 7.03 (d, J = 8.0, 2H), 3.50 (s, 3H), 2.30 (d, J = 29.4, 3H). HRMS calcd for C22H18F3N40 [M + H] + 41 1 .14; found 41 1 .1 .
Synthesis of compound 290: N-(6-methoxvpvridin-2-vl)-N-methvl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000237_0002
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II). M/Z = 428.1 (M+1 ), r.t = 1 .87 mins.
Synthesis of compound 291 : N-(4-cvanophenvl)-3-(4-{[2-
(dimethylamino)ethyl]carbamoyl}phe 2-a]pyrazine-6-carboxamide
Figure imgf000237_0003
The compound was synthesized using I-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z = 468.2(M+1 ), r.t = 0.88 mins.
Synthesis of compound 292: 3-{4-[(2S)-2-amino-2-cvclopropylacetamido1ph
cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000238_0001
The compound was synthesized using a protocol described in 212. 1 H NMR (400 MHz, MeOD) δ 8.73 (s, 1 H), 8.61 (s, 1 H), 7.88 (s, 1 H), 7.80 (s, 2H), 7.54 (s, 4H), 7.32 (s, 2H), 3.45 (s, 3H), 3.31 (s, 1 H), 1.22 (s, 2H), 0.72 (s, 3H), 0.50 (s, 1 H) .ESI-MS m/z 466 [M+1 ]+. RT: 1 .08 min.
Synthesis of compound 293: N-(4-cyano-2-fluorophenyl)-N-methvl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000238_0002
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II). MS m/z 440.1 (M+H)+; r.t. = 1.757.
Synthesis of compound 294: N,4,4-trimethvl-N-|3-[4-(trifluoromethyl)phenvl1imidazo[1 ,2- a]pyrazin-6-yl}piperidine-1 -carboxamide
Figure imgf000238_0003
294
A solution of NHMe core 1-21 (1 .0 equiv.) in dichloromethane was treated with triphosgene (0.5 equiv.) and allowed to stir at rt for 3h. The amine (1 .5 equiv.) was added, followed by Et3N (5.0 equiv.), and the resulting mixture was allowed to stir at rt overnight. The reaction mixture was concentrated, redissolved in 10% MeOH/DMSO, and purified by mass-triggered HPLC. 1 H NMR (400 MHz, CDCI3) δ 9.12 (d, J = 1 .3, 1 H), 8.23 (d, J = 1.3, 1 H), 7.92 (s, 1 H), 7.82 (d, J = 8.1 , 2H), 7.68 (d, J = 8.1 , 2H), 3.31 (s, 3H), 3.30 - 3.24 (m, 4H), 1 .24 - 1.20 (m, 4H), 0.87 (s, 6H). MS m/z 432.2; (M+H)+; r.t. = 1 .91. PAT054787-WO-PCT
Synthesis of compound 295: 3-[6-(2-aminoacetamido)pyridin-3-vl1-N-(4-cyanophenvO-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000239_0001
The compound was synthesized using a procedure analogous to one use for synthesis of 212. 1 H NMR (400 MHz, MeOD) δ 8.89 (d, J = 1 .3Hz, 1 H), 8.80 (s, 1 H), 8.25 (s, 1 H), 8.21 - 8.16 (m, 1 H), 8.14 (s, 1 H), 7.67 (d, J = 8.6Hz, 2H), 7.41 (d, J = 8.6Hz, 2H), 7.24 (d, J = 9.3Hz, 1 H), 3.56 (s, 3H), 3.31 (dt, J = 1 .6Hz, 3.2Hz, 2H). ESI-MS m/z 427 [M+1 ]. RT: 0.87 min.
Synthesis of compound 296: N-(2-methoxypvridin-4-vD-N-methvl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2- e
Figure imgf000239_0002
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II). MS m/z 428.1 (M+H)+; r.t. = 1.428.
Synthesis of compound 297: N-(4-cvanophenvl)-N-methvl-3-(6-methylpvridin-3-vl)imidazo[1 ,2- a]pyrazine-6-carboxamide
Figure imgf000239_0003
The compound was synthesized using I-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z =369.2(M+1 ), r.t = 1 .34 mins.
Synthesis of compound 298: N-(1 -ethyl-1 H-pyrazol-5-yl)-N-methyl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000240_0001
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II). M/Z =415.2(M+1 ), r.t = 1 .61 mins.
Synthesis of compound 299: N-methyl-N-(2-methylpvridin-4-vl)-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2- e
Figure imgf000240_0002
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II). MS m/z 412.2 (M+H)+; r.t. = 1.164.
Synthesis of compound 300: tert-butvl N-{2-[(4-{6-[(4- cyanophenyl)(methyl)carbamoyl]imidazo[1 ,2-a]pyrazin-3-yl}phenyl)amino]-2- methylpropyljcarbamate
Figure imgf000240_0003
The compound was synthesized using I-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z =540.3(M+1 ), r.t = 1 .75mins.
Synthesis of compound 301 : N-(6-chloropyridin-3-vl)-3-(1 H-indol-5-vn-N-methvlimidazo[1 ,2- a]pyrazine-6-carboxamide
Figure imgf000240_0004
PAT054787-WO-PCT
The compound was synthesized using 1-57 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z =403.1 (M+1 ), r.t = 1 .34 mins.
Synthesis of compound 302: 3-(4-methoxv-2-methylphenyl)-N-[6-(4-methoxv-2- methylphenyl)pyridin-3-yl]-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000241_0001
The compound was synthesized using 1-19 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z = 494.2(M+1 ), r.t = 1 .50 mins.
Synthesis of compound 303: N-(4-methoxvpvridin-3-vl)-N-methvl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000241_0002
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II). M/Z =428.1 (M+1 ), r.t = 1 .33 mins.
Synthesis of compound 304: N-(6-chloro-5-methvlpyridin-3-vl)-N-methvl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2- e
Figure imgf000241_0003
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II) using I-48. MS m/z 446.1 (M+H)+; r.t. = 1 .726.
Synthesis of compound 305: 7-fluoro-4-((3-[4-(trifluoromethyl)phenvl1imidazo[1 12-a1pvrazin-6- yl}carbonyl)-3,4-dihydro-2H-1 ,4-benzoxazine
Figure imgf000242_0001
The compound was synthesized using 1-74 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. 1H-NMR (400 MHz, DMSO-d6): 9.17 (s, 1 H), 8.98 (s, 1 H), 8.31 (s, 1 H), 8.02 (d, J= 8.35 Hz, 2H), 7.97 (d, J - 8.35 Hz, 2H), 7.8 (bs, 1 H), 6.69-6.85 (m, 2H), 4.32(bs, 2H), 3.96 (bs, 2H).LC-MS: 99.39%; 443.08(M+H).
Synthesis of compound 306: (l3-[4-(trifluoromethvl)phenvl1imidazo[1 ,2-alpyrazin-6- yl}carbonyl)-3,4-dihydro-2H-1 ,4-benzoxazine
Figure imgf000242_0002
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II). MS m/z 425.1 (M+H)+; r.t. = 1.781 .
Synthesis of compound 307: 3-(4-{[1 -(aminomethyl)cyclopropane]amido}phenyl)-N-(4- cyanophenyl)-N-methylimidazo[1 ,2- e
Figure imgf000242_0003
The compound was synthesized using a protocol described in 212. 1 H NMR (400 MHz, MeOD) 5 8.82 (s, 1 H), 8.71 (s, 1 H), 7.96 (s, 1 H), 7.84 (d, J = 8.7Hz, 2H), 7.68 (d, J= 8.6Hz, 2H), 7.60 (d, J= 8.6Hz, 2H), 7.41 (d, J = 8.6Hz, 2H), 3.56 (s, 3H), 3.21 (s, 2H), 1 .60 (s, 2H), 1 .23 (s, 2H).ESI-MS m/z 466 [M+1 ]. RT: 0.98 min.
Synthesis of compound 308: N-methyl-6-(trifluoromethyl)-N-{3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}pyridine-3-carboxamide
Figure imgf000243_0001
The compound was synthesized using a procedure analogous to one use for synthesis of 24. MS m/z 466.1 (M+H)+; r.t. = 1 .526.
Synthesis of compound 309: N-methyl-N-(4-methylpvridin-3-vl)-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000243_0002
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II). M/Z = 412.2(M+1 ), r.t = 1 .33 mins.
Synthesis of compound 310: N-(4-ethoxvpvridin-2-vl)-N-methyl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2- e
Figure imgf000243_0003
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II). M/Z = 442.2(M+1 ), r.t = 1 .60 mins.
Synthesis of compound 311 : 4-methoxv-N-methvl-N-{3-[4-(trifluoromethvl)phenvl1imidazo[1 ,2- a]pyrazin-6-yl}benzamide
Figure imgf000243_0004
The compound was synthesized using a procedure analogous to one use for synthesis of 24.
1 H NMR (400 MHz, CDCI3) δ 9.09 (d, J = 1 .3, 1 H), 7.88 (s, 1 H), 7.76 (s, 1 H), 7.65 (d, J = 8.2, PAT054787-WO-PCT
2H), 7.37 (d, J = 8.8, 2H), 7.14 (d, J = 8.1 , 2H), 6.83 (d, J - 6.9, 2H), 3.77 (s, 3H), 3.55 (s, 3H). HRMS calcd for C22H18F3N402 [M + H] + 427.18; found 427.2.
Synthesis of compound 312: N-(6-chloropvridin-3-vl)-N-methvl-3-|1 H-pyrrolo[2,3-blpvridin-5- yl}imidazo[1 ,2-a]pyrazine-6-carboxa
Figure imgf000244_0001
The compound was synthesized using I-57 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. 1H NMR (400 MHz, MeOD) δ 8.86 (s, 1 H), 8.68 - 8.61 (m, 1 H), 8.51 - 8.44 (m, 1 H), 8.30 - 8.23 (m, 2H), 8.07 - 8.04 (m, 1 H), 7.95 (s, 1 H), 7.84 - 7.74 (m, 2H), 7.60 - 7.55 (m, 1 H), 3.55 (s, 3H), .ESI-MS m/z 404 [M+1 ]. RT: 1.14 min
Synthesis of compound 313: N-methvl-N-f4-(1 H-1 .2.4-triazol-1 -vl)ph
(trifluoromethyl)phenyl]imidazo[1 ,2- e
Figure imgf000244_0002
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II). 1 H NMR (300 MHz, CDCI3) 8.86 (d, J = 1 .17 Hz, 1 H), 8.75 (s, 1 H), 8.54 (s, 1 H), 8.1 1 (s, 1 H), 7.97 (s, 1 H), 7.80 - 7.89 (m, J = 8.21 Hz, 2H), 7.68 - 7.74 (m, J = 8.20 Hz, 2H), 7.59 - 7.68 (m, 1 H), 7.30 (d, J= 8.50 Hz, 2H), 3.58 (s, 3H). ESI-MS m/z 464 [M+H]+.
Synthesis of compound 314: N-(4-cvanophenvl)-3-(4-methanesulfonamidophenvl)-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamid
Figure imgf000244_0003
PAT054787-WO-PCT
The compound was synthesized using 1-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z =447.1 (M+1 ), r.t = 1 .26 mins.
Synthesis of compound 315: 4-(|3-[4-(trifluoromethyl)phenyl1imidazo[1 .2-alpyrazin-6- yl}carbonyl)-3,4-dihydro-2H-1 ,4-benzoxazine-7-carbonitrile
Figure imgf000245_0001
Oxalyl chloride (0.10 mL of a 2.0 M solution in dichloromethane) was added dropwise to a solution of carboxylic acid (20 mg, 0.065 mmol), DMF (1 drop) and dichloromethane (1 .0 mL). After 5 minutes at room temperature, the solvent was removed under reduced pressure. After 30 minutes on the vacuum pump, fresh was added followed by a solution of 3,4-dihydro-2H- benzo[b][1 ,4]oxazine-7-carbonitrile (18 mg, 0.1 12 mmol) in dichloromethane (1.0 mL).
Triethylamine (0.20 mL, 0.195 mmol) was added and the reaction stirred at room temperature for 1 hour. The solvent was removed and the residue was purified using mass trigger HPLC. MS m/z 450.1 (M+H)+; r.t. = 1 .835.
Synthesis of compound 316: 6-methanesulfonyl-1 -(l3-[4-(trifluoromethyl)phenvl1imidazo[1 ,2- a]pyrazin-6-yl}carbonyl)-1 ,2,3,4-tetrahydroquinoline
Figure imgf000245_0002
The compound was synthesized using a procedure similar to one used for the synthesis of 128. MS m/z 501.1 (M+H)+; r.t. = 2.050.
Synthesis of compound 317 : N-(5-methanesulfonylpyridin-2-yl)-N-methyl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000246_0001
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II). 1 H NMR (400 MHz, MeOD) δ 9.05 (s, 1 H), 8.76 (s, 1 H), 8.73 (s, 1 H), 8.24 (d, J = 8.6Hz, 1 H), 8.15 (s, 1 H), 7.96 (s, 4H), 7.55 (d, J = 8.6Hz, 1 H), 3.66 (s, 3H), 3.20 (s, 3H).ESI-MS m/z 476[M+1 ]. RT: 1 .32 min.
Synthesis of compound 318: methyl N-[4-(6-{[methyl(5-methylpyridin-2- yl)amino]methyl}imidazo[1 ,2-a]pyrazin-3-yl)phenyl]carbamate
Figure imgf000246_0002
The compound was synthesized analogous to 1-15 followed by Suzuki coupling protocol described in 228. MS m/z 403.2 (M+H)+; r.t. = 1.055.
Synthesis of compound 319: 3-(1 H-indol-2-vl)-N-[6-(1 H-indol-2-yl)pyridin-3-yl]-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000246_0003
The compound was synthesized using 1-19 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z = 484.1 (M+1 ), r.t = 1 .80 mins.
Synthesis of compound 320: N-(6-chloropvridin-3-vl)-N-methvl-3-(3-methyl-1 H-indazol-5- yl)imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000246_0004
PAT054787-WO-PCT
The compound was synthesized using 1-57 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. 1H NMR (400 MHz, MeOD) δ 8.95 (s, 1 H), 8.1 1 - 8.07 (m, 1 H), 7.71 (d, J = 8.2Hz, 2H), 7.45 (s, 3H), 7.17 - 7.08 (m, 2H), 3.54 (s, 3H), 2.66 (s, 3H). ESI-MS m/z 418 [M+1 ]. RT: 1.18 min.
Synthesis of compound 321 : N-methyl-N-[5-(morpholin-4-vl)pyridin-2-vH-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2- e
Figure imgf000247_0001
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II). M/Z = 483.2(M+1 ), r.t = 1 .37 mins.
Synthesis of compound 322: 4-fluoro-N-methvl-N-|3-[4-(trifluoromethyl)phenvl1imidazo[1 12- a]pyrazin-6-yl}piperidine-1 -carboxamide
Figure imgf000247_0002
The compound was synthesized using similar to synthesis of 24. M/Z = 422.2(M+1 ), r.t = 1 mins.
Synthesis of compound 323: N-(4-cyanophenvl)-3-(6-methanesulfonamidopyridin-3-vl)-N methylimidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000247_0003
The compound was synthesized using I-59 and an appropriate boronic acid/ester using < procedure similar Suzuki coupling protocol described in 228. MS m/z 448.1 (M+H)+; r.t. PAT054787-WO-PCT
Synthesis of compound 324: 3-{4-[(1 -amino-2-methvlpropan-2-vl)aminolphenvl)-N-(4- cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxarnide
Figure imgf000248_0001
The compound was synthesized using I-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. 1H NMR (400 MHz, MeOD) δ 8.91 - 8.52 (m, 3H), 8.06 - 7.79 (m, 2H), 7.74 - 7.65 (m, 1 H), 7.62 - 7.51 (m, 1 H), 7.50 - 7.34 (m, 2H), 7.07 - 6.86 (m, 2H), 3.56 (s, 3H), 3.20 - 3.07 (m, 2H), 1 .44 (s, 6H). ESI-MS m/z 440 [M+1 ]. RT: 1 .09 min.
Synthesis of compound 325: 3-(1 -benzofuran-5-vl)-N-(6-chloropyridin-3-vD-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000248_0002
The compound was synthesized using I-57 and an appropriate boronic acid/ester using procedure similar Suzuki coupling protocol described in 228. M/Z = 404.1 (M+1 ), r.t = 1 .
Synthesis of compound 326: N-methyl-N-(pyridin-3-yl)-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000248_0003
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II) using 1-41. MS m/z 398.1 (M+H)+; r.t. = 1 .136.
Synthesis of compound 327: N-methyl-N-(5-methvlpyrazin-2-vl)-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000249_0001
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II). M/Z = 413.1 (M+1 ), r.t = 1 .60 mins.
Synthesis of compound 328: N-methvl-N-(5-methylpyrazin-2-vl)-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2- e
Figure imgf000249_0002
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II). M/Z =412.1 (M+1 ), r.t = 1 .53 mins.
Synthesis of compound 329: N-methyl-3-[4-(trifluoromethyl)phenvH-N-[2- (trifluoromethyl)pyridin-4-yl]imidazo[1 -a]pyrazine-6-carboxamide
Figure imgf000249_0003
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II) using I-54. MS m/z 466.1 (M+H)+; r.t. = 1 .639.
Synthesis of compound 330: N-(6-chloropyridin-3-vl)-N-methvl-3-[4-(1 H-pyrazol-1 - yl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000249_0004
PAT054787-WO-PCT
The compound was synthesized using 1-57 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. 1H NMR (400 MHz, MeOD) δ 8.99 (s, 1 H), 8.86 - 8.60 (m, 2H), 8.40 (s, 1 H), 8.35 - 8.21 (m, 1 H), 8.20 - 7.96 (m, 3H), 7.92 - 7.67 (m, 3H), 7.53 - 7.35 (m, 1 H), 6.61 (s, 1 H), 3.54 (s, 3H).ESI-MS m/z 430 [M+1 ]. RT: 1 .43 min.
Synthesis of compound 331 : 5-{6-[(4-cyanophenyl)(methyl)carbamovl1imidazo[1 ,2-alpyrazin- 3-yl}-N-methylpyridine-2-carboxami
Figure imgf000250_0001
The compound was synthesized using 1-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z =412.2(M+1 ), r.t = 1 .16 mins.
Synthesis of compound 332: N-(6-chloropvridin-3-vl)-3-[3-fluoro-4-(trifluoromethvl)phenyl1-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000250_0002
The compound was synthesized using I-57 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z =450.1 (M+1 ), r.t = 1 .68 mins.
Synthesis of compound 333: N-(4-cyanophenyl)-3-(2-methoxvpyrimidin-5-vl)-N- methylimidazo[1 ,2-a]pyrazine-6-car
Figure imgf000250_0003
The compound was synthesized using 1-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z =386.2 (M+1 ), r.t = 1 .17 mins. PAT054787-WO-PCT
Synthesis of compound 334: N-(4-ethvlpvridin-2-vl)-3-[4-ftrifluoromethvl)phenvl1irnidazo[1 ,2- a]pyrazine-6-carboxamide
Figure imgf000251_0001
he compound was synthesized using a procedure analogous to one use for synthesis of 72
(method II). 1 H NMR (300 MHz, DMSO- /6) ppm 10.27 (s, 1 H) 9.33 (d, J=1 .47 Hz, 1 H) 9.15 (d, J=1.47 Hz, 1 H) 8.35 (s, 1 H) 8.29 (d, J=4.98 Hz, 1 H) 8.16 (s, 1 H) 7.96 - 8.1 1 (m, 4 H) 7.07 - 7.15 (m, 1 H) 2.69 (q, J=7.33 Hz, 2 H) 1 .22 (t, J=7.62 Hz, 3 H); MS (ESI) for C2i H16F3N50 : 412 (M + H+).
Synthesis of compound 335: N-(4-cyanophenyl)-3-(6-methoxvpyrazin-2-vl)-N- methylimidazo[1 ,2-a]pyrazine-6-car
Figure imgf000251_0002
The compound was synthesized using I-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z = 386.2 (M+1 ), r.t = 1.24 mins.
Synthesis of compound 336: N-(6-chloropvridin-3-yl)-3-(6-methoxvpyridin-3-yl)-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000251_0003
The compound was synthesized using I-57 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z =395.1 (M+1 ), r.t = 1 .27 mins.
Synthesis of compound 337: N-methyl-3-[4-(trifluoromethvl)phenvH-N-[5- (trifluoromethyl)pyridin-2-yl]imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000252_0001
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II). M/Z = 507.23(M+1 ), r.t = 1.24 mins.
Synthesis of compound 338: N-methyl-3-[4-(trifluoromethyl)phenvl1-N-[5- (trifluoromethyl)pyridin-2-yl]imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000252_0002
The compound was synthesized analogous to 1-15 followed by Suzuki coupling protocol described in 228. MS m/z 361.2 (M+H)+; r.t. = 1.074.
Synthesis of compound 339: N-(4-cyanophenyl)-N-methvl-3-[4-(3-methyl-1 1214-oxadiazol-5- yl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000252_0003
The compound was synthesized using I-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z =436.1 (M+1 ), r.t = 1 .49 mins.
Synthesis of compound 340: N-(6-chloropvridin-3-vl)-N-methyl-3-[4-(morpholin-4- yl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000252_0004
PAT054787-WO-PCT
The compound was synthesized using 1-57 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z =449.1 (M+1 ), r.t = 1 .36 mins.
Synthesis of compound 341 : N.3-bis(4-cyanophenyl)-N-methvl-2-(trifluoromethyl)imidazo[1 ,2- a]pyrazine-6-carboxamide
Figure imgf000253_0001
The compound was synthesized using I-59 and an appropriate boronic acid/ester using < procedure similar Suzuki coupling protocol described in 228. MS m/z 447.0 (M+H)+; r.t.
Synthesis of compound 342: N-(2,6-dichloropvridin-3-vD-N-methvl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2- e
Figure imgf000253_0002
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II) using I-43. MS m/z 466.0 (M+H)+; r.t. = 1 .860.
Synthesis of compound 343: N-(6-chloropvridin-3-vl)-3-[4-(cvclopropylcarbamovl)phi methylimidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000253_0003
The compound was synthesized using I-57 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z = 447.1 (M+1 ), r.t = 1 .25 mins.
Synthesis of compound 344: N-(4-cvanophenvl)-3-[2-(dimethvlamino)pvrimidin-5-vl1-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000254_0001
The compound was synthesized using 1-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z =399.2(M+1 ), r.t = 1 .23 mins.
Synthesis of compound 345: N-methyl-N-(6-methylpvridin-2-vl)-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000254_0002
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II). M/Z = 412.2 (M+1 ), r.t = 1 .51 mins.
Synthesis of compound 346: N-[2-(difluoromethoxv)phenvll-N-methvl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000254_0003
compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II). MS m/z 463.1 (M+H)+; r.t. = 1.804.
Synthesis of compound 347: 4-cvano-N-methvl-N-|3-[4-(trifluoromethvl)phenvl1imidazo[1 ,2- a]pyrazin-6-yl}benzen -1 -sulfonamide
Figure imgf000254_0004
A solution of NHMe core 1-21 (1 .0 equiv.) in CH2CI2 was treated with sulfonyl chloride (1 .5 equiv.) and Et3N (5.0 equiv.) at room temperature. The resulting mixture was allowed to stir at PAT054787-WO-PCT
60 °C overnight. The reaction mixture was concentrated, redissolved in 10% MeOH/DMSO, and purified by mass-triggered HPLC. 1 H NMR (400 MHz, CDCI3) δ 8.88 (d, J= 1.3, 1 H), 8.55 (d, J = 1.3, 1 H), 8.02 (s, 1 H), 7.86 (d, J = 8.2, 2H), 7.82 - 7.71 (m, 6H), 3.25 (s, 3H). M/Z = 458.1 (M+1 ). r.t = 2.1 1 mins.
Synthesis of compound 348: N-methyl-3-[4-(trifluoromethyl)phenvl1-N-[4- (trifluoromethyl)pyridin-2-yl]imidazo[1 -a]pyrazine-6-carboxamide
Figure imgf000255_0001
compound was synthesized using a procedure analogous to one use for synthesis of 72
(method II). M/Z = 466.10(M+1 ), r.t = 1.98 mins.
Synthesis of compound 349: N-(6-chloropvridin-3-vl)-3-(1 H-indazol-5-vl)-N-methvlimidazo[1 ,2- a]pyrazine-6-carboxamide
Figure imgf000255_0002
The compound was synthesized using I-57 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. 1H NMR (400 MHz, MeOD) δ 8.99 - 8.94 (m, 1 H), 8.89 - 8.84 (m, 1 H), 8.82 - 8.73 (m, 1 H), 8.25 (s, 3H), 8.06 (s, 1 H), 7.80 (s, 3H), 3.56 (s, 3H).ESI-MS m/z 404 [M+1 ]. RT: 1 .16 min.
Synthesis of compound 350: 2,2-dimethvl-4-({3-[4-(trifluoromethyl)phenvl1imidazo[1 ,2- a]pyrazin-6-yl}carbonyl)-3,4-dihydro-2H-1 ,4-benzoxazine-7-carbonitrile
Figure imgf000255_0003
PAT054787-WO-PCT
The compound was synthesized using 1-56 a procedure analogous to one use for synthesis of 72 (method II). MS m/z 478.1 (M+H)+; r.t. - 1 .997.
Synthesis of compound 351 : N-(4-cyanophenyl)-3-(6-fluoropyridin-2-vl)-N-methvlimidazo[1 12- a]pyrazine-6-carboxamide
Figure imgf000256_0001
The compound was synthesized using 1-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z = 373.10(M+1 ), r.t = 1 .31 mins.
Synthesis of compound 352: 3-[4-(1 -carbamoyl-1 -methylethoxy)phenyl]-N-(4-cyanophenyl)-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000256_0002
The compound was synthesized using I-59 and I-67 using a procedure similar Suzuki coupling protocol described in 228. 1 H NMR (400 MHz, MeOD) δ 8.90 - 8.68 (m, 2H), 8.06 - 7.95 (m, 1 H), 7.68 (d, J = 8.5Hz, 2H), 7.55 (d, J = 8.7Hz, 2H), 7.41 (d, J = 8.5Hz, 2H), 7.19 (d, J = 8.7Hz, 2H), 3.56 (s, 3H), 1 .62 (s, 6H). ESI-MS m/z 455 [M+1 ]. RT: 1.29 min.
Synthesis of compound 353: N-(5-methoxypyridin-2-vl)-N-methvl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2- e
Figure imgf000256_0003
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II). 1 H NMR (400 MHz, MeOD) δ 9.18 - 9.13 (m, 1 H), 8.93 - 8.88 (m, 1 H), 8.72 - 8.66 PAT054787-WO-PCT
(m, 1 H), 8.24 - 8.17 (m, 1 H), 8.1 1 (s, 1 H), 7.93 (s, 2H), 7.43 - 7.27 (m, 3H), 3.84 (s, 3H), 3.54 (s, 3H).ESI-MS m/z 428 [M+1 ]. RT: 1 .55 min.
Synthesis of compound 354: 3-(3-chloropvridin-2-vl)-N-(4-cvanophenvl)-N-methvlirriiclazo[112- a]pyrazine-6-carboxamide
Figure imgf000257_0001
The compound was synthesized using 1-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z = 389(M+1 ), r.t = 1 .28 mins.
Synthesis of compound 355: N-(5-chloropyridin-3-vl)-N-methvl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2- e
Figure imgf000257_0002
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II) using I-49. MS m/z 432.1 (M+H)+; r.t. = 1 .71 1 .
Synthesis of compound 356: N-methyl-N-(1 ,3-thiazol-2-yl)-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000257_0003
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method III). MS m/z 404.1 (M+H)+; r.t. = 2.190.
Synthesis of compound 357: N-(6-chloropyridin-3-yl)-3-[6-(dimethylamino)pyridin-3-yl1-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000258_0001
The compound was synthesized using 1-57 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z =408(M+1 ), r.t = 0.926 mins.
Synthesis of compound 358: -(4-methoxvpvridin-2-yl)-N-methyl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2- e
Figure imgf000258_0002
The compound was synthesized using a procedure similar to one used for the synthesis of 128. M/Z = 428.1 (M+1 ), r.t = 1 .52 mins.
Synthesis of compound 359: N-{6-[(2S)-2-(methoxvmethyl)pyrrolidin-1 -yllpyridin-3-vl)-N- methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000258_0003
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II). M/Z = 51 1.3 (M+1 ), r.t = 1 .43 mins.
Synthesis of compound 360: N-(6-chloropyridin-3-yl)-3-(213-dihydro-1 14-benzodioxin-6-yl)-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000258_0004
PAT054787-WO-PCT
The compound was synthesized using 1-57 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z = 422.10 (M+1 ), r.t = 1 .43 mins.
Synthesis of compound 361 : 3-(4-acetamidophenvl)-N-methvl-N-(5-methylpvridin-2- yl)imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000259_0001
The compound was synthesized using I-78 and an appropriate boronic acid/ester using procedure similar Suzuki coupling protocol described in 228. M/Z = 401.2(M+1 ), r.t = 0.
Synthesis of compound 362: -[(4-cyanophenvl)methvl1-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2- e
Figure imgf000259_0002
The compound was synthesized using I-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. 1H NMR (300 MHz, CDCI3) 9.07- 9.14 (dd, J= 1 .5 Hz, 2H), 8.39 (t, broad, 1 H), 8.02 (s, 1 H), 7.46 - 7.86 (m, J = 8.4 Hz, 4.74 - 4.76 (d, J = 6.0 Hz, 2H). ESI-MS m/z 422 [M+H]+.
Synthesis of compound 363: N-(4-cyanophenyl)-N-methyl-3-[4-(propane-2- sulfonamido)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000259_0003
The compound was synthesized using I-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z = 475.1 (M+1 ), r.t = 1 .50 mins. PAT054787-WO-PCT
Synthesis of compound 364: N-(6-chloropvridin-3-vl)-N-methvl-3-[2-(propan-2-vl)-1 ,3-thiazol- 4-yl]imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000260_0001
The compound was synthesized using I-57 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z = 413.1 ( +1 ), r.t = 1 .60 mins.
Synthesis of compound 365: N-methvl-N-[6-(1 H-1 .2.4-triazol-1 -vl)pvridin-3-vll-3-r4- (trifluoromethyl)phenyl]imidazo[1 ,2- e
Figure imgf000260_0002
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II) using I-45. MS m/z 465.1 (M+H)+; r.t. = 1 .541 .
Synthesis of compound 366: N-methyl-4-(trifluoromethoxy)-N-(3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-
Figure imgf000260_0003
The compound was synthesized using a procedure analogous to one use for synthesis of 24. 1 H NMR (400 MHz, CDCI3) δ 9.08 (s, 1 H), 7.86 (s, 1 H), 7.82 (s, 1 H), 7.64 (d, J = 8.0, 2H), 7.42 (d, J = 8.7, 2H), 7.14 (d, J = 8.0, 4H), 3.51 (s, 3H). HRMS calcd for C22H15F6N402 [M + H] + 481 .1 ; found 481 .2.
Synthesis of compound 367: N-(6-chloropvridin-3-yl)-N-methvl-3-[6-(5-methyl-1 ,3,4-oxadiazol- 2-yl)pyridin-3-yl]imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000261_0001
The compound was synthesized using 1-57 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z = 446.10(M), r.t = 1 .46 mins.
Synthesis of compound 368: N-(1 -ethvl-1 H-pyrazol-5-vl)-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000261_0002
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II). 1 H NMR (300 MHz, DMSO-c/6) ppm 1.31 (t, J=7.18 Hz, 3 H), 4.04 (q, J=7.33 Hz, 3 H), 6.24 (d, J=1.76 Hz, 1 H), 7.43 (d, J=1.76 Hz, 1 H), 7.94 - 8.1 1 (m, 4 H), 8.33 (s, 1 H), 9.09 (d, J=1.46 Hz, 1 H), 9.31 (d, J=1.47 Hz, 1 H). ESI-MS m/z 401 [M+H]+.
Synthesis of compound 369: 3-(4-cyanophenvl)-N-methyl-N-[4- (trifluoromethyl)phenyl]imidazo[1 ,2- e
Figure imgf000261_0003
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II). MS m/z 422.2 (M+H)+; r.t. = 2.030.
Synthesis of compound 370: N-benzvl-N-methvl-3-[4-(trifluoromethyl)phenvl1imidazo[1 ,2- a]pyrazine-6-carboxamide
Figure imgf000262_0001
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II). 1 H NMR (300 MHz, CDCI3) 9.1 1 (d, J= 1 1 .72 Hz, 1 H), 8.86 (d, J= 7.62 Hz, 1 H), 8.00 (br. s., 1 H), 7.83 (br. s., 2H), 7.64 - 7.79 (m, 2H), 7.28 - 7.46 (m, 5H), 4.65 - 5.09 (m, 2H), 2.97 - 3.31 (m, 3H). ESI-MS m/z 41 1 [M+H]+.
Synthesis of compound 371 : 2-C-3-[4-(trifluoromethvl)phenvl1imidazo[1 ,2-a]pyrazine-6- pyridine-2,5-dicarboxamide
Figure imgf000262_0002
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II). 1 H NMR (300 MHz, DMSO-c/6) ppm 10.52 (s, 1 H) 9.33 (d, J=1 .47 Hz, 1 H) 9.16 (d, J=1.47 Hz, 1 H) 8.88 (dd, J=2.05, 0.88 Hz, 1 H) 8.27 - 8.40 (m, 3 H) 8.04 (q, J=8.40 Hz, 5 H) 7.53 (br. s., 1 H) ; MS (ESI) for C20H13F3N6O2 : 427 (M + H+).
Synthesis of compound 372: 3-[4-(2-aminoethoxv)phenvl1-N-(4-cvanophenvl)-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide
PAT054787-WO-PCT
Figure imgf000263_0001
Synthesis of methyl 3-(4-(cyanomethoxy)phenyl)imidazo[1 ,2-a]pyrazine-6-carboxylate (372a):
To a solution of methyl 3-bromoimidazo[1 ,2-a]pyrazine-6-carboxylate I-4 (0.15g, 0.585 mmol, 1 eq), in THF/water (4:1 ) 10 mL was added the (4-(cyanomethoxy)phenyl)boronic acid (0.189 g, 0.732 mmol, 1.25 eq) followed by DPP-Pd (cat) and K2HP04 (0.4 g, 2.34 mmol, 4 eq). The reaction vial was sealed and heated under microwave condition for 45 min at 150 °C. The formation of the product peak was checked via LC/MS and the desired compound was isolated via flash column chromatography using ethyl acetate/hexane (0-100%). The isolated product was used for the next step.
Synthesis of methyl 3-(4-(2-aminoethoxy)phenyl)imidazo[1 ,2-a]pyrazine-6-carboxylate (372b):
To a solution of 3-(4-(cyanomethoxy)phenyl)imidazo[1 ,2-a]pyrazine-6-carboxylate (350 mg, 1.13 mmol, 1 eq), in EtOH (8 mL) was cooled down to 0 °C and was added NiCI2 (220 mg, 1.70mmol, 1.5eq), followed by NaBH4 (64mg, 1 .70mmols, 1 .5eq). The reaction mixture was stirred at 0°C for 10 minutes and checked via LC/MS for the desired compound peak. The product was then isolated via flash column chromatography using ethyl acetate/hexane (0- 100%). The isolated product was used for the next step. PAT054787-WO-PCT
Synthesis of methyl 3-(4-(2-((4-methoxybenzyl)amino)ethoxy)phenyl)imidazo[1 ,2- a]pyrazine-6-carboxylate (372c):
To a solution of methyl 3-(4-(2-aminoethoxy)phenyl)imidazo[1 ,2-a]pyrazine-6-carboxylate (260 mg, 0.832 mmol, 1 eq) in DCM was added the PMB-CI (195 mg, 1.25 mmol, 1 .5 eq), followed by DIEA (268 mg, 2.08 mmol, 2.5 eq). The reaction mixture was stirred at rt for 12 hrs and then was quenched with water, followed by extraction with ethyl acetate (3X15 mL). The desired compound was purified by using flash column chromatography by eluting with 0-100 % ethyl acetate/hexane.
Synthesis of 3-(4-(2-((4-methoxybenzyl)amino)ethoxy)phenyl)imidazo[1 ,2-a]pyrazine-6- carbonyl chloride (372d):
To a solution of methyl 3-(4-(2-((4-methoxybenzyl)amino)ethoxy)phenyl)imidazo[1 ,2-a]pyrazine- 6-carboxylate (0.28g, 0.647 mmol, 1 eq), was added 2 N NaOH (2 mL) and CH3CN (6 mL). The reaction mixture was stirred at rt for 12 hrs and then the solvents were removed under vacuo. To the dry acid was then added the oxalyl chloride followed by DMF (cat) and the reaction mixture was stirred at room temperature overnight. Next day all the solvents were removed under vacuo and the crude reaction mixture was used for the next step.
Synthesis of N-(4-cyanophenyl)-3-(4-(2-((4-methoxybenzyl)amino)ethoxy)phenyl)-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide (372e):
To a solution of 3-(4-(2-((4-methoxybenzyl)amino)ethoxy)phenyl)imidazo[1 ,2-a]pyrazine-6- carbonyl chloride in DCM was added the 4-(methylamino)benzonitrile (60 mg, 0.457 mmol, 1 .25 eq) pre-dissolved (in DCM) drop wise over 10 minutes. The reaction mixture was stirred at room temperature overnight. The reaction was quenched with sodium carbonate solution and extracted the organics by using ethyl acetate (3 x 15 mL). The crude product was isolated and was used for the next step.
Synthesis of 372: To a solution of N-(4-cyanophenyl)-3-(4-(2-((4- methoxybenzyl)amino)ethoxy)phenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide (60 mg, 0.1 12 mmol, 1 eq), dissolved in ethanol was added a few drops of AcOH. To this reaction mixture was then added the Pd/C (5%, 25 mg). The reaction mixture was kept under hydrogen PAT054787-WO-PCT by balloon for ½ hr. The desired product was isolated via flash column chromatography. 1 H NMR (400 MHz, MeOD) δ 8.12 - 8.07 (m, 1 H), 7.68 (d, J - 8.5Hz, 2H), 7.61 (s, 1 H), 7.42 (s, 2H), 7.28 (s, 3H), 6.95 (s, 2H), 4.36 (s, 2H), 4.05 (d, J = 5.4Hz, 2H), 3.34 (d, 3H). ESI-MS m/z 413 [M+1 ]. RT: 1 .02 min.
Synthesis of compound 373: 3-(6-acetamidopyridin-3-vl)-N-methvl-N-(5-methylpvridin-2- yl)imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000265_0001
The compound was synthesized using I-78 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z = 402.2(M+1 ), r.t = 0.92 mins.
Synthesis of compound 374: 4-({3-[4-(trifluoromethvl)phenvl1imidazo[1 .2-alpvrazin-6- yl}carbonyl)morpholine
Figure imgf000265_0002
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II). 1 H NMR (300 MHz, CDCI3) 9.10 (d, J = 1 .47 Hz, 1 H), 8.87 (d, J = 1 .46 Hz, 1 H), 8.02 (s, 1 H), 7.79 - 7.89 (m, J= 8.20 Hz, 2H), 7.67 - 7.79 (m, J = 8.21 Hz, 2H), 3.64 - 3.73 (m, 4H), 2.40 - 2.60 (m, 4H). ESI-MS m/z 377 [M+H]+.
Synthesis of compound 375: N-[4-(aminomethvl)phenvl1-N-methvl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2- e
Figure imgf000265_0003
PAT054787-WO-PCT
The compound was synthesized using a procedure analogous to one use for synthesis of 212. M/Z =426.1 (M+1 ), r.t = 1.15 mins.
Synthesis of compound 376: N-(4-cyanophenyl)-2-methyl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2- e
Figure imgf000266_0001
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II) using intermediate 285-III. MS m/z 422.1 (M+H)+; r.t. = 2.092.
Synthesis of compound 377: N13-bis(4-cyanophenvl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide
Figure imgf000266_0002
The compound was synthesized using I-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. MS m/z 379.2 (M+H)+; r.t. = 1.910
Synthesis of compound 378: N-(4-cvanophenvl)-N-methyl-3-(2-methvlpvridin-4-vl)imidazo[1 ,2- a]pyrazine-6-carboxamide
Figure imgf000266_0003
The compound was synthesized using I-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z =369.1 (M+1 ), r.t = 0.94 mins.
Synthesis of compound 379: N-(6-chloropvridin-3-vl)-N-methvl-3-(2-oxo-213-dihydro-1 H-indol- 5-yl)imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000267_0001
The compound was synthesized using 1-57 and an appropriate boronic acid/ester using procedure similar Suzuki coupling protocol described in 228. M/Z = 419.1 ( + ), r.t = 1 .
Synthesis of compound 380: 3-(2-aminopvrimidin-5-vl)-N-(4-cvanophenvl)-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000267_0002
The compound was synthesized using I-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z =371 .2.1 (M+1 ), r.t = 0.99 mins.
Synthesis of compound 381 : N-(6-chloropvridin-3-vl)-3-ethenvl-N-methvlimidazo[1 ,2- a]pyrazine-6-ca
Figure imgf000267_0003
To a solution of 3-bromo-N-(4-chlorophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide (40 mg, 0.109 mmols, 1 eq), in THF/water (4:1 ) was added tributyl vinyl tin (30mg, 0.109 mmols, 1 eq) was added. The reaction mixture was heated at 90 °C for one hour. The desired compound N-(4-chlorophenyl)-N-methyl-3-vinylimidazo[1 ,2-a]pyrazine-6-carboxamide 5mg (0.0159mmol, 15%) was isolated via preparative HPLC. M/Z = 313(M+1 ), r.t = 1 .1 1 min.
Synthesis of compound 382: N-(5-cvclobutvlpyridin-2-vl)-N-methvl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000268_0001
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II), using interemediate 1-68. 1H NMR (400 MHz, MeOD) δ 9.02 (s, 1 H), 8.84 - 8.71 (m, 1 H), 8.64 - 8.51 (m, 1 H), 8.15 (s, 1 H), 8.12 - 8.05 (m, 1 H), 7.93 (d, J = 3.0Hz, 3H), 7.76 (s, 2H), 3.59 (s, 3H), 1.43 (d, J = 15.0Hz, 9H). ESI-MS m/z 454 [M+1 ]. RT: 1 .49 min.
Synthesis of compound 383: N-{[4-(morpholin-4-vl)phenvl1methvl)-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2- e
Figure imgf000268_0002
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II). 1 H NMR (300 MHz, DMSO-c/6) d ppm 2.97 - 3.08 (m, 4 H) 3.63 - 3.75 (m, 4 H) 4.39 (d, J=6.45 Hz, 2 H) 6.86 (m, J=8.79 Hz, 2 H) 7.20 (m, J=8.79 Hz, 2 H) 7.91 - 8.04 (m, 4 H) 8.25 (s, 1 H) 8.97 (d, J=1 .47 Hz, 1 H) 9.20 (d, J=1 .17 Hz, 1 H) 9.24 (t, J=6.30 Hz, 1 H); MS (ESI) for C25H22F3N502: 482 (M + H)+.
Synthesis of compound 384: N-(6-tert-butvlpyridin-3-vl)-N-methyl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2- e
Figure imgf000268_0003
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II). M/Z 454.2 [M+1]. RT: 1 .49 min.
Synthesis of compound 385: -(4-cyanophenyl)-N-methyl-3-(pyridin-4-v0imidazo[1 ,2- a]pyrazine-6-carboxamide
Figure imgf000269_0001
The compound was synthesized using 1-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z =355.2(M+1 ), r.t = 0.74 mins.
Synthesis of compound 386: N-(2-aminoethvl)-N-(4-cyanophenyl)-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000269_0002
386-1 was synthesized using a procedure analogous to one use for synthesis of 72 (method II) using I-33.
Figure imgf000269_0003
386-1 386
TFA (0.20 mL) was added to a solution of tert-butyl (2-(N-(4-cyanophenyl)-3-(4- (trifluoromethyl)phenyl)imidazo[1 ,2-a]pyrazine-6-carboxamido)ethyl)carbamate (20 mg, 0.036 mmol) and dichloromethane (1 .0 mL). The reaction stirred at room temperature for 2 hours. The solvent was removed and the crude product was purified by mass-trigger HPLC. LC/MS m/z 451 .1 (M+H)+; r.t. = 1 .367.
Synthesis of compound 387: N-(6-chloropvridin-3-yl)-3-(1 H-indol-2-yl)-N-methylimidazo[1 ,2- a]pyrazine-6-carboxamide
Figure imgf000270_0001
The compound was synthesized using 1-57 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z =1 .56(M+1 ), r.t = 403.1 mins.
Synthesis of compound 388: N-(6-chloropvridin-3-vl)-3-|4-[(dimethvlamino)methyl1phenvl]-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000270_0002
The compound was synthesized using I-57 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z = 421.2(M+1 ), r.t = 0.97 mins.
Synthesis of compound 389: N-(4-cyano-1 H-imidazol-5-yl)-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000270_0003
The compound was synthesized using a procedure analogous to one use for synthesis of 128. 1 H NMR (300 MHz, DMSO-d6) δ ppm 9.32 (d, J=1.46 Hz, 1 H) 9.12 (d, J=1.17 Hz, 1 H) 8.34 (s, 1 H) 7.97 - 8.1 1 (m, 4 H) 7.80 (s, 1 H); MS : 398 (M + H)+.
Synthesis of compound 390: N-methvl-N-(3-methylpyridin-2-vl)-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000270_0004
PAT054787-WO-PCT
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II). 1 H NMR (300 MHz, DMSO-c/6) ppm 9.32 (d, J=1.46 Hz, 1 H) 9.12 (d, J=1.17 Hz, 1 H) 8.34 (s, 1 H) 7.97 - 8.1 1 (m, 4 H) 7.80 (s, 1 H); MS : 398 (M + H)+.
Synthesis of compound 391 : N-(4-cvanophenvl)-N-methvl-3-|1 -methyl-1 H-pvrazolo[3,4- b]pyridin-5-yl}imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000271_0001
The compound was synthesized using I-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z =409.1 (M+1 ), r.t = 1 .26 mins.
Synthesis of compound 392: 4-((3-[4-(trifluoromethvl)phenvl1imidazo[1 .2-a1pvrazin-6- yl}methyl)morpholine
Figure imgf000271_0002
The compound was synthesized procedure analogous to the synthesis of 1-15 and followed Suzuki coupling protocol described in 228. H-NMR (400 MHz, CDCL3): 9.18 (d, J= 1 .31 Hz, 1 H), 8.28 (s, 1 H), 7.93 (s, 1 H), 7.85 (d, J = 7.91 Hz, 2H), 7.72 (d, J = 7.91 Hz, 2H), 3.68-3.76 (m, 6H), 2.56-2.58 (m, 4H).LC-MS: 98.95%, 363.3 (M+H).
Synthesis of compound 393: 5-(6-[(4-cvanophenvl)(methyl)carbamovl1imidazo[1 ,2-a1pvrazin- 3-yl}pyridine-2-carboxamide
Figure imgf000271_0003
PAT054787-WO-PCT
The compound was synthesized using 1-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. MS m/z 398.1 (M+H)+; r.t. = 1 .1 10.
Synthesis of compound 394: N-[6-(dimethylamino)pvridin-3-yl1-N-methyl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2- e
Figure imgf000272_0001
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II). M/Z =441 .2 (M+1 ), r.t = 1 .25 mins.
Synthesis of compound 395: N-(6-methoxypyridazin-3-yl)-N-methvl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2- e
Figure imgf000272_0002
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II). M/Z = 429.1 (M+1 ), r.t = 1 .35 mins.
Synthesis of compound 396: 3-(3-amino-1 H-indazol-5-yl)-N-(4-cvanophenyl)-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000272_0003
The compound was synthesized using I-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. MS m/z 409.2 (M+H)+; r.t. = 1 .081 .
Synthesis of compound 397: 1 -({3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6- yl}carbonyl)piperidine-3-carboxamide
Figure imgf000273_0001
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II). 1 H NMR (300 MHz, DMSO- /6) ppm 9.18 (d, J=1.47 Hz, 1 H) 8.78 (d, J=1.47 Hz, 1 H) 8.27 (s, 1 H) 7.98 (q, J=8.69 Hz, 4 H) 7.19 - 7.49 (m, 1 H) 6.75 - 6.97 (m, 1 H) 4.22 - 4.57 (m, 1 H) 3.93 (d, J=1 1 .72 Hz, 1 H) 2.75 - 3.04 (m, 1 H) 2.27 - 2.43 (m, 1 H) 1 .36 - 2.04 (m, 4 H) ; MS (ESI) for C2oH18F3N502 : 418 (M + H+).
Synthesis of compound 398: N-(6-chloropyridin-3-yl)-N-methvl-3-[4- (methylamino)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000273_0002
The compound was synthesized using I-57 and an appropriate boronic acid/ester using procedure similar Suzuki coupling protocol described in 228. M/Z =441 .2 (M+1 ), r.t = 1 .
Synthesis of compound 399: N-(2-methoxvpyrimidin-5-yl)-N-methvl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2- e
Figure imgf000273_0003
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II). M/Z = 429.1 (M+1 ), r.t = 1 .35 mins.
Synthesis of compound 400: -(4-cvanophenyl)-N-methvl-3-(6-{[2-(morpholin-4- yl)ethyl]amino}pyridin-3-yl)imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000274_0001
The compound was synthesized using 1-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z = 483.2 (M+1 ), r.t = 0.93 mins.
Synthesis of compound 401 : N-(4-cyanophenyl)-3-(6-cyanopyridin-3-yl)-N-methylimidazo[112- a]pyrazine-6-carboxamide
Figure imgf000274_0002
The compound was synthesized using 1-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z =380.2(M+1 ), r.t = 1 .28 mins.
Synthesis of compound 402: 3-{4-[(1 -amino-2-methylpropan-2-yl)oxy]phenyl}-N-(4- cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000274_0003
The compound was synthesized using a protocol described in 212. 1 H NMR (400 MHz, CDCI3) δ 8.81 (s, 1 H), 8.74 (s, 1 H), 8.23 - 8.06 (m, 1 H), 7.84 (s, 1 H), 7.53 (d, J = 8.6HZ, 2H), 7.42 (d, J = 8.4Hz, 2H), 7.19 - 7.12 (m, 3H), 5.23 (m, 2H), 3.49 (s, 3H), 2.1 1 (s, 2H), 1 .41 (s, 6H). ESI-MS m/z 441 [M+1 ]. RT: 1.1 1 min.
Synthesis of compound 403: 6-N-(6-chloropyridin-3-vl)-6-N-methyl-3-N-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-3,6-dicarboxamide PAT054787-WO-PCT
Figure imgf000275_0001
Synthesis of methyl 3-((4-(trifluoromethyl)phenyl)carbamoyl)imidazo[1 ,2-a]pyrazine-6- carboxylate (403a): To a solution of methyl 3-bromoimidazo[1 ,2-a]pyrazine-6-carboxylate I-4 (0.35g, 1.36 mmol, 1 eq) in THF at -78 °C was added n-BuLi (1.70 mmol, 1 .25 eq) drop by drop over ½ hr. The reaction mixture was stirred at -78 °C for 2 more hours at which point the isocyanate was added (pre-dissolved in THF) at this low temperature. The reaction mixture was stirred at -78 °C for 3 more hours and then was quenched at - 78 °C with saturated ammonium chloride solution. The organics were extracted with ethyl acetate (3x30 ml_), combined all the organics and dried over magnesium sulfate and isolated the desired compound via column chromatography. Yield = 132 mg (0.362 mmol, 27 %).
Synthesis of 3-((4-(trifluoromethyl)phenyl)carbamoyl)imidazo[1 ,2-a]pyrazine-6-carbonyl chloride (403b):
To a solution of methyl 3-((4-(trifluoromethyl)phenyl)carbamoyl)imidazo[1 ,2-a]pyrazine-6- carboxylate (130 mg, 0.356 mmols, 1 eq) in THF /water (6:1 ) 6 mL was added LiOH (24 mg, 1.07 mmols, 3 eq). The reaction mixture was stirred at room temperature overnight. Removed all solvents, added the oxalyl chloride followed by catalytic DMF. Next day removed all solvents under vacuo and used for the next step.
Synthesis of compound 403:
To a solution of 3-((4 (trifluoromethyl)phenyl)carbamoyl) imidazo[1 ,2-a]pyrazine-6-carbonyl chloride (19 mg, 0.051 mmol, 1 eq) dissolved in DCM was added the 6-chloro-N-methylpyridin- PAT054787-WO-PCT
3-amine (18 mg, 0.128 mmols, 2.5 eq) followed by DIEA (16 mg, 0.128 mmol, 2.5 eq). The reaction mixture was stirred at room temperature for 6 hrs. The compound was purified using preparative HPLC and isolated as a TFA salt. M/Z = 475.1 (M+1 ), r.t = 1.72 mins.
Synthesis of compound 404: 5-C-3-[4-(trifluoromethyl)phenyl1imidazo[1 ,2-alpvrazine-6-1 H- imidazole-4,5-dicarboxamide
Figure imgf000276_0001
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II). 1 H NMR (300 MHz, DMSO-c/6) ppm 7.44 (s, 1 H), 7.93 - 8.14 (m, 4 H), 8.34 (s, 1 H), 9.13 (d, J=1.17 Hz, 1 H), 9.33 (d, J=1.47 Hz, 1 H). ESI-MS m/z 416 [M+H]+.
Synthesis of compound 405: N-[1 -(4-chlorophenvl)ethvl1-N-methyl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000276_0002
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II). M/Z =459.1 .2(M+1 ), r.t = 1.93 mins.
Synthesis of compound 406: N-l4-[(1 ,3-thiazol-2-vDsulfamovllphenvl)-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2- e
Figure imgf000276_0003
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II). 1 H NMR (300 MHz, DMSO-cfe) ppm 6.77 (d, J=4.40 Hz, 1 H), 7.20 (d, J=4.69 Hz, PAT054787-WO-PCT
1 H), 7.72 - 7.85 (m, 1 H), 7.97 - 8.12 (m, 6 H), 8.33 (s, 1 H), 9.13 (d, J=1 .17 Hz, 1 H), 9.31 (d, J=1 .47 Hz, 1 H), 10.93 (s, 1 H). ESI-MS m/z 545 [M+H]+.
Synthesis of compound 407: N-(6-chloropyridin-3-yl)-N-methyl-3-[6-(methylamino)pyridin-3- yl]imidazo[1 ,2-a]pyrazine-6-carboxa
Figure imgf000277_0001
The compound was synthesized using I-57 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. 1H NMR (400 MHz, MeOD) δ 9.10 - 9.04 (m, 1 H), 8.91 - 8.87 (m, 1 H), 8.50 - 8.41 (m, 2H), 8.27 - 8.13 (m, 3H), 7.50 - 7.40 (m, 2H), 3.54 (s, 3H), 3.18 - 3.04 (m, 3H). ESI-MS m/z 394 [M+H]+. RT: 0.90 min.
Synthesis of compound 408: 3-[4-(2-amino-2-methvlpropanamido)phenvl1-N-(4-cvanophenyQ- N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000277_0002
The compound was synthesized using a protocol described in 212. M/Z = 454.1 (M+1 ), r.t = 1.02 mins.
Synthesis of compound 409: 3-[4-(2-aminoethoxv)phenyl1-N-methvl-N-(5-methylpvridin-2- yl)imidazo[1 ,2-a]pyrazine-6-carboxa
Figure imgf000277_0003
The compound was synthesized using I-78 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. 1H NMR (400 MHz, MeOD) δ 8.13 (s, 1 H), 7.68 (s, 2H), 7.44 (s, 3H), 7.31 - 7.25 (m, 1 H), 7.16 (d, J = 8.8Hz, 3H), 5.00 (s, 2H), 4.09 (s, 2H), 3.26 (s, 3H), 2.26 (s, 3H). ESI-MS m/z 403 [M+H]+. RT: 1 .12 min. PAT054787-WO-PCT
Synthesis of compound 410: N-(6-chloropvridin-3-vl)-N-methvl-3-[4-(1 ,3,4-oxadiazol-2- yl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000278_0001
The compound was synthesized using I-57 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. 1H NMR (400 MHz, MeOD) δ 9.09
- 8.97 (m, 1 H), 8.85 (s, 1 H), 8.80 - 8.72 (m, 1 H), 8.70 - 8.61 (m, 1 H), 8.32 - 8.23 (m, 1 H), 8.17
- 8.06 (m, 2H), 7.94 (s, 2H), 7.82 - 7.76 (m, 1 H), 7.50 - 7.40 (m, 1 H), 3.55 (d, J= 2.6Hz, 3H).ESI-MS m/z 431 [M+H]+. RT: 1 .25 min.
Synthesis of compound 411 : 6-fluoro-1 -((8-methvl-3-[4-(trifluoromethvl)phenvl1imidazo[1 ,2- a]pyrazin-6-yl}carbonyl)-1 ,2,3,4-tetrahydr
Figure imgf000278_0002
1 H NMR (400 MHz, DMSO-d6 at 80°C): δ 8.95 (s, 1 H), 7.75-7.85(m, 5H), 7.23(bs, 1 H), 6.99 (m, 1 H), 6.8 (bs, 1 H), 3.67 (m, 2H), 2.81 (m, 2H), 2.15 (s, 3H), 1 .94 (m, 2H). LC-MS: 98.42%; 455.10 (M+H).
Synthesis of compound 412: N-(5-cyclopentylpvridin-2-yl)-N-methyl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2- e
Figure imgf000278_0003
The compound was synthesized using a procedure analogous to one use for synthesis of 72
(method II). 1 H NMR (400 MHz, MeOD) δ 9.00 - 8.85 (m, 1 H), 8.79 - 8.48 (m, 2H), 8.27 - 8.04
(m, 2H), 7.92 (d, J= 5.1 Hz, 3H), 7.78 - 7.65 (m, 1 H), 7.31 - 7.21 (m, 1 H), 3.57 (s, 3H), 3.08 - PAT054787-WO-PCT
2.96 (m, 1 H), 2.04 (s, 2H), 1 .93 - 1 .64 (m, 4H), 1 .64 - 1 .44 (m, 2H).ESI-MS m/z 466 [M+H]+. RT: 1 .90 min.
Synthesis of compound 413: N-(6-chloropvridin-3-vl)-N-methvl-3-[6-(trifluoromethvl)pyridin-3- yl]imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000279_0001
The compound was synthesized using I-57 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. 1H NMR (400 MHz, MeOD) δ 9.26 - 9.01 (m, 2H), 8.88 - 8.70 (m, 1 H), 8.45 (d, J= 8.1 Hz, 1 H), 8.25 (d, J= 1 1.4Hz, 2H), 8.07 (d, J = 8.2Hz, 1 H), 7.79 (s, 1 H), 7.45 (d, J = 8.5Hz, 1 H), 3.54 (s, 3H).ESI-MS m/z 433 [M+H]+. RT: 1 .45 min.
Synthesis of compound 414: N-[2-(4-fluorophenvl)propan-2-vl1-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2- e
Figure imgf000279_0002
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II). 1 H NMR (300 MHz, DMSO- /6) ppm 9.25 (d, J=1.47 Hz, 1 H) 8.90 (d, J=1.46 Hz, 1 H) 8.60 (s, 1 H) 8.28 (s, 1 H) 7.91 - 8.05 (m, 4 H) 7.40 - 7.50 (m, 2 H) 7.03 - 7.16 (m, 2 H) 1.74 (s, 6 H) ; MS (ESI) for C23 H18F4N40 : 443 (M + H+).
Synthesis of compound 415: methyl N-(5-{6-[methyl(5-methylpyridin-2- yl)carbamoyl]imidazo[1 ,2-a]pyrazin- -yl}pyridin-2-yl)carbamate
Figure imgf000279_0003
PAT054787-WO-PCT
The compound was synthesized using 1-78 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z =418.2(M+1 ), r.t = 1 .01 mins.
Synthesis of compound 416: N-methyl-N-{[1.2.41triazolo[4.3-alpvridin-5-vl)-3-[4- (trifluorometh l)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000280_0001
Oxalyl chloride (0.123 mg, 0.97 mmol) was added drop wise to a solution of 3-(4- (trifluoromethyl)phenyl)imidazo[1 ,2-a]pyrazine-6-carboxylic acid (30 mg, 0.097 mmol), DMF (1 drop) and dry dichloromethane (3 mL) at room temperature (gas evolution). After 30 minutes at room temperature, the solvent was removed in vacuo. The crude acid chloride was dissolved in dry dichloromethane (5 mL) and a solution of W-methyl-[1 ,2,4]triazolo[4,3-a]pyridin-5-amine I-28 (41 mg, 0.279 mmol in 2.0 mL of dichloromethane) was added drop wise at room temperature. Triethylamine (28 mg, 0.279 mmol) was added and the reaction stirred at room temperature for 3 hours. The solvent was removed in vacuo and the crude material was purified by reverse phase HPLC to yield the desired product. The product was characterized by reverse phase HPLC using method B. (ES, m/z): [M + H+] 438.1 . Retention time = 1 .43 mins.
Synthesis of compound 417: 4-tert-butyl-N-methyl-N-{3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2- a]pyrazin-6-yl}benzamide
Figure imgf000280_0002
1 H N R (400 MHz, CDCI3) δ 9.1 1 (d, J = 1 .3, 1 H), 7.88 (s, 1 H), 7.71 (s, 1 H), 7.63 (d, J = 8.2, 2H), 7.41 - 7.30 (m, 4H), 7.01 (d, J = 7.9, 2H), 3.58 (s, 3H), 1 .24 (s, 9H). HRMS calcd for C25H24F3N4O [M + H] + 453.18; found 453.2. PAT054787-WO-PCT
Synthesis of compound 418: N-(6-chloropvridin-3-vl)-3-[3-(dimethvlamino)phenvl1-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000281_0001
The compound was synthesized using I-57 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. 1H NMR (400 MHz, MeOD) δ 8.99 (s, 1 H), 8.88 - 8.62 (m, 2H), 8.25 (s, 1 H), 8.05 (s, 1 H), 7.77 (s, 1 H), 7.56 (s, 1 H), 7.44 (d, J = 8.5Hz, 1 H), 7.23 (d, J = 22.3Hz, 2H), 3.54 (s, 6H), 3.15 (s, 3H).ESI-MS m/z 407 [M+H]+. RT: 1 .10 min.
Synthesis of compound 419: N-(6-chloropvridin-3-vl)-3-(4-methanesulfonamidophenvl)-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000281_0002
The compound was synthesized using I-57 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z = 457.1 (M+1 ), r.t = 1 .23 mins.
Synthesis of compound 420: N-methyl-N-(2-methylpvridin-3-vl)-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000281_0003
412.2(M+1 ), r.t = 1 .37 mins.
Synthesis of compound 421 : N-methyl-N-(5-methvlpyrimidin-2-vl)-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000282_0001
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II). M/Z = 435(M+1 ), r.t = 1 .76 mins.
Synthesis of compound 422: N-(6-chloropvridin-3-vl)-3-(4-fluorophenvl)-N-methylimidazo[1 ,2- a]pyrazine-6-carboxamide
Figure imgf000282_0002
The compound was synthesized using I-57 and an appropriate boronic acid/ester using procedure similar Suzuki coupling protocol described in 228. M/Z = 382.0(M+1 ), r.t = 1 .
Synthesis of compound 423: N-methyl-N-(4-phenyl-1 ,3-thiazol-2-yl)-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2- e
Figure imgf000282_0003
The compound was synthesized using I-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. 1H NMR (400 MHz, CDCI3): δ 9.2 (s, 1 H), 8.99 (s, 1 H), 8.06 (s, 1 H), 7.94 (d, J = 7.47 Hz, 2H), 7.76-7.84 (m, 4H), 7.43 (m, 2H), 7.26-7.29 (m, 2H), 4.06 (s, 3H).LC-MS: 99.2%; 480.03 (M+H).
Synthesis of compound 424: cyanophenyl)-N-methvl-3-(3-methyl-1 H-indazol-5-yl)imidazo[1 ,2- a]pyrazine-6-carboxamide
Figure imgf000282_0004
PAT054787-WO-PCT
The compound was synthesized using 1-59 and 1-29 using a procedure similar Suzuki coupling protocol described in 228. M/Z =408.1 (M+1 ), r.t = 1.26 mins.
Synthesis of compound 425: N-(4-acetylphenyl)-N-methyl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2- e
Figure imgf000283_0001
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II). M/Z =439.1 (M+1 ), r.t = 1 .61 mins.
Synthesis of compound 426: 1 -({3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6- yl}methyl)piperidin-2-one
Figure imgf000283_0002
The compound was synthesized using a protocol described for the synthesis of 1-15. 1 H NMR (400 MHz, CD3OD): δ 9.06 (s, 1 H), 8.57(s, 1 H), 8.07 (s, 1 H), 7.89-7.94 (m, 4H), 4.67 (s, 2H), 3.55 (t, J = 5.71 Hz, 2H), 2.37 (t, J = 5.71 Hz, 2H), 1.81 -1.82 (m, 4H).LC-MS: 97.99%; 375.23
(M+H).
Synthesis of compound 427: N-(4-cvanophenvl)-3-[4-(dimethvlcarbamovQph
methylimidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000283_0003
The compound was synthesized using I-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z =425.1 (M+1 ), r.t = 1 .33 mins. PAT054787-WO-PCT
Synthesis of compound 428: N-(4-cvanophenvl)-3-(1 H-indol-5-yl)-N-methylimidazo[1 ,2- a]pyrazine-6-carboxamide
Figure imgf000284_0001
The compound was synthesized using I-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z =393.2(M+1 ), r.t = 1 .76 mins.
Synthesis of compound 429: N-(6-chloropyridin-3-yl)-3-[4-(difluoromethoxy)phenyl1-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000284_0002
The compound was synthesized using I-57 and an appropriate boronic acid/ester using < procedure similar Suzuki coupling protocol described in 228. MS m/z 430.1 (M+H)+; r.t.
Synthesis of compound 430: N-(4-fluoro-2-methoxyphenvl)-N-methvl-3-[4
(trifluoromethyl)phenyl]imidazo[1 ,2-
Figure imgf000284_0003
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II). MS m/z 445.1 (M+H)+; r.t. = 1.736.
Synthesis of compound 431 : N-(3,4-difluorophenyl)-3-(4-methoxyphenyl)-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000285_0001
The compound was synthesized using 1-65 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. MS m/z 395.2 (M+H)+; r.t. = 1 .990.
Synthesis of compound 432: N-(4-chlorophenvl)-N-methvl-3-(4-methylphenvl)imidazo[1 .2- a]pyrazine-6-carboxamide
Figure imgf000285_0002
The compound was synthesized using 1-11 and an appropriate boronic acid/ester using < procedure similar Suzuki coupling protocol described in 228. MS m/z 377.2 (M+H)+; r.t.
Synthesis of compound 433: 3-[4-(difluoromethoxv)phenvl1-N-(4-fluorophenvl)-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000285_0003
The compound was synthesized using I-64 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. 1H NMR (400 MHz, DMSO) δ 8.82 (s, 1 H), 8.72 (s, 1 H), 8.09 (s, 1 H), 7.75 (d, J = 8.7, 2H), 7.42 (d, J = 8.6, 2H), 7.39 (t, J = 76, 1 H), 7.31 (s, 2H), 7.12 (t, J = 8.6, 2H), 3.40 (s, 3H); MS m/z 413.1 (M+H)+; r.t. = 1 .050.
Synthesis of compound 434: N-(5-bromopvhmidin-2-vl)-N-methyl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000286_0001
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II). MS m/z 477.0 (M+H)+; r.t. = 2.310.
Synthesis of compound 435: N-(5-chloropyridin-2-vl)-N-methvl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2- e
Figure imgf000286_0002
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II) using I-36. MS m/z 432.1 (M+H)+; r.t. = 2.200.
Synthesis of compound 436: N-methyl-N-[4-(propan-2-yloxy)phenyl1-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2- e
Figure imgf000286_0003
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II). MS m/z 455.1 (M+H)+; r.t. = 2.270.
Synthesis of compound 437: 4-[((3-[4-(dimethvlamino)phenvl1imidazo[1 ,2-a1pyrazin-6- yl}methyl)(methyl)amino]benzonitril
Figure imgf000286_0004
PAT054787-WO-PCT
The compound was synthesized using 1-15 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. MS m/z 383.1 (M+H)+; r.t. = 1 .447.
Synthesis of compound 438: N-(4-cyanophenyl)-3-[3-(dimethylamino)phenyl1-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000287_0001
The compound was synthesized using I-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z =397.1 (M+1 ), r.t = 1 .27 mins.
Synthesis of compound 439: 3-(6-chloropvridin-3-vl)-N-(4-cvanophenvl)-N-methvlimidazo[112- a]pyrazine-6-carboxamide
Figure imgf000287_0002
The compound was synthesized using 1-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z =389.1 (M+1 ), r.t = 1 .73 mins.
Synthesis of compound 440: N-(3-methoxvphenvl)-N-methvl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2- e
Figure imgf000287_0003
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II). MS m/z 427.1 (M+H)+; r.t. = 1.692.
Synthesis of compound 441 : N-(4-cyanophenyl)-3-(4-methoxv-2-methylphenyl)-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000288_0001
The compound was synthesized using 1-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z =398.2(M+1 ), r.t = 1 .94 mins.
Synthesis of compound 442: N-(7-chloro-1 ,3-benzothiazol-2-yl)-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2- e
Figure imgf000288_0002
The compound was synthesized using I-72 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. 1H NMR (300 MHz, DMSO-c/6) ppm 7.41 (d, J=9.38 Hz, 1 H), 7.69 (d, J=8.50 Hz, 1 H), 8.05 (q, J=8.40 Hz, 5 H), 8.31 (s, 1 H), 9.29 (s, 3 H). ESI-MS m/z 474 [M+H]+.
Synthesis of compound 443: 4-fluoro-N-methvl-N-(3-{4-[5-(methylamino)-1 ,3,4-thiadiazol-2- yl]phenyl}imidazo[1 ,2-a]pyrazin-6-yl)benzamide
Figure imgf000288_0003
1 H NMR (400 MHz, MeOD) δ 8.95 (s, 1 H), 8.14 (s, 1 H), 7.92 (s, 1 H), 7.82 (d, J = 8.3, 2H), 7.35 (dd, J = 5.3, 8.7, 2H), 7.26 (d, J = 8.3, 2H), 6.99 (t, J = 8.7, 2H), 3.46 (s, 3H), 3.03 (s, 3H). HRMS calcd for C23H17FN7OS [M + H] + 460.13; found 460.1.
Synthesis of compound 444: 3-{6-[(6-fluoro-1 ,2,3,4-tetrahydroquinolin-1 - yl)carbonyl]imidazo[1 ,2-a]pyrazin-3-yl}-N,N-dimethylaniline
Figure imgf000289_0001
The compound was synthesized using 1-72 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. LCMS: Rt = 1.20 min, ES+-MS m/z 416 [ +H]+.
Synthesis of compound 445: N^-bis -ftrifluoromethyDphenyllimidazofl ^-alpyrazine-B- carboxamide
Figure imgf000289_0002
DCM/Et3N, r.t.
I-7 445
N,3-bis(4-(trifluoromethyl)phenyl)imidazo[1 ,2-a]pyrazine-6-carboxamide was prepared according to the procedure described for the synthesis of N-(4-cyanophenyl)-N-methyl-3-(4- (trifluoromethyl)phenyl)imidazo[1 ,2-a]pyrazine-6-carboxamide by substituting 4- trifluoromethylaniline for 4-cyano-N-methyl aniline. LC/MS m/z 451 .1 (M+H)+; r.t. = 2.650
Synthesis of compound 446: N-(4-cvanophenyl)-N-methyl-3-l4-[5-(methvlamino)-1 ,3,4- oxadiazol-2-yl]phenyl}imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000289_0003
To a solution of 3-bromo-N-(4-cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide (125 mg, 0.351 mmols, 1 eq) I-59 in THF/water (4:1 ) 12 mL was added N-methyl-5-(4-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)-1 ,3,4-oxadiazol-2-amine I-60 (158 mg, 0.526mmol, 1.5eq) followed by Pd-DPP (10 mol%) and K2HP04 (152 mg, 0.88 mmol, 2.5 eq). The reaction mixture was heated at 150 °C for 1 hr. The reaction was quenched with sodium carbonate solution and the reaction mixture was extracted with ethyl acetate (3 x 15 mL). The organics were combined and dried over sodium sulfate and were using flash column chromatography. PAT054787-WO-PCT
The reaction yielded 12 mg of the desired compound. 1H NMR (400 MHz, MeOD) δ 8.98 - 8.87 (m, 1 H), 8.78 - 8.70 (m, 1 H), 8.1 1 (s, 2H), 7.91 - 7.74 (m, 2H), 7.67 (s, 2H), 7.62 - 7.55 (m, 1 H), 7.47 - 7.38 (m, 2H), 3.56 (s, 3H), 2.67 (s, 3H).ESI-MS m/z 451 [M+H]+. RT: 1 .50 min.
Synthesis of compound 447: 4-{6-[(7-fluoro-313-dimethyl-3,4-dihvdro-2H-1 14-benzoxazin-4- yl)carbonyl]imidazo[1 ,2-a]pyrazin-3-yl}benzamide
Figure imgf000290_0001
The compound was synthesized using 1-71 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. 1H NMR (400 MHz, CDCI3): δ 8.88 (s, 2H), 7.99-8.02 (m, 3H), 7.66 (d, J = 7.9 Hz, 2H), 6.67-6.7 (m, 1 H), 6.27-6.36 (m, 2H), 4.09 (s, 2H), 1 .59 (s, 6H).LC-MS: 97.98%; 446 (M+H).
Synthesis of compound 448: 4-(6-[(6-fluoro-1 ,2,3,4-tetrahydroquinolin-1 - yl)carbonyl]imidazo[1 ,2-a]pyrazin-3-yl}benzamide
Figure imgf000290_0002
The compound was synthesized using I-72 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. LCMS: Rt = 1.00 min, ES+-MS m/z 416 [M+H]+.
Synthesis of compound 449: N-(4-fluorophenvl)-N-methyl-3-[4-(1 ,3,4-thiadiazol-2- yl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000290_0003
PAT054787-WO-PCT
The compound was synthesized using 1-64 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. 1H NMR (400 MHz, MeOD) δ 9.59 - 9.50 (m, 1 H), 8.93 - 8.71 (m, 2H), 8.32 - 8.20 (m, 2H), 8.16 - 8.06 (m, 1 H), 7.87 - 7.73 (m, 2H), 7.38 - 7.22 (m, 2H), 7.15 - 6.98 (m, 2H), 3.51 (s, 3H).ESI-MS m/z 431 [M+1 ]. RT: 1 .65 min.
Synthesis of compound 450: 4-{6-[(6-fluoro-1 ,2,3,4-tetrahydroquinolin-1 - yl)carbonyl]imidazo[1 ,2-a]pyrazin-3-yl}-N-methylbenzamide
Figure imgf000291_0001
The compound was synthesized using I-72 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. LCMS: Rt = 1.06 min, ES+-MS m/z 430 [M+H]+.
Synthesis of compound 451 : N-(4-|6-[(7-fluoro-3,3-dimethyl-3,4-dihvdro-2H-1 ,4-benzoxazin-4- yl)carbonyl]imidazo[1 ,2-a]pyrazin-3-yl}phenyl)acetamide
Figure imgf000291_0002
The compound was synthesized using 1-71 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. 1H NMR (400 MHz, in CDCI3): δ 8.84 (d, J = 3.5 Hz, 2H), 7.89 (s, 1 H), 7.72 (d, J = 8.3 Hz, 2H), 7.5 (d, J = 8.3 Hz, 2H), 7.29 (s, 1 H), 6.62-6.69 (m, 1 H), 6.25-6.37 (m, 2H), 4.08 (s, 2H), 2.25 (s, 3H), 1 .54-1.58 (m, 6H).LC-MS: 98.7%; 460 (M+H).
Synthesis of compound 452: N-methvl-4-(6-[N-methyl(4-fluorobenzene)amido1imidazo[1 ,2- a]pyrazin-3-yl}benzamide
Figure imgf000292_0001
1 H NMR (400 MHz, MeOD) δ 8.98 (s, 1 H), 8.24 (s, 1 H), 7.98 (s, 1 H), 7.86 (d, J = 8.4, 2H), 7.36 (dd, J = 5.3, 8.8, 2H), 7.26 (d, J = 8.4, 2H), 7.02 (t, J = 8.7, 2H), 3.60 - 3.35 (m, 3H), 2.88 (s, 3H).HRMS calcd for C22H19FN502 [M + H] + 404.14; found 404.1 .
Synthesis of compound 453: N-methyl-N-(4-sulfamovlphenyl)-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000292_0002
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II). 1 H NMR (400 MHz, MeOD) δ 8.80 (d, J= 10.6Hz, 2H), 8.10 (s, 1 H), 7.93 (d, J = 8.3Hz, 2H), 7.82 (dd, J= 8.4Hz, 17.6Hz, 4H), 7.42 (d, J= 8.6Hz, 2H), 3.56 (s, 3H). ESI-MS m/z 476 [M+1 ]. RT: 1 .74 min.
Synthesis of compound 454: 4-{6-[(7-fluoro-3,4-dihvdro-2H-1 .4-benzoxazin-4- yl)carbonyl]imidazo[1 ,2-a]pyrazin-3-yl}benzamide
Figure imgf000292_0003
The compound was synthesized using I-74 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. 1H NMR (400 MHz, DMSO-d6 at 90 <C): 9.07 (s, 1 H), 8.88 (s, 1 H), 8.17 (s, 1 H), 8.06 (d, J= 8.4 Hz, 2H), 7.81 (d, J = 8.3 Hz, 2H), 7.57-7.60 (m, 2H), 6.72-6.75 (m, 1 H), 6.60-6.64 (m, 1 H), 4.32-4.34 (t, J= 4.6 Hz, 2H), 3.97- 3.99 (t, J = 4.4 Hz, 2H).LC-MS: 97.7%, 418.14 (M+H). PAT054787-WO-PCT
Synthesis of compound 455: 4-{6-[N-methvl(4-fluorobenzene)amido1imidazo[1 ,2-alpyrazin-3- yljbenzamide
Figure imgf000293_0001
The compound was synthesized using a procedure similar to synthesis of 24. 1 H NMR (400 MHz, MeOD) δ 9.03 (s, 1 H), 8.31 (s, 1 H), 8.05 (s, 1 H), 7.93 (d, J = 8.4, 2H), 7.36 (dd, J = 6.7, 10.1 , 2H), 7.27 (d, J = 8.3, 2H), 7.02 (t, J = 8.8, 2H), 3.47 (s, 3H). HRMS calcd for C21 H17FN502 [M + H] + 390.13; found 390.1.
Synthesis of compound 456: -fluoro-N-methvl-N-(3-l1 H-pyrrolo[2.3-blpvridin-5-vl)imidazo[1 ,2- a]pyrazin-6-yl)benzamide
Figure imgf000293_0002
The compound was synthesized using a procedure similar to synthesis of 24. MS m/z 387.0 (M+H)+; r.t. = 1 .488.
Synthesis of compound 457: 1 -{[3-(2,3-dihydro-1 -benzofuran-5-yl)imidazo[1 ,2-a]pyrazin-6- yl]carbonyl}-6-fluoro-1 ,2,3,4-tetrahydroq
Figure imgf000293_0003
The compound was synthesized using I-72 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. LCMS: R, = 1.37 min, ES+-MS m/z 415 [M+H]+.
Synthesis of compound 458: 3-(4-carbamoylphenyl)-N-methyl-N-(5-methylpyridin-2- yl)imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000294_0001
The compound was synthesized using 1-78 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. 1H NMR (400 MHz, METHANOL- ck) ppm 2.31 (s, 3 H) 3.55 (s, 3 H) 7.22 (d, J=8.28 Hz, 1 H) 7.63 (dd, J=7.78, 2.01 Hz, 1 H) 7.78 (d, J=0.10 Hz, 2 H) 8.06 (s, 1 H) 8.10 - 8.14 (m, 3 H) 8.66 (d, J=1.25 Hz, 1 H) 8.86 (d, J=1 .26 Hz, 1 H); MS (ESI) for C21 H18N602: 387 (M + H)+.
Synthesis of compound 459: 4-{6-[(7-fluoro-3,4-dihydro-2H-1 ,4-benzoxazin-4- yl)carbonyl]imidazo[1 ,2-a]pyrazin-3- -N-methylbenzamide
Figure imgf000294_0002
The compound was synthesized using I-74 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. 1H NMR (400 MHz, METHANOL- d4) ppm 9.05 (s, 1 H) 8.98 (d, J=1.00 Hz, 1 H) 8.13 (s, 1 H) 8.04 (d, J=8.00 Hz, 2 H) 7.83 (d, J=7.80 Hz, 2 H) 6.69 (dd, J=9.91 , 2.89 Hz, 1 H) 6.57 (br. s., 1 H) 4.38 (br. s., 2 H) 4.03 - 4.13 (m, 2 H) 2.96 (s, 3 H); MS (ESI) for C23H18FN503: 432 (M + H+).
Synthesis of compound 460: 6-fluoro-1 -|[3-(3-methanesulfonvlphenyl)imidazo[1 ,2-a1pvrazin-6- yl]carbonyl}-1 ,2,3,4-tetrahydroquinoline
Figure imgf000294_0003
The compound was synthesized using I-72 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. LCMS: R, = 1.19 min, ES+-MS m/z 451 [M+H]+. PAT054787-WO-PCT
Synthesis of compound 461 : 3-[6-(4-acetvlpiperazin-1 -vnpvridin-3-vl1-N-(4-cvanophenvl)-N- methylimidazo[1 ,2-a]pyrazine-6-car
Figure imgf000295_0001
The compound was synthesized using I-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. LCMS: Rt = 0.81 min, ES+-MS m/z 481 [ +H]+.
Synthesis of compound 462: 6-fluoro-1 -|[3-(4-methanesulfonylphenyl)imidazo[1 12-alpyrazin-6- yl]carbonyl}-1 ,2,3,4-tetrahydroquinoline
Figure imgf000295_0002
The compound was synthesized using I-72 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. LCMS: R, = 1.19 min, ES+-MS m/z 451 [M+H]+.
Synthesis of compound 463: 1 -{[3-(1 -ethyl-1 H-pyrazol-4-yl)imidazo[1 ,2-a]pyrazin-6- yl]carbonyl}-6-fluoro-1 ,2,3,4-tetrahydroq
Figure imgf000295_0003
The compound was synthesized using I-72 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. LCMS: Rt = 1.14 min, ES+-MS m/z 391 [M+H]+. PAT054787-WO-PCT
Synthesis of compound 464: N-(4-cvanophenvl)-N-methvl-3-[6-(piperazin-1 -vl)pyridin-3- yl]imidazo[1 ,2-a]pyrazine-6-carboxamide
The compound was synthesized using I-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. LCMS: R, = 0.76 min, ES+-MS m/z 439 Da [M+H]+.
Synthesis of compound 465: N-(4-cvanophenvl)-3-(furan-2-vl)-N-methylimidazo[1 ,2- a]pyrazine-6-carboxamide
Figure imgf000296_0002
The compound was synthesized using I-72 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. LCMS: Rt = 0.86 min, ES+-MS m/z 472 Da [M+H]+.
Synthesis of compound 466: N-(4-cvanophenyl)-3-(furan-2-vl)-N-methylimidazo[1 ,2- a]pyrazine-6-carboxamide
Figure imgf000296_0003
The compound was synthesized using 1-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. LCMS: R, = 1.12 min, ES+-MS m/z 344 Da [M+H]+.
Synthesis of compound 467: 6-f luoro-1 -({3-[2-(piperazin-1 -yl)pyridin-4-yl]imidazo[1 ,2- a]pyrazin-6-yl}carbonyl)-1 ,2,3,4-tetrahydroquinoline
Figure imgf000297_0001
The compound was synthesized using 1-72 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. LCMS: Rt = 0.83 min, ES+-MS m/z 458 Da [M+H]+.
Synthesis of compound 468: N-(4-chlorophenvl)-N-methvl-3-[4-(1 ,3,4-thiadiazol-2- yl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000297_0002
The compound was synthesized using intermediates 1-11 and 1-61 with a Suzuki coupling protocol described in 228. 1 H NMR (400 MHz, MeOD) δ 9.54 (s, 1 H), 8.89 - 8.74 (m, 2H), 8.33 - 8.19 (m, 2H), 8.1 1 (s, 1 H), 7.85 - 7.72 (m, 2H), 7.43 - 7.17 (m, 4H), 3.52 (s, 3H). ESI-MS m/z 447 [M+1 ]. RT: 1 .75 min.
Synthesis of compound 469: N-methvl-3-[4-(methvlcarbamovl)phenvl1-N-(5-methylpvridin-2- yl)imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000297_0003
The compound was synthesized using I-78 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. 1H NMR (400 MHz, METHANOL- d4) ppm 8.86 (d, J=1.26 Hz, 1 H) 8.66 (d, J=1 .25 Hz, 1 H) 8.10 (s, 1 H) 8.04 - 8.07 (m, 3 H) 7.78 (d, J=8.28 Hz, 2 H) 7.63 (dd, J=8.16, 2.38 Hz, 1 H) 7.22 (d, J=8.53 Hz, 1 H) 3.55 (s, 3 H) 2.98 (s, 3 H) 2.31 (s, 3 H); MS (ESI) for C22H20N6O2 : 401 (M + H+). PAT054787-WO-PCT
Synthesis of compound 470: N-cvclohexvl-4-{6-[(6-fluoro-1 ,2,3,4-tetrahvdroguinolin-1 - yl)carbonyl]imidazo[1 ,2-a]pyrazin-3-yl}benzamide
Figure imgf000298_0001
The compound was synthesized using I-72 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. LCMS: R, = 1.43 min, ES+-MS m/z 498 Da [M+H]+.
Synthesis of compound 471 : 4-fluoro-N-methvl-N-[3-(1 -methyl-1 H-indazol-5-yl)imidazo[1 ,2- a]pyrazin-6-yl]benzamide
Figure imgf000298_0002
The compound was synthesized using similar to syntheisis of 24. 1 H NMR (400 MHz, MeOD) δ 8.99 (s, 1 H), 8.20 (s, 1 H), 8.01 (s, 1 H), 7.95 (s, 1 H), 7.61 (d, J = 8.6, 2H), 7.36 - 7.29 (m, 2H), 7.13 (d, J = 10.2, 1 H), 7.02 (dd, J = 7.8, 9.7, 2H), 4.04 (s, 3H), 3.42 (d, J = 17.2, 3H). HRMS calcd for C22H18FN60 [M + H] + 401 .14; found 401.1 .
Synthesis of compound 472: 1 -[4-(5-{6-[(6-fluoro-1 ,2,3,4-tetrahydroquinolin-1 - yl)carbonyl]imidazo[1 ,2-a]pyrazin-3-yl}pyridin-2-yl)piperazin-1 -yl]ethan-1 -one.
Figure imgf000298_0003
The compound was synthesized using I-72 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. LCMS: R, = 0.94 min, ES+-MS m/z 500 Da [M+H]+. PAT054787-WO-PCT
Synthesis of compound 473: 6-fluoro-1 -((3-[3-(morpholin-4-vlmethvl)phenvl1imidazo[1 ,2- a]pyrazin-6-yl}carbonyl)-1 ,2,3,4-tetrahydroquinoline
Figure imgf000299_0001
The compound was synthesized using I-72 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. LCMS: Rt = 0.93 min, ES+-MS m/z 472 Da [M+H]+.
Synthesis of compound 474: N-(5-methvlpvridin-2-vl)-3-[4-(trifluoromethvl)phenvl1imidazo[1 .2- a]pyrazine-6-carbox
Figure imgf000299_0002
The compound was synthesized using a procedure analogous to one use for synthesis of 78 (method II). 1 H NMR (300 MHz, DMSO- /6) ppm 10.26 (s, 1 H) 9.32 (d, J=1 .17 Hz, 1 H) 9.13 (d, J=1.17 Hz, 1 H) 8.34 (s, 1 H) 8.24 (s, 1 H) 8.16 (d, J=8.20 Hz, 1 H) 7.97 - 8.10 (m, 4 H) 7.71 - 7.78 (m, 1 H) 2.29 (s, 3 H) ; MS (ESI) for
Figure imgf000299_0003
398 (M + H)+.
Synthesis of compound 475: N-(4-ethylpyridin-2-vl)-N-methvl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000299_0004
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II). 1 H NMR (300 MHz, DMSO-cfe) ppm 9.46 (d, J=1.46 Hz, 1 H) 9.19 (d, J=1.17 Hz, 1 H) 8.17 - 8.27 (m, 2 H) 7.94 - 8.14 (m, 5 H) 6.73 (dd, J=6.74, 2.05 Hz, 1 H) 3.82 (s, 3 H) 2.62 (q, J=7.33 Hz, 2 H) 1 .1 1 - 1 .26 (m, 3 H) ; MS (ESI) for C22H18F3N50 : 426 (M + H+). PAT054787-WO-PCT
Synthesis of compound 476: N-(4-cvanophenvl)-N-methvl-3-l4-[5-(methvlamino)-1 ,3,4- thiadiazol-2-yl]phenyl}imidazo[1 ,2-
Figure imgf000300_0001
The compound was synthesized using I-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. 1 H NMR (400 MHz, DMSO) δ 8.91 (d, J = 1 .4 Hz, 1 H), 8.82 (d, J = 1.3 Hz, 1 H), 8.21 (s, 1 H), 8.09 - 7.94 (m, 3H), 7.90 - 7.80 (m, 2H), 7.80 - 7.71 (m, 2H), 7.55 - 7.38 (m, 2H), 3.48 (s, 3H), 2.97 (d, J= 4.8 Hz, 3H). MS m/z 467.1 (M+H)+; r.t. = 1 .287.
Synthesis of compound 477: 4-(6-{[(4-chlorophenyl)(methyl)amino]methyl}imidazo[1 ,2- a]pyrazin-3-yl)benzamide
Figure imgf000300_0002
The compound was synthesized using I-63 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. 1H NMR (400 MHz, DMSO) δ 9.13 (d, J = 1 .3, 1 H), 8.52 (s, 1 H), 8.12 (s, 2H), 8.05 (d, J = 8.4, 2H), 7.74 (d, J = 8.4, 2H), 7.51 (s, 1 H), 7.16 (d, J = 9.1 , 2H), 6.84 (d, J = 9.1 , 2H), 4.68 (s, 2H), 3.06 (s, 3H); MS m/z 392.1 (M+H)+; r.t. = 1 .459.
Synthesis of compound 478: N-(4-fluorophenvl)-N-methvl-3-f4-[5-(methylamino)-11314- oxadiazol-2-yl]phenyl}imidazo[1 ,2-a]pyrazine-6-carboxamide;
Figure imgf000300_0003
PAT054787-WO-PCT
The compound was synthesized using 1-64 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. 1H NMR (400 MHz, MeOD) δ 8.93 - 8.57 (m, 3H), 8.18 - 8.00 (m, 2H), 7.84 - 7.63 (m, 2H), 7.39 - 7.17 (m, 2H), 7.16 - 6.95 (m, 2H), 3.51 (s, 3H), 3.03 (s, 3H). ESI-MS m/z 444 [M+1]. RT: 1 .54 min.
Synthesis of compound 479: 4-[(|3-[4-(difluoromethoxy)phenyl1imidazo[1 ,2-alpyrazin-6- yl}methyl)(methyl)amino]benzonitrile
Figure imgf000301_0001
The compound was synthesized using 1-15 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. 1 H NMR (400 MHz, DMSO) δ 9.1 1 (d, J = 1 .3 Hz, 1 H), 8.59 (d, J = 1 .0 Hz, 1 H), 8.04 (s, 1 H), 7.91 - 7.67 (m, 2H), 7.65 - 7.46 (m, 2H), 7.44 - 7.31 (m, 2H), 6.96 (dd, J = 5.0, 6.9, 2H), 4.78 (s, 2H), 3.15 (s, 3H). M/Z
=406.1 (M+1 ), r.t = 1 .61 mins.
Synthesis of compound 480: N-(4-chlorophenyl)-N-methyl-3-(1 -methyl-1 H-indazol-5- yl)imidazo[1 ,2-a]pyrazine-6-carboxamide;
Figure imgf000301_0002
The compound was synthesized using 1-11 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. MS m/z 417.1 (M+H)+; r.t. = 1 .541 .
Synthesis of compound 481 : N-(4-cvanophenvl)-N-methvl-3-[4-(1 H-pyrazol-5- yl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000301_0003
PAT054787-WO-PCT
The compound was synthesized using 1-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. 1 H NMR (400 MHz, DMSO) δ 8.89 (d, J = 1 .4 Hz, 1 H), 8.81 (d, J = 1.2 Hz, 1 H), 8.17 (s, 1 H), 8.06 (s, 2H), 7.81 - 7.73 (m, 5H), 7.54 - 7.43 (m, 2H), 6.87 (d, J = 2.2 Hz, 1 H), 3.45 (s, 3H). M/Z =420.2(M+1 ), r.t = 1 .34 mins.
Synthesis of compound 482: methyl N-(4-{6-[(4-cyanophenyl)(methyl)carbamoyl]imidazo[1 ,2- a]pyrazin-3-yl}phenyl)carbamate
Figure imgf000302_0001
The compound was synthesized using I-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z = 427.2(M+1 ), r.t = 1 .43 mins.
Synthesis of compound 483: N-(4-chlorophenyl)-N-methyl-3-|4-[5-(methylamino)-1 ,3,4- oxadiazol-2-yl]phenyl}imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000302_0002
The compound was synthesized using 1-1 1 and I-60 using a procedure similar Suzuki coupling protocol described in 228. 1 H NMR (400 MHz, CD2CI2) δ 8.76 (s, 2H), 8.22 - 8.07 (m, 2H), 7.97 (s, 1 H), 7.67 (d, J= 8.4Hz, 2H), 7.30 (d, J= 8.6Hz, 2H), 7.14 (d, J= 8.3Hz, 2H), 3.51 (s, 3H), 3.14 (d, J= 5.2Hz, 3H). ESI-MS m/z 460 [M+H]+. RT: 1.55 min.
Synthesis of compound 484: N-(4-cyanophenyl)-N-methyl-3-[4-(1 H-pyrazol-3- yl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000302_0003
PAT054787-WO-PCT
The compound was synthesized using 1-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. 1H NMR (400 MHz, DMSO) δ 8.88 (d, J = 1 .3, 1 H), 8.80 (d, J = 1 .1 , 1 H), 8.17 (d, J = 9.1 , 1 H), 8.03 (dd, J = 7.8, 26.7, 2H), 7.92 - 7.53 (m, 5H), 7.51 - 7.41 (m, 2H), 6.86 (d, J = 1 .9, 1 H), 3.51 - 3.43 (m, 3H); MS m/z 420.1 (M+H)+; r.t. = 1 .327.
Synthesis of compound 485: N-(4-cvanophenvl)-3-(4-acetamidophenvl)-N-methylimidazo[1 ,2- a]pyrazine-6-carboxamide
Figure imgf000303_0001
The compound was synthesized using I-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. M/Z 41 1 [M+1 ]+. RT: 1.21 min.
Synthesis of compound 486: 3-(4-carbamovlphenvl)-N-(4-chlorophenyl)-N-methylimidazo[1 ,2- a]pyrazine-6-carboxamide
Figure imgf000303_0002
The compound was synthesized using 1-11 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. 1H NMR (400 MHz, DMSO) δ 8.86 (s, 1 H), 8.81 (d, J = 1.2, 1 H), 8.19 (s, 1 H), 8.16 (s, 1 H), 8.09 (d, J = 8.3, 2H), 7.78 (d, J = 8.3, 2H), 7.55 (s, 1 H), 7.33 (q, J = 8.8, 4H), 3.42 (s, 3H); MS m/z 406.0 (M+H)+; r.t. = 1 .319.
Synthesis of compound 487: N-(4-cyanophenyl)-N-methyl-3-(1 -methyl-1 H-indazol-5- yl)imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000303_0003
PAT054787-WO-PCT
The compound was synthesized using 1-59 and an appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. 1 H NMR (400 MHz, DMSO) δ 8.78 (d, J = 1 .4 Hz, 1 H), 8.72 (d, J = 1.3 Hz, 1 H), 8.15 (d, J = 0.9 Hz, 1 H), 8.06 (d, J - 1 .8 Hz, 2H), 7.84 (d, J = 8.8 Hz, 1 H), 7.74 - 7.68 (m, 2H), 7.64 (dd, J = 1 .6 Hz, 8.7 Hz, 1 H), 7.49 - 7.38 (m, 2H), 4.04 (s, 3H), 3.40 (s, 3H). M/Z -408.1 (M+1 ), r.t = 1 .58 mins.
Synthesis of compound 488: N-[3-(6-acetamidopyridin-3-yl)imidazo[1 ,2-alpyrazin-6-yl1-4- fluoro-N-methylbenzamide
Figure imgf000304_0001
The compound was synthesized using a procedure similar to synthesis of 24. MS m/z 405.1 (M+H)+; r.t. = 1 .437.
Synthesis of compound 489: N-(6-chloropyridin-3-yl)-N-methvl-3-(1 -methyl-1 H-indazol-5- yl)imidazo[1 ,2-a]pyrazine-6-carboxa
Figure imgf000304_0002
The compound was synthesized using I-57 and appropriate boronic acid/ester using a procedure similar Suzuki coupling protocol described in 228. MS m/z 418.1 (M+H)+; r.t.
Synthesis of compound 490: N-(4-fluoropyridin-2-vl)-N-methvl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2- e
Figure imgf000304_0003
The compound was synthesized using 1-40 following a procedure analogous to one use for synthesis of 72 (method II). MS m/z 416.1 (M+H)+; r.t. = 1 .638. PAT054787-WO-PCT
Synthesis of compound 491 : N-methyl-N-(5-methylpyridin-2-'
(trifluoromethyl)phenyl]imidazo[1 ,2- e
Figure imgf000305_0001
The compound was synthesized using a procedure analogous to one use for synthesis of 78 (method II). 1 H NMR (400 MHz, CDCI3) δ 8.85 (d, J = 1 .4, 1 H), 8.66 (d, J = 1.3, 1 H), 8.04 (d, J = 2.2, 1 H), 7.92 (s, 1 H), 7.81 (d, J = 8.2, 2H), 7.70 (d, J = 8.1 , 2H), 7.45 (dd, J = 2.1 , 8.1 , 1 H), 7.04 (d, J = 8.1 , 1 H), 3.56 (s, 3H), 2.28 (s, 3H); MS m/z 412.2 (M+H)+; r.t. = 1 .456.
Synthesis of compound 492: N-(2-methoxvpvridin-3-vD-N-methvl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000305_0002
The compound was synthesized using I-46 following a procedure analogous to one use for synthesis of 72 (method II). MS m/z 428.1 (M+H)+; r.t. = 1 .616.
Synthesis of compound 493: N-(4-cvanophenyl)-N-methvl-3-[4-(1 ,3,4-thiadiazol-2- yl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000305_0003
The compound was synthesized using I-59 and I-60 using a procedure similar Suzuki coupling protocol described in 228. 1 H NMR (400 MHz, MeOD) δ 9.62 - 9.46 (m, 2H), 8.37 - 8.23 (m, 2H), 8.22 - 8.06 (m, 2H), 7.97 - 7.83 (m, 2H), 7.76 - 7.62 (m, 2H), 7.50 - 7.39 (m, 2H), 3.57 (s, 3H). ESI-MS m/z 438 [M+H]+. RT: 1 .65 min. PAT054787-WO-PCT Synthesis of compound 494: n.1-dioxido-2H-benzorb1f1.41thiazin-4(3H)-yl)(3-(4-
(trifluoromethyl)phenyl)imidazori ,2-alpyrazin-6-yl)methanone
Figure imgf000306_0001
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II). MS m/z 473.1 (M+H)+; r.t. = 1.646.
Synthesis of compound 495: 4-{6-[N-methyl(4-cyanobenzene)amido]imidazo[1 ,2-a]pyrazin-3- yljbenzamide
Figure imgf000306_0002
The compound was synthesized using a procedure similar to synthesis of 24. MS m/z 473.1 (M+H)+; r.t. = 1 .646.
Synthesis of compound 496: N-(2-chloro-1 ,3-thiazol-5-ylVN-methyl-3-[4
(trifluoromethyl)phenyl]imidazo[1 ,2- e
Figure imgf000306_0003
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method III). MS m/z 438.0 (M+H)+; r.t. = 1 .779.
Synthesis of compound 497: 4-({3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6- yl}carbonyl)-1 ,2,3,4-tetrahydroquinoxalin-2-one
Figure imgf000306_0004
PAT054787-WO-PCT
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II). MS m/z 438.0 (M+H)+; r.t. - 1.548.
Synthesis of compound 498: N-methvl-N-|3-[4-(trifluoromethyl)phenvl1imidazo[1 ,2-a]pyrazin- 6-yl}pyrimidine-5-carboxamide
Figure imgf000307_0001
The compound was synthesized using a procedure similar to synthesis of 24. MS m/z 399.1 (M+H)+; r.t. = 1 .671 .
Synthesis of compound 499: N-methyl-N-(6-phenylpvridin-3-vl)-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000307_0002
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II) using I-53. MS m/z 474.1 (M+H)+; r.t. = 1 .749.
Synthesis of compound 500: N-methyl-N^-bis -itrifluoromethvDphenyllimidazofl ,2- a]pyrazine-6-carboxamide
Figure imgf000307_0003
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method III). MS m/z 465.1 (M+H)+; r.t. = 2.260.
Synthesis of compound 501 : N-(4-methanesulfonylphenvl)-N-methvl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide
Figure imgf000308_0001
The compound was synthesized using 1-64 and an appropriate boronic acid/ester using < procedure similar Suzuki coupling protocol described in 228. MS m/z 475.1 (M+H)+; r.t.
Synthesis of compound 502: N-(3-chloro-4-cvanophenvl)-N-methvl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2- e
Figure imgf000308_0002
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II). MS m/z 456.0 (M+H)+; r.t. = 2.150.
Synthesis of compound 503: N-(4-cvano-2-methoxvphenvD-N-methyl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2- e
Figure imgf000308_0003
The compound was synthesized using a procedure analogous to one use for synthesis of 72 (method II). MS m/z 452.1 (M+H)+; r.t. - 1.690.
It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference for all purposes.

Claims

PAT054787-WO-PCT CLAIMS WE CLAIM:
1. A compound of Formula I,
Figure imgf000309_0001
or a pharmaceutical acceptable salt, tautomer or stereoisomer thereof, wherein
n is 0, 1 or 2;
p is 0, 1 , 2 or 3;
Ring A is selected from the group consisting of C6-i0aryl, C5-i0heteroaryl and fused bicyclyls comprising a C5-6heterocycloalkyl fused to a phenyl;
Ring B represents the imidazo[1 ,2-a]pyrazine fused ring depicted in Formula 1 ;
Ring C is selected from the group consisting of phenyl, C5-ioheteroaryl, C5-6cycloalkyl, C5-6heterocycloalkyl, and fused bicyclyl comprising a C5-6heterocycloalkyl fused to a phenyl;
L is selected from the group consisting of *-CH2N(R2)-, *-C(0)-, *-C(0)N(R2)-, *-C(0)N(R2)C(R3a)(R3b)-, *-N(R2)C(R3a)(R3b)-, *-N(R2)C(0)-, *-N(R2)S02-, and Ci.6alkylene, wherein
* represents the point of attachment of L to Ring B;
R2 is selected from the group consisting of hydrogen, d-4alkyl and
R0-Ci-4alkylene, wherein R0 is selected from the group consisting of Ci-4alkyl, Ci- 4alkoxy, amino, Ci-4alkylamino, C5-6heteroaryl and C5-6heterocycloalkyl, wherein the C5.6heteroaryl and C5.6heterocycloalkyl of R0 are each unsubstituted or substituted with 1 to 2 substituents independently selected from the group consisting of C1-4alkyl, halo and amino;
R3a and R3b are each independently selected from the group consisting of hydrogen and C1 4alkyl, or R3a and R3b is taken together with the carbon to which both attached to form a cyclopropyl; PAT054787-WO-PCT each Pt! is independently selected from the group consisting of halo, cyano, -OR4, -
C(0)R5, -C(0)NR6R7, -NR8R9, -NHC(O)R10, -NHS02R11 ; -S02R12, Ci-6alkyl, phenyl, C5. gheteroaryl, and C4.6heterocycoalkyl, wherein
R4 is Ci.6alkyl or phenyl, wherein the d-6alkyl is unsubstituted or substituted by 1 to 3 substituents independently selected from the group consisting of halo, cyano, Ci-4alkyl, amino, di-Ci-4alkylamino, and -C(0)NH2);
R5 is hydrogen, Ci-6alkyl or Ci-6alkoxy;
R6, R8 and Rn are each independently hydrogen or Ci-4alkyl;
R7 and Rg are each independently selected from the group consisting of hydrogen, Ci-4alkyl, Ci-4alkoxy, and C3.6cycloalkyl, wherein the Ci.4alkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of amino, C1-4alkyl, d- alkylamino, di-C1-4alkylamino, Ci.
4alkoxycarbonylamino, and C5-6heterocycloalkyl;
R10 is d-ealkyl, d-6alkoxy or C3-6cycloalkyl, wherein the C1-6alkyl of R10 is unsubstituted or substituted by 1 -2 substituents independently selected from amino and C3-6cycloalkyl, and the C3.6cycloalkyl of R10 is unsubstituted or substituted by 1 to 2 substituents independently selected from the group consisting of amino and amino- C1-4alkyl,
R12 is C1-4alkyl, amino or d-4alkylamino;
the C1-6alkyl of is unsubstituted or substituted with 1 -3 substituents independently selected from the group consisting of halo, cyano, methoxy, amino, Ci-4alkylamino, C5-6cycloalkyl, and phenyl; and
the phenyl, C5-6heteroaryl and C3.6heterocycoalkyl of Ri are each independently unsubstituted or substituted with 1 to 2 substituents independently selected from the grounp consisting of d-4alkyl, amino, d.4alkylamino, -C(0)CH3, and benzyl;
Ri5 and Ri6 are each independently hydrogen, d-4alkyl or haloCi-4alkyl;
each R17 is independently selected from the group consisting of cyano, halo, oxo, ORi8, -C(0)Ri9, -NR20R2i , -S02R22, -S02NHR23, C1-4alkyl, phenyl, C5-9heteroaryl, C3.
ecycloalkyl and C4.6heterocycloalkyl, wherein
Ri8 is selected from the group consisting of hydrogen, d_4alkyl, haloC1-4alkyl and phenyl; PAT054787-WO-PCT Rig is selected from the group consisting of hydrogen, C^alkyl, amino, and
Ci-4alkylamino;
R20, R21 and R22 are each independently hydrogen or Chalky;
R23 is hydrogen, Ci-4alkyl, or C5-6heteroaryl;
the Ci-4alkyl of Ri7 is unsubstituted or substituted with 1 -3 substituents independently selected from the group consisting of halo, d-4alkoxy and amino; and the phenyl, C5-9heteroaryl, C3-6cycloalkyl and C4-6heterocycloalkyl of Ri7 are each independently unsubstituted or substituted by 1 to 2 substituents independently selected from the group consisting of Ci- alkyl, halo-Ci-4alkyl, Ci-4alkoxy-Ci-4alkyl, and Ci-4alkoxy.
2. The compound of claim 1 , wherein L is selected from the group consisting of *-CH2N(R2)-, *-C(0)-, *-C(0)N(R2)-, *-C(0)N(R2)C(R3a)(R3b)-, *-N(R2)C(0)-, *-N(R2)S02-, and C^alkylene, wherein
* represents the point of attachment of L to Ring B;
R2 is C1_4alkyl;
R3a and R3b are each independently selected from the group consisting of hydrogen and C1-4alkyl, or R3a and R3b is taken together with the carbon to which both attached to form a cyclopropyl.
3. The compound according to claim 1 or claim 2, wherein Ring A is C6-i0aryl or C5-i0heteroaryl.
4. The compound according to any one of claims 1 to 3, wherein Ring C is selected from the group consisting of phenyl, C5-i0heteroaryl and C5-ioheterocycloalkyl.
5. The compound according to any one of claims 1 to 4, wherein each is independently
selected from the group consisting of trifluoromethyl, -C(0)NH2, -C(0)NHCH3, - C(0)NH(CH2)2N(CH3)2, and -NHC(0)CH(NH2)-cycloalkyl.
6. The compound according to any one of claims 1 to 5, wherein each R17 is independently selected from the group consisting of fluoro, chloro, bromo, cyano, methyl, ethyl, t-butyl, PAT054787-WO-PCT trifluoromethyl, methoxymethyl, aminomethyl, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, phenoxy, oxo, dimethylamino, methylsulfonyl, and aminocarbonyl.
7. The compound of claim 1 , wherein the compound is of Formula 1 A:
Figure imgf000312_0001
wherein
n is 1 ;
p is 1 ;
L is *-C(0)N(R2)- or *-CH2N(R2)-, wherein
* denotes the point of attachment of L to Ring B,
R2 is Ci-4alkyl or R0-Ci-4alkylene, wherein R0 is selected from the group consisting of Ci-4alkoxy, amino, d-4alkylamino, C5-6heteroaryl and C5- eheterocycloalkyl, wherein the C5-6heteroaryl and C5-6heterocycloalkyl are each independently unsubstituted or substituted by 1 -2 substituents independently selected from the group consisting of C^alkyl, halo, amino, and oxo;
Ring A is pheny or pyridyl;
Ring C is pheny or pyridyl;
each R is trifluoromethyl, *-C(0)NH2, or *-C(0)NHCH3;
each R17 is chloro, fluoro, or cyano.
8. The compound of claim 1 selected from the group consisting of:
N-(4-cyanophenyl)-3-(6-(3-(dimethylamino)propoxy)pyridin-3-yl)-N-methylimidazo[1 ,2- a]pyrazine-6-carboxamide;
4-(((3-(4-(1 H-pyrazol-5-yl)phenyl)imidazo[1 ,2-a]pyrazin-6- yl)methyl)(methyl)amino)benzonitrile;
N-((3-(4-(1 H-pyrazol-5-yl)phenyl)imidazo[1 ,2-a]pyrazin-6-yl)methyl)-4-fluoro-N- methylaniline;
4-(((3-(4-chlorophenyl)imidazo[1 ,2-a]pyrazin-6-yl)methyl)(methyl)amino)benzonitrile; PAT054787-WO-PCT N-((3-(4-(1 H-pyrazol-5-yl)phenyl)imidazo[1 ,2-a]pyrazin-6-yl)methyl)-4-chloro-N- methylaniline;
N-(5-chloro-3-fluoropyridin-2-yl)-N-methyl-3-(4-(trifluoromethyl)phenyl)imidazo[1 ,2- a]pyrazine-6-carboxamide;
5-methanesulfonyl-1 -({3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6- yl}carbonyl)-2,3-dihydro-1 H-indole;
4-fluoro-N-methyl-N-((3-(1 -methyl-1 H-indazol-5-yl)imidazo[1 ,2-a]pyrazin-6- yl)methyl)aniline;
N-((3-(4-(1 H-pyrazol-1 -yl)phenyl)imidazo[1 ,2-a]pyrazin-6-yl)methyl)-4-chloro-N- met ylaniline;
N-((3-(4-(1 H-pyrazol-1 -yl)phenyl)imidazo[1 ,2-a]pyrazin-6-yl)methyl)-4-chloro-N- met ylaniline;
3-(4-carbamoylphenyl)-N-(4-fluorophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide;
N-methyl-N-(1 -methyl-1 H-benzo[d][1 ,2,3]triazol-5-yl)-3-(4- (trifluoromethyl)phenyl)imidazo[1 ,2-a]pyrazine-6-carboxamide;
N-(4-chlorophenyl)-N-methyl-3-[4-(1 H-pyrazol-5-yl)phenyl]imidazo[1 ,2-a]pyrazine-6- carboxamide;
N-(1 ,3-benzothiazol-2-yl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2- a]pyrazine-6-carboxamide;
[4-(5-amino-1 ,3,4-oxadiazol-2-yl)phenyl]-N-(4-chlorophenyl)-N-methylimidazo[1 ,2- a]pyrazine-6-carboxamide;
N-(3-methoxypyridin-2-yl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2- a]pyrazine-6-carboxamide;
3-(4-chlorophenyl)-N-(4-methanesulfonylphenyl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide;
N-{[3-(4-chlorophenyl)imidazo[1 ,2-a]pyrazin-6-yl]methyl}-4-fluoro-N-methylaniline; N-(4-cyanophenyl)-N-methyl-3-(5-methylpyridin-2-yl)imidazo[1 ,2-a]pyrazine-6- carboxamide;
N-(4-cyanophenyl)-3-(2,4-dichlorophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide; PAT054787-WO-PCT N-({3-[4-(difluoromethoxy)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}methyl)-4-fluoro-N- methylaniline;
3- (4-carbamoylphenyl)-N-(3,4-difluorophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide;
N-(2,4-difluorophenyl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6- carboxamide;
N-methyl-4-(morpholin-4-yl)-N-{3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6- yljbenzamide;
4- [({3-[4-(5-amino-1 ,3,4-thiadiazol-2-yl)phenyl]imidazo[1 ,2-a]pyrazin-6- yl}methyl)(methyl)amino]benzonitrile;
3-(4-chloro-2-methylphenyl)-N-(4-cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide;
3-(2-chloropyridin-4-yl)-N-(4-cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide;
({3-[4-(5-amino-1 ,3,4-thiadiazol-2-yl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}methyl)-6- chloro-N-methylpyridin-3-amine;
N-(4-cyanophenyl)-3-(3,5-difluoropyridin-2-yl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide;
N-(4-cyanophenyl)-3-(4-methoxy-3-methylphenyl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide;
3-[2-chloro-4-(trifluoromethyl)phenyl]-N-(4-cyanophenyl)-N-methylimidazo[1 ,2- a]pyrazine-6-carboxam ide ;
N-(3-chloro-4-fluorophenyl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2- a]pyrazine-6-carboxamide;
3- acetyl-N-(6-chloropyridin-3-yl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide;
4- chloro-N-methyl-N-{[3-(1 -methyl-1 H-indazol-5-yl)imidazo[1 ,2-a]pyrazin-6- yl]methyl}aniline;
N-(3-chlorophenyl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6- carboxamide;
4-(6-{[(4-fluorophenyl)(methyl)amino]methyl}imidazo[1 ,2-a]pyrazin-3-yl)-N,N- dimethylaniline; PAT054787-WO-PCT 4-(6-{[(4-chlorophenyl)(methyl)amino]methyl}imidazo[1 ,2-a]pyrazin-3-yl)-N,N- dimethylaniline;
N-(4-cyanophenyl)-N-methyl-3-[4-(methylcarbamoyl)phenyl]imidazo[1 ,2-a]pyrazine-6- carboxamide;
N-(5-ethylpyridin-2-yl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6- carboxamide;
N-methyl-N-[2-(trifluoromethoxy)phenyl]-3-[4-(trifluoromethyl)phenyl]irriidazo[1 ,2- a]pyrazine-6-carboxamide;
N-(2,4-dichlorophenyl)-3-(4-methoxyphenyl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide;
N-(3-chloro-4-methoxyphenyl)-N-(4-cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide;
N-methyl-N-(4-phenoxyphenyl)-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6- carboxamide;
4-chloro-N-{[3-(4-chlorophenyl)imidazo[1 ,2-a]pyrazin-6-yl]methyl}-N-methylaniline;
N,5-dimethyl-N-{[3-(1 -methyl-1 H-indazol-5-yl)imidazo[1 ,2-a]pyrazin-6- yl]methyl}pyridin-2-amine;
N-(4-cyanophenyl)-N-methyl-3-[3-(1 H-pyrazol-4-yl)phenyl]imidazo[1 ,2-a]pyrazine-6- carboxamide;
N,5-dimethyl-N-({3-[4-(1 H-pyrazol-5-yl)phenyl]imidazo[1 ,2-a]pyrazin-6- yl}methyl)pyridin-2-amine;
N-(4-cyanophenyl)-3-(3-methoxyphenyl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide;
N-(2,4-dichlorophenyl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine- 6-carboxamide;
N-[4-(difluoromethoxy)phenyl]-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2- a]pyrazine-6-carboxamide;
N-methyl-N-[4-(1 -methyl-1 H-pyrazol-4-yl)phenyl]-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide;
N-(3-bromo-4-fluorophenyl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2- a]pyrazine-6-carboxamide;
3H PAT054787-WO-PCT
N-(3,4-difluorophenyl)-N-methyl-3-(1 ^
6-carboxamide;
N-(2-fluoropyridin-3-yl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine- 6-carboxamide;
N-(3,4-dichlorophenyl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazi 6-carboxamide;
N-(4-chloro-3-methylphenyl)-N-me
a]pyrazine-6-carboxamide;
N-(4-cyanophenyl)-3-[4-(difluoromethyl)phenyl]-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide;
N-(6-bromopyridin-3-yl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine^ 6-carboxamide;
N-(4-c loro-2-methoxyphenyl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2- a]pyrazine-6-carboxamide;
3- [4-chloro-3-(trifluoromethyl)phenyl]-N-(4-cyanophenyl)-N-methylimidazo[1 ,2- a]pyrazine-6-carboxamide;
N-(2,4-dichlorophenyl)-N-methyl-3-(4-methylphenyl)imidazo[1 ,2-a]pyrazine-6- carboxamide;
4- [methyl({[3-(1 -methyl-1 H-indazol-5-yl)imidazo[1 ,2-a]pyrazin-6- yl]methyl})amino]benzonitrile;
N-(5-fluoropyridin-2-yl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine- 6-carboxamide;
4-chloro-N-({3-[4-(difluoromethoxy)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}methyl)-N- methylaniline;
N-(4-cyanophenyl)-3-(2-fluoro-4-methoxyphenyl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide;
N-(5-fluoropyridin-3-yl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine- 6-carboxamide;
N-(4-cyanophenyl)-3-(4-methoxyp enyl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide;
N-methyl-N-[4-(2-methyl-2H-1 ,2,3,4-tetrazol-5-yl)phenyl]-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide; PAT054787-WO-PCT N-(4-fluorophenyl)-3-(4-methoxyphenyl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide;
3-(4-chlorophenyl)-N-(2,4-dichlorophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide;
3-(4-chloro-3-fluorophenyl)-N-(4-cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide;
N-(4-cyanophenyl)-N-[2-(dimethylamino)ethyl]-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide;
N-(2-c lorophenyl)-N-methyl-3-[4-(trifluoromet yl)phenyl]imidazo[1 ,2-a]pyrazine-6- carboxamide;
3-[4-(5-amino-1 ,3,4-thiadiazol-2-yl)phenyl]-N-(4-cyanophenyl)-N-methylimidazo[1 ,2- a]pyrazine-6-carboxamide;
N-(4-cyanophenyl)-3-[4-(1 ,1 -difluoroethyl)phenyl]-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide;
N-(4-cyanophenyl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6- carboxamide;
N-(4-cyanophenyl)-3-[4-(dimethylamino)phenyl]-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide;
N-(6-chloropyridin-3-yl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine- 6-carboxamide;
N-(6-fluoropyridin-3-yl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine- 6-carboxamide;
N-(6-chloropyridin-3-yl)-N-methyl-3-(4-methylphenyl)imidazo[1 ,2-a]pyrazine-6- carboxamide;
N-(4-chlorophenyl)-N-(6-chloropyridin-3-yl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide;
N-(4-cyanophenyl)-N-methyl-3-[6-(pyrrolidin-1 -yl)pyridin-3-yl]innidazo[1 ,2-a]pyrazine- 6-carboxamide;
N-(5-cyanopyridin-2-yl)-N-methyl-3-(1 -methyl-1 H-indazol-5-yl)imidazo[1 ,2-a]pyrazine- 6-carboxamide;
N-(6-chloropyridin-3-yl)-N-methyl-3-(1 -methyl-1 H-indol-5-yl)imidazo[1 ,2-a]pyrazine-6- carboxamide; PAT054787-WO-PCT N-(5-cyanopyridin-2-yl)-3-[4-(difluoromethoxy)phenyl]-N-methylimidazo[1 ,2- a]pyrazine-6-carboxamide;
N-(6-fluoropyridin-2-yl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-
6-carboxamide;
N-(4-cyanophenyl)-N-methyl-3-[4-(1 H-pyrazol-1 -yl)phenyl]imidazo[1 ,2-a]pyrazine-6- carboxamide;
N-(6-methoxypyridin-3-yl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2- a]pyrazine-6-carboxamide;
N-(5-cyanopyridin-2-yl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine- 6-carboxamide;
N-(4-cyanophenyl)-3-(6-methoxypyridin-3-yl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide;
N-(5-chloropyrazin-2-yl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine- 6-carboxamide;
N-(4-cyanophenyl)-N-(propan-2-yl)-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2- a]pyrazine-6-carboxamide;
N-(5-chloropyrimidin-2-yl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2- a]pyrazine-6-carboxamide;
N-(6-chloropyridazin-3-yl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2- a]pyrazine-6-carboxamide;
N-(5-cyanopyridin-2-yl)-3-[4-(difluoromethyl)phenyl]-N-methylimidazo[1 ,2-a]pyrazine- 6-carboxamide;
N-(6-bromopyridazin-3-yl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2- a]pyrazine-6-carboxamide;
N-(5-bromopyrazin-2-yl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine- 6-carboxamide;
3-(4-carbamoylphenyl)-N-(5-cyanopyridin-2-yl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide;
N-methyl-N-(pyridin-2-yl)-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6- carboxamide;
N-(6-chloropyridin-3-yl)-3-(4-methoxyphenyl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide; PAT054787-WO-PCT N-(4-fluorophenyl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6- carboxamide;
N-(4-chlorophenyl)-3-[4-(difluoromethoxy)phenyl]-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide;
3-(4-chlorophenyl)-N-(4-fluorophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; 3-(4-carbamoylphenyl)-N-(4-cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide;
N-(3,4-difluorophenyl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6- carboxamide;
N-(4-fluorophenyl)-N-methyl-3-(1 -methyl-1 H-indazol-5-yl)imidazo[1 ,2-a]pyrazine-6- carboxamide;
N-(4-fluorophenyl)-N-methyl-3-(1 -methyl-1 H-indazol-5-yl)imidazo[1 ,2-a]pyrazine-6- carboxamide;
N-(4-fluorophenyl)-N-methyl-3-(4-methylphenyl)imidazo[1 ,2-a]pyrazine-6- carboxamide;
N,3-bis(4-chlorophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide;
N-(2-methoxyphenyl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6- carboxamide;
6-fluoro-1 -({3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}carbonyl)-1 ,2,3,4- tetrahydroquinoline;
3-(4-chlorophenyl)-N-(3,4-difluorophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide;
N-(4-cyanophenyl)-N-methyl-3-(4-methylphenyl)imidazo[1 ,2-a]pyrazine-6- carboxamide;
N-(4-cyanophenyl)-N-ethyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6- carboxamide;
N-(4-cyanophenyl)-N-methyl-3-[4-(propan-2-yl)phenyl]imidazo[1 ,2-a]pyrazine-6- carboxamide;
N-(4-cyanophenyl)-N-methyl-3-[4-(trifluoromethoxy)phenyl]imidazo[1 ,2-a]pyrazine-6- carboxamide;
N-(4-cyanophenyl)-N-methyl-3-[4-(methylamino)phenyl]irriidazo[1 ,2-a]pyrazine-6- carboxamide; PAT054787-WO-PCT 3-(4-tert-butylphenyl)-N-(4-cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide;
N-(2-fluorophenyl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6- carboxamide;
N-[4-(1 -cyano-1 -methylethyl)phenyl]-N-(4-cyanophenyl)-N-methylimidazo[1 ,2- a]pyrazine-6-carboxamide;
3-[4-(dimethylamino)phenyl]-N-(4-fluorophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide;
N-(4-c lorophenyl)-3-[4-(dimethylamino)phenyl]-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide;
N-(4-cyanophenyl)-N-methyl-3-(1 -methyl-1 H-indol-5-yl)imidazo[1 ,2-a]pyrazine-6- carboxamide;
3-(4-aminophenyl)-N-(4-cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4-cyanophenyl)-3-[4-(furan-2-yl)phenyl]-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide;
N-(4-cyano-3-fluorophenyl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2- a]pyrazine-6-carboxam ide ;
N-(3,4-difluorophenyl)-N-methyl-3-(1 -methyl-1 H-indol-5-yl)imidazo[1 ,2-a]pyrazine-6- carboxamide;
N-(4-methanesulfonylphenyl)-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6- carboxamide;
N-(4-cyanophenyl)-3-(4-methanesulfonylphenyl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide;
N-(4-cyanophenyl)-3-[4-(1 -methoxyethyl)phenyl]-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide;
N-(4-methanesulfonylphenyl)-N-methyl-3-[4-(1 H-pyrazol-5-yl)phenyl]imidazo[1 ,2- a]pyrazine-6-carboxamide;
3-(4-chlorophenyl)-N-(4-cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide;
N-(4-cyanophenyl)-N-[2-(oxan-4-yl)ethyl]-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2- a]pyrazine-6-carboxamide;
3-(4-acetylphenyl)-N-(4-cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; PAT054787-WO-PCT N-(3,4-difluorophenyl)-N-methyl-3-(4-methylphenyl)imidazo[1 ,2-a]pyrazine-6- carboxamide;
N-(4-fluorophenyl)-N-methyl-3-(1 -methyl-1 H-indol-5-yl)imidazo[1 ,2-a]pyrazine-6- carboxamide;
N-(3-fluorophenyl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6- carboxamide;
N-(4-cyanophenyl)-N-methyl-3-[4-(2,2,2-trifluoroethoxy)phenyl]imidazo[1 ,2- a]pyrazine-6-carboxamide;
N-(4-methoxyphenyl)-N-met yl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6- carboxamide;
N-(4-cyanophenyl)-3-[2-fluoro-4-(trifluoromethyl)phenyl]-N-methylimidazo[1 ,2- a]pyrazine-6-carboxamide;
N-(4-c lorophenyl)-N-methyl-3-(1 -methyl-1 H-indol-5-yl)imidazo[1 ,2-a]pyrazine-6- carboxamide;
3-[4-(difluoromethoxy)phenyl]-N-(3,4-difluorophenyl)-N-methylimidazo[1 ,2-a]pyrazine- 6-carboxamide;
3-(1 H-1 ,3-benzodiazol-5-yl)-N-(4-cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide;
N-(3,4-difluorophenyl)-N-methyl-3-[4-(1 H-pyrazol-1 -yl)phenyl]imidazo[1 ,2-a]pyrazine- 6-carboxamide;
N-(4-cyanophenyl)-3-(1 H-indazol-5-yl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide;
N-(6-cyanopyridin-3-yl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine- 6-carboxamide;
N-(6-cyanopyridin-3-yl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine- 6-carboxamide;
N-(4-cyanophenyl)-N-methyl-3-(2-methyl-2H-indazol-5-yl)imidazo[1 ,2-a]pyrazine-6- carboxamide;
N-(4-cyanophenyl)-N-methyl-3-(2-methyl-2H-indazol-5-yl)imidazo[1 ,2-a]pyrazine-6- carboxamide;
N-(4-cyanophenyl)-N-methyl-3-[2-methyl-4-(trifluoromethyl)phenyl]imidazo[1 ,2- a]pyrazine-6-carboxamide; PAT054787-WO-PCT N-(4-fluorophenyl)-N-methyl-3-[4-(1 H-pyrazol-1 -yl)phenyl]imidazo[1 ,2-a]pyrazine-6 carboxamide;
N-(4-cyanophenyl)-N-methyl-3-[4-(propane-2-sulfonyl)phenyl]imidazo[1 ,2-a]pyrazine- 6-carboxamide;
N-(4-cyanophenyl)-3-(4-fluorophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide; N-(4-cyanophenyl)-3-(1 H-indazol-6-yl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide;
3-(4-chloro-3-cyanophenyl)-N-(4-cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide;
N-(4-cyanophenyl)-N-methyl-3-[2-(propan-2-yl)-1 ,3-thiazol-4-yl]imidazo[1 ,2- a]pyrazine-6-carboxamide;
N-(4-cyanophenyl)-N-methyl-3-(quinolin-6-yl)imidazo[1 ,2-a]pyrazine-6-carboxamide;
N-(4-cyanophenyl)-3-[4-(cyclopropylcarbamoyl)phenyl]-N-methylimidazo[1 ,2- a]pyrazine-6-carboxam ide ;
N-(3,4-difluorophenyl)-3-[4-(dimethylamino)phenyl]-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide;
N-(4-cyanophenyl)-3-[4-(3,5-dimethyl-1 H-pyrazol-1 -yl)phenyl]-N-methylimidazo[1 ,2- a]pyrazine-6-carboxam ide ;
3-(4-carbamoylphenyl)-N-(6-chloropyridin-3-yl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide;
N-(4-cyanophenyl)-N-methyl-3-[4-(propan-2-yloxy)phenyl]imidazo[1 ,2-a]pyrazine-6- carboxamide;
N-(4-cyanophenyl)-N-methyl-3-[4-(5-methyl-1 ,3,4-oxadiazol-2-yl)phenyl]imidazo[1 ,2- a]pyrazine-6-carboxam ide ;
3-[4-(dimethylamino)phenyl]-N-(4-methanesulfonylphenyl)-N-methylimidazo[1 ,2- a]pyrazine-6-carboxamide;
N-(4-cyanophenyl)-3-[4-(2,5-dioxoimidazolidin-4-yl)phenyl]-N-methylimidazo[1 ,2- a]pyrazine-6-carboxamide;
methyl 4-{6-[(4-cyanophenyl)(methyl)carbamoyl]imidazo[1 ,2-a]pyrazin-3-yl}benzoate;
N-(4-cyanophenyl)-3-(isoquinolin-6-yl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide; PAT054787-WO-PCT N-(4-cyanophenyl)-N-methyl-3-(1 -oxo-1 ,2-dihydroisoquinolin-6-yl)imidazo[1 ,2- a]pyrazine-6-carboxam ide ;
N-(4-cyanophenyl)-3-[3-fluoro-4-(trifluoromethyl)phenyl]-N-methylimidazo[1 ,2- a]pyrazine-6-carboxamide;
N-(4-cyanophenyl)-N-methyl-3-(6-propoxypyridin-3-yl)imidazo[1 ,2-a]pyrazine-6- carboxamide;
N-methyl-N-[2-(trifluoromethyl)phenyl]-3-[4-(trifluoromethyl)phenyl]irriidazo[1 ,2- a]pyrazine-6-carboxamide;
3-(4-carbamoylphenyl)-N-(4-methanesulfonylphenyl)-N-methylimidazo[1 ,2-a]pyrazine- 6-carboxamide;
N-methyl-N-[4-(trifluoromethoxy)phenyl]-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2- a]pyrazine-6-carboxamide;
N-methyl-N-(1 -methyl-1 H-imidazol-2-yl)-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2- a]pyrazine-6-carboxamide;
N-(4-cyanophenyl)-N-methyl-3-[3-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6- carboxamide;
5-fluoro-1 -({3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}carbonyl)-2,3- dihydro-1 H-indole;
N-(4-cyanophenyl)-N-methyl-3-(4-phenoxyphenyl)imidazo[1 ,2-a]pyrazine-6- carboxamide;
3-(1 -benzyl-1 H-pyrazol-4-yl)-N-(4-cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide;
3-[4-chloro-2-(trifluoromethyl)phenyl]-N-(4-cyanophenyl)-N-methylimidazo[1 ,2- a]pyrazine-6-carboxam ide ;
N-(4-cyanophenyl)-N-methyl-3-[4-(1 H-1 ,2,3,4-tetrazol-5-yl)phenyl]imidazo[1 ,2- a]pyrazine-6-carboxamide;
N-(4-cyanophenyl)-N-methyl-3-[4-(pyrrolidin-1 -yl)phenyl]imidazo[1 ,2-a]pyrazine-6- carboxamide;
N-(5-cyanopyridin-2-yl)-N-methyl-3-[4-(1 H-pyrazol-5-yl)phenyl]imidazo[1 ,2-a]pyrazine- 6-carboxamide;
N-(3-bromophenyl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6- carboxamide; PAT054787-WO-PCT N-(4-cyanophenyl)-N-methyl-3-(5-sulfamoylpyridin-3-yl)imidazo[1 ,2-a]pyrazine-6- carboxamide;
N-(4-cyanophenyl)-3-{4-[met oxy(methyl)carbamoyl]phenyl}-N-methylimidazo[1 ,2- a]pyrazine-6-carboxamide;
3-[4-(aminomethyl)phenyl]-N-(4-cyanophenyl)-N-methylirTiidazo[1 ,2-a]pyrazine-6- carboxamide;
N-(4-cyanophenyl)-N-methyl-3-[6-(trifluoromethyl)pyridin-3-yl]imidazo[1 ,2-a]pyrazine- 6-carboxamide;
N-(4-cyanophenyl)-3-[4-(diethylcarbamoyl)phenyl]-N-met ylimidazo[1 ,2-a]pyrazine-6- carboxamide;
N-(4-cyanophenyl)-N-methyl-3-(1 -methyl-1 H-pyrazol-4-yl)imidazo[1 ,2-a]pyrazine-6- carboxamide;
N-methyl-N-[(6-methylpyridin-2-yl)methyl]-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2- a]pyrazine-6-carboxamide;
3-(3-cyanophenyl)-N-(4-cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide;
N-[(4-fluorophenyl)methyl]-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2- a]pyrazine-6-carboxamide;
N-(4-cyanophenyl)-N-methyl-3-[4-(pyrrolidin-2-yl)phenyl]imidazo[1 ,2-a]pyrazine-6- carboxamide;
N-methyl-N-(pyridin-3-ylmethyl)-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6- carboxamide;
N-(4-cyanophenyl)-N-methyl-3-(pyridin-3-yl)imidazo[1 ,2-a]pyrazine-6-carboxamide; 3-(5-chloropyridin-2-yl)-N-(4-cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide;
N-(4-cyanophenyl)-3-[4-(dimethylsulfamoyl)phenyl]-N-methylimidazo[1 ,2-a]pyrazine- 6-carboxamide;
N-(4-cyanophenyl)-N-methyl-3-[2-(4-methylpiperidin-1 -yl)-1 ,3-thiazol-4-yl]imidazo[1 ,2- a]pyrazine-6-carboxamide;
N-(4-cyanophenyl)-N-methyl-3-(3-methylphenyl)imidazo[1 ,2-a]pyrazine-6- carboxamide;
N-(4-cyanophenyl)-N-methyl-3-(1 H-pyrazol-4-yl)imidazo[1 ,2-a]pyrazine-6- carboxamide; PAT054787-WO-PCT N-(4-cyanophenyl)-N-methyl-3-(1 -methyl-2,3-dihydro-1 H-indol-5-yl)imidazo[1 ,2- a]pyrazine-6-carboxamide;
3-(2,1 ,3-benzoxadiazol-5-yl)-N-(4-cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide;
N-(4-cyanophenyl)-N-methyl-3-{3-methyl-3H-imidazo[4,5-b]pyridin-6-yl}imidazo[1 ,2- a]pyrazine-6-carboxam ide ;
N-(4-cyanophenyl)-N-methyl-3-(2-oxo-2,3-dihydro-1 H-indol-5-yl)imidazo[1 ,2- a]pyrazine-6-carboxam ide ;
N-(4-methanesulfonylphenyl)-N-methyl-3-(1 -methyl-1 H-indazol-5-yl)imidazo[1 ,2- a]pyrazine-6-carboxam ide ;
N-methyl-N-{4-[3-(trifluoromethyl)-1 H-pyrazol-1 -yl]phenyl}-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide;
N-(4-cyanophenyl)-3-{4-[(dimethylamino)methyl]phenyl}-N-methylimidazo[1 ,2- a]pyrazine-6-carboxam ide ;
N-(4-cyanophenyl)-N-methyl-3-[4-(1 -methyl-1 H-pyrazol-5-yl)phenyl]imidazo[1 ,2- a]pyrazine-6-carboxam ide ;
3- [4-(difluoromethoxy)phenyl]-N-(4-methanesulfonylphenyl)-N-methylimidazo[1 ,2- a]pyrazine-6-carboxam ide ;
4- [3-(4-carbamoylphenyl)imidazo[1 ,2-a]pyrazin-6-yl]benzamide;
N-(4-cyanophenyl)-N-methyl-3-[5-(2-oxopyrrolidin-1 -yl)pyrazin-2-yl]imidazo[1 ,2- a]pyrazine-6-carboxam ide ;
3- {4-[(2S)-2-amino-2-cyclohexylacetamido]phenyl}-N-(4-cyanophenyl)-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide;
4- [methyl({3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6- yl}methyl)amino]benzonitrile;
N-(4-cyanophenyl)-3-[4-(difluoromethoxy)phenyl]-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide;
N-(4-bromophenyl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6- carboxamide;
N-(6-chloropyridin-3-yl)-N-methyl-3-[4-(piperidin-1 -yl)phenyl]imidazo[1 ,2-a]pyrazine-6- carboxamide; PAT054787-WO-PCT N-(4-chlorophenyl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6- carboxamide;
6-chloro-1 -({3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}carbonyl)-1 ,2,3,4- tetrahydroquinoline;
N-(4-chlorophenyl)-3-(4-methoxyphenyl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide;
N-(2-chloro-5-methylpyridin-3-yl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2- a]pyrazine-6-carboxamide;
N-(3-fluoropyridin-2-yl)-N-methyl-3-[4-(trifluoromethyl)p enyl]imidazo[1 ,2-a]pyrazine- 6-carboxamide;
4-(6-{[(4-fluorophenyl)(methyl)amino]methyl}imidazo[1 ,2-a]pyrazin-3-yl)benzamide; 4-(6-{[(4-cyanophenyl)(methyl)amino]methyl}imidazo[1 ,2-a]pyrazin-3-yl)benzamide; N-(6-c loropyridin-3-yl)-N-methyl-3-[4-(1 H-pyrazol-5-yl)phenyl]imidazo[1 ,2-a]pyrazine- 6-carboxamide;
methyl N-[4-(6-{[(4-cyanophenyl)(methyl)amino]methyl}imidazo[1 ,2-a]pyrazin-3- yl)phenyl]carbamate
N-[5-(6-{[(4-cyanophenyl)(methyl)amino]methyl}imidazo[1 ,2-a]pyrazin-3-yl)pyridin-2- yl]acetamide;
3- [4-(5-amino-1 ,3,4-oxadiazol-2-yl)phenyl]-N-(4-fluorophenyl)-N-methylimidazo[1 ,2- a]pyrazine-6-carboxamide;
N-(4-chlorophenyl)-N-methyl-3-[4-(methylcarbamoyl)phenyl]imidazo[1 ,2-a]pyrazine-6- carboxamide;
4- {6-[(6-fluoro-2,2-dimethyl-1 ,2,3,4-tetrahydroquinolin-1 -yl)carbonyl]imidazo[1 ,2- a]pyrazin-3-yl}benzamide;
6-fluoro-2,2-dimethyl-1 -({3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6- yl}carbonyl)-1 ,2,3,4-tetrahydroquinoline;
6-chloro-N-methyl-N-({3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6- yl}methyl)pyridin-3-amine;
3- (4-cyanophenyl)-N-(4-methanesulfonylphenyl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide;
4- (6-{[methyl(5-methylpyridin-2-yl)amino]methyl}imidazo[1 ,2-a]pyrazin-3-yl)benzami PAT054787-WO-PCT 6-fluoro-1 -({3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}methyl)-1 ,2,3,4- tetrahydroquinoline;
N,5-dimethyl-N-({3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6- yl}methyl)pyridin-3-amine;
N-(4-cyanophenyl)-3-(6-acetamidopyridin-3-yl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide;
N-(6-chloropyridin-3-yl)-3-[4-(1 ,1 -difluoroethyl)phenyl]-N-methylimidazo[1 ,2- a]pyrazine-6-carboxamide;
N-(4-cyanophenyl)-N-(2-methoxyethyl)-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2- a]pyrazine-6-carboxam ide ;
N-methyl-3-[4-(trifluoromethyl)phenyl]-N-[6-(trifluoromethyl)pyridin-3-yl]imidazo[1 ,2- a]pyrazine-6-carboxamide;
N-(4-cyanophenyl)-N-methyl-3-[4-(1 ,3,4-oxadiazol-2-yl)phenyl]imidazo[1 ,2-a]pyrazine- 6-carboxamide;
N-({3-[4-(difluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}methyl)-N,5- dimethylpyridin-2-amine;
N-[5-(6-{[methyl(5-methylpyridin-2-yl)amino]methyl}imidazo[1 ,2-a]pyrazin-3-yl)pyridin- 2-yl]acetamide;
N-(4-cyanophenyl)-N-methyl-3-{1 H-pyrrolo[2,3-b]pyridin-5-yl}imidazo[1 ,2-a]pyrazine- 6-carboxamide;
N-(4-fluorophenyl)-N-methyl-3-[4-(methylcarbamoyl)phenyl]imidazo[1 ,2-a]pyrazine-6- carboxamide;
methyl N-(4-{6-[(6-chloropyridin-3-yl)(methyl)carbamoyl]imidazo[1 ,2-a]pyrazin-3- yl}phenyl)carbamate;
N-(4-cyanophenyl)-N-methyl-3-[6-(methylamino)pyridin-3-yl]imidazo[1 ,2-a]pyrazine-6- carboxamide;
3-[4-(2-aminoacetamido)phenyl]-N-(4-cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine- 6-carboxamide;
3-[4-(5-amino-1 ,3,4-oxadiazol-2-yl)phenyl]-N-(4-cyanophenyl)-N-methylimidazo[1 ,2- a]pyrazine-6-carboxamide;
N-methyl-N-(pyridin-4-yl)-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6- carboxamide; PAT054787-WO-PCT N-(2-methoxy-5-methylpyridin-3-yl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imid a]pyrazine-6-carboxamide;
N-methyl-N-(5-methylpyridin-3-yl)-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-
6-carboxamide;
N-(2-methoxy-5-methylpyridin-3-yl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2- a]pyrazine-6-carboxamide;
ethyl 6-[(6-chloropyridin-3-yl)(methyl)carbamoyl]imidazo[1 ,2-a]pyrazine-3-carboxylate; ethyl N-(4-{6-[(4-cyanophenyl)(methyl)carbamoyl]imidazo[1 ,2-a]pyrazin-3- yl}phenyl)carbamate;
3-(4-{[(1 S,2R)-2-aminocyclopentane]amido}phenyl)-N-(4-cyanophenyl)-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide;
3- {4-[(3S)-3-amino-4-methylpentanamido]phenyl}-N-(4-cyanophenyl)-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide;
N-(4-fluorophenyl)-N-methyl-3-[4-(1 H-pyrazol-5-yl)phenyl]imidazo[1 ,2-a]pyrazine-6- carboxamide;
N-(3,4-difluorophenyl)-N-methyl-3-[4-(1 H-pyrazol-5-yl)phenyl]imidazo[1 ,2-a]pyrazine- 6-carboxamide;
4- chloro-N-methyl-N-{3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6- yljbenzamide;
methyl N-(5-{6-[(4-cyanophenyl)(methyl)carbamoyl]imidazo[1 ,2-a]pyrazin-3-yl}pyridin- 2-yl)carbamate;
Propan-2-yl N-(4-{6-[(4-cyanophenyl)(methyl)carbamoyl]imidazo[1 ,2-a]pyrazin-3- yl}phenyl)carbamate;
N-(6-chloropyridin-3-yl)-N-methyl-3-{4-[5-(methylamino)-1 ,3,4-thiadiazol-2- yl]phenyl}imidazo[1 ,2-a]pyrazine-6-carboxamide;
N,4-dimethyl-N-({3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}methyl)aniline;
5- chloro-N-methyl-N-{3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}pyridine- 2-carboxamide;
N-(6-chloropyridin-3-yl)-3-[4-(difluoromethyl)phenyl]-N-methylimidazo[1 ,2-a]pyrazine- 6-carboxamide;
3-{4-[(2S)-2-amino-3-methylbutanamido]phenyl}-N-(4-cyanophenyl)-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide; PAT054787-WO-PCT
6- chloro-N-methyl-N-{3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}pyridine- 3-carboxamide;
4-fluoro-N-methyl-N-{3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6- yljbenzamide;
3-{4-[(3R)-3-aminobutanamido]phenyl}-N-(4-cyanophenyl)-N-methylimidazo[1 ,2- a]pyrazine-6-carboxam ide ;
3-[4-(2-amino-2-cyclobutylacetamido)phenyl]-N-(4-cyanophenyl)-N- met ylimidazo[1 ,2-a]pyrazine-6-carboxamide;
3-{4-[(2S)-2-aminopropanamido]phenyl}-N-(4-cyanop enyl)-N-methylimidazo[1 ,2- a]pyrazine-6-carboxamide;
3-(6-aminopyridin-3-yl)-N-(4-cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide;
3-[4-(cyanomethoxy)phenyl]-N-(4-cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide;
1 -({3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}carbonyl)-1 ,2,3,4- tetrahydroquinoline-6-carbonitrile;
N-(6-chloropyridin-3-yl)-3-[2-fluoro-4-(trifluoromethyl)phenyl]-N-methylimidazo[1 ,2- a]pyrazine-6-carboxamide;
N-methyl-4-(trifluoromethyl)-N-{3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6- yljbenzamide;
N-methyl-N-(6-methylpyridin-3-yl)-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine- 6-carboxamide;
3-{4-[(2-amino-2-methylpropyl)amino]phenyl}-N-(4-cyanophenyl)-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide;
N-(6-chloropyridin-3-yl)-3-(4-acetamidophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide;
N-(6-chloropyridin-3-yl)-3-(2-fluoro-4-methoxyphenyl)-N-methylimidazo[1 ,2- a]pyrazine-6-carboxamide;
7- fluoro-4-({3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}methyl)-3,4- dihydro-2H-1 ,4-benzoxazine;
3-{4-[(2R)-2-aminopropanamido]phenyl}-N-(4-cyanophenyl)-N-methylimidazo[1 ,2- a]pyrazine-6-carboxamide; PAT054787-WO-PCT 4-cyano-N-methyl-N-{3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6- yljbenzamide;
N-(4-cyanophenyl)-3-{4-[2-(dimethylamino)ethoxy]phenyl}-N-methylimidazo[1 ,2- a]pyrazine-6-carboxamide;
N-(4-cyanophenyl)-N,2-dimethyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6- carboxamide;
3-{4-[(2R)-2-amino-3-methylbutanamido]phenyl}-N-(4-cyanophenyl)-N- met ylimidazo[1 ,2-a]pyrazine-6-carboxamide;
N,5-dimethyl-N-({3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6- yl}methyl)pyridin-2-amine;
N-(6-methoxy-5-methylpyridin-3-yl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2- a]pyrazine-6-carboxam ide ;
N,4-dimethyl-N-{3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}benzamide;
N-(6-methoxypyridin-2-yl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2- a]pyrazine-6-carboxamide;
N-(4-cyanophenyl)-3-(4-{[2-(dimethylamino)ethyl]carbamoyl}phenyl)-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide;
3-{4-[(2S)-2-amino-2-cyclopropylacetamido]phenyl}-N-(4-cyanophenyl)-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide;
N-(4-cyano-2-fluorophenyl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2- a]pyrazine-6-carboxamide;
N,4,4-trimethyl-N-{3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}piperidine-1 - carboxamide;
3-[6-(2-aminoacetamido)pyridin-3-yl]-N-(4-cyanophenyl)-N-methylimidazo[1 ,2- a]pyrazine-6-carboxamide;
N-(2-methoxypyridin-4-yl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2- a]pyrazine-6-carboxamide;
N-(4-cyanophenyl)-N-methyl-3-(6-methylpyridin-3-yl)imidazo[1 ,2-a]pyrazine-6- carboxamide;
N-(1 -ethyl-1 H-pyrazol-5-yl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2- a]pyrazine-6-carboxamide; PAT054787-WO-PCT
N-methyl-N-(2-methylpyridin-4-yl)-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine- 6-carboxamide;
tert-butyl N-{2-[(4-{6-[(4-cyanophenyl)(methyl)carbamoyl]imidazo[1 ,2-a]pyrazin-3- yl}phenyl)amino]-2-methylpropyl}carbamate;
N-(6-chloropyridin-3-yl)-3-(1 H-indol-5-yl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide;
3-(4-methoxy-2-methylphenyl)-N-[6-(4-methoxy-2-methylphenyl)pyridin-3-yl]-N- met ylimidazo[1 ,2-a]pyrazine-6-carboxamide;
N-(4-methoxypyridin-3-yl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2- a]pyrazine-6-carboxam ide ;
N-(6-c loro-5-methylpyridin-3-yl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2- a]pyrazine-6-carboxamide;
7-fluoro-4-({3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}carbonyl)-3,4- dihydro-2H-1 ,4-benzoxazine;
({3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}carbonyl)-3,4-dihydro-2H-1 ,4- benzoxazine;
3- (4-{[1 -(aminomethyl)cyclopropane]amido}phenyl)-N-(4-cyanophenyl)-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide;
N-methyl-6-(trifluoromethyl)-N-{3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6- yl}pyridine-3-carboxamide;
N-methyl-N-(4-methylpyridin-3-yl)-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine- 6-carboxamide;
N-(4-ethoxypyridin-2-yl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine- 6-carboxamide;
4- methoxy-N-methyl-N-{3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6- yljbenzamide;
N-(6-chloropyridin-3-yl)-N-methyl-3-{1 H-pyrrolo[2,3-b]pyridin-5-yl}imidazo[1 ,2- a]pyrazine-6-carboxamide;
N-methyl-N-[4-(1 H-1 ,2,4-triazol-1 -yl)phenyl]-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2- a]pyrazine-6-carboxamide;
N-(4-cyanophenyl)-3-(4-methanesulfonamidophenyl)-N-methylimidazo[1 ,2-a]pyrazine- 6-carboxamid; PAT054787-WO-PCT 4-({3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}carbonyl)-3,4-dihydro-2H-
1 ,4-benzoxazine-7-carbonitrile;
6-methanesulfonyl-1 -({3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6- yl}carbonyl)-1 ,2,3,4-tetrahydroquinoline;
N-(5-methanesulfonylpyridin-2-yl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2- a]pyrazine-6-carboxam ide ;
methyl N-[4-(6-{[methyl(5-methylpyridin-2-yl)amino]methyl}imidazo[1 ,2-a]pyrazin-3- yl)phenyl]carbamate;
3- (1 H-indol-2-yl)-N-[6-(1 H-indol-2-yl)pyridin-3-yl]-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide;
N-(6-chloropyridin-3-yl)-N-methyl-3-(3-methyl-1 H-indazol-5-yl)imidazo[1 ,2-a]pyrazine- 6-carboxamide;
N-methyl-N-[5-(morpholin-4-yl)pyridin-2-yl]-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2 a]pyrazine-6-carboxamide;
4- fluoro-N-methyl-N-{3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6- yl}piperidine-1 -carboxamide;
N-(4-cyanophenyl)-3-(6-methanesulfonamidopyridin-3-yl)-N-methylimidazo[1 ,2- a]pyrazine-6-carboxamide;
3-{4-[(1 -amino-2-methylpropan-2-yl)amino]phenyl}-N-(4-cyanophenyl)-N- methylimidazo[1 ,2-a]pyrazine-6-carboxamide;
3-(1 -benzofuran-5-yl)-N-(6-chloropyridin-3-yl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide;
N-methyl-N-(pyridin-3-yl)-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6- carboxamide;
N-methyl-N-(5-methylpyrazin-2-yl)-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine- 6-carboxamide;
N-methyl-N-(5-methylpyrazin-2-yl)-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine- 6-carboxamide;
N-methyl-3-[4-(trifluoromethyl)phenyl]-N-[2-(trifluoromethyl)pyridin-4-yl]imidazo[1 ,2- a]pyrazine-6-carboxamide;
N-(6-chloropyridin-3-yl)-N-methyl-3-[4-(1 H-pyrazol-1 -yl)phenyl]imidazo[1 ,2-a]pyrazine- 6-carboxamide; PAT054787-WO-PCT
5-{6-[(4-cyanophenyl)(methyl)carbamoyl]imidazo[1 ,2-a]pyrazin-3-yl}-N-methylpyridine^ 2-carboxamide;
N-(6-chloropyridin-3-yl)-3-[3-fluoro-4-(trifluoromethyl)phenyl]-N-methylimidazo[1 ,2- a]pyrazine-6-carboxamide;
N-(4-cyanophenyl)-3-(2-methoxypyrimidin-5-yl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide;
N-(4-ethylpyridin-2-yl)-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6- carboxamide;
N-(4-cyanophenyl)-3-(6-methoxypyrazin-2-yl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide;
N-(6-chloropyridin-3-yl)-3-(6-methoxypyridin-3-yl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide;
N-methyl-3-[4-(trifluoromethyl)phenyl]-N-[5-(trifluoromethyl)pyridin-2-yl]imidazo[1 ,2- a]pyrazine-6-carboxamide;
N-methyl-3-[4-(trifluoromethyl)phenyl]-N-[5-(trifluoromethyl)pyridin-2-yl]imidazo[1 ,2- a]pyrazine-6-carboxamide;
N-(4-cyanophenyl)-N-methyl-3-[4-(3-methyl-1 ,2,4-oxadiazol-5-yl)phenyl]irriidazo[1 ,2- a]pyrazine-6-carboxam ide ;
N-(6-chloropyridin-3-yl)-N-methyl-3-[4-(morpholin-4-yl)phenyl]imidazo[1 ,2-a]pyrazine- 6-carboxamide;
N,3-bis(4-cyanophenyl)-N-methyl-2-(trifluoromethyl)imidazo[1 ,2-a]pyrazine-6- carboxamide;
N-(2,6-dichloropyridin-3-yl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2- a]pyrazine-6-carboxamide;
N-(6-chloropyridin-3-yl)-3-[4-(cyclopropylcarbamoyl)phenyl]-N-methylimidazo[1 ,2- a]pyrazine-6-carboxamide;
N-(4-cyanophenyl)-3-[2-(dimethylamino)pyrimidin-5-yl]-N-methylimidazo[1 ,2- a]pyrazine-6-carboxamide;
N-methyl-N-(6-methylpyridin-2-yl)-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine- 6-carboxamide;
N-[2-(difluoromethoxy)phenyl]-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2- a]pyrazine-6-carboxamide; PAT054787-WO-PCT
4-cyano-N-methyl-N-{3-[4-(trifluorom
1 -sulfonamide;
N-methyl-3-[4-(trifluoromethyl)phenyl]-N-[4-(trifluoromethyl)pyridin-2-yl]imidazo[1 ,2- a]pyrazine-6-carboxamide;
N-(6-chloropyridin-3-yl)-3-(1 H-indazol-5-yl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide;
2,2-dimethyl-4-({3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}carbonyl)-3,4- dihydro-2H-1 ,4-benzoxazine-7-carbonitrile;
N-(4-cyanophenyl)-3-(6-fluoropyridin-2-yl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide;
3-[4-(1 -carbamoyl-1 -methylethoxy)phenyl]-N-(4-cyanophenyl)-N-methylimidazo[1 ,2- a]pyrazine-6-carboxam ide ;
N-(5-methoxypyridin-2-yl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2- a]pyrazine-6-carboxamide;
3-(3-chloropyridin-2-yl)-N-(4-cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide;
N-(5-chloropyridin-3-yl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine- 6-carboxamide;
N-methyl-N-(1 ,3-thiazol-2-yl)-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6- carboxamide;
N-(6-chloropyridin-3-yl)-3-[6-(dimethylamino)pyridin-3-yl]-N-methylimidazo[1 ,2- a]pyrazine-6-carboxamide;
N-(4-methoxypyridin-2-yl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2- a]pyrazine-6-carboxamide;
N-{6-[(2S)-2-(methoxymethyl)pyrrolidin-1 -yl]pyridin-3-yl}-N-methyl-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide;
N-(6-chloropyridin-3-yl)-3-(2,3-dihydro-1 ,4-benzodioxin-6-yl)-N-methylimidazo[1 ,2- a]pyrazine-6-carboxam ide ;
3-(4-acetamidophenyl)-N-methyl-N-(5-methylpyridin-2-yl)imidazo[1 ,2-a]pyrazine-6- carboxamide;
N-[(4-cyanophenyl)methyl]-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6- carboxamide; PAT054787-WO-PCT N-(4-cyanophenyl)-N-methyl-3-[4-(propane-2-sulfonamido)phenyl]imidazo[1 ,2- a]pyrazine-6-carboxamide;
N-(6-chloropyridin-3-yl)-N-methyl-3-[2-(propan-2-yl)-1 ,3-thiazol-4-yl]imidazo[1 ,2- a]pyrazine-6-carboxamide;
N-methyl-N-[6-(1 H-1 ,2,4-triazol- 1 -yl)pyridin-3-yl]-3-[4- (trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide;
N-methyl-4-(trifluoromethoxy)-N-{3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6- yljbenzamide;
N-(6-c loropyridin-3-yl)-N-methyl-3-[6-(5-methyl-1 ,3,4-oxadiazol-2-yl)pyridin-3- yl]imidazo[1 ,2-a]pyrazine-6-carboxamide;
N-(1 -ethyl- 1 H-pyrazol-5-yl)-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6- carboxamide;
3-(4-cyanophenyl)-N-methyl-N-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6- carboxamide;
N-benzyl-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide;
2- C-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-pyridine-2,5-dicarboxamide;
3- [4-(2-aminoethoxy)phenyl]-N-(4-cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide;
3- (6-acetamidopyridin-3-yl)-N-methyl-N-(5-methylpyridin-2-yl)imidazo[1 ,2-a]pyrazine- 6-carboxamide;
4- ({3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}carbonyl)morpholine;
N-[4-(aminomethyl)phenyl]-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2- a]pyrazine-6-carboxamide;
N-(4-cyanophenyl)-2-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6- carboxamide;
N,3-bis(4-cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide;
N-(4-cyanophenyl)-N-methyl-3-(2-methylpyridin-4-yl)imidazo[1 ,2-a]pyrazine-6- carboxamide;
N-(6-chloropyridin-3-yl)-N-methyl-3-(2-oxo-2,3-dihydro-1 H-indol-5-yl)imidazo[1 ,2- a]pyrazine-6-carboxamide;
3-(2-aminopyrimidin-5-yl)-N-(4-cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide; PAT054787-WO-PCT N-(6-chloropyridin-3-yl)-3-ethenyl-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide;
N-(5-cyclobutylpyridin-2-yl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2- a]pyrazine-6-carboxamide;
N-{[4-(morpholin-4-yl)phenyl]methyl}-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2- a]pyrazine-6-carboxamide;
N-(6-tert-butylpyridin-3-yl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2- a]pyrazine-6-carboxamide;
N-(4-cyanophenyl)-N-methyl-3-(pyridin-4-yl)imidazo[1 ,2-a]pyrazine-6-carboxamide;
N-(2-aminoethyl)-N-(4-cyanophenyl)-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2- a]pyrazine-6-carboxamide;
N-(6-chloropyridin-3-yl)-3-(1 H-indol-2-yl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide;
N-(6-chloropyridin-3-yl)-3-{4-[(dimethylamino)methyl]phenyl}-N-methylimidazo[1 ,2- a]pyrazine-6-carboxamide;
N-(4-cyano-1 H-imidazol-5-yl)-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6- carboxamide;
N-methyl-N-(3-methylpyridin-2-yl)-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine- 6-carboxamide;
N-(4-cyanophenyl)-N-methyl-3-{1 -methyl-1 H-pyrazolo[3,4-b]pyridin-5-yl}imidazo[1 ,2- a]pyrazine-6-carboxamide;
4- ({3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}methyl)morpholine;
5- {6-[(4-cyanophenyl)(methyl)carbamoyl]imidazo[1 ,2-a]pyrazin-3-yl}pyridine-2- carboxamide;
N-[6-(dimethylamino)pyridin-3-yl]-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2- a]pyrazine-6-carboxamide;
N-(6-methoxypyridazin-3-yl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2- a]pyrazine-6-carboxam ide ;
3-(3-amino-1 H-indazol-5-yl)-N-(4-cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide;
1 -({3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}carbonyl)piperidine-3- carboxamide; PAT054787-WO-PCT N-(6-chloropyridin-3-yl)-N-methyl-3-[4-(methylamino)phenyl]imidazo[1 ,2-a]pyrazin carboxamide;
N-(2-methoxypyrimidin-5-yl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2- a]pyrazine-6-carboxamide;
N-(4-cyanophenyl)-N-methyl-3-(6-{[2-(morpholin-4-yl)ethyl]amino}pyridin-3- yl)imidazo[1 ,2-a]pyrazine-6-carboxamide;
N-(4-cyanophenyl)-3-(6-cyanopyridin-3-yl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide;
3-{4-[(1 -amino-2-methylpropan-2-yl)oxy]phenyl}-N-(4-cyanophenyl)-N- met ylimidazo[1 ,2-a]pyrazine-6-carboxamide;
6-N-(6-chloropyridin-3-yl)-6-N-methyl-3-N-[4-(trifluoromethyl)phenyl]imidazo[1 ,2- a]pyrazine-3,6-dicarboxamide;
5- C-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-1 H-imidazole-4,5- dicarboxamide;
N-[1 -(4-chlorophenyl)ethyl]-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2- a]pyrazine-6-carboxam ide ;
N-{4-[(1 ,3-thiazol-2-yl)sulfamoyl]phenyl}-3-[4-(trifluoromethyl)phenyl]irriiclazo[ ,2- a]pyrazine-6-carboxam ide ;
N-(6-chloropyridin-3-yl)-N-methyl-3-[6-(methylamino)pyridin-3-yl]imidazo[1 ,2- a]pyrazine-6-carboxamide;
3-[4-(2-amino-2-methylpropanamido)phenyl]-N-(4-cyanophenyl)-N-methylimidazo[1 ,2- a]pyrazine-6-carboxamide;
3-[4-(2-aminoethoxy)phenyl]-N-methyl-N-(5-methylpyridin-2-yl)imidazo[1 ,2-a]pyrazine- 6-carboxamide;
N-(6-chloropyridin-3-yl)-N-methyl-3-[4-(1 ,3,4-oxadiazol-2-yl)phenyl]imidazo[1 ,2- a]pyrazine-6-carboxamide;
6- fluoro-1 -({8-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}carbonyl)- 1 ,2,3,4-tetrahydroquinoline;
N-(5-cyclopentylpyridin-2-yl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2- a]pyrazine-6-carboxamide;
N-(6-chloropyridin-3-yl)-N-methyl-3-[6-(trifluoromethyl)pyridin-3-yl]imidazo[1 ,2- a]pyrazine-6-carboxamide; PAT054787-WO-PCT
N-[2-(4-fluorophenyl)propan-2-yl]-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine- 6-carboxamide;
methyl N-(5-{6-[methyl(5-methylpyridin-2-yl)carbamoyl]imidazo[1 ,2-a]pyrazin-3- yl}pyridin-2-yl)carbamate;
N-methyl-N-{[1 ,2,4]triazolo[4,3-a]pyridin-5-yl}-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2- a]pyrazine-6-carboxam ide ;
4-tert-butyl-N-methyl-N-{3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6- yljbenzamide;
N-(6-chloropyridin-3-yl)-3-[3-(dimethylamino)phenyl]-N-methylimidazo[1 ,2-a]pyraz 6-carboxamide;
N-(6-chloropyridin-3-yl)-3-(4-methanesulfonamidophenyl)-N-methylimidazo[1 ,2- a]pyrazine-6-carboxam ide ;
N-methyl-N-(2-methylpyridin-3-yl)-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine- 6-carboxamide;
N-methyl-N-(5-methylpyrimidin-2-yl)-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2- a]pyrazine-6-carboxamide;
N-(6-chloropyridin-3-yl)-3-(4-fluorophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide;
N-methyl-N-(4-phenyl-1 ,3-thiazol-2-yl)-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2- a]pyrazine-6-carboxamide;
cyanophenyl)-N-methyl-3-(3-methyl-1 H-indazol-5-yl)imidazo[1 ,2-a]pyrazine-6- carboxamide;
N-(4-acetylphenyl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6- carboxamide;
1 -({3-[4-(trif luoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}methyl)piperidin-2-one; N-(4-cyanophenyl)-3-[4-(dimethylcarbamoyl)phenyl]-N-methylimidazo[1 ,2-a]pyrazine- 6-carboxamide;
N-(4-cyanophenyl)-3-(1 H-indol-5-yl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide;
N-(6-chloropyridin-3-yl)-3-[4-(difluoromethoxy)phenyl]-N-methylimidazo[1 ,2- a]pyrazine-6-carboxamide;
N-(4-fluoro-2-methoxyphenyl)-N-methyl-3-[4 (trifluoromethyl)phenyl]imidazo[1 ,2- a]pyrazine; PAT054787-WO-PCT N-(3,4-difluorophenyl)-3-(4-methoxyphenyl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide;
N-(4-chlorophenyl)-N-methyl-3-(4-methylphenyl)imidazo[1 ,2-a]pyrazine-6- carboxamide;
3- [4-(difluoromethoxy)phenyl]-N-(4-fluorophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide;
N-(5-bromopyrimidin-2-yl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2- a]pyrazine-6-carboxamide;
N-(5-chloropyridin-2-yl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine- 6-carboxamide;
N-methyl-N-[4-(propan-2-yloxy)phenyl]-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2- a]pyrazine-6-carboxamide;
4- [({3-[4-(dimethylamino)phenyl]imidazo[1 ,2-a]pyrazin-6- yl}methyl)(methyl)amino]benzonitrile;
N-(4-cyanophenyl)-3-[3-(dimethylamino)phenyl]-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide;
3- (6-chloropyridin-3-yl)-N-(4-cyanophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide;
N-(3-methoxyphenyl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6- carboxamide;
N-(4-cyanophenyl)-3-(4-methoxy-2-methylphenyl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide;
N-(7-chloro-1 ,3-benzothiazol-2-yl)-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine- 6-carboxamide;
4- fluoro-N-methyl-N-(3-{4-[5-(methylamino)-1 ,3,4-thiadiazol-2-yl]phenyl}imidazo[1 ,2- a]pyrazin-6-yl)benzamide;
3-{6-[(6-fluoro-1 ,2,3,4-tetrahydroquinolin-1 -yl)carbonyl]imidazo[1 ,2-a]pyrazin-3-yl}- N,N-dimethylaniline;
N,3-bis[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamide;
N-(4-cyanophenyl)-N-methyl-3-{4-[5-(methylamino)-1 ,3,4-oxadiazol-2- yl]phenyl}imidazo[1 ,2-a]pyrazine-6-carboxamide; PAT054787-WO-PCT
4-{6-[(7-fluoro-3,3-dimethyl-3,4-dihydro-2H-1 ,4-benzoxazin-4-yl)carbonyl]imidazo[1 ,2- a]pyrazin-3-yl}benzamide;
4-{6-[(6-fluoro-1 ,2,3,4-tetrahydroquinolin-1 -yl)carbonyl]imidazo[1 ,2-a]pyrazin-3- yljbenzamide;
N-(4-fluorophenyl)-N-methyl-3-[4-(1 ,3,4-thiadiazol-2-yl)phenyl]imidazo[1 ,2-a]pyrazine- 6-carboxamide;
4-{6-[(6-fluoro-1 ,2,3,4-tetrahydroquinolin-1 -yl)carbonyl]imidazo[1 ,2-a]pyrazin-3-yl}-N- met ylbenzamide;
N-(4-{6-[(7-fluoro-3,3-dimethyl-3,4-dihydro-2H-1 ,4-benzoxazin-4- yl)carbonyl]imidazo[1 ,2-a]pyrazin-3-yl}phenyl)acetamide;
N-methyl-4-{6-[N-methyl(4-fluorobenzene)amido]imidazo[1 ,2-a]pyrazin-3- yljbenzamide;
N-methyl-N-(4-sulfamoylphenyl)-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6- carboxamide;
4-{6-[(7-fluoro-3,4-dihydro-2H-1 ,4-benzoxazin-4-yl)carbonyl]imidazo[1 ,2-a]pyrazin-3- yljbenzamide;
4-{6-[N-methyl(4-fluorobenzene)amido]imidazo[1 ,2-a]pyrazin-3-yl}benzamide;
4-fluoro-N-methyl-N-(3-{1 H-pyrrolo[2,3-b]pyridin-5-yl}imidazo[1 ,2-a]pyrazin-6- yl)benzamide;
1 -{[3-(2,3-dihydro-1 -benzofuran-5-yl)imidazo[1 ,2-a]pyrazin-6-yl]carbonyl}-6-fluoro- 1 ,2,3,4-tetrahydroquinoline;
3- (4-carbamoylphenyl)-N-methyl-N-(5-methylpyridin-2-yl)imidazo[1 ,2-a]pyrazine-6- carboxamide;
4- {6-[(7-fluoro-3,4-dihydro-2H-1 ,4-benzoxazin-4-yl)carbonyl]imidazo[1 ,2-a]pyrazin-3- yl}-N-methylbenzamide;
6-fluoro-1 -{[3-(3-methanesulfonylphenyl)imidazo[1 ,2-a]pyrazin-6-yl]carbonyl}-1 ,2,3,4- tetrahydroquinoline;
3-[6-(4-acetylpiperazin-1 -yl)pyridin-3-yl]-N-(4-cyanophenyl)-N-methylimidazo[1 ,2- a]pyrazine-6-carboxamide;
6-fluoro-1 -{[3-(4-methanesulfonylphenyl)imidazo[1 ,2-a]pyrazin-6-yl]carbonyl}-1 ,2,3,4- tetrahydroquinoline; PAT054787-WO-PCT 1 -{[3-(1 -ethyl-1 H-pyrazol-4-yl)imidazo[1 ,2-a]pyrazin-6-yl]carbonyl}-6-fluoro-1 ,2,3,4- tetrahydroquinoline;
N-(4-cyanophenyl)-N-methyl-3-[6-(piperazin-1 -yl)pyridin-3-yl]imidazo[1 ,2-a]pyra^ 6-carboxamide;
N-(4-cyanophenyl)-3-(furan-2-yl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxamide;
N-(4-cyanophenyl)-3-(furan-2-yl)-N-methylimidazo[1 ,2-a]pyrazine-6-carboxarriide;
6-fluoro-1 -({3-[2-(piperazin-1 -yl)pyridin-4-yl]imidazo[1 ,2-a]pyrazin-6-yl}carbonyl)- 1 ,2,3,4-tetrahydroquinoline;
N-(4-chlorophenyl)-N-methyl-3-[4-(1 ,3,4-thiadiazol-2-yl)phenyl]imidazo[1 ,2-a]pyrazi 6-carboxamide;
N-methyl-3-[4-(methylcarbamoyl)phenyl]-N-(5-methylpyridin-2-yl)imidazo[1 ,2- a]pyrazine-6-carboxamide;
N-cyclohexyl-4-{6-[(6-fluoro-1 ,2,3,4-tetrahydroquinolin-1 -yl)carbonyl]imidazo[1 ,2- a]pyrazin-3-yl}benzamide;
4-fluoro-N-methyl-N-[3-(1 -methyl-1 H-indazol-5-yl)imidazo[1 ,2-a]pyrazin-6- yl]benzamide;
1 -[4-(5-{6-[(6-fluoro-1 ,2,3,4-tetrahydroquinolin-l -yl)carbonyl]imidazo[1 ,2-a]pyrazin-3- yl}pyridin-2-yl)piperazin-1 -yl]ethan-1 -one;
6-fluoro-1 -({3-[3-(morpholin-4-ylmethyl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}carbonyl)- 1 ,2,3,4-tetrahydroquinoline;
N-(5-methylpyridin-2-yl)-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6- carboxamide;
N-(4-ethylpyridin-2-yl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6- carboxamide;
N-(4-cyanophenyl)-N-methyl-3-{4-[5-(methylamino)-1 ,3,4-thiadiazol-2- yl]phenyl}imidazo[1 ,2-a]pyrazine-6-carboxamide;
4-(6-{[(4-chlorophenyl)(methyl)amino]methyl}imidazo[1 ,2-a]pyrazin-3-yl)benzamide;
N-(4-fluorophenyl)-N-methyl-3-{4-[5-(methylamino)-1 ,3,4-oxadiazol-2- yl]phenyl}imidazo[1 ,2-a]pyrazine-6-carboxamide;
4-[({3-[4-(difluoromethoxy)phenyl]imidazo[1 ,2-a]pyrazin-6- yl}methyl)(methyl)amino]benzonitrile; PAT054787-WO-PCT N-(4-chlorophenyl)-N-methyl-3-(1 -methyl-1 H-indazol-5-yl)imidazo[1 ,2-a]pyrazine-6- carboxamide;
N-(4-cyanophenyl)-N-methyl-3-[4-(1 H-pyrazol-5-yl)phenyl]imidazo[1 ,2-a]pyrazine-6- carboxamide;
methyl N-(4-{6-[(4-cyanophenyl)(methyl)carbamoyl]imidazo[1 ,2-a]pyrazin-3- yl}phenyl)carbamate;
N-(4-chlorophenyl)-N-methyl-3-{4-[5-(methylamino)-1 ,3,4-oxadiazol-2- yl]phenyl}imidazo[1 ,2-a]pyrazine-6-carboxamide;
N-(4-cyanophenyl)-N-methyl-3-[4-(1 H-pyrazol-3-yl)phenyl]imidazo[1 ,2-a]pyrazine-6- carboxamide;
N-(4-cyanophenyl)-3-(4-acetamidophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide;
3- (4-carbamoylphenyl)-N-(4-chlorophenyl)-N-methylimidazo[1 ,2-a]pyrazine-6- carboxamide;
N-(4-cyanophenyl)-N-methyl-3-(1 -methyl-1 H-indazol-5-yl)imidazo[1 ,2-a]pyrazine-6- carboxamide;
N-[3-(6-acetamidopyridin-3-yl)imidazo[1 ,2-a]pyrazin-6-yl]-4-fluoro-N-methylbenzamide; N-(6-chloropyridin-3-yl)-N-methyl-3-(1 -methyl-1 H-indazol-5-yl)imidazo[1 ,2-a]pyrazine- 6-carboxamide;
N-(4-fluoropyridin-2-yl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine- 6-carboxamide;
N-methyl-N-(5-methylpyridin-2-yl)-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine- 6-carboxamide;
N-(2-methoxypyridin-3-yl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2- a]pyrazine-6-carboxamide;
N-(4-cyanophenyl)-N-methyl-3-[4-(1 ,3,4-thiadiazol-2-yl)phenyl]imidazo[1 ,2-a]pyrazine- 6-carboxamide;
(1 ,1-dioxido-2H-benzo[b][1 ,4]thiazin-4(3H)-yl)(3-(4- (trifluoromethyl)phenyl)imidazo[1 ,2-a]pyrazin-6-yl)methanone;
4- {6-[N-methyl(4-cyanobenzene)amido]imidazo[1 ,2-a]pyrazin-3-yl}benzamide;
N-(2-chloro-1 ,3-thiazol-5-yl)-N-methyl-3-[4 (trifluoromethyl)phenyl]imidazo[1 ,2- a]pyrazine-6-carboxamide; PAT054787-WO-PCT 4-({3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}carbonyl)-1 ,2,3,4- tetrahydroquinoxalin-2-one;
N-methyl-N-{3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazin-6-yl}pyrimidine-5- carboxamide;
N-methyl-N-(6-phenylpyridin-3-yl)-3-[4-(trifluoromethyl)phenyl]imida ,2-a]pyrazine- 6-carboxamide;
N-methyl-N,3-bis[4-(trifluoromethyl)phenyl]imidazo[1 ,2-a]pyrazine-6-carboxamid
N-(4-methanesulfonylphenyl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2- a]pyrazine-6-carboxamide;
N-(3-chloro-4-cyanophenyl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2- a]pyrazine-6-carboxamide; and
N-(4-cyano-2-methoxyphenyl)-N-methyl-3-[4-(trifluoromethyl)phenyl]imidazo[1 ,2- a]pyrazine-6-carboxamide.
9. A pharmaceutical composition comprising at least one compound of any one of claims 1 to 8 or a pharmaceutically acceptable salt, or stereoisomer thereof, and a pharmaceutically acceptable carrier, diluent or excipient.
10. The pharmaceutical composition according to Claim 9 further comprising a second agent, wherein the second agent is an antimalarial drug selected from artemisinin, artemether, artesunate, arteflene, dihydroartemisinin, chlorproguanil, trimethoprim, chloroquine, quinine, mefloquine, amodiaquine, atovaquone, proguanil, lumefantrine, piperaquine, pyronaridine, halofantrine, pyrimethamine-sulfadoxine, quinacrine, pyrimethamine-dapsone, quinidine, amopyroquine, sulphonamides, primaquine, ferroquine, tafenoquine, arterolane, and pyronaridine.
1 1 . A method for treating, preventing, inhibiting, ameliorating, or eradicating the pathology and/or symptomology of a disease caused by a Plasmodium parasite, comprising administering to a subject a therapeutically effective amount of a compound according to any one of claims 1 -8 or a composition according to either claim 9 or claim 10, wherein the administering may optionally be in combination with a second agent. PAT054787-WO-PCT
12. The method according to claim 1 1 , wherein the disease is malaria.
13. The method according to either claim 1 1 or 12, wherein the Plasmodium parasite is at the blood stages or at the hepatic stages.
14. The method according to any one of claims 1 1 to 13, wherein the Plasmodium parasite is selected from group consisting of Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, and Plasmodium malaria.
15. The method according to any one of claims 1 1 to 14, wherein the second agent is selected from a kinase inhibitor, an anti-malarial drug and an anti-inflammatory agent, and wherein the anti-malarial drug is selected from artemisinin, artemether, artesunate, arteflene, dihydroartemisinin, chlorproguanil, trimethoprim, chloroquine, quinine, mefloquine, amodiaquine, atovaquone, proguanil, lumefantrine, piperaquine, pyronaridine, halofantrine, pyrimethamine-sulfadoxine, quinacrine, pyrimethamine-dapsone, quinidine, amopyroquine, sulphonamides, primaquine, ferroquine, tafenoquine, arterolane, and pyronaridine.
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