WO2011097491A1 - Benzimidazole antiviral agents - Google Patents

Benzimidazole antiviral agents Download PDF

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Publication number
WO2011097491A1
WO2011097491A1 PCT/US2011/023763 US2011023763W WO2011097491A1 WO 2011097491 A1 WO2011097491 A1 WO 2011097491A1 US 2011023763 W US2011023763 W US 2011023763W WO 2011097491 A1 WO2011097491 A1 WO 2011097491A1
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Prior art keywords
methyl
carbonyl
benzimidazol
piperazinone
cyclopropyl
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PCT/US2011/023763
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French (fr)
Inventor
Anna Banka
John G Catalano
Jing Fang
Andrew James Peat
Vincent Tai
Elizabeth Turner
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Glaxosmithkline Llc
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Publication of WO2011097491A1 publication Critical patent/WO2011097491A1/en

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    • 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
    • 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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/7056—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing five-membered rings with nitrogen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/21—Interferons [IFN]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom

Definitions

  • HCV hepatitis C virus
  • HCV is a hepacivirus member of the Flaviviridae family of RNA viruses that affect animals and humans.
  • the genome is a single ⁇ 9.6-kilobase strand of RNA, and consists of one open reading frame that encodes for a polyprotein of ⁇ 3000 amino acids flanked by untranslated regions at both 5' and 3' ends (5'- and 3'-UTR).
  • the polyprotein serves as the precursor to at least 10 separate viral proteins critical for replication and assembly of progeny viral particles.
  • HCV polyprotein The organization of structural and non-structural proteins in the HCV polyprotein is as follows: C-E1-E2-p7-NS2-NS3-NS4a-NS4b- NS5a-NS5b. Because the replicative cycle of HCV does not involve any DNA intermediate and the virus is not integrated into the host genome, HCV infection can theoretically be cured. While the pathology of HCV infection affects mainly the liver, the virus is found in other cell types in the body including peripheral blood lymphocytes.
  • HCV is major causative agent for post-transfusion and for sporadic hepatitis.
  • Infection by HCV is insidious in a high proportion of chronically infected (and infectious) carriers who may not experience clinical symptoms for many years.
  • An estimated 170 million chronic carriers worldwide are at risk of developing liver disease. See, for example, Szabo, et al., Pathol. Oncol.Res. 2003, 9:215-221 , and Hoofnagle JH, Hepatology 1997, 26:15S-20S.
  • In the United States alone 2.7 million are chronically infected with HCV, and the number of HCV- related deaths in 2000 was estimated between 8,000 and 10,000, a number that is expected to increase significantly over the next years.
  • IFN- alpha interferon alpha
  • ribavirin the standard treatment for chronic HCV.
  • IFN-alpha belongs to a family of naturally occurring small proteins with characteristic biological effects such as antiviral, immunoregulatory, and antitumoral activities that are produced and secreted by most animal nucleated cells in response to several diseases, in particular viral infections.
  • IFN-alpha is an important regulator of growth and differentiation affecting cellular
  • a number of approaches are being pursued to combat the virus. These include, for example, application of antisense oligonucleotides or ribozymes for inhibiting HCV replication. Furthermore, low-molecular weight compounds that directly inhibit HCV proteins and interfere with viral replication are considered as attractive strategies to control HCV infection.
  • the viral targets the NS3/4a protease/helicase and the NS5b RNA-dependent RNA polymerase are considered the most promising viral targets for new drugs. Indeed, compounds said to be useful for treating HCV infections are disclosed, for example, in
  • WO2005/051318 Chounduru, et al.
  • WO2009/023179 Schomitz, et al.
  • antiviral activity can also be achieved by targeting host cell proteins that are necessary for viral replication.
  • antiviral activity can be achieved by inhibiting host cell cyclophilins.
  • a potent TLR7 agonist has been shown to reduce HCV plasma levels in humans.
  • Flaviviridae family of viruses and further in view of the limited treatment options, there is a strong need for new effective drugs for treating infections cause by these viruses.
  • Z is optionally a bond or (d-C 3 )alkylene
  • W is selected from CH or N;
  • A is selected from the group consisting of hydrogen, halo, (C C 6 )alkyl, (C r C 6 )alkoxy, (C C 6 )alkenyl, (C C 6 )alkynyl, (C 3 -C 14 )cycloalkyl, aryl, hydroxyl, -NR 6 R 6 , -NR 6 C(0)NR 6 R 6 , -OR 6 (R 5 ) m , -OR 6 (R 5 ) y , -R 6 (R 5 ) m , -alkyl(R 5 ) 2 R 6 , -S0 2 NR 6 R 6 , -C(0)NR 6 R 6 , -OR 7 , -R 6 R 7 , -S0 2 R 6 , -NR 6 C(S)NR 6 R 6 , ⁇ NR 6 S(0) 2 R 6 , -alkylR 9 R 6 , -NR 6 C(0)OR 6 , -NR 6 C(0)
  • R 2 is independently selected from the group consisting of hydroxyl, oxo, (CrC 6 )alkyl, (C 3 -Ci 4 )cycloalkyl, -alkylR 8 , and aryl, or optionally two R 2 alkyl groups, together with any intervening atoms, form a spiro or fused (C 3 -C 14 )cycloalkyl ring;
  • R 2' , R 3 , R 3' and R 4' are independently selected from the group consisting of hydrogen, (C C 6 )alkyl, (C 3 -C 14 )cycloalkyl, and -alkylR 8 ; wherein said alkyl or cycloalkyl group is optionally substituted with one to three R 12 groups;
  • R 4 is selected from the group consisting of hydrogen, hydroxyl, halo, nitrile, (CrC 6 )alkyl, (C C 6 )alkoxy, (d-C ⁇ alkenyl, (C C 6 )alkynyl, (C 3 -C 14 )cycloalkyl, aryl, -aryl(R 2 ) y , -arylR 12 , -OR 6 (R 5 ) y , -OR 6 (R 5 ) m , -R 6 (R 5 ) m , -alkyl(R 5 ) y R 6 , -aikyl(R 5 ) x (R 6 ) y ,
  • R 5 is independently selected from the group consisting of hydrogen and halo
  • R 6 is independently selected from the group consisting of hydrogen and (C C 6 )alkyl
  • R 7 is (C 3 -C 14 )cycloalkyl
  • R 8 is hydroxyl
  • R 9 is carboxyl
  • R 10 is independently selected from the group consisting of (C C 6 )alkyl, (CrC 6 )alkoxy, (CrC 6 )alkenyl, (C 1 -C 6 )alkynyl, hydroxyl, oxo, carboxyl, cyano, halo,
  • R 11 is independently selected from the group consisting of (Ci-C 6 )alkyl, (CrC 6 )all oxy, (C C 6 )alkenyl, (C C 6 )alkynyl, oxo, dioxo, hydroxyl, -NR 6 R 6 , -NR 6 C(0)R 6 , -OC(0)R 6 , -OR 6 (R 5 ) m , -OR 6 (R 5 ) y , -R 6 (R 5 ) m , -alkyl(R 5 ) y R 6 , halo, -C(0)NR 6 R 6 , -S0 2 NR 6 R 6 , -S0 2 R 6 , -alkylR 8 , -alkylR 9 , -alkylR 9 R 6 , (C 3 -C 14 )cycloalkyl, aryl, phosphate, (C 2 -C 6 )heterocyclic having
  • R 12 is independently selected from the group consisting of (C C 6 )alkyl, (C C 6 )alkoxy, oxo, halo, hydroxyl, carboxyl, cyano, -OR 6 (R 5 ) m , -OR 6 (R 5 ) y , -R 6 (R 5 ) m , and -NR 6 R 6 ;
  • R 14 is selected from the group consisting of
  • R 15 is independently selected from the group consisting of (C 1 -C 6 )alkyl, (C C 6 )alkoxy, -OR 8 , halo, oxo, dioxo, nitrile, -N0 2 , and -C0 2 R 8 ;
  • each m is independently an integer from 1 to 3;
  • each n is independently an integer from 1 to 4.
  • each y is independently an integer from 1 to 3.
  • composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof.
  • a method for treating a viral infection in a patient mediated at least in part by a virus in the Flaviviridae family of viruses comprising administering to said patient a composition comprising a compound Formula (I), or a pharmaceutically acceptable salt or solvate thereof.
  • the viral infection is mediated by hepatitis C virus.
  • Alkyl refers to monovalent saturated aliphatic hydrocarbyl groups having from 1 to 14 carbon atoms and, in some embodiments, from 1 to 6 carbon atoms.
  • (C x .C y )alkyl refers to alkyl groups having from x to y carbon atoms. This term includes, by way of example, linear and branched hydrocarbyl groups such as methyl (CH 3 -), ethyl (CH 3 CH 2 -), n-propyl
  • Alkylidene or “alkylene” refers to divalent saturated aliphatic hydrocarbyl groups having from 1 to 10 carbon atoms and, in some embodiments, from 1 to 6 carbon atoms.
  • (C u _v)alkylene refers to alkylene groups having from u to v carbon atoms.
  • the alkylidene and alkylene groups include branched and straight chain hydrocarbyl groups.
  • (C ⁇ 6 )alkylene is meant to include methylene, ethylene, propylene, 2-methypropylene, pentylene, and so forth.
  • (C x -C y )alkenyl refers to alkenyl groups having from x to y carbon atoms and is meant to include for example, ethenyl, propenyl, isopropylene, 1 ,3-butadienyl, and the like.
  • Alkynyl refers to a linear monovalent hydrocarbon radical or a branched monovalent hydrocarbon radical containing at least one triple bond.
  • alkynyl is also meant to include those hydrocarbyl groups having one triple bond and one double bond.
  • (C 2 -C 6 )all ynyl is meant to include ethynyl, propynyl, and the like.
  • Alkoxy refers to the group -O-alkyl wherein alkyl is defined herein. Alkoxy includes, by way of example, methoxy, ethoxy, /7-propoxy, isopropoxy, n-butoxy, i-butoxy, sec-butoxy, and n-pentoxy.
  • Acyl refers to the groups H-C(O)-, alkyl-C(O)-, alkenyl-C(O)-, alkynyl-C(O)-, cycloalkyl-C(O)-, aryl-C(O)-, heteroaryl-C(O)-, and heterocyclic-C(O)-.
  • Acyl includes the "acetyl” group CH 3 C(0)-.
  • Acylamino refers to the groups -NR 20 C(O)alkyl, -NR 20 C(O)cycloalkyl,
  • R 20 is hydrogen or alkyl
  • Acyloxy refers to the groups alkyl-C(0)0-, alkenyl-C(0)0-, alkynyl-C(0)0-, aryl-C(0)0-, cycloalkyl-C(0)0-, heteroaryl-C(0)0-, and heterocyclic-C(0)0-.
  • Amino refers to the group -NR 21 R 22 where R 2 and R 22 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclic, -S0 2 -alkyl, -S0 2 -alkenyl, -S0 2 -cycloalkyl, -S0 2 -aryl, -S0 2 -heteroaryl, and -S0 2 -heterocyclic, and wherein R 21 and R 22 are optionally joined together with the nitrogen bound thereto to form a heterocyclic group.
  • R 21 is hydrogen and R 22 is alkyl
  • the amino group is sometimes referred to herein as alkylamino.
  • R 21 and R 22 are alkyl, the amino group is sometimes referred to herein as dialkylamino.
  • a monosubstituted amino it is meant that either R 21 or R 22 is hydrogen but not both.
  • a disubstituted amino it is meant that neither R 21 nor R 22 are hydrogen.
  • Hydroxyamino refers to the group -NHOH.
  • Alkoxyamino refers to the group -NHO-alkyl wherein alkyl is defined herein.
  • Aminocarbonyl refers to the group -C(0)NR 26 R 27 where R 26 and R 27 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclic, hydroxy, alkoxy, amino, and acylamino, and where R 26 and R 27 are optionally joined together with the nitrogen bound thereto to form a heterocyclic group.
  • Aryl refers to an aromatic group of from 6 to 14 carbon atoms and no ring heteroatoms and having a single ring (e.g. , phenyl) or multiple condensed (fused) rings (e.g. , naphthyl or anthryl).
  • aryl applies when the point of attachment is at an aromatic carbon atom (e.g., 5,6,7,8 tetrahydronaphthalene-2-yl is an aryl group as its point of attachment is at the 2-position of the aromatic phenyl ring).
  • Cyano or “carbonitrile” or “nitrile” refers to the group -CN.
  • Cycloalkyi refers to a saturated or partially saturated cyclic group of from 3 to
  • cycloalkyi 14 carbon atoms and no ring heteroatoms and having a single ring or multiple rings including fused, bridged, and spiro ring systems.
  • cycloalkyi applies when the point of attachment is at a non-aromatic carbon atom (e.g. 5,6,7,8,-tetrahydronaphthalene-5-yl).
  • cycloalkyi includes cycloalkenyl groups, such as cyclohexenyl.
  • cycloalkyi groups include, for instance, adamantyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclooctyl, cyclopentenyi, and cyclohexenyl.
  • Examples of cycloalkyi groups that include multiple bicycloalkyl ring systems are bicyclohexyl, bicyclopentyl, bicyclooctyl, and the like. Two such bic cloalkyl multiple ring structures are exemplified and named below: bicyclohexyl, and bicyclohexyl.
  • (C u -C v )cycloalkyl refers to cycloalkyi groups having u to v carbon atoms.
  • spiro cycloalkyi or "cycloalkyi” also refers to a 3 to 10 member cyclic substituents formed by replacement of two hydrogen atoms at a common carbon atom in a cyclic ring structure or in an alkylene group having 2 to 9 carbon atoms, as exemplified, in one embodiment by the following structure, wherein the cyclopropyl group shown here attached to bonds marked with wavy lines and any intervening carbon atoms is substituted with a spiro cycloalkyi group:
  • Fused cycloalkyi refers to a 3 to 10 member cyclic substituent formed by the replacement of two hydrogen atoms at different carbon atoms in a cycloalkyi ring structure, as exemplified by the following structure wherein the cycloalkyi group shown here contains bonds marked with wavy lines which are bonded to carbon atoms that are substituted with a fused cycloalkyi group:
  • Halo or "halogen” refers to fluoro, chloro, bromo, and iodo.
  • Haloalkoxy refers to substitution of alkoxy groups with 1 to 5 (e.g. when the alkoxy group has at least 2 carbon atoms) or in some embodiments 1 to 3 halo groups (e.g. trifluoromethoxy).
  • Heteroaryl refers to an aromatic group of from 1 to 14 carbon atoms and 1 to 6 heteroatoms selected from oxygen, nitrogen, and sulfur and includes single ring (e.g. imidazolyl) and multiple ring systems (e.g. benzimidazol-2-yl and benzimidazol-6-yl).
  • single ring e.g. imidazolyl
  • multiple ring systems e.g. benzimidazol-2-yl and benzimidazol-6-yl.
  • the term “heteroaryl” applies if there is at least one ring heteroatom and the point of attachment is at an atom of an aromatic ring (e.g.
  • the nitrogen and/or the sulfur ring atom(s) of the heteroaryl group are optionally oxidized to provide for the N-oxide (N ⁇ 0), sulfinyl, or sulfonyl moieties.
  • heteroaryl includes, but is not limited to, pyridyl, furanyl, thienyl, thiazolyl, isothiazolyl, triazolyl, imidazolyl, imidazolinyl, isoxazolyl, pyrrolyl, pyrazolyl, pyridazinyl, pyrimidinyl, purinyl, phthalazyl, naphthylpryidyl, benzofuranyl,
  • Heterocyclic or “heterocycle” or “heterocycloalkyl” or “heterocyclyl” refers to a saturated or partially saturated cyclic group having from 1 to 14 carbon atoms and from 1 to 6 heteroatoms selected from nitrogen, sulfur, phosphorus or oxygen and includes single ring and multiple ring systems including fused, bridged, and spiro ring systems.
  • heterocyclic For multiple ring systems having aromatic and/or non-aromatic rings, the terms “heterocyclic”, “heterocycle”, “heterocycloalkyl”, or “heterocyclyl” apply when there is at least one ring heteroatom and the point of attachment is at an atom of a non-aromatic ring (e.g.
  • the nitrogen, phosphorus and/or sulfur atom(s) of the heterocyclic group are optionally oxidized to provide for the N-oxide, phosphinane oxide, sulfinyl, sulfonyl moieties.
  • the heterocyclyi includes, but is not limited to, tetrahydropyranyl, piperidinyl, piperazinyl, 3-pyrrolidinyl, 2- pyrrolidon-1-yl, morpholinyl, and pyrrolidinyl.
  • a prefix indicating the number of carbon atoms (e.g. , C3-C-10) refers to the total number of carbon atoms in the portion of the heterocyclyi group exclusive of the number of heteroatoms.
  • heterocycle and heteroaryl groups include, but are not limited to, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, pyridone, indolizine, isoindole, indole, dihydroindole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1 ,2,3,4-tetra
  • fused heterocyclic refers to a 3 to 10 member cyclic substituent formed by the replacement of two hydrogen atoms at different carbon atoms in a cycloalkyi ring structure, as exemplified by the following structure wherein the cycloalkyi group shown here contains bonds marked with wavy lines which are bonded to carbon atoms that are substituted with a fused heterocyclic group:
  • Compound refers to a compound encompassed by the generic formulae disclosed herein, any subgenus of those generic formulae, and any forms of the compounds within the generic and subgeneric formulae, including the racemates, stereoisomers, and tautomers of the compound or compounds.
  • Oxazolidine refers to a 5-membered heterocyclic ring containing one nitrogen and one oxygen as heteroatoms and also contains three carbons as exemplified by any of the following structures, wherein the oxazolidine groups shown here are bonded to a parent molecule, which is indicated by a wavy line in the bond to the parent molecule:
  • Oxazoiidinone refers to a 5-membered heterocyclic ring containing one nitrogen and one oxygen as heteroatoms and also contains three carbons and is substituted at one of the three carbons by an oxo group as exemplified by any of the following structures, wherein the oxazoiidinone groups shown here are bonded to a parent molecule, which is indicated by a wavy line in the
  • Oxazolidinedione refers to a 5-membered heterocyclic ring containing one nitrogen and one oxygen as heteroatoms and also contains three carbons and is substituted at two of the three carbons by oxo groups as exemplified by any of the following structures, wherein the oxazolidinedione groups shown here are bonded to a parent molecule, which is indicated by a wavy line in the bond to the parent molecule:
  • Racemates refers to a mixture of enantiomers.
  • the compounds of Formula I, or pharmaceutically acceptable salts thereof are enantiomerically enriched with one enantiomer wherein all of the chiral carbons referred to are in one configuration.
  • reference to an enantiomerically enriched compound or salt is meant to indicate that the specified enantiomer will comprise more than 50% by weight of the total weight of all enantiomers of the compound or salt.
  • Solvate or “solvates” of a compound refer to those compounds, as defined above, which are bound to a stoichiometric or non-stoichiometric amount of a solvent.
  • Solvates of a compound includes solvates of all forms of the compound.
  • solvents are volatile, non-toxic, and/or acceptable for administration to humans in trace amounts. Suitable solvates include water.
  • Stereoisomer or “stereoisomers” refer to compounds that differ in the chirality of one or more stereocenters. Stereoisomers include enantiomers and diastereomers.
  • “Pharmaceutically acceptable salt” refers to pharmaceutically acceptable salts derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, and
  • salts of organic or inorganic acids such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, and oxalate.
  • Suitable salts include those described in P. Heinrich Stahl, Camille G. Wermuth (Eds.), Handbook of Pharmaceutical Salts Properties, Selection, and Use; 2002.
  • Patient refers to mammals and includes humans and non-human mammals.
  • Treating" or “treatment” of a disease in a patient refers to 1) preventing the disease from occurring in a patient that is predisposed or does not yet display symptoms of the disease; 2) inhibiting the disease or arresting its development; or 3) ameliorating or causing regression of the disease.
  • a dotted line adjacent to an unbroken line means that a double bond may or may not be present (and if not present, that the adjacent atoms are covalently bound via a single bond).
  • Such single bond or double bond substitution patterns are well known to the skilled artisan.
  • substituents that are not explicitly defined herein are arrived at by naming the terminal portion of the functionality followed by the adjacent functionality toward the point of attachment.
  • substituent "arylalkyloxycarbonyl” refers to the group (aryl)-(alkyl)-0-C(0)-.
  • C(R X ) 2 it should be understood that the two R x groups can be the same, or they can be different if R x is defined as having more than one possible identity.
  • certain substituents are drawn as -R x R y , where the "-" indicates a bond adjacent to the parent molecule and R y being the terminal portion of the functionality.
  • impermissible substitution patterns e.g., methyl substituted with 5 fiuoro groups. Such impermissible substitution patterns are well known to the skilled artisan.
  • Z is optionally a bond or (C C 3 )alkylene
  • W is selected from CH or N;
  • A is selected from the group consisting of hydrogen, halo, (C C 6 )alkyl, (C C 6 )alkoxy, (C C 6 )alkenyl, (C C 6 )alkynyl, (C 3 -C 14 )cycloalkyl, aryl, hydroxyl, -NR 6 R 6 , -NR 6 C(0)NR 6 R 6 , -OR 6 (R 5 ) m , -OR 6 (R 5 ) y , -R 6 (R 5 ) m , -alkyl(R 5 ) 2 R 6 , -S0 2 NR 6 R 6 , -C(0)NR 6 R 6 , -OR 7 , -R 6 R 7 , -S0 2 R 6 , -NR 6 C(S)NR 6 R 6 , -NR 6 S(0) 2 R 6 , -alkylR 9 R 6 , -NR 6 C(0)OR 6 , -NR 6 C(0)R 6
  • R 1 is selected from the group consisting of hydrogen, halo, cyano, hydroxyl, (C C 6 )alkyl, (C C 6 )alkoxy, (CrC 6 )alkenyl, (C C 6 )alkynyl, -C(0)N(R 6 ) 2 , -R 9 R 6 , -S0 2 NR 6 R 6 , -R 14 R 15 , -R 14 (R 15 ) 2 , -S0 2 R 6 , -OSi, -OSi(R 6 ) 3 , (C 3 -C 14 )cycloalkyl, (C 3 - C 14 )cycloalkenyl, -(C 3 -C )cycloaIkenyl-R , aryl, (C 2 -C 6 )heterocyclic having 1-3 heteroatoms selected from S, N and O, and (C 2 -C 6 )heteroaryl having 1-3 heteroatoms selected from
  • R 2 is independently selected from the group consisting of hydroxyl, oxo, (C C 6 )alkyl, (C 3 -C 4 )cycloalkyl, -alkylR 8 , and aryl, or optionally two R 2 alkyl groups, together with any intervening atoms, form a spiro or fused (C 3 -C 14 )cycloalkyl ring;
  • R 2' , R 3 , R 3' and R 4' are independently selected from the group consisting of hydrogen, (C C 6 )alkyl, (C 3 -C 1 )cycloalkyl, and -alkylR 8 ; wherein said alkyl or cycloalkyl group is optionally substituted with one to three R 12 groups;
  • R 4 is selected from the group consisting of hydrogen, hydroxyl, halo, nitrile, (C C 6 )alkyl, (C C 6 )alkoxy, (C C 6 )alkenyl, (C C 6 )alkynyl, (C 3 -C 1 )cycloalkyl, aryl, -aryl(R 12 ) y , -arylR 12 , -OR 6 (R 5 ) y , -OR 6 (R 5 ) y , -OR 6 (R 5 ) m , -R 6 (R 5 ) m , -alkyl(R 5 ) y R 6 , -alkyl(R 5 ) x (R 6 ) y , -alkylR 9 R 6 , -C(0)R 14 , -R 9 R 6 , -R 9 R 14 , -R 9 R 7 , -NR 6 R 6 , -NR 6 C(0)
  • R 5 is independently selected from the group consisting of hydrogen and halo
  • R 6 is independently selected from the group consisting of hydrogen and (C C 6 )alkyl
  • R 7 is (C 3 -C 4 )cycloalkyl
  • R 8 is hydroxyl
  • R 9 is carboxyl
  • R 10 is independently selected from the group consisting of (C C 6 )alkyl, (Ci-C 6 )alkoxy, (CrC 6 )alkenyl, (CrC 6 )alkynyl, hydroxyl, oxo, carboxyl, cyano, halo,
  • R 11 is independently selected from the group consisting of (C-i-CeJalkyl, (C C 6 )alkoxy, (C C 6 )alkenyl, (C C 6 )alkynyl, oxo, dioxo, hydroxyl, -NR 6 R 6 , -NR 6 C(0)R 6 , -OC(0)R 6 , -OR 6 (R 5 ) m , -OR 6 (R 5 ) y , -R 6 (R , -alkyl(R 5 ) y R 6 , halo, -C(0)NR 6 R 6 , -S0 2 NR 6 R 6 , -SO2R 6 , -alkylR 8 , -alkylR 9 , -alkylR 9 R 6 , (C 3 -Ci 4 )cycloalkyl, aryl, phosphate, (C 2 -C 6 )heterocyclic having 1-3 heteroatoms selected
  • R 12 is independently selected from the group consisting of (Ci-C 6 )alkyl, (C C 6 )alkoxy, oxo, halo, hydroxyl, carboxyl, cyano, -OR 6 (R 5 ) m , -OR 6 (R 5 ) y , -R 6 (R 5 ) m , and -NR 6 R 6 ;
  • R 14 is selected from the group consisting of (CrCn)heterocyclic and (CrC ⁇ heteroaryl, each independently having one to three heteroatoms selected from N and O;
  • R 15 is independently selected from the group consisting of (Ci-C 6 )alkyl, (CrC 6 )alkoxy,
  • each m is independently an integer from 1 to 3;
  • each n is independently an integer from 1 to 4.
  • each y is independently an integer from 1 to 3.
  • A is selected from the group consisting of hydrogen, (C C 6 )alkyl, halo, hydroxyl, (C C 6 )alkoxy, -OR 7 , -OR 6 (R 5 ) m , -OR 6 (R 5 ) y , -R 6 (R 5 ) m , (C 3 -C 14 )cycloalkyl, -NR 6 R 6 , - R 6 (C 3 -C 14 )cycloalkyl, (C 2 -C 6 )heterocyclic having 1-3 heteroatoms selected from S, N and O, and (C 2 -C 6 )heteroaryl having 1-3 heteroatoms selected from S, N, and O; wherein R 10 is absent.
  • A is selected from the group consisting of hydrogen, hydroxyl, bromo, fluoro, chloro, methyl, ethyl, propyl, butyl, pentyl, cyclopropyl, cyclopropylmethyl, dimethylamino, cyclopropyloxy, methoxy, ethoxy, propoxy, trifluoromethoxy, difluoromethoxy, pyrazolyl, furanyl, pyrrolyl, triazolyl, thiophenyl, tetrahydrofuranyl, tetrahydropyranyl, pyridyl, and imidazolyl.
  • R is selected from the group consisting of hydrogen, (C C 6 )alkyl, (C 3 - C 14 )cycloalkyl, -OSi, -OSi(R 6 ) 3 , aryl, (C 2 -C 6 )heterocyclic having 1-3 heteroatoms selected from S, N and O, and (C 2 -C 6 )heteroaryl having 1-3 heteroatoms selected from S, N, and O; wherein said alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclic group is optionally substituted with one to three R 11 groups.
  • R 1 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, pentyl, cyano, carboxyl, hydroxyl, acetate, thiazolyl, cyclopropyl, cyclobutyl, bicyclohexyl, bicyclopentyl, bicyclooctyl, cyclohexyl, cyclopentyl, cyclopentenyl, cyclohexenyl, cycloheptyl, phenyl, benzyl, pyridyl, pyridinyl, pyrrolidinyl, piperidinyl, thiophenyl, oxazolidinone, oxazolidine, oxazplidinedione, pyrazolyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, and thienyl
  • R 1 is selected from the group consisting of pyrrolidinyl, oxazolidinone, oxazolidine, oxazolidinedione, cyclopentyl, cyclobutyl, cyclohexyl, and bicyclohexyl.
  • R 2 is selected from the group consisting of oxo, methyl, and ethyl, and n is integer from 1 to 2.
  • R 3 is selected from the group consisting of hydrogen, (Ci-C 6 )alkyl, and (C 3 - C 4 )cycloalkyl; wherein said alkyl or cycloalkyi group is optionally substituted with one to three R 12 groups.
  • R 3 is selected from the group consisting of hydrogen, methyl, ethyl, and propyl.
  • R 4 is selected from the group consisting of hydrogen, hydroxyl, (C
  • C 6 )alkyl (C C 6 )alkenyl, (Ci-C 6 )alkoxy, amino, dimethyamino, halo, nitrile, (C 3 -C 14 )cycloalkyl, aryl, -aryl(R 12 ) x , -aryl(R 2 ) y , -OR 6 (R 5 ) y , -OR 6 (R 5 ) m , -R 6 (R 6 ) m , -alkyl(R 5 ) y R 6 , and (C 2 - C 6 )heterocyclic having 1-3 heteroatoms selected from S, N and O.
  • R 4 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, fluorophenyl, difluorophenyl, phenyl, difluoromethoxy, piperidinylcarbonyl, cyclohexylmethyl, amino, phenylmethylamino, methyloxyethylamino, methylpropenyl, pyrrolyl, pyrrolidinyl, oxazolyl, pyridinyl, dimethylamino, methylcarboxylate, methylamino, isopropylene, methoxy, ethoxy, cyciopropyl, cyclobutyl, cyclohexyl, cyclopentyl, chloro, fluoro, bromo, difluoroethyl, and trifluoromethyl.
  • R 1 is selected from the group consisting of hydroxyl, dioxo, oxo, nitrile, - OC(0)R 6 , -alkylR 8 , -R 6 (R 5 ) m , halo, (C C 6 )alkyl, phosphate, and (C C 6 )alkoxy; or optionally two R 11 groups, together with any intervening atoms, form a fused cyciopropyl ring; wherein said fused cyciopropyl ring is optionally substituted with one to two R 12 groups.
  • R 11 is selected from the group consisting of hydroxyl, dioxo, oxo, fluoro, difluoro, and phosphate.
  • R 11 is selected from the group consisting of hydroxyl and phosphate.
  • R 12 is selected from the group consisting of halo, nitrile, and hydroxyl.
  • Z is optionally a bond or methylene
  • W is selected from CH or N;
  • A is selected from the group consisting of hydrogen, bromo, fluoro, chloro, methyl, ethyl, propyl, butyl, pentyl, cyclopropyl, cyclopropyloxy, methoxy, ethoxy, propoxy, difluoromethoxy, pyrazolyl, furanyl, pyrrolyl, triazolyl, thiophenyl,
  • R 1 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, pentyl, cyano, carboxyl, acetate, thiazolyl, cyclopropyl, bicyclohexyl, cyclobutyl, bicyclopentyl, bicyclooctyl, cyclohexyl, cyclopentyl, cyclopentenyl, cyclohexenyl, cycloheptyl, phenyl, benzyl, pyridyl, pyridinyl, pyrrolidinyl, piperidinyl, thiophenyl, oxazolidinone, pyrazolyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, and thienyl, wherein R 1 is optionally substituted with one to three R 11 ;
  • R 2 is independently selected from the group consisting of hydrogen, oxo, methyl, ethyl, cyclopropyl, hydroxymethyl, and phenyl, or optionally two R 2 groups, together with any intervening atoms, form a spiro or fused cycloalkyl ring;
  • R 3 is selected from the group consisting of hydrogen, methyl, ethyl, and propyl
  • R 4 is selected from the group consisting of hydrogen, methyl, ethyl, isopropyl,
  • R 11 is independently selected from the group consisting of hydroxyl, oxo, hydroxymethyl, acyloxy, fluoro, trifluoromethyl, methoxy, phosphate, and methyl; and n is zero or an integer from 1 to 4.
  • Z is optionally a bond or methylene
  • W is selected from CH or N;
  • A is selected from the group consisting of hydrogen, (CrC 6 )alkoxy, halo, and (C 3 - C 4 )cycloalkyl;
  • R 1 is selected from the group consisting of (C 3 -C 14 )cycloalkyl and (C 2 -C 6 )heterocyclic having 1-2 heteroatoms selected from N and O, wherein R is optionally substituted with one to three R 11 ;
  • R 2 is oxo
  • R 3 is selected from the group consisting of hydrogen, methyl, ethyl, and propyl
  • R 4 is trifluoromethyl
  • R 11 is independently selected from the group consisting of phosphate, fluoro, hydroxyl, and oxo;
  • n zero or 1.
  • Z is optionally a bond or methylene
  • W is selected from CH or N;
  • A is selected from the group consisting of hydroxyl and cyclopropyl
  • R 1 is selected from the group consisting of oxazolidinone, cyclopentyl, cyclobutyl, bicyclohexyl, and cyclohexyl, wherein R 1 is optionally substituted with one to three R 11 ; R 2 is oxo;
  • R 3 is selected from the group consisting of hydrogen, methyl, ethyl, and propyl
  • R 4 is trifluoromethyl
  • R 11 is independently selected from the group consisting of phosphate, fluoro, hydroxyl, and oxo;
  • n zero or 1.
  • a pharmaceutical composition comprising a pharmaceutically acceptable diluent and a therapeutically effective amount of a compound as defined in a compound of Formula (I).
  • a method for treating a viral infection in a mammal mediated at least in part by a virus in the Flaviviridae family of viruses which method comprises administering to a mammal, that has been diagnosed with said viral infection or is at risk of developing said viral infection, a compound of Formula (I).
  • a method for treating a viral infection in a mammal mediated at least in part by a virus in the Flaviviridae family of viruses which method comprises administering to a mammal, that has been diagnosed with said viral infection or is at risk of developing said viral infection, a compound of Formula (I), wherein said virus is hepatitis C virus.
  • a method for treating a viral infection in a mammal mediated at least in part by a virus in the Flaviviridae family of viruses comprises administering to a mammal, that has been diagnosed with said viral infection or is at risk of developing said viral infection, a compound of Formula (I), further comprising administration of a therapeutically effective amount of one or more agents active against hepatitis C virus.
  • a method for treating a viral infection in a mammal mediated at least in part by a virus in the Flaviviridae family of viruses comprises administering to a mammal, that has been diagnosed with said viral infection or is at risk of developing said viral infection, a compound of Formula (I), further comprising administration of a therapeutically effective amount of one or more agents active against hepatitis C virus, wherein said agent active against hepatitis C virus is an inhibitor of HCV protease, HCV polymerase, HCV helicase, HCV entry, HCV assembly, HCV egress, HCV replicase, HCV NS5A protein, or inosine 5'-monophosphate dehydrogenase,
  • a method for treating a viral infection in a mammal mediated at least in part by a virus in the Flaviviridae family of viruses comprises administering to a mammal, that has been diagnosed with said viral infection or is at risk of developing said viral infection, a compound of Formula (I), further comprising administration of a therapeutically effective amount of one or more agents active against hepatitis C virus, wherein said agent active against hepatitis C virus is interferon.
  • a method for treating a viral infection in a mammal mediated at least in part by a virus in the Flaviviridae family of viruses comprises administering to a mammal, that has been diagnosed with said viral infection or is at risk of developing said viral infection, a compound of Formula (I), further comprising administration of a therapeutically effective amount of one or more agents active against hepatitis C virus, wherein said agent active against hepatitis C virus is ribavirin.
  • a method for treating a viral infection in a mammal mediated at least in part by a virus in the Flaviviridae family of viruses comprises administering to a mammal, that has been diagnosed with said viral infection or is at risk of developing said viral infection, a compound of Formula (I), further comprising administration of a therapeutically effective amount of one or more agents active against hepatitis C virus, wherein said agent active against hepatitis C virus is interferon in combination with ribavirin.
  • the compound of the present invention is chosen from the compounds set forth in Table 1.
  • the compound of the present invention or a
  • the compound(s) of the present invention is chosen from the compounds set forth in Table 1 and/or Table 2.
  • the provided chemical entities may contain one or more chiral centers and such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as stereoisomer-enriched mixtures. All such stereoisomers (and enriched mixtures) are included within the scope of this specification, unless otherwise indicated. Pure stereoisomers (or enriched mixtures) may be prepared using, for example, optically active starting materials or stereoselective reagents well-known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents and the like.
  • the starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof.
  • many of the starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Ernka-Chemce or Sigma (St. Louis, Missouri, USA).
  • Others may be prepared by procedures, or obvious modifications thereof, described in standard reference texts such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley and Sons, 1991), Rodd's Chemistry of Carbon
  • reaction times and conditions are intended to be approximate, e.g., taking place at about atmospheric pressure within a temperature range of about -78 °C to about 110 °C over a period of about 1 to about 24 hours; reactions left to run overnight average a period of about 16 hours.
  • solvent each mean a solvent inert under the conditions of the reaction being described in conjunction therewith, including, for example, benzene, toluene, acetonitrile, tetrahydrofuranyl (“THF”), dimethylformamide (“DMF”), chloroform, methylene chloride (or dichloromethane), diethyl ether, methanol, N- methylpyrrolidone (“NMP”), pyridine and the like.
  • solvent solvent inert under the conditions of the reaction being described in conjunction therewith, including, for example, benzene, toluene, acetonitrile, tetrahydrofuranyl (“THF”), dimethylformamide (“DMF”), chloroform, methylene chloride (or dichloromethane), diethyl ether, methanol, N- methylpyrrolidone (“NMP”), pyridine and the like.
  • THF tetrahydrofuranyl
  • DMF dimethylformamide
  • Isolation and purification of the chemical entities and intermediates described herein can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, extraction, crystallization, column chromatography, thin-layer chromatography or thick-layer chromatography, or a combination of these procedures.
  • suitable separation and isolation procedures can be had by reference to the examples herein below. However, other equivalent separation or isolation procedures can also be used.
  • the (R)- and (S)-isomers may be resolved by methods known to those skilled in the art, for example by formation of diastereoisomeric salts or complexes which may be separated, for example, by crystallization; via formation of diastereoisomeric derivatives which may be separated, for example, by crystallization, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer-specific reagent, for example enzymatic oxidation or reduction, followed by separation of the modified and unmodified enantiomers; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support, such as silica with a bound chiral ligand or in the presence of a chiral solvent.
  • a specific enantiomer may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer to the other
  • Scheme 1 shows a representative general synthesis of certain substituted benzimidazole carboxylic acids.
  • Diamines (I) readily available from the nitration and subsequent reduction of appropriately substituted anilines, can be cyclized via a variety of methods known to those skilled in the art to the benzimidazoles (II).
  • Hydrolysis of the trichloromethyl substitituent affords the substituted 1W-benzimidazole-2-carboxylic acids (III) which can be coupled to appropriately substituted amines via coupling reagents known to those skilled in the art thereby giving the amides (V).
  • Alkylation of the benzimidazole nitrogen can yield compounds (VI).
  • intermediates (II) can be transformed to intermediates (IV) via hydrolysis/alkylation (or vice-versa) and intermediates (IV) can be coupled to appropriately substituted amines via coupling reagents known to those skilled in the art thereby giving the amides (VI).
  • N-[(dimethylamino)(3H-[1 ,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylidene]-N- methylmethanaminium hexafluorophosphate (HATU) 130 mg, 0.34 mmol was added to a stirring mixture of 5-bromo-7-(trifluoromethyl)-1 W-benzimidazole-2-carboxylic acid (96 mg, 0.31 mmol), 1-cyclopentyl-2-piperazinone (64 mg, 0.31 mmol), and N,N-diisopropylethylamine (0.22 mL, 1.2 mmol) in N,N-dimethylformamide (3.0 mL).
  • N-Boc-glycine methyl ester (1.758 mL, 11.89 mmol) in N,N-dimethylformamide (30 mL) was cooled to 5 °C then allyl bromide (1.544 mL, 17.84 mmol) was added followed by sodium hydride (0.713 g, 17.84 mmol) . The mixture was stirred for 2 hours, quenched with saturated ammonium chloride and extracted 2 times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated.
  • HATU hexafluorophosphate
  • DIAD (8.11 mL, 41.7 mmol) was added to a solution of (cis)-bicyclo[3.1.0]hexan- 3-ol (3.15 g, 32.1 mmol), 1 H-isoindole-1 ,3(2H)-dione (6.14 g, 41.7 mmol), and
  • triphenylphosphine (10.94 g, 41.7 mmol) in THF (300 mL) at 0 °C. After 1 hour at 0 °C, the starting alcohol appeared to be gone by TLC. The reaction was warmed to RT and stirred overnight. Water (25 mL) and EtOAc (50 mL) were added. The organic layer was separated, washed with brine, dried over MgS0 4 , filtered and concentrated to give a yellow solid.
  • oxazolidine-2, 4-dione To sodium 6-bromo-1-methyl-4-(trifluoromethyl)-1f/-benzimidazole-2-carboxylate (200 mg; 0.58 mmol) in N,N-dimethylformamide (5 mL) was added 3-(4-piperidinyl)-1 ,3- oxazolidine-2,4-dione (150 mg; 0.70 mmol), A/-ethyl-A/-(1-methylethyl)-2-propanamine (224 mg; 1.74 mmol), and N-[(dimethylamino)(3H-[1 ,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylidene]-N- methylmethanaminium hexafluorophosphate (HATU) (265 mg; 0.70 mmol).
  • HATU N-[(dimethylamino)(3H-[1 ,2,3]triazol
  • the reaction mixture was stirred for 48 hours.
  • the reaction was then treated by the addition of sodium dithionite (40 g) in water (150 mL) and stirred for an additional 48 hours.
  • the mixture was diluted with EtOAc and the combined organic layers were washed with saturated NH 4 CI (2x), brine, dried Na 2 S0 4 , filtered, and concentrated to give a brownish oily solid.
  • the residue was concentrated from toluene then taken up in EtOAc and water.
  • the combined organics were washed with saturated NaHC0 3 , brine, dried Na 2 S0 4 , filtered, and concentrated to give a brownish oil with solids.
  • the aqueous phase was extracted with DCM (3x) and the combine organics were washed with saturated NaHC0 3 , brine, dried MgS0 4 , filtered, and concentrated.
  • the residue was treated with DMF (10 mL) and cooled to 0 °C.
  • the reaction was treated with imidazole (0.304 g, 4.46 mmol) then by the addition of TBSCI (0.403 g, 2.68 mmol).
  • the reaction was stirred at room temperature for 2 hours and diluted with water and extracted with EtOAc.
  • the combined organics were washed with LiCI (3x), saturated NaHC0 3 , brine, dried MgS0 , filtered, and concentrated.
  • the reaction was then treated by the drop-wise (1 drop every 3-5 second) addition of 0.5M in THF bromo(cyclopentyl)zinc (1.018 ml, 0.509 mmol) .
  • the reaction was stirred at room temperature for the 48 hours.
  • the reaction was treated with additional copper(l) iodide (0.019 g, 0.102 mmol), PdCI 2 (dppf)-CH 2 CI 2 adduct (0.028 g, 0.034 mmol) and then with 0.5 M in THF bromo(cyclopentyl)zinc (1.018 ml, 0.509 mmol).
  • the reaction was stirred for an additional 90 minutes.
  • reaction was then treated by the drop-wise (1 drop every 3-5 second) addition of 0.5M in THF bromo(cyclohexyl)zinc (0.799 ml, 0.399 mmol) .
  • the reaction was stirred at room temperature overnight.
  • the reaction was treated with additional copper(l) iodide (0.015 g, 0.080 mmol) and 0.5 M in THF

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Abstract

Provided are compounds of Formula (I) and (II) and pharmaceutically acceptable salts thereof, their pharmaceutical compositions, their methods of preparation, and their use for treating viral infections mediated by a member of the Flaviviridae family of viruses such as hepatitis C virus (HCV).

Description

BENZIMIDAZOLE ANTIVIRAL AGENTS
CROSS REFERENCE TO RELATED PATENTS AND PATENT APPLICATIONS
[0001] This application is a Patent Cooperation Treaty application and claims the priority benefit of U.S. Provisional Patent Application No. 61/301 ,337, filed February 4, 2010, which is incorporated herein by reference in its entirety.
FIELD OF THE INVENTION
[0002] Provided are compounds, pharmaceutical compositions, their methods of preparation, and their use for treating viral infections mediated by a member of the Flaviviridae family of viruses such as hepatitis C virus (HCV).
BACKGROUND OF THE INVENTION
[0003] Chronic infection with HCV is a major health problem associated with chronic liver disease, cirrhosis, hepatocellular carcinoma, and liver failure. HCV is a hepacivirus member of the Flaviviridae family of RNA viruses that affect animals and humans. The genome is a single ~9.6-kilobase strand of RNA, and consists of one open reading frame that encodes for a polyprotein of ~3000 amino acids flanked by untranslated regions at both 5' and 3' ends (5'- and 3'-UTR). The polyprotein serves as the precursor to at least 10 separate viral proteins critical for replication and assembly of progeny viral particles. The organization of structural and non-structural proteins in the HCV polyprotein is as follows: C-E1-E2-p7-NS2-NS3-NS4a-NS4b- NS5a-NS5b. Because the replicative cycle of HCV does not involve any DNA intermediate and the virus is not integrated into the host genome, HCV infection can theoretically be cured. While the pathology of HCV infection affects mainly the liver, the virus is found in other cell types in the body including peripheral blood lymphocytes.
[0004] HCV is major causative agent for post-transfusion and for sporadic hepatitis.
Infection by HCV is insidious in a high proportion of chronically infected (and infectious) carriers who may not experience clinical symptoms for many years. An estimated 170 million chronic carriers worldwide are at risk of developing liver disease. See, for example, Szabo, et al., Pathol. Oncol.Res. 2003, 9:215-221 , and Hoofnagle JH, Hepatology 1997, 26:15S-20S. In the United States alone 2.7 million are chronically infected with HCV, and the number of HCV- related deaths in 2000 was estimated between 8,000 and 10,000, a number that is expected to increase significantly over the next years.
[0005] At present, the standard treatment for chronic HCV is interferon alpha (IFN- alpha) in combination with ribavirin and this requires at least six months of treatment. IFN-alpha belongs to a family of naturally occurring small proteins with characteristic biological effects such as antiviral, immunoregulatory, and antitumoral activities that are produced and secreted by most animal nucleated cells in response to several diseases, in particular viral infections. IFN-alpha is an important regulator of growth and differentiation affecting cellular
communication and immunological control. Treatment of HCV with interferon has frequently been associated with adverse side effects such as fatigue, fever, chills, headache, myalgias, arthralgias, mild alopecia, psychiatric effects and associated disorders, autoimmune phenomena and associated disorders and thyroid dysfunction. Ribavirin, an inhibitor of inosine 5'-monophosphate dehydrogenase (IMPDH), enhances the efficacy of IFN-alpha in the treatment of HCV. Despite the introduction of ribavirin, more than 50% of the patients do not eliminate the virus with the current standard therapy of interferon-alpha (IFN) and ribavirin. By now, standard therapy of chronic hepatitis C has been changed to the combination of pegylated IFN-alpha plus ribavirin. However, a number of patients still have significant side effects, primarily related to ribavirin. Ribavirin causes significant hemolysis in 10-20% of patients treated at currently recommended doses, and the drug is both teratogenic and embryotoxic. Even with recent improvements, a substantial fraction of patients do not respond with a sustained reduction in viral load and there is a clear need for more effective antiviral therapy of HCV infection.
[0006] A number of approaches are being pursued to combat the virus. These include, for example, application of antisense oligonucleotides or ribozymes for inhibiting HCV replication. Furthermore, low-molecular weight compounds that directly inhibit HCV proteins and interfere with viral replication are considered as attractive strategies to control HCV infection. Among the viral targets, the NS3/4a protease/helicase and the NS5b RNA-dependent RNA polymerase are considered the most promising viral targets for new drugs. Indeed, compounds said to be useful for treating HCV infections are disclosed, for example, in
WO2005/051318 (Chunduru, et al.) and WO2009/023179 (Schmitz, et al.). These references disclose methods for preparing the compounds, compositions comprising the compounds, compositions comprising the compounds and additional compounds, and methods of treating HCV. [0007] Besides targeting viral genes and their transcription and translation products, antiviral activity can also be achieved by targeting host cell proteins that are necessary for viral replication. For example, antiviral activity can be achieved by inhibiting host cell cyclophilins. Alternatively, a potent TLR7 agonist has been shown to reduce HCV plasma levels in humans.
[0008] In view of the worldwide epidemic level of HCV and other members of the
Flaviviridae family of viruses, and further in view of the limited treatment options, there is a strong need for new effective drugs for treating infections cause by these viruses.
SUMMARY OF THE INVENTION
[0009] In accordance with one embodiment of the present invention, there is provided a compound of Formula (I):
(I)
Figure imgf000004_0001
or a pharmaceutically acceptable salt thereof, wherein:
Z is optionally a bond or (d-C3)alkylene;
W is selected from CH or N;
A is selected from the group consisting of hydrogen, halo, (C C6)alkyl, (CrC6)alkoxy, (C C6)alkenyl, (C C6)alkynyl, (C3-C14)cycloalkyl, aryl, hydroxyl, -NR6R6, -NR6C(0)NR6R6, -OR6(R5)m, -OR6(R5)y, -R6(R5)m, -alkyl(R5)2R6, -S02NR6R6, -C(0)NR6R6, -OR7, -R6R7, -S02R6, -NR6C(S)NR6R6, ~NR6S(0)2R6, -alkylR9R6, -NR6C(0)OR6, -NR6C(0)R6, (C2-C6)heteroaryl having 1-3 heteroatoms selected from S, N, and O, (C2-C6)heterocyclic having 1-3 heteroatoms selected from S, N and O; wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclic group is optionally substituted with one to three R10 groups; R1 is selected from the group consisting of hydrogen, halo, cyano, hydroxyl, (C C6)alkyl, (C C6)alkoxy, (C C6)alkenyl, (C C6)alkynyl, -C(0)N(R6)2, -R9R6,
-S02NR6R6, -R14R15, -R1 (R15)2, -S02R6, -OSi, -OSi(R6)3, (C3-C14)cycloalkyl, (C3- C14)cycloalkenyl, -(C3-C 4)cycloalkenyl-R8, aryl, (C2-C6)heterocyclic having 1-3 heteroatoms selected from S, N and O, and (C2-C6)heteroaryl having 1-3 heteroatoms selected from S, N, and O; wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclic group is optionally substituted with one to three R1 groups;
R2 is independently selected from the group consisting of hydroxyl, oxo, (CrC6)alkyl, (C3-Ci4)cycloalkyl, -alkylR8, and aryl, or optionally two R2 alkyl groups, together with any intervening atoms, form a spiro or fused (C3-C14)cycloalkyl ring;
R2', R3, R3' and R4' are independently selected from the group consisting of hydrogen, (C C6)alkyl, (C3-C14)cycloalkyl, and -alkylR8; wherein said alkyl or cycloalkyl group is optionally substituted with one to three R12 groups;
R4 is selected from the group consisting of hydrogen, hydroxyl, halo, nitrile, (CrC6)alkyl, (C C6)alkoxy, (d-C^alkenyl, (C C6)alkynyl, (C3-C14)cycloalkyl, aryl, -aryl(R 2)y, -arylR12, -OR6(R5)y, -OR6(R5)m, -R6(R5)m, -alkyl(R5)yR6, -aikyl(R5)x(R6)y,
-alkylR9R6, -C(0)R14, -R9R6, -R9R14, -R9R7, -NR6R6, -NR6C(0)NR6R6,
-S02NR6R6, -NR6R6R11, -C(0)NR6R6, -OR7, -R6R7, -S02R6, -NR6C(S)NR6R6, -NR6S(0)2R6, -alkylR9R6, -NR6C(0)OR6, -NR6C(0)R6, (C2-C6) heteroaryl having 1-3 heteroatoms selected from S, N, and O, and (C2-C6)heterocyclic having 1-3 heteroatoms selected from S, N and O; wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclic group is optionally substituted with one to three R10 groups;
R5 is independently selected from the group consisting of hydrogen and halo;
R6 is independently selected from the group consisting of hydrogen and (C C6)alkyl;
R7 is (C3-C14)cycloalkyl;
R8 is hydroxyl;
R9 is carboxyl;
R10 is independently selected from the group consisting of (C C6)alkyl, (CrC6)alkoxy, (CrC6)alkenyl, (C1-C6)alkynyl, hydroxyl, oxo, carboxyl, cyano, halo,
-C(0)NH2, -S02NH2, -SR6, -S(0)R6, -S(0)2R6, -S(0)2NR6R6, -NR6R6,
-NR6C(0)NR6R6, -NR6C(S)NR6R6, -NR6S(0)2R6 -NR6C(0)OR6, -NR6C(0)R6, -C(NR6)NR6R6, -C(0)NR6R6, -C(0)OR6, -C(0)R6, (C3-C14)cycloalkyl, aryl, (C2- C6)heterocyclic having 1-3 heteroatoms selected from S, N and O, and (C2- C6)heteroaryl having 1-3 heteroatoms selected from S, N, and O;
R11 is independently selected from the group consisting of (Ci-C6)alkyl, (CrC6)all oxy, (C C6)alkenyl, (C C6)alkynyl, oxo, dioxo, hydroxyl, -NR6R6, -NR6C(0)R6, -OC(0)R6, -OR6(R5)m, -OR6(R5)y, -R6(R5)m, -alkyl(R5)yR6, halo, -C(0)NR6R6, -S02NR6R6, -S02R6, -alkylR8, -alkylR9, -alkylR9R6, (C3-C14)cycloalkyl, aryl, phosphate, (C2-C6)heterocyclic having 1-3 heteroatoms selected from S, N and O, and (C2-C6)heteroaryl having 1-3 heteroatoms selected from S, N, and O; or optionally two R11 groups, together with any intervening atoms, form a fused (C3- C14)cycloalkyl ring or a fused (C2-C6)heterocyclic ring having 1-3 heteroatoms selected from S, N and O; wherein said fused cycloalkyl ring or fused heterocyclic ring is optionally substituted with one to three R12 groups;
R12 is independently selected from the group consisting of (C C6)alkyl, (C C6)alkoxy, oxo, halo, hydroxyl, carboxyl, cyano, -OR6(R5)m, -OR6(R5)y, -R6(R5)m, and -NR6R6;
R14 is selected from the group consisting of
Figure imgf000006_0001
each independently having one to three heteroatoms selected from N and O;
R15 is independently selected from the group consisting of (C1-C6)alkyl, (C C6)alkoxy, -OR8, halo, oxo, dioxo, nitrile, -N02, and -C02R8;
each m is independently an integer from 1 to 3;
each n is independently an integer from 1 to 4; and
each y is independently an integer from 1 to 3.
[0010] Also provided is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof.
[0011] Also provided are synthetic intermediates, methods for preparing the compounds of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, and compositions thereof and for their therapeutic uses. In some embodiments, provided is a method for treating a viral infection in a patient mediated at least in part by a virus in the Flaviviridae family of viruses, comprising administering to said patient a composition comprising a compound Formula (I), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the viral infection is mediated by hepatitis C virus. Those and other embodiments are further described in the text that follows. DETAILED DESCRIPTION OF REPRESENTATIVE EMBODIMENTS
[0012] Throughout this application, references are made to various embodiments relating to compounds, compositions, and methods. The various embodiments described are meant to provide a variety of illustrative examples and should not be construed as descriptions of alternative species. Rather it should be noted that the descriptions of various embodiments provided herein may be of overlapping scope. The embodiments discussed herein are merely illustrative and are not meant to limit the scope of the present invention.
[0013] It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of the present invention. In this specification and in the claims that follow, reference will be made to a number of terms that shall be defined to have the following meanings.
[0014] "Alkyl" refers to monovalent saturated aliphatic hydrocarbyl groups having from 1 to 14 carbon atoms and, in some embodiments, from 1 to 6 carbon atoms. "(Cx.Cy)alkyl" refers to alkyl groups having from x to y carbon atoms. This term includes, by way of example, linear and branched hydrocarbyl groups such as methyl (CH3-), ethyl (CH3CH2-), n-propyl
(CH3CH2CH2-), isopropyl ((CH3)2CH-), n-but l (CH3CH2CH2CH2-), isobutyl ((CH3)2CHCH2-), sec-butyl ((CH3)(CH3CH2)CH-), f-butyl ((CH3)3C-), n-pentyl (CH3CH2CH2CH2CH2-), and neopentyl ((CH3)3CCH2-).
[0015] "Alkylidene" or "alkylene" refers to divalent saturated aliphatic hydrocarbyl groups having from 1 to 10 carbon atoms and, in some embodiments, from 1 to 6 carbon atoms.
"(Cu_v)alkylene" refers to alkylene groups having from u to v carbon atoms. The alkylidene and alkylene groups include branched and straight chain hydrocarbyl groups. For example "(C^ 6)alkylene" is meant to include methylene, ethylene, propylene, 2-methypropylene, pentylene, and so forth.
[0016] "Alkenyl" refers to a linear or branched hydrocarbyl group having from 2 to 10 carbon atoms and in some embodiments from 2 to 6 carbon atoms or 2 to 4 carbon atoms and having at least 1 site of vinyl unsaturation (>C=C<). For example, (Cx-Cy)alkenyl refers to alkenyl groups having from x to y carbon atoms and is meant to include for example, ethenyl, propenyl, isopropylene, 1 ,3-butadienyl, and the like.
[0017] "Alkynyl" refers to a linear monovalent hydrocarbon radical or a branched monovalent hydrocarbon radical containing at least one triple bond. The term "alkynyl" is also meant to include those hydrocarbyl groups having one triple bond and one double bond. For example, (C2-C6)all ynyl is meant to include ethynyl, propynyl, and the like.
[0018] "Alkoxy" refers to the group -O-alkyl wherein alkyl is defined herein. Alkoxy includes, by way of example, methoxy, ethoxy, /7-propoxy, isopropoxy, n-butoxy, i-butoxy, sec-butoxy, and n-pentoxy.
[0019] "Acyl" refers to the groups H-C(O)-, alkyl-C(O)-, alkenyl-C(O)-, alkynyl-C(O)-, cycloalkyl-C(O)-, aryl-C(O)-, heteroaryl-C(O)-, and heterocyclic-C(O)-. Acyl includes the "acetyl" group CH3C(0)-.
[0020] "Acylamino" refers to the groups -NR20C(O)alkyl, -NR20C(O)cycloalkyl,
-NR20C(O)alkenyl, -NR20C(O)alkynyl, -NR20C(O)aryl, -NR20C(O)heteroaryl, and
-NR20C(O)heterocyclic, wherein R20 is hydrogen or alkyl.
[0021] "Acyloxy" refers to the groups alkyl-C(0)0-, alkenyl-C(0)0-, alkynyl-C(0)0-, aryl-C(0)0-, cycloalkyl-C(0)0-, heteroaryl-C(0)0-, and heterocyclic-C(0)0-.
[0022] "Amino" refers to the group -NR21R22 where R2 and R22 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclic, -S02-alkyl, -S02-alkenyl, -S02-cycloalkyl, -S02-aryl, -S02-heteroaryl, and -S02-heterocyclic, and wherein R21 and R22 are optionally joined together with the nitrogen bound thereto to form a heterocyclic group. When R21 is hydrogen and R22 is alkyl, the amino group is sometimes referred to herein as alkylamino. When R21 and R22 are alkyl, the amino group is sometimes referred to herein as dialkylamino. When referring to a monosubstituted amino, it is meant that either R21 or R22 is hydrogen but not both. When referring to a disubstituted amino, it is meant that neither R21 nor R22 are hydrogen.
[0023] "Hydroxyamino" refers to the group -NHOH.
[0024] "Alkoxyamino" refers to the group -NHO-alkyl wherein alkyl is defined herein.
[0025] "Aminocarbonyl" refers to the group -C(0)NR26R27 where R26 and R27 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclic, hydroxy, alkoxy, amino, and acylamino, and where R26 and R27 are optionally joined together with the nitrogen bound thereto to form a heterocyclic group.
[0026] "Aryl" refers to an aromatic group of from 6 to 14 carbon atoms and no ring heteroatoms and having a single ring (e.g. , phenyl) or multiple condensed (fused) rings (e.g. , naphthyl or anthryl). For multiple ring systems, including fused, bridged, and spiro ring systems having aromatic and non-aromatic rings that have no ring heteroatoms, the term "aryl" applies when the point of attachment is at an aromatic carbon atom (e.g., 5,6,7,8 tetrahydronaphthalene-2-yl is an aryl group as its point of attachment is at the 2-position of the aromatic phenyl ring).
[0027] "Cyano" or "carbonitrile" or "nitrile" refers to the group -CN.
[0028] "Cycloalkyi" refers to a saturated or partially saturated cyclic group of from 3 to
14 carbon atoms and no ring heteroatoms and having a single ring or multiple rings including fused, bridged, and spiro ring systems. For multiple ring systems having aromatic and non- aromatic rings that have no ring heteroatoms, the term "cycloalkyi" applies when the point of attachment is at a non-aromatic carbon atom (e.g. 5,6,7,8,-tetrahydronaphthalene-5-yl). The term "cycloalkyi" includes cycloalkenyl groups, such as cyclohexenyl. Examples of cycloalkyi groups include, for instance, adamantyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclooctyl, cyclopentenyi, and cyclohexenyl. Examples of cycloalkyi groups that include multiple bicycloalkyl ring systems are bicyclohexyl, bicyclopentyl, bicyclooctyl, and the like. Two such bic cloalkyl multiple ring structures are exemplified and named below:
Figure imgf000009_0001
bicyclohexyl, and bicyclohexyl.
[0029] "(Cu-Cv)cycloalkyl" refers to cycloalkyi groups having u to v carbon atoms.
[0030] The term "spiro cycloalkyi" or "cycloalkyi" also refers to a 3 to 10 member cyclic substituents formed by replacement of two hydrogen atoms at a common carbon atom in a cyclic ring structure or in an alkylene group having 2 to 9 carbon atoms, as exemplified, in one embodiment by the following structure, wherein the cyclopropyl group shown here attached to bonds marked with wavy lines and any intervening carbon atoms is substituted with a spiro cycloalkyi group:
Figure imgf000009_0002
[0031] "Fused cycloalkyi" refers to a 3 to 10 member cyclic substituent formed by the replacement of two hydrogen atoms at different carbon atoms in a cycloalkyi ring structure, as exemplified by the following structure wherein the cycloalkyi group shown here contains bonds marked with wavy lines which are bonded to carbon atoms that are substituted with a fused cycloalkyi group:
Figure imgf000010_0001
[0032] "Halo" or "halogen" refers to fluoro, chloro, bromo, and iodo.
[0033] "Haloalkoxy" refers to substitution of alkoxy groups with 1 to 5 (e.g. when the alkoxy group has at least 2 carbon atoms) or in some embodiments 1 to 3 halo groups (e.g. trifluoromethoxy).
[0034] "Hydroxy" or "hydroxyl" refers to the group -OH.
[0035] "Heteroaryl" refers to an aromatic group of from 1 to 14 carbon atoms and 1 to 6 heteroatoms selected from oxygen, nitrogen, and sulfur and includes single ring (e.g. imidazolyl) and multiple ring systems (e.g. benzimidazol-2-yl and benzimidazol-6-yl). For multiple ring systems, including fused, bridged, and spiro ring systems having aromatic and non-aromatic rings, the term "heteroaryl" applies if there is at least one ring heteroatom and the point of attachment is at an atom of an aromatic ring (e.g. 1 ,2,3,4-tetrahydroquinolin-6-yl and 5,6,7,8- tetrahydroquinolin-3-yl). In some embodiments, the nitrogen and/or the sulfur ring atom(s) of the heteroaryl group are optionally oxidized to provide for the N-oxide (N→0), sulfinyl, or sulfonyl moieties. More specifically the term heteroaryl includes, but is not limited to, pyridyl, furanyl, thienyl, thiazolyl, isothiazolyl, triazolyl, imidazolyl, imidazolinyl, isoxazolyl, pyrrolyl, pyrazolyl, pyridazinyl, pyrimidinyl, purinyl, phthalazyl, naphthylpryidyl, benzofuranyl,
tetrahydrobenzofuranyl, isobenzofuranyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, indolyl, isoindolyl, indolizinyl, dihydroindolyl, indazolyl, indolinyl, benzoxazolyl, quinolyl, isoquinolyl, quinolizyl, quianazolyl, quinoxalyl, tetrahydroquinolinyl, isoquinolyl, quinazolinonyl, benzimidazolyl, benzisoxazolyl, benzothienyl, benzopyridazinyl, pteridinyl, carbazolyl, carbolinyl, phenanthridinyl, acridinyl, phenanthrolinyl, phenazinyl, phenoxazinyl, phenothiazinyl, and phthalimidyl.
[0036] "Heterocyclic" or "heterocycle" or "heterocycloalkyl" or "heterocyclyl" refers to a saturated or partially saturated cyclic group having from 1 to 14 carbon atoms and from 1 to 6 heteroatoms selected from nitrogen, sulfur, phosphorus or oxygen and includes single ring and multiple ring systems including fused, bridged, and spiro ring systems. For multiple ring systems having aromatic and/or non-aromatic rings, the terms "heterocyclic", "heterocycle", "heterocycloalkyl", or "heterocyclyl" apply when there is at least one ring heteroatom and the point of attachment is at an atom of a non-aromatic ring (e.g. 1 ,2,3,4-tetrahydroquinoline-3-yl, 5,6,7,8-tetrahydroquinoline-6-yl, and decahydroquinolin-6-yl). In one embodiment, the nitrogen, phosphorus and/or sulfur atom(s) of the heterocyclic group are optionally oxidized to provide for the N-oxide, phosphinane oxide, sulfinyl, sulfonyl moieties. More specifically the heterocyclyi includes, but is not limited to, tetrahydropyranyl, piperidinyl, piperazinyl, 3-pyrrolidinyl, 2- pyrrolidon-1-yl, morpholinyl, and pyrrolidinyl. A prefix indicating the number of carbon atoms (e.g. , C3-C-10) refers to the total number of carbon atoms in the portion of the heterocyclyi group exclusive of the number of heteroatoms.
[0037] Examples of heterocycle and heteroaryl groups include, but are not limited to, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, pyridone, indolizine, isoindole, indole, dihydroindole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1 ,2,3,4-tetrahydroisoquinoline, 4,5,6,7-tetrahydrobenzo[b]thiophene, thiazole, thiazolidine, thiophene, benzo[b]thiophene, morpholine, thiomorpholine (also referred to as thiamorpholine), piperidine, pyrrolidine, and tetrahydrofuranyl.
[0038] "Fused heterocyclic" refers to a 3 to 10 member cyclic substituent formed by the replacement of two hydrogen atoms at different carbon atoms in a cycloalkyi ring structure, as exemplified by the following structure wherein the cycloalkyi group shown here contains bonds marked with wavy lines which are bonded to carbon atoms that are substituted with a fused heterocyclic group:
Figure imgf000011_0001
[0039] "Compound", "compounds", "chemical entity", and "chemical entities" as used herein refers to a compound encompassed by the generic formulae disclosed herein, any subgenus of those generic formulae, and any forms of the compounds within the generic and subgeneric formulae, including the racemates, stereoisomers, and tautomers of the compound or compounds.
[0040] "Oxazolidine" refers to a 5-membered heterocyclic ring containing one nitrogen and one oxygen as heteroatoms and also contains three carbons as exemplified by any of the following structures, wherein the oxazolidine groups shown here are bonded to a parent molecule, which is indicated by a wavy line in the bond to the parent molecule:
Figure imgf000012_0001
[0041] "Oxazoiidinone" refers to a 5-membered heterocyclic ring containing one nitrogen and one oxygen as heteroatoms and also contains three carbons and is substituted at one of the three carbons by an oxo group as exemplified by any of the following structures, wherein the oxazoiidinone groups shown here are bonded to a parent molecule, which is indicated by a wavy line in the
Figure imgf000012_0002
[0042] "Oxazolidinedione" refers to a 5-membered heterocyclic ring containing one nitrogen and one oxygen as heteroatoms and also contains three carbons and is substituted at two of the three carbons by oxo groups as exemplified by any of the following structures, wherein the oxazolidinedione groups shown here are bonded to a parent molecule, which is indicated by a wavy line in the bond to the parent molecule:
Figure imgf000012_0003
[0043] "Oxo" or "carbonyl" both refer to a functional group composed of a preexisting carbon atom that is already part of a parent structure, but then is double-bonded to an oxygen atom as follows: C=0.
[0044] "Racemates" refers to a mixture of enantiomers. In an embodiment of the invention, the compounds of Formula I, or pharmaceutically acceptable salts thereof, are enantiomerically enriched with one enantiomer wherein all of the chiral carbons referred to are in one configuration. In general, reference to an enantiomerically enriched compound or salt, is meant to indicate that the specified enantiomer will comprise more than 50% by weight of the total weight of all enantiomers of the compound or salt.
[0045] "Solvate" or "solvates" of a compound refer to those compounds, as defined above, which are bound to a stoichiometric or non-stoichiometric amount of a solvent. Solvates of a compound includes solvates of all forms of the compound. In certain embodiments, solvents are volatile, non-toxic, and/or acceptable for administration to humans in trace amounts. Suitable solvates include water.
[0046] "Stereoisomer" or "stereoisomers" refer to compounds that differ in the chirality of one or more stereocenters. Stereoisomers include enantiomers and diastereomers.
[0047] "Tautomer" refer to alternate forms of a compound that differ in the position of a proton, such as enol-keto and imine-enamine tautomers, or the tautomeric forms of heteroaryl groups containing a ring atom attached to both a ring -NH- moiety and a ring =N- moiety such as pyrazoles, imidazoles, benzimidazoles, triazoles, and tetrazoles.
[0048] "Pharmaceutically acceptable salt" refers to pharmaceutically acceptable salts derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, and
tetraalkylammonium, and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, and oxalate. Suitable salts include those described in P. Heinrich Stahl, Camille G. Wermuth (Eds.), Handbook of Pharmaceutical Salts Properties, Selection, and Use; 2002.
[0049] "Patient" refers to mammals and includes humans and non-human mammals.
[0050] "Treating" or "treatment" of a disease in a patient refers to 1) preventing the disease from occurring in a patient that is predisposed or does not yet display symptoms of the disease; 2) inhibiting the disease or arresting its development; or 3) ameliorating or causing regression of the disease.
[0051] Where indicated in the structure of Formula (I), a dotted line adjacent to an unbroken line means that a double bond may or may not be present (and if not present, that the adjacent atoms are covalently bound via a single bond). Such single bond or double bond substitution patterns are well known to the skilled artisan.
[0052] "Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. For example, the phrase "may be optionally substituted with" means that the particular functional group or substituent may or may not be present and that this description includes both the instance where the functional group or substituent is present and the instance where it is not.
[0053] Unless indicated otherwise, the nomenclature of substituents that are not explicitly defined herein are arrived at by naming the terminal portion of the functionality followed by the adjacent functionality toward the point of attachment. For example, the substituent "arylalkyloxycarbonyl" refers to the group (aryl)-(alkyl)-0-C(0)-. In a term such as "C(RX)2", it should be understood that the two Rx groups can be the same, or they can be different if Rx is defined as having more than one possible identity. In addition, certain substituents are drawn as -RxRy, where the "-" indicates a bond adjacent to the parent molecule and Ry being the terminal portion of the functionality. Similarly, it is understood that the above definitions are not intended to include impermissible substitution patterns (e.g., methyl substituted with 5 fiuoro groups). Such impermissible substitution patterns are well known to the skilled artisan.
[0054] In one embodiment of the present invention, there is provided a compound of
Formula (I):
(I)
Figure imgf000014_0001
or a pharmaceutically acceptable salt thereof, wherein:
Z is optionally a bond or (C C3)alkylene;
W is selected from CH or N;
A is selected from the group consisting of hydrogen, halo, (C C6)alkyl, (C C6)alkoxy, (C C6)alkenyl, (C C6)alkynyl, (C3-C14)cycloalkyl, aryl, hydroxyl, -NR6R6, -NR6C(0)NR6R6, -OR6(R5)m, -OR6(R5)y, -R6(R5)m, -alkyl(R5)2R6, -S02NR6R6, -C(0)NR6R6, -OR7, -R6R7, -S02R6, -NR6C(S)NR6R6, -NR6S(0)2R6, -alkylR9R6, -NR6C(0)OR6, -NR6C(0)R6, (C2-C6)heteroaryl having 1-3 heteroatoms selected from S, N, and O, (C2-C6)heterocyclic having 1-3 heteroatoms selected from S, N and O; wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclic group is optionally substituted with one to three R10 groups;
R1 is selected from the group consisting of hydrogen, halo, cyano, hydroxyl, (C C6)alkyl, (C C6)alkoxy, (CrC6)alkenyl, (C C6)alkynyl, -C(0)N(R6)2, -R9R6, -S02NR6R6, -R14R15, -R14(R15)2, -S02R6, -OSi, -OSi(R6)3, (C3-C14)cycloalkyl, (C3- C14)cycloalkenyl, -(C3-C )cycloaIkenyl-R , aryl, (C2-C6)heterocyclic having 1-3 heteroatoms selected from S, N and O, and (C2-C6)heteroaryl having 1-3 heteroatoms selected from S, N, and O; wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclic group is optionally substituted with one to three R11 groups;
R2 is independently selected from the group consisting of hydroxyl, oxo, (C C6)alkyl, (C3-C 4)cycloalkyl, -alkylR8, and aryl, or optionally two R2 alkyl groups, together with any intervening atoms, form a spiro or fused (C3-C14)cycloalkyl ring;
R2', R3, R3' and R4' are independently selected from the group consisting of hydrogen, (C C6)alkyl, (C3-C1 )cycloalkyl, and -alkylR8; wherein said alkyl or cycloalkyl group is optionally substituted with one to three R12 groups;
R4 is selected from the group consisting of hydrogen, hydroxyl, halo, nitrile, (C C6)alkyl, (C C6)alkoxy, (C C6)alkenyl, (C C6)alkynyl, (C3-C1 )cycloalkyl, aryl, -aryl(R12)y, -arylR12, -OR6(R5)y, -OR6(R5)m, -R6(R5)m, -alkyl(R5)yR6, -alkyl(R5)x(R6)y, -alkylR9R6, -C(0)R14, -R9R6, -R9R14, -R9R7, -NR6R6, -NR6C(0)NR6R6,
-S02NR6R6, -NR6R6R11, -C(0)NR6R6, -OR7, -R6R7, -S02R6, -NR6C(S)NR6R6, -NR6S(0)2R6, -alkylR9R6, -NR6C(0)OR6, -NR6C(0)R6, (C2-C6)heteroaryl having 1-3 heteroatoms selected from S, N, and O, and (C2-C6)heterocyclic having 1-3 heteroatoms selected from S, N and O; wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclic group is optionally substituted with one to three R10 groups;
R5 is independently selected from the group consisting of hydrogen and halo;
R6 is independently selected from the group consisting of hydrogen and (C C6)alkyl;
R7 is (C3-C 4)cycloalkyl;
R8 is hydroxyl;
R9 is carboxyl;
R10 is independently selected from the group consisting of (C C6)alkyl, (Ci-C6)alkoxy, (CrC6)alkenyl, (CrC6)alkynyl, hydroxyl, oxo, carboxyl, cyano, halo,
-C(0)NH2, -S02NH2, -SR6, -S(0)R6, -S(0)2R6, -S(0)2NR6R6, -NR6R6, -NR6C(0)NR6R6, -NR6C(S)NR6R6, -NR6S(0)2R6 -NR6C(0)OR6, -NR6C(0)R6, -C(NR6)NR6R6, -C(0)NR6R6, -C(0)OR6, -C(0)R6, (C3-C14)cycloalkyl, aryl, (C2- C6)heterocyclic having 1-3 heteroatoms selected from S, N and O, and (C2- C6)heteroaryl having 1-3 heteroatoms selected from S, N, and O;
R11 is independently selected from the group consisting of (C-i-CeJalkyl, (C C6)alkoxy, (C C6)alkenyl, (C C6)alkynyl, oxo, dioxo, hydroxyl, -NR6R6, -NR6C(0)R6, -OC(0)R6, -OR6(R5)m, -OR6(R5)y, -R6(R , -alkyl(R5)yR6, halo, -C(0)NR6R6, -S02NR6R6, -SO2R6, -alkylR8, -alkylR9, -alkylR9R6, (C3-Ci4)cycloalkyl, aryl, phosphate, (C2-C6)heterocyclic having 1-3 heteroatoms selected from S, N and O, and (C2-C6)heteroaryl having 1-3 heteroatoms selected from S, N, and O; or optionally two R 1 groups, together with any intervening atoms, form a fused (C3- C 4)cycloalkyl ring or a fused (C2-C6)heterocyclic ring having 1-3 heteroatoms selected from S, N and O; wherein said fused cycloalkyl ring or fused heterocyclic ring is optionally substituted with one to three R12 groups;
R12 is independently selected from the group consisting of (Ci-C6)alkyl, (C C6)alkoxy, oxo, halo, hydroxyl, carboxyl, cyano, -OR6(R5)m, -OR6(R5)y, -R6(R5)m, and -NR6R6;
R14 is selected from the group consisting of (CrCn)heterocyclic and (CrC^heteroaryl, each independently having one to three heteroatoms selected from N and O; R15 is independently selected from the group consisting of (Ci-C6)alkyl, (CrC6)alkoxy,
-OR8, halo, oxo, dioxo, nitrile, -N02, and -C02R8;
each m is independently an integer from 1 to 3;
each n is independently an integer from 1 to 4; and
each y is independently an integer from 1 to 3.
[0055] In another embodiment of the present invention, there is provided a compound of
Formula (I), wherein Z is a bond or methylene.
[0056] In another embodiment of the present invention, there is provided a compound of
Formula (I), wherein Z is a bond.
[0057] In another embodiment of the present invention, there is provided a compound of
Formula (I), wherein W is CH.
[0058] In another embodiment of the present invention, there is provided a compound of
Formula (I), wherein W is N.
[0059] In another embodiment of the present invention, there is provided a compound of
Formula (I), wherein A is selected from the group consisting of hydrogen, (C C6)alkyl, halo, hydroxyl, (C C6)alkoxy, -OR7, -OR6(R5)m, -OR6(R5)y, -R6(R5)m, (C3-C14)cycloalkyl, -NR6R6, - R6(C3-C14)cycloalkyl, (C2-C6)heterocyclic having 1-3 heteroatoms selected from S, N and O, and (C2-C6)heteroaryl having 1-3 heteroatoms selected from S, N, and O; wherein R10 is absent.
[0060] In another embodiment of the present invention, there is provided a compound of
Formula (I), wherein A is selected from the group consisting of hydrogen, hydroxyl, bromo, fluoro, chloro, methyl, ethyl, propyl, butyl, pentyl, cyclopropyl, cyclopropylmethyl, dimethylamino, cyclopropyloxy, methoxy, ethoxy, propoxy, trifluoromethoxy, difluoromethoxy, pyrazolyl, furanyl, pyrrolyl, triazolyl, thiophenyl, tetrahydrofuranyl, tetrahydropyranyl, pyridyl, and imidazolyl.
[0061] In another embodiment of the present invention, there is provided a compound of
Formula (I), wherein A is selected from the group consisting of methoxy, ethoxy, hydroxyl, cyclopropyl, methyl, ethyl, butyl, bromo, chloro, furanyl, dimethylamino, and trifluoromethoxy.
[0062] In another embodiment of the present invention, there is provided a compound of
Formula (I), wherein A is selected from the group consisting of halo, (C3-C14)cycloalkyl, and (C2- C6)heteroaryl having 1-3 heteroatoms selected from S, N, and O.
[0063] In another embodiment of the present invention, there is provided a compound of
Formula (I), wherein A is selected from the group consisting of bromo, furanyl, dimethylamino, butyl, trifluoromethoxy, and cyclopropyl.
[0064] In another embodiment of the present invention, there is provided a compound of
Formula (I), wherein A is cyclopropyl.
[0065] In another embodiment of the present invention, there is provided a compound of
Formula (I), wherein R is selected from the group consisting of hydrogen, (C C6)alkyl, (C3- C14)cycloalkyl, -OSi, -OSi(R6)3, aryl, (C2-C6)heterocyclic having 1-3 heteroatoms selected from S, N and O, and (C2-C6)heteroaryl having 1-3 heteroatoms selected from S, N, and O; wherein said alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclic group is optionally substituted with one to three R11 groups.
[0066] In another embodiment of the present invention, there is provided a compound of
Formula (I), wherein R1 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, pentyl, cyano, carboxyl, hydroxyl, acetate, thiazolyl, cyclopropyl, cyclobutyl, bicyclohexyl, bicyclopentyl, bicyclooctyl, cyclohexyl, cyclopentyl, cyclopentenyl, cyclohexenyl, cycloheptyl, phenyl, benzyl, pyridyl, pyridinyl, pyrrolidinyl, piperidinyl, thiophenyl, oxazolidinone, oxazolidine, oxazplidinedione, pyrazolyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, and thienyl; wherein R1 is optionally substituted with one to three R11 groups.
[0067] In another embodiment of the present invention, there is provided a compound of
Formula (I), wherein R1 is selected from the group consisting of pyrrolidinyl, oxazolidinone, oxazolidine, oxazolidinedione, cyclopentyl, cyclobutyl, cyclohexyl, and bicyclohexyl.
[0068] In another embodiment of the present invention, there is provided a compound of
Formula (I), wherein R1 is oxazolidinone.
[0069] In another embodiment of the present invention, there is provided a compound of
Formula (I), wherein R1 is oxazolidine. [0070] In another embodiment of the present invention, there is provided a compound of
Formula (I), wherein R1 is oxazolidinedione.
[0071] In another embodiment of the present invention, there is provided a compound of
Formula (I), wherein R1 is cyclobutyl.
[0072] In another embodiment of the present invention, there is provided a compound of
Formula (I), wherein R1 is bicyclohexyl.
[0073] In another embodiment of the present invention, there is provided a compound of
Formula (I), wherein R1 is cyclopentyl.
[0074] In another embodiment of the present invention, there is provided a compound of
Formula (I), wherein R1 is cyclohexyl.
[0075] In another embodiment of the present invention, there is provided a compound of
Formula (I), wherein R1 is substituted with two R11 groups.
[0076] In another embodiment of the present invention, there is provided a compound of
Formula (I), wherein the R11 group is absent.
[0077] In another embodiment of the present invention, there is provided a compound of
Formula (I), wherein R1 is substituted with one R11 group.
[0078] In another embodiment of the present invention, there is provided a compound of
Formula (I), wherein R1 is substituted with one to two groups selected from oxo and hydroxyl.
[0079] In another embodiment of the present invention, there is provided a compound of
Formula (I), wherein R2 is selected from the group consisting of oxo, methyl, and ethyl, and n is integer from 1 to 2.
[0080] In another embodiment of the present invention, there is provided a compound of
Formula (I), wherein R2 is methyl and n is 1.
[0081] In another embodiment of the present invention, there is provided a compound of
Formula (I), wherein R2 is oxo and n is 1.
[0082] In another embodiment of the present invention, there is provided a compound of
Formula (I), wherein R2 is oxo and n is 2.
[0083] In another embodiment of the present invention, there is provided a compound of
Formula (I), wherein R2 is absent and n is zero.
[0084] In another embodiment of the present invention, there is provided a compound of
Formula (I), wherein R3 is selected from the group consisting of hydrogen, (Ci-C6)alkyl, and (C3- C 4)cycloalkyl; wherein said alkyl or cycloalkyi group is optionally substituted with one to three R12 groups. [0085] In another embodiment of the present invention, there is provided a compound of
Formula (I), wherein R3 is selected from the group consisting of hydrogen, methyl, ethyl, and propyl.
[0086] In another embodiment of the present invention, there is provided a compound of
Formula (I), wherein R3 is methyl.
[0087] In another embodiment of the present invention, there is provided a compound of
Formula (I), wherein R4 is selected from the group consisting of hydrogen, hydroxyl, (C
C6)alkyl, (C C6)alkenyl, (Ci-C6)alkoxy, amino, dimethyamino, halo, nitrile, (C3-C14)cycloalkyl, aryl, -aryl(R12)x, -aryl(R 2)y, -OR6(R5)y, -OR6(R5)m, -R6(R6)m, -alkyl(R5)yR6, and (C2- C6)heterocyclic having 1-3 heteroatoms selected from S, N and O.
[0088] In another embodiment of the present invention, there is provided a compound of
Formula (I), wherein R4 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, fluorophenyl, difluorophenyl, phenyl, difluoromethoxy, piperidinylcarbonyl, cyclohexylmethyl, amino, phenylmethylamino, methyloxyethylamino, methylpropenyl, pyrrolyl, pyrrolidinyl, oxazolyl, pyridinyl, dimethylamino, methylcarboxylate, methylamino, isopropylene, methoxy, ethoxy, cyciopropyl, cyclobutyl, cyclohexyl, cyclopentyl, chloro, fluoro, bromo, difluoroethyl, and trifluoromethyl.
[0089] In another embodiment of the present invention, there is provided a compound of
Formula (I), wherein R4 is trifluoromethyl.
[0090] In another embodiment of the present invention, there is provided a compound of
Formula (I), wherein R 1 is selected from the group consisting of hydroxyl, dioxo, oxo, nitrile, - OC(0)R6, -alkylR8, -R6(R5)m, halo, (C C6)alkyl, phosphate, and (C C6)alkoxy; or optionally two R11 groups, together with any intervening atoms, form a fused cyciopropyl ring; wherein said fused cyciopropyl ring is optionally substituted with one to two R12 groups.
[0091] In another embodiment of the present invention, there is provided a compound of
Formula (I), wherein R11 is selected from the group consisting of hydroxyl, dioxo, oxo, fluoro, difluoro, and phosphate.
[0092] In another embodiment of the present invention, there is provided a compound of
Formula (I), wherein R11 is selected from the group consisting of hydroxyl and phosphate.
[0093] In another embodiment of the present invention, there is provided a compound of
Formula (I), wherein R11 is phosphate.
[0094] In another embodiment of the present invention, there is provided a compound of
Formula (I), wherein R11 is hydroxyl. [0095] In another embodiment of the present invention, there is provided a compound of
Formula (I), wherein R12 is selected from the group consisting of halo, nitrile, and hydroxyl.
[0096] In another embodiment of the present invention, there is provided a compound of
Formula (I), wherein R12 is absent.
[0097] In another embodiment of the present invention, there is provided a compound of
Formula (I), wherein m is three.
[0098] In another embodiment of the present invention, there is provided a compound of
Formula (I), wherein y is two.
[0099] In another embodiment of the present invention, there is provided a compound of
Formula (I), wherein n is one.
[00100] In another embodiment of the invention, there is provided a compound of Formula (II):
(ll)
Figure imgf000020_0001
or a pharmaceutically acceptable salt thereof, wherein:
Z is optionally a bond or methylene;
W is selected from CH or N;
A is selected from the group consisting of hydrogen, bromo, fluoro, chloro, methyl, ethyl, propyl, butyl, pentyl, cyclopropyl, cyclopropyloxy, methoxy, ethoxy, propoxy, difluoromethoxy, pyrazolyl, furanyl, pyrrolyl, triazolyl, thiophenyl,
tetrahydrofuranyl, tetrahydropyranyl, pyridyl, and imidazolyl;
R1 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, pentyl, cyano, carboxyl, acetate, thiazolyl, cyclopropyl, bicyclohexyl, cyclobutyl, bicyclopentyl, bicyclooctyl, cyclohexyl, cyclopentyl, cyclopentenyl, cyclohexenyl, cycloheptyl, phenyl, benzyl, pyridyl, pyridinyl, pyrrolidinyl, piperidinyl, thiophenyl, oxazolidinone, pyrazolyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, and thienyl, wherein R1 is optionally substituted with one to three R11;
R2 is independently selected from the group consisting of hydrogen, oxo, methyl, ethyl, cyclopropyl, hydroxymethyl, and phenyl, or optionally two R2 groups, together with any intervening atoms, form a spiro or fused cycloalkyl ring;
R3 is selected from the group consisting of hydrogen, methyl, ethyl, and propyl;
R4 is selected from the group consisting of hydrogen, methyl, ethyl, isopropyl,
dimethylamino, methylamino, isopropylene, methoxy, ethoxy, cyclopropyl, chloro, fluoro, bromo, difluoroethyl, and trifluoromethyl;
R11 is independently selected from the group consisting of hydroxyl, oxo, hydroxymethyl, acyloxy, fluoro, trifluoromethyl, methoxy, phosphate, and methyl; and n is zero or an integer from 1 to 4.
[00101] In another embodiment of the invention, there is provided a compound of
Formula (II):
Figure imgf000021_0001
or a pharmaceutically acceptable salt thereof, wherein:
Z is optionally a bond or methylene;
W is selected from CH or N;
A is selected from the group consisting of hydrogen, (CrC6)alkoxy, halo, and (C3- C 4)cycloalkyl;
R1 is selected from the group consisting of (C3-C14)cycloalkyl and (C2-C6)heterocyclic having 1-2 heteroatoms selected from N and O, wherein R is optionally substituted with one to three R11;
R2 is oxo; R3 is selected from the group consisting of hydrogen, methyl, ethyl, and propyl;
R4 is trifluoromethyl;
R11 is independently selected from the group consisting of phosphate, fluoro, hydroxyl, and oxo; and
n is zero or 1.
[00102] In another embodiment of the invention, there is provided a compound of Formula (II):
Figure imgf000022_0001
or a pharmaceutically acceptable salt thereof, wherein:
Z is optionally a bond or methylene;
W is selected from CH or N;
A is selected from the group consisting of hydroxyl and cyclopropyl;
R1 is selected from the group consisting of oxazolidinone, cyclopentyl, cyclobutyl, bicyclohexyl, and cyclohexyl, wherein R1 is optionally substituted with one to three R11; R2 is oxo;
R3 is selected from the group consisting of hydrogen, methyl, ethyl, and propyl;
R4 is trifluoromethyl;
R11 is independently selected from the group consisting of phosphate, fluoro, hydroxyl, and oxo; and
n is zero or 1.
[00103] In another embodiment of the invention, there is provided a compound selected from the group consisting of: 4-{[5-bromo-7-(trifluoromethyl)-1 H-benzimidazol-2-yl]carbonyl}-1-cyclopentyl-2-piperazinone,
4-{[6-bromo-1-ethyl-4-(trifluoromethyl)-1 H-benzimidazol-2-yl]carbonyl}-1-cyclopentyl-2- piperazinone,
4-{[6-bromo-1-methyl-4-(trifluoromethyl)-1 H-benzimidazol-2-yl]carbonyl}-1-cyclopentyl-2- piperazinone,
4-{[6-bromo-1 -propyl-4-(trifluoromethyl)-1 H-benzimidazol-2-yl]carbonyl}-1 -cyclopentyl-2- piperazinone,
4-{[6-bromo-1-methyl-4-(trifluoromethyl)-1 H-benzimidazol-2-yl]carbonyl}-1-cyclobutyl-2- piperazinone,
4-{[6-cyclopropyl-1-methyl-4-(trifluoromethyl)-1 H-benzimidazol-2-yl]carbonyl}-1-(4- hydroxycyclohexyl)-2-piperazinone,
4-{[6-cyclopropyl-1 -methyl-4-(trifluoromethyl)-1 H-benzimidazol-2-yl]carbonyl}-1 -(trans-4- hydroxycyclohexyl)-2-piperazinone,
4-(4-{[6-cyclopropyl-1 -methyl-4-(trifluoromethyl)-1 H-benzimidazol-2-yl]carbonyl}-2-oxo-1 - piperazinyl)cyclohexyl dihydrogen phosphate,
trans-4-(4-{[6-cyclopropyl-1-methyl-4-(trifluoromethyl)-1 H-benzimidazol-2-yl]carbonyl}-2-oxo-1- piperazinyl)cyclohexyl dihydrogen phosphate,
1-[bicyclo[3.1.0]hex-3-yl]-4-{[6-cyclopropyl-1-methyl-4-(trifluoromethyl)-1 H-benzimidazol-2- yl]carbonyl}-2-piperazinone,
1- [(trans)-bicyclo[3.1.0]hex-3-yl]-4-{[6-cyclopropyl-1-methyl-4-(trifluoromethyl)-1 H-benzimidazol-
2- yl]carbonyl}-2-piperazinone,
1 -(cyclobutylmethyl)-4-{[6-cyclopropyI-1 -methyl-4-(trifluoromethyl)-1 H-benzimidazol-2- yl]carbonyl}-2-piperazinone,
4-{[6-cyclopropyl-1-methyl-4-(trifluoromethyl)-1 H-benzimidazol-2-yl]carbonyl}-1-[3- hydroxycyclopentyl]-2-piperazinone,
4-{[6-cyciopropyl-1-methyl-4-(trifluoromethyi)-1 H-benzimidazol-2-yl]carbonyl}-1-[(1 R,3R)-3- hydroxycyclopentyl]-2-piperazinone,
3- (1 -{[6-bromo-1 -methyl-4-(trifluoromethyl)-1 H-benzimidazol-2-yl]carbonyl}-4-piperidinyl)-1 ,3- oxazolidin-2-one,
3-(1 -{[6-bromo-1 -methyl-4-(trifluoromethyl)-1 H-benzimidazol-2-yl]carbonyl}-4-piperidinyl)-1 ,3- oxazolidine-2,4-dione,
3-(1-{[6-cyclopropyl-1-methyl-4-(trifluoromethyl)-1 H-benzimidazol-2-yl]carbonyl}-4-piperidinyl)- 1 ,3-oxazolidin-2-one, 3-(1-{[6-cyclopropyl-1-methyl-4-(trifluoro
1 ,3-oxazolidine-2,4-dione,
3- (1-{[6-(3-furanyl)-1-methyl-4-(trifluoromethyl)-1 H-benzimidazol-2-yl]carbonyl}-4-piperidinyl)- 1 ,3-oxazolidin-2-one,
4- [(4-bromo-6-cyclopropyl-1-methyl-1 H-benzimidazol-2-yl)carbonyl]-1-(trans-4-{[(1 ,1- dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2-piperazinone,
4-[(4-bromo-6-cyclopropyl-1 -methyl-1 H-benzimidazol-2-yl)carbonyl]-1-(trans-4- hydroxycyclohexyl)-2-piperazinone,
4-[(7-bromo-5-cyclopropyl-1 -methyl-1 H-benzimidazol-2-yl)carbonyl]-1-(trans-4- hydroxycyclohexyl)-2-piperazinone,
4-[(4,6-dicyclopropyl-1 -methyl-1 H-benzimidazol-2-yl)carbonyl]-1-(trans-4-hydroxycyclohexyl)-2- piperazinone,
6-cyclopropyl-2-{[4-(trans-4-hydroxycyclohexyl)-3-oxo-1 -piperazinyl]carbonyl}-1 -methyl-1 H- benzimidazole-4-carbonitrile,
4-[(6-cyclopropyl-1-methyl-1 H-benzimidazol-2-yl)carbonyl]-1-(trans-4-hydroxycyclohexyl)-2- piperazinone,
4-[(6-cyclopropyl-4-ethyl-1 -methyl-1 H-benzimidazol-2-yl)carbonyl]-1-(trans-4- hydroxycyclohexyl)-2-piperazinone,
4-{[6-cyclopropyl-1-methyl-4-(1-methylethenyl)-1 H-benzimidazol-2-yl]carbonyl}-1-(trans-4- hydroxycyclohexyl)-2-piperazinone,
4-[(6-cyclopropyl-1 -methyl-4-phenyl-1 H-benzimidazol-2-yl)carbonyl]-1 -(trans-4- hydroxycyclohexyl)-2-piperazinone,
4-[(6-cyclopropyl-1 ,4-dimethyl-1 H-benzimidazol-2-yl)carbonyl]-1-(trans-4-hydroxycyclohexyl)-2- piperazinone,
4-{[6-cyclopropyl-1 -methyl-4-(1 -methylethyl)-1 H-benzimidazol-2-yl]carbonyl}-1 -(trans-4- hydroxycyclohexyl)-2-piperazinone,
4-[(6-cyclopropyl-4-hydroxy-1 -methyl-1 H-benzimidazol-2-yl)carbonyl]-1-(trans-4- hydroxycyclohexyl)-2-piperazinone,
4-(4-cyclobutyl-6-cyclopropyl-1 -methyl-1 H-benzo[d]imidazole-2-carbonyl)-1-((1 r,4r)-4- hydroxycyclohexyl)piperazin-2-one,
4-[(4-cyclopentyl-6-cyclopropyl-1 -methyl-1 H-benzimidazol-2-yl)carbonyl]-1-(trans-4- hydroxycyclohexyl)-2-piperazinone,
4-{[6-cyclopropyl-4-(3-fluorophenyl)-1 -methyl-1 H-benzimidazol-2-yl]carbonyl}-1-(trans-4- hydroxycyclohexyl)-2-piperazinone, 4-{[6-cyclopropyl-4-(4-fluorophenyl)-1-methyl-1 H-benzimidazol-2-yl]carbonyl}-1-(trans-4- hydroxycyclohexyl)-2-piperazinone,
4-{[6-cyclopropyl-4-(3,5-difluorophenyl)-1-methyl-1 H-benzimidazol-2-yl]carbonyl}-1-(trans-4- hydroxycyclohexyl)-2-piperazinone,
4-{[6-cyclopropyl-1 -methyl-4-(methyloxy)-1 H-benzimidazol-2-yl]carbonyl}-1 -(trans-4- hydroxycyclohexyl)-2-piperazinone,
4-({6-cyclopropyl-4-[(difluoromethyl)oxy]-1-methyl-1 H-benzimidazol-2-yl}carbonyl)-1-(trans-4- hydroxycyclohexyl)-2-piperazinone,
4-{[6-cyclopropyl-4-(ethyloxy)-1 -methyl-1 H-benzimidazol-2-yl]carbonyl}-1 -(trans-4- hydroxycyclohexyl)-2-piperazinone,
4-({6-cyclopropyl-1-methyl-4-[(1-methylethyl)oxy]-1 H-benzimidazol-2-yl}carbonyl)-1-(trans-4- hydroxycyclohexyl)-2-piperazinone,
4-[(4-cyclohexyl-6-cyclopropyl- 1 -methyl- 1 H-benzimidazol-2-yl)carbony I]- 1 -(trans-4- hydroxycyclohexyl)-2-piperazinone,
4-{[6-cyclopropyl-1-methyl-4-(1-pyrrolidinyl)-1 H-benzimidazol-2-yl]carbonyl}-1-(trans-4- hydroxycyclohexyl)-2-piperazinone,
methyl 6-cyclopropyl-2-{[4-(trans-4-hydroxycyclohexyl)-3-oxo-1-piperazinyl]carbonyl}-1-methyl- 1 H-benzimidazole-4-carboxylate,
4-{[6-cyclopropyl-1-methyl-4-(1-piperidinylcarbonyl)-1 H-benzimidazol-2-yl]carbonyl}-1-(trans-4- hydroxycyclohexyl)-2-piperazinone,
4-{[6-cyclopropyl-1 -methyl-4-(2-methylpropyl)-1 H-benzimidazol-2-yl]carbonyl}-1 -(trans-4- hydroxycyclohexyl)-2-piperazinone,
4-{[4-(cyclohexylmethyl)-6-cyclopropyl-1 -methyl-1 H-benzimidazol-2-yl]carbonyl}-1-(trans-4- hydroxycyclohexyl)-2-piperazinone,
4-({6-cyclopropyl-1-methyl-4-[(phenylmethyl)amino]-1 H-benzimidazol-2-yl}carbonyl)-1-(trans-4- hydroxycyclohexyl)-2-piperazinone,
4-[(6-cyclopropyl-1 -methyl-4-{[2-(methyloxy)ethyl]amino}-1 H-benzimidazol-2-yl)carbonyl]-1 - (trans-4-hydroxycyclohexyl)-2-piperazinone,
4-{[6-cyclopropyl-1-methyl-4-(1 H-pyrrol-2-yl)-1 H-benzimidazol-2-yl]carbonyl}-1-(trans-4- hydroxycyclohexyl)-2-piperazinone,
4-{[6-cyclopropyl-1 -methyl-4-(trifluoromethyl)-1 H-benzimidazol-2-yl]carbonyl}-1 -(cis-4- hydroxycyclohexyl)-2-piperazinone, 4-{[6-cyclopropyl-1-methyl-4-(trifluorom
dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2-piperazinone,
4-{[5-cyclopropyl-1 -methyl-7-(trifluoromethyl)-1 H-benzimidazol-2-yl]carbonyl}-1 -(trans-4-{[(1 , 1 - dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2-piperazinone,
4-{[5-cyclopropyl-1-methyl-7-(trifluoromethyl)-1 H-benzimidazol-2-yl]carbonyl}-1-(trans-4- hydroxycyclohexyl)-2-piperazinone,
4-{[4-bromo-6-(1 ,1-dimethylethyl)-1-methyl-1 H-benzimidazol-2-yl]carbonyl}-1-(trans-4- hydroxycyciohexyl)-2-piperazinone,
4-{[4-cyclopropyl-6-(1 , 1 -dimethylethyl)-1 -methyl-1 H-benzimidazol-2-yl]carbonyl}-1 -(trans-4- hydroxycyclohexyl)-2-piperazinone,
4-{[6-bromo-4-(1 ,1-dimethylethyl)-1 -methyl-1 H-benzimidazol-2-yl]carbonyl}-1-(trans-4- hydroxycyclohexyl)-2-piperazinone,
4-{[6-cyclopropyl-4-(1 , 1 -dimethylethyl)-1 -methyl-1 H-benzimidazol-2-yl]carbonyl}-1 -(trans-4- hydroxycyclohexyl)-2-piperazinone,
4-[(4,6-dicyclopropyl-1 ,5-dimethyl-1 H-benzimidazol-2-yl)carbonyl]-1-(trans-4- hydroxycyclohexyl)-2-piperazinone,
4-({6-cyclopropyl-1-methyl-4-[(1 E)-1 -methyl-1 -propen-1-yl]-1 H-benzimidazol-2-yl}carbonyl)-1- (trans-4-hydroxycyclohexyl)-2-piperazinone,
4-({6-cyclopropyl-1 -methyl-4-[(1 Z)-1 -methyl-1 -propen-1 -yl]-1 H-benzimidazol-2-yl}carbonyl)-1 - (trans-4-hydroxycyclohexyl)-2-piperazinone,
4-[(5,7-dicyclopropyl-1 ,4-dimethyl-1 H-benzimidazol-2-yl)carbonyl]-1-(trans-4- hydroxycyclohexyl)-2-piperazinone,
4-[(4,6-dicyclopropyl-1 ,7-dimethyl-1 H-benzimidazol-2-yl)carbonyl]-1-(trans-4- hydroxycyclohexyl)-2-piperazinone,
4-[(4-amino-6-cyclopropyl-1 -methyl-1 H-benzimidazol-2-yl)carbonyl]-1-(trans-4- hydroxycyclohexyl)-2-piperazinone,
4-{[6-cyclopropyl-4-(dimethylamino)- -methyl-1 H-benzimidazol-2-yl]carbonyl}-1-(trans-4- hydroxycyclohexyl)-2-piperazinone,
1-cyclobutyl-4-{[6-cyclopropyl-1-methyl-4-(trifluoromethyl)-1 H-benzimidazol-2-yl]carbonyl}-5- ethyl-2-piperazinone,
(5R)-4-{[6-cyclopropyl-4-(1 ,1-dimethylethyl)-1-methyl-1 H-benzimidazol-2-yl]carbonyl}-1-(trans-4- hydroxycyclohexyl)-5-methyl-2-piperazinone,
(5R)-4-{[6-(dimethylamino)-1-methyl-4-(trifluoromethyl)-1 H-benzimidazol-2-yl]carbonyl}-1 -(trans- 4-hydroxycyclohexyl)-5-methyl-2-piperazinone, (5R)-4-{[6-cyclopropyl-1-methyl-4-(trifluoromethyl)-1 H-benzimidazol-2-yl]carbonyl}-1-(trans-4- hydroxycyclohexyl)-5-methyl-2-piperazinone,
4-{[6-(dimethylamino)-1 -methyl-4-(trifluoromethyl)-1 H-benzimidazol-2-yl]carbonyl}-1 -(trans-4- hydroxycyclohexyl)-2-piperazinone,
4-{[6-cyclopropyl-1-methyl-4-(1 ,3-oxazol-5-yl)-1 H-benzimidazol-2-yl]carbonyl}-1-(trans-4- hydroxycyclohexyl)-2-piperazinone,
1-cyclobutyl-4-{[6-(3-furanyl)-1-methyl-4-(trifluoromethyl)-1 H-benzimidazol-2-yl]carbonyl}-2- piperazinone,
1-cyclobutyl-4-{[6-cyclopropyl-1-methyl-4-(trifluoromethyl)-1 H-benzimidazol-2-yl]carbonyl}-2- piperazinone,
3-(1-{[6-(3-furanyl)-1-methyl-4-(trifluoromethyl)-1 H-benzimidazol-2-yl]carbonyl}-4-piperi 1 ,3-oxazolidine-2,4-dione,
3-(1 -{[6-cyclopropyl-4-(1 , 1 -dimethylethyl)-1 -methyl-1 H-benzimidazol-2-yl]carbonyl}-4- piperidinyl)-1 ,3-oxazolidin-2-one,
3- (1 -{[6-cyclopropyl-4-(1 , 1 -dimethylethyl)-1 -methyl-1 H-benzimidazol-2-yl]carbonyl}-4- piperidinyl)-1 ,3-oxazolidine-2,4-dione,
4- {[6-cyclopropyl-4-(2-fluorophenyl)-1 -methyl-1 H-benzimidazol-2-yl]carbonyl}~1-(trans-4- hydroxycyclohexyl)-2-piperazinone,
4-{[6-cyclopropyl-4-(2,4-difluorophenyl)-1-methyl-1 H-benzimidazol-2-yl]carbonyl}-1-(trans-4- hydroxycyclohexyl)-2-piperazinone,
4-{[6-cyclopropyl-4-(2,5-difluorophenyl)-1-methyl-1 H-benzimidazol-2-yl]carbonyl}-1-(trans-4- hydroxycyclohexyl)-2-piperazinone,
4-{[6-cyclopropyl-1-methyl-4-(2-pyridinyl)-1 H-benzimidazol-2-yl]carbonyl}-1-(trans-4- hydroxycyclohexyl)-2-piperazinone,
4-{[6-cyclopropyl-1-methyl-4-(3-pyridinyl)-1 H-benzimidazol-2-yl]carbonyl}-1-(trans-4- hydroxycyclohexyl)-2-piperazinone,
4-{[6-cyclopropyl-1 -methyl-4-(4-pyridinyl)-1 H-benzimidazol-2-yl]carbonyl}-1 -(trans-4- hydroxycyclohexyl)-2-piperazinone,
4-({4-bromo-1-methyl-6-[(trifluoromethyl)oxy]-1 H-benzimidazol-2-yl}carbonyl)-1-(trans-4- hydroxycyclohexyl)-2-piperazinone,
4-({4-(3-fluorophenyl)-1-methyl-6-[(trifluoromethyl)oxy]-1 H-benzimidazol-2-yl}carbonyl)-1 -(trans- 4-hydroxycyclohexyl)-2-piperazinone,
-({4-cyclopropyl-1-methyl-6-[(trifluoromethyl)oxy]-1 H-benzimidazol-2-yl}carbonyl)-1-(trans-4- hydroxycyclohexyl)-2-piperazinone,
4-{[6-cyclopropyl-1-methyl-4-(trifluoromethyl)-1 H-benzimidazol-2-yl]carbony
hydroxy-3-cyclopenten-1-yl]-2-piperazinone,
4-{[6-cyclopropyl-1-methyl-4-(trifluoromethyl)-1/-/-benzimidazol-2-yl]carbonyl}-1- [(1 SR,3SR,5Sf?)-2,2-difluorobicyclo[3.1.0]hex-3-yl]-2-piperazinone,
1- (3-cyclopenten-1-yl)-4-{[6-cyclopropyl-1-methyl-4-(trifluoromethyl)-1 H-benzimidazol-2- yl]carbonyl}-2-piperazinqne,
4-{[6-cyclopropyl-1 -methyl-4-(trifluoromethyl)-1 H-benzimidazol-2-yl]carbonyl}-1 -[(1 R,2R,3R,5R)-
2- hydroxybicyclo[3.1.0]hex-3-yl]-2-piperazinone,
4-{[6-cyclopropyl-1-methyl-4-(trifluoro^
2-hydroxybicyclo[3.1 ,0]hex-3-yl]-2-piperazinone, and
4-{[6-cyclopropyl-1-methyl-4-(trifluoromethyl)-1 H-benzimidazol-2-yl]carbonyl}-1-[2- hydroxybicyclo[3.1.0]hex-3-yl]-2-piperazinone., or a pharmaceutically acceptable salt thereof.
[00104] In another embodiment of the invention, there is provided those compounds in Table 1 and Table 2. In yet another embodiment of the invention there is provided those compounds in Table 1.
[00105] In another embodiment of the invention, there is provided a compound having the structure:
Figure imgf000028_0001
, or a pharmaceutically acceptable salt thereof.
[00106] In another embodiment of the invention, there is provided a compound having the structure:
Figure imgf000029_0001
H , or a pharmaceutically acceptable salt thereof.
[00107] In another embodiment of the invention, there is provided a compound having the struct
Figure imgf000029_0002
, or a pharmaceutically acceptable salt thereof.
[00108] In another embodiment of the invention, there is provided a compound having the structure:
O
O— P— OH
I
0H , or a pharmaceutically acceptable salt thereof.
[00109] In another embodiment of the invention, there is provided a compound of Formula (I), wherein the compound or salt of the compound is used in the manufacture of a medicament for use in the treatment of a viral infection in a human.
[00110] In another embodiment of the invention, there is provided a pharmaceutical composition comprising a pharmaceutically acceptable diluent and a therapeutically effective amount of a compound as defined in a compound of Formula (I).
[00111] In another embodiment of the invention, there is provided a method for treating a viral infection in a mammal mediated at least in part by a virus in the Flaviviridae family of viruses which method comprises administering to a mammal, that has been diagnosed with said viral infection or is at risk of developing said viral infection, a compound of Formula (I).
[00112] In another embodiment of the invention, there is provided a method for treating a viral infection in a mammal mediated at least in part by a virus in the Flaviviridae family of viruses which method comprises administering to a mammal, that has been diagnosed with said viral infection or is at risk of developing said viral infection, a compound of Formula (I), wherein said virus is hepatitis C virus.
[00113] In another embodiment of the invention, there is provided a method for treating a viral infection in a mammal mediated at least in part by a virus in the Flaviviridae family of viruses which method comprises administering to a mammal, that has been diagnosed with said viral infection or is at risk of developing said viral infection, a compound of Formula (I), further comprising administration of a therapeutically effective amount of one or more agents active against hepatitis C virus. [00114] In another embodiment of the invention, there is provided a method for treating a viral infection in a mammal mediated at least in part by a virus in the Flaviviridae family of viruses which method comprises administering to a mammal, that has been diagnosed with said viral infection or is at risk of developing said viral infection, a compound of Formula (I), further comprising administration of a therapeutically effective amount of one or more agents active against hepatitis C virus, wherein said agent active against hepatitis C virus is an inhibitor of HCV protease, HCV polymerase, HCV helicase, HCV entry, HCV assembly, HCV egress, HCV replicase, HCV NS5A protein, or inosine 5'-monophosphate dehydrogenase,
[00115] In another embodiment of the invention, there is provided a method for treating a viral infection in a mammal mediated at least in part by a virus in the Flaviviridae family of viruses which method comprises administering to a mammal, that has been diagnosed with said viral infection or is at risk of developing said viral infection, a compound of Formula (I), further comprising administration of a therapeutically effective amount of one or more agents active against hepatitis C virus, wherein said agent active against hepatitis C virus is interferon.
[00116] In another embodiment of the invention, there is provided a method for treating a viral infection in a mammal mediated at least in part by a virus in the Flaviviridae family of viruses which method comprises administering to a mammal, that has been diagnosed with said viral infection or is at risk of developing said viral infection, a compound of Formula (I), further comprising administration of a therapeutically effective amount of one or more agents active against hepatitis C virus, wherein said agent active against hepatitis C virus is ribavirin.
[00117] In another embodiment of the invention, there is provided a method for treating a viral infection in a mammal mediated at least in part by a virus in the Flaviviridae family of viruses which method comprises administering to a mammal, that has been diagnosed with said viral infection or is at risk of developing said viral infection, a compound of Formula (I), further comprising administration of a therapeutically effective amount of one or more agents active against hepatitis C virus, wherein said agent active against hepatitis C virus is interferon in combination with ribavirin.
[00118] In yet further embodiments, the compound of the present invention, or a pharmaceutically acceptable salt thereof, is chosen from the compounds set forth in Table 1.
SVCA_258875.1 30 Table 1
Compound
Structure Name
Number
4-{[5-bromo-7-(trifluoromethyl)-1 H- benzimidazol-2-yl]carbonyl}-1-cyclopentyl-2~ piperazinone
4-{[6-bromo-1-ethyl-4-(trifluoromethyl)-1 H- benzimidazol-2-yl]carbonyl}-1-cyclopentyl-2- piperazinone
4-{[6-bromo-1 -methyl-4-(trifluoromethyl)-1 H- benzimidazol-2-yl]carbonyl}-1-cyclopentyl-2- piperazinone
4-{[6-bromo-1 -propyl-4-(trifluoromethyl)-1 H- benzimidazol-2-yl]carbonyl}-1-cyclopentyl-2- piperazinone
Figure imgf000032_0001
Figure imgf000033_0001
trans-4-(4-{[6-cyclopropyl-1-methyl-4- (trifluoromethyl)-1 H-benzimidazol-2- yl]carbonyl}-2-oxo-1-piperazinyl)cyclohexyl dihydrogen phosphate
1 -[bicyclo[3.1.0]hex-3-yl]-4-{[6-cyclopropyl- 1 - methyl-4-(trifluoromethyl)-1 H-benzimidazol- 2-yl]carbonyl}-2-piperazinone
1 -[(trans)-bicyclo[3.1.0]hex-3-yl]-4-{[6- cyclopropyl-1 -methyl-4-(trifluoromethyl)-1 H- benzimidazol-2-yl]carbonyl}-2-piperazinone
1 -(cyclobutylmethyl)-4-{[6-cyclopropyl-1 - methyl-4-(trifluoromethyl)-1 H-benzimidazol- 2-yl]carbonyl}-2-piperazinone 4-{[6-cyclopropyl-1-methyl-4- (trifluoromethyl)-1 H-benzimidazol-2- yl]carbonyl}-1-[3-hydroxycyclopentyl]-2- piperazinone
4-{[6-cyclopropyl-1-methyl-4- (trifluoromethyl)-1 H-benzimidazol-2- yl]carbonyl}-1-[(1 R,3R)-3- hydroxycyclopentyl]-2-piperazinone
3-(1-{[6-bromo-1-methyl-4-(trifluoromethyl)- 1 H-benzimidazol-2-yl]carbonyl}-4- piperidinyl)-1 ,3-oxazolidin-2-one
3-(1 -{[6-bromo-1 -methyl-4-(trifluoromethyl)- 1 H-benzimidazol-2-yl]carbonyl}-4- piperidinyl)-1 ,3-oxazolidine-2,4-dione
Figure imgf000036_0001
Figure imgf000037_0001
4-[(6-cyclopropyl-1 -methyl-1 H-benzimidazol- 2-yl)carbonyl]-1-(trans-4-hydroxycyclohexyl)- 2-piperazinone
Figure imgf000038_0001
4-[(6-cyclopropyl-4-ethyl-1-methyi-1 H- benzimidazol-2-yl)carbonyl]-1-(trans-4- hydroxycyclohexyl)-2-piperazinone
4-{[6-cyclopropyl-1 -methyl-4-(1 - methylethenyl)-1 H-benzimidazol-2- yl]carbonyl}-1-(trans-4-hydroxycyclohexyl)-2- piperazinone
Figure imgf000038_0002
4-[(6-cyclopropyl-1-methyl-4-phenyl-1 H- benzimidazol-2-yl)carbonyl]-1-(trans-4- hydroxycyclohexyl)-2-piperazinone
Figure imgf000038_0003
Figure imgf000039_0001
4-{[6-cyclopropyl-4-(4-fluorophenyl)-1- methyl-1 H-benzimidazol-2-yl]carbonyl}-1- (trans-4-hydroxycyclohexyi)-2-piperazinone
4-{[6-cyclopropyl-4-(3 , 5-dif luorophenyl)- 1 - methyl-1 H-benzimidazol-2-yl]carbonyl}-1 - (trans-4-hydroxycyclohexyl)-2-piperazinone
4-{[6-cyclopropyl-1-methyl-4-(methyloxy)- 1 H-benzimidazol-2-yl]carbonyl}-1 -(trans-4- hydroxycyclohexyl)-2-piperazinone
4-({6-cyc!opropyl-4-[(difluoromethyl)oxy]-1- methyl-1 H-benzimidazol-2-yl}carbonyl)-1- (trans-4-hydroxycyclohexyl)-2-piperazinone
4-{[6-cyclopropyl-4-(ethyloxy)-1 -methyl-1 H- benzimidazol-2-yl]carbonyl}-1-(trans-4- hydroxycyclohexyi)-2-piperazinone
Figure imgf000040_0001
Figure imgf000041_0001
Figure imgf000042_0001
Figure imgf000043_0001
4-{[4-bromo-6-(1 ,1 -dimethylethyl)-1-methyl- 1 H-benzimidazol-2-yl]carbonyl}-1-(trans-4- hydroxycyclohexyl)-2-piperazinone
4-{[4-cyclopropyl-6-(1 ,1 -dimethylethyl)-1 - methyl-1 H-benzimidazol-2-yl]carbonyl}-1- (trans-4-hydroxycyclohexyl)-2-piperazinone
4-{[6-bromo-4-(1 , 1-dimethylethyl)-1-methyl- 1 H-benzimidazol~2-yl]carbonyl}-1 -(trans-4- hydroxycyclohexyl)-2-piperazinone
4-{[6-cyclopropyl-4-(1 ,1-dimethylethyl)-1- methyl-1 H-benzimidazol-2-yl]carbonyl}-1- (trans-4-hydroxycyclohexyl)-2-piperazinone
4-[(4,6-dicyclopropyl-1 ,5-dimethyl-1 H- benzimidazol-2-yl)carbonyl]-1-(trans-4- hydroxycyclohexyl)-2-piperazinone
4-({6-cyclopropyl-1-methyl-4-[(1 E)-1-methyl-
1 -propen-1 -yl]-1 H-benzimidazol-2- yl}carbonyl)-1-(trans-4-hydroxycyclohexyl)-2- piperazinone
Figure imgf000044_0001
4-({6-cyclopropyl- 1 -methy l-4-[( 1 Z)- 1 -methyl-
1 -propen-1 -yl]-1 H-benzimidazol-2-
56
yl}carbonyl)-1-(trans-4-hydroxycyclohexyl)-2- piperazinone
4-[(5,7-dicyclopropyl-1 ,4-dimethyl-1 H-
57 benzimidazol-2-yl)carbonyl]-1-(trans-4- hydroxycyclohexyl)-2-piperazinone
4-[(4,6-dicyclopropyl-1 ,7-dimethyl-1 H-
58 benzimidazol-2-yl)carbonyl]-1-(trans-4- hydroxycyclohexyl)-2-piperazinone
4-[(4-amino-6-cyclopropyl-1 -methyl-1 H-
59 benzimidazol-2-yl)carbonyl]-1-(trans-4- hydroxycyclohexyl)-2-piperazinone
4-{[6-cyclopropyl-4-(dimethylamino)-1-
60 methyl-1 H-benzimidazol-2-yl]carbonyl}-1 - (trans-4-hydroxycyclohexyl)-2-piperazinone
Figure imgf000045_0001
Figure imgf000046_0001
Figure imgf000047_0001
Figure imgf000048_0001
Figure imgf000049_0001
4-{[6-cyclopropyl-1-methyl-4- (trifluoromethyl)-1 H-benzimidazol-2- yl]carbonyl}-1 -[2-hydroxybicyclo[3.1.0]hex-3- yl]-2-piperazinone
[00119] The compounds of Table 1 were synthesized according to the Synthetic
Methods, General Schemes, and the Examples described below.
[00120] In other embodiments, the compound of the present invention, or a
pharmaceutically acceptable salt thereof, is chosen from the compounds set forth in Table 2.
Table 2
Figure imgf000050_0001
Figure imgf000051_0001
51
Figure imgf000052_0001
Figure imgf000053_0001
53
Figure imgf000054_0001
[00121] The compounds of Table 2 may be synthesized according to the following synthetic methods, schemes, and the Examples.
[00122] In certain embodiments, the compound(s) of the present invention, or a pharmaceutically acceptable salt thereof, is chosen from the compounds set forth in Table 1 and/or Table 2.
Synthetic Methods
[00123] The methods of synthesis for the provided chemical entities employ readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given; other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures. [00124] Additionally, the methods of this invention may employ protecting groups which prevent certain functional groups from undergoing undesired reactions. Suitable protecting groups for various functional groups as well as suitable conditions for protecting and deprotecting particular functional groups are well known in the art. For example, numerous protecting groups are described in T. W. Greene and G. M. Wuts, Protecting Groups in Organic Synthesis, Third Edition, Wiley, New York, 1999, and references cited therein.
[00125] Furthermore, the provided chemical entities may contain one or more chiral centers and such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as stereoisomer-enriched mixtures. All such stereoisomers (and enriched mixtures) are included within the scope of this specification, unless otherwise indicated. Pure stereoisomers (or enriched mixtures) may be prepared using, for example, optically active starting materials or stereoselective reagents well-known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents and the like.
[00126] The starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many of the starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Ernka-Chemce or Sigma (St. Louis, Missouri, USA). Others may be prepared by procedures, or obvious modifications thereof, described in standard reference texts such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley and Sons, 1991), Rodd's Chemistry of Carbon
Compounds, Volumes 1-5 and Supplemental (Elsevier Science Publishers, 1989), Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition), and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989).
[00127] Unless specified to the contrary, the reactions described herein take place at atmospheric pressure, generally within a temperature range from -78 °C to 200 °C. Further, except as employed in the Examples or as otherwise specified, reaction times and conditions are intended to be approximate, e.g., taking place at about atmospheric pressure within a temperature range of about -78 °C to about 110 °C over a period of about 1 to about 24 hours; reactions left to run overnight average a period of about 16 hours.
[00128] The terms "solvent," "organic solvent," and "inert solvent" each mean a solvent inert under the conditions of the reaction being described in conjunction therewith, including, for example, benzene, toluene, acetonitrile, tetrahydrofuranyl ("THF"), dimethylformamide ("DMF"), chloroform, methylene chloride (or dichloromethane), diethyl ether, methanol, N- methylpyrrolidone ("NMP"), pyridine and the like.
[00129] Isolation and purification of the chemical entities and intermediates described herein can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, extraction, crystallization, column chromatography, thin-layer chromatography or thick-layer chromatography, or a combination of these procedures. Specific illustrations of suitable separation and isolation procedures can be had by reference to the examples herein below. However, other equivalent separation or isolation procedures can also be used.
[00130] When desired, the (R)- and (S)-isomers may be resolved by methods known to those skilled in the art, for example by formation of diastereoisomeric salts or complexes which may be separated, for example, by crystallization; via formation of diastereoisomeric derivatives which may be separated, for example, by crystallization, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer-specific reagent, for example enzymatic oxidation or reduction, followed by separation of the modified and unmodified enantiomers; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support, such as silica with a bound chiral ligand or in the presence of a chiral solvent. Alternatively, a specific enantiomer may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer to the other by asymmetric transformation.
EXAMPLES
[00131] The following examples serve to more fully describe the manner of making and using the above-described invention. It is understood that these examples in no way serve to limit the true scope of the invention, but rather are presented for illustrative purposes. In the examples below and the synthetic schemes above, the following abbreviations have the following meanings. If an abbreviation is not defined, it has its generally accepted meaning.
aqueous
microliters
micromolar
nuclear magnetic resonance
tert-butoxycarbonyl
broad
benzyloxycarbonyl doublet
chemical shift
degrees celcius
dichloromethane
doublet of doublets
Dulbeco's Modified Eagle's Medium
N,N-dimethylformamide
dimethylsulfoxide
ethyl acetate
gram
hours
hepatitus C virus
high performance liquid chromatography hertz
International Units
inhibitory concentration at 50% inhibition coupling constant (given in Hz unless otherwise indicated)
multiplet
molar
parent mass spectrum peak plus H+ milligram
milliliter
millimolar
millimole
mass spectrum
nanomolar
parts per million
sufficient amount
singlet
saturated
triplet
trifluoroacetic acid [00132] Scheme 1 shows a representative general synthesis of certain substituted benzimidazole carboxylic acids. Diamines (I), readily available from the nitration and subsequent reduction of appropriately substituted anilines, can be cyclized via a variety of methods known to those skilled in the art to the benzimidazoles (II). Hydrolysis of the trichloromethyl substitituent affords the substituted 1W-benzimidazole-2-carboxylic acids (III) which can be coupled to appropriately substituted amines via coupling reagents known to those skilled in the art thereby giving the amides (V). Alkylation of the benzimidazole nitrogen can yield compounds (VI). Alternatively, intermediates (II) can be transformed to intermediates (IV) via hydrolysis/alkylation (or vice-versa) and intermediates (IV) can be coupled to appropriately substituted amines via coupling reagents known to those skilled in the art thereby giving the amides (VI).
[00133] Additional synthetic protocols useful in making the synthetic intermediates and final compounds herein may be found in PCT Published Application No. WO2009/023179 filed on August 8, 2008 and entitled "Certain Nitrogen Containing Bicyclic Chemical Entities for Treating Viral Infections."
Scheme 1
Figure imgf000058_0001
Scheme 2
Figure imgf000059_0001
Example 1
4-{[5-bromo-7-(trifluoromethyl)-1H-benzimidazol-2-yl]carbonyl}-1-cyclopi
piperazinone
(Compound 1)
Figure imgf000059_0002
Step A
5-bromo-2-(trichloromethyl)-7-(trifluoromethyl)-1H-benz imidazole
[00134] 5-bromo-3-(trifluoromethyl)-1 ,2-benzenediamine (850 mg, 3.33 mmol) was dissolved in acetic acid (10 mL) before methyl 2,2,2-trichloromethylacetimidatate (0.495 ml_, 4.00 mmol) was added dropwise. The mixture was stirred at room temperature for 1 hour. Water was added and the mixture extracted with ethyl acetate. The organic phase was washed with water, dried over sodium sulfate, and concentrated to give the title compound (1.3 g, 93%). LCMS: m/z 381 , 383, 385 (M+1).
Step B 5-bromo-7-(trifluoromethyl)-1H-benzimidazole-2-carboxylic acid
[00135] 1 N Sodium hydroxide (6.0 mL, 6.0 mmol) was cooled to 5 °C before 5-bromo-2- (trichloromethyl)-7-(trifluoromethyl)-1H-benzimidazole (320 mg, 0.837 mmol) was added. The mixture was stirred for 1 hour and acidified to pH = 2 with 1 N hydrochloric acid. The precipitate was collected by filtration and the filter cake was washed with water before being dried under vacuum to give the title compound (220 mg, 84%). LCMS: m/z 309, 311 (M+1).
Step C
1, 1 -dimethyl ethyl [2-(cyclopentylamino)ethyl] carbamate
[00136] A mixture of 1 ,1-dimethylethyl (2-bromoethyl)carbamate (1.32 g, 5.87 mmol), cyclopentyiamine (0.58 mL, 5.87 mmol) and potassium carbonate (1.62 g, 11.74 mmol) in DMF (10 mL) was heated at 60 °C for 30 minutes. The reaction mixture was diluted with EtOAc and water was added. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated to a yellow oil. The crude product was carried on to the next step without further purification.
Step D
1, 1-dimethylethyl {2-[(bromoacetyl)(cyclopentyl)amino]ethyl}carbamate
[00137] To a cooled solution of bromoacetyl bromide (0.38 mL, 4.39 mmol) in dichloromethane (8 mL) was added a solution of 1 ,1-dimethylethyl [2- (cyclopentylamino)ethyl]carbamate (0.911 g, 3.99 mmol) and triethylamine (0.61 mL, 4.39 mmol) in dichloromethane (6 mL). The mixture was stirred while cooling in an ice bath for 30 min. The solvent was evaporated and EtOAc and water were added to the residue. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated. Purification by silica gel chromatography (EtOAc:hexane) gave the title compound (0.706 g, 51%). ES-LCMS m/z: 349 (M+1).
Step E
1-cyclopentyl-2-piperazinone
[00138] TFA (2 mL, 26.0 mmol) was added to a solution of 1 ,1-dimethylethyl {2- [(bromoacetyl)(cyclopentyl)amino]ethyl}carbamate (0.680 g, 1.947 mmol) in dichloromethane (10 mL). The mixture was stirred at room temperature for 30 minutes. The solvent was evaporated to give a colorless oil which was dissolved in ethanol (10 mL). Potassium carbonate (807 mg, 5.84 mmol) was added and the mixture was heated at reflux for 30 minutes. The solvent was evaporated and the residue was taken up in DCM and water. The aqueous layer was back-extracted with DCM. The combined organic layers were dried over sodium sulfate and concentrated. Purification by silica gel chromatography (MeOH:DCM) afforded the title compound (0.112 g, 34%) as a colorless oil. 1H NMR (400 MHz, chloroform- ) δ ppm 4.76 - 4.96 (m, 1 H) 3.43 (s, 2 H) 3.08 - 3.17 (m, 2 H) 2.90 - 3.03 (m, 2 H) 1.90 (br. s., 1 H) 1.65 - 1.77 (m, 2 H) 1.54 - 1.65 (m, 2 H) 1.46 - 1.54 (m, 2 H) 1.34 - 1.45 (m, 2 H).
Step F
4-{[5-bromo- 7-(trifluorom ethyl)-1 H-benz imidazol-2-yl]carbonyl}- 1 -cycl opentyl-2-piperazinone
[00139] N-[(dimethylamino)(3H-[1 ,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylidene]-N- methylmethanaminium hexafluorophosphate (HATU) (130 mg, 0.34 mmol) was added to a stirring mixture of 5-bromo-7-(trifluoromethyl)-1 W-benzimidazole-2-carboxylic acid (96 mg, 0.31 mmol), 1-cyclopentyl-2-piperazinone (64 mg, 0.31 mmol), and N,N-diisopropylethylamine (0.22 mL, 1.2 mmol) in N,N-dimethylformamide (3.0 mL). The mixture was stirred for 1 hour and diluted with ethyl acetate. The organic phase was washed with water, washed with 5% lithium chloride, and concentrated. The residue was purified by silica chromatography (EtOAc/DCM) to give an oily residue that was dissolved in chloroform. Hexanes were added and the mixture concentrated. The resulting white powder was dried under vacuum to give the title compound (100 mg; 70%). ES-LCMS: m/z 459, 461 (M+1). 1H NMR (DMSO-d6) δ ppm 13.68 - 13.93 (m, 1 H), 7.88 - 8.07 (m, 1 H), 7.74 (s, 1 H), 4.85 - 5.08 (m, 1 H), 4.65 - 4.85 (m, 1 H), 4.48 - 4.65 (m, 1 H), 4.21 (s, 1 H), 3.85 (br. s., 1 H), 3.40 (br. s., 1 H), 2.64 (s, 1 H), 1.64 (d, 4 H), 1.48 (br. s., 4 H).
Exam le 2
4-{[6-bmmo-1-ethyl-4-(trifluoromethyl)-1H-benzimidazol-2-yl]carbo
piperazinone
(Compound 2)
Figure imgf000062_0001
[00140] 4-{[5-bromo-7-(trifluoromethyl)-1/4-benzimidazol-2-yl]carbonyl}-1-cyclopentyl-2- piperazinone (23 mg, 0.050 mmol) was dissolved in N,N-dimethylformamide (0.20 ml_) before cesium carbonate (24.5 mg, 0.075 mmol) and ethyl iodide (0.016 mL, 0.20 mmol) were added. The mixture was stirred for 5 hours, quenched with water, and extracted with ethyl acetate. The organic phase was washed with water, washed with 5% lithium chloride, concentrated, and dried under vacuum to give the title compound (22 mg; 81 %). LCMS: m/z 487, 489 (M+1). 1H NMR (CHLOROFORM-d) δ ppm 7.77 - 7.82 (m, 1 H), 7.72 (s, 1 H), 4.83 - 5.09 (m, 1 H), 4.63 (s, 1 H), 4.37 - 4.55 (m, 3 H), 4.23 - 4.33 (m, 1 H), 3.91 - 3.99 (m, 1 H), 3.37 - 3.55 (m, 2 H), 1.81 - 1.97 (m, 2 H), 1.57 - 1.80 (m, 4 H), 1.43 - 1.57 (m, 5 H).
Example 3
4-{[6-bro o-1- ethyl-4-(trifluoro ethyl)-1H-benzi idazol-2-yl]carbon
piperazinone
Figure imgf000062_0002
[00141] To a mixture 4-{[5-bromo-7-(trifluoromethyl)-1/- -benzimidazol-2-yl]carbonyl}-1- cyclopentyl-2-piperazinone (30 mg, 0.065 mmol) and cesium carbonate (32 mg, 0.098 mmol) in N,N-dimethyiformamide (0.50 mL) was added iodomethane (8.2 pL, 0.13 mmol). The mixture was stirred overnight at room temperature, quenched with water, and extracted with ethyl acetate. The organic phase was concentrated and the residue was purified by silica
chromatography eluting with a gradient of 0% to 50% of ethyl acetate in dichloromethane to give the title compound (26 mg; 76%). LCMS: m/z 473, 475 (M+1). 1H NMR (METHANOL-^) δ ppm 8.10 - 8.18 (m, 1 H), 7.72 (s, 1 H), 4.53 (s, 1 H), 4.36 (s, 1 H), 4.06 (d, 2 H), 3.96 - 4.01 (m, 1 H), 3.49 (br. s., 2 H), 3.31 (s, 1 H), 3.26 - 3.29 (m, 2 H), 1.66 - 1.91 (m, 4 H), 1.60 (br. s., 4 H).
Example 4
4-{[6-bromo-1-propyl-4-(trifluoromethyl)-1H-benzimidazol-2-yl]carbonyl}-1-cyclopen^ piperazinone
(Compound 4)
Figure imgf000063_0001
[00142] To a mixture 4-{[5-bromo-7-(trifluoromethyl)-1 -/-benzimidazol-2-yl]carbonyl}-1- cyclopentyl-2-piperazinone (30 mg, 0.065 mmol) and cesium carbonate (31.9 mg, 0.098 mmol) in N,N-dimethylformamide (0.50 mL) was added iodopropane (44 mg, 0.26 mmol). The mixture was stirred overnight at room temperature, quenched with water, and extracted with ethyl acetate. The organic phase was concentrated and the residue purified by silica chromatography eluting with a gradient of 0% to 30% of ethyl acetate in dichloromethane to give the title compound (23 mg; 70%). LCMS: m/z 501 , 503 (M+1). 1H NMR (METHANOL-^) δ ppm 8.16 (d, 1 H), 7.73 (s, 1 H), 4.84 (s, 2 H), 4.46 (s, 1 H), 4.33 - 4.43 (m, 2 H), 4.00 (dt, 2 H), 3.38 - 3.55 (m, 2 H), 1.67 - 1.93 (m, 6 H), 1.49 - 1.67 (m, 4 H), 0.90 (q, 3 H).
Example 5
4-{[6-bromo-1-methyl-4-(trifluoromethyl)-1H-benzimidazo!-2-yl]carbonyl}-1-cyclo^
piperazinone
(Compound 5)
Figure imgf000064_0001
Step A
methyl 5-bromo-7-(trifluoromethyl)-1H~benzimidazole-2~carboxylate
[00143] To a solution of 5-bromo-2-(trichloromethyl)-7-(trifluoromethyl)-1 f -benzimidazole (0.96 g, 2.5 mmol) in methanol (20 mL) was added sodium carbonate (0.399 g, 3.77 mmol). The mixture was refluxed for 2 hours and concentrated. The residue was taken up in ethyl acetate, washed with water, and concentrated. The residue was dissolved in acetone (20 mL) before p-toluenesulfonic acid monohydrate (2.39 g, 12.6 mmol) was added and the mixture heated to reflux for 2 hours. The mixture was concentrated and the residue taken up in ethyl acetate. The solution was washed with water, dried over sodium sulfate, concentrated, and the residue purified by silica chromatography eluting with 15% ethyl acetate in dichloromethane to yield the title compound (465 mg; 57%). LCMS: m/z 323, 325 (M+1).
Step B
methyl 6-bromo-1-methyl-4-(trifluoromethyl)-1H-benzimidazole-2-carboxylate
[00144] To a mixture of methyl 5-bromo-7-(trifluoromethyl)-1 -/-benzimidazole-2- carboxylate (520 mg, 1.61 mmol) and cesium carbonate (1050 mg, 3.22 mmol) in N,N- dimethylformamide (10 mL) was added iodomethane (0.151 mL, 2.41 mmol). The mixture was stirred overnight at room temperature. The reaction was diluted with ethyl acetate, washed with water, washed with brine, and washed with 5% lithium chloride. The organic phase was dried over sodium sulfate and concentrated to give the title compound (523 mg; 96%). LCMS: m/z 337, 339 (M+1). 1H NMR (CHLOROFORM-d) δ ppm 7.83 (s, 1 H), 7.78 (s, 1 H), 4.19 (s, 3 H), 4.06 (s, 3 H).
Step C
1 -cyclobutyl-2-piperaz inone hydrochloride
[00145] 1-Cyclobutyl-2-piperazinone (0.108 g, 14% over 3 steps) was prepared from cyclobutylamine (0.350 g, 4.92 mmol) by the procedure described for herein. 1H NMR (400 MHz, chloroform-c/) δ ppm 4.77 - 5.20 (m, 1 H) 3.49 (s, 2 H) 3.31 (t, J=5.46 Hz, 2 H) 3.07 (t, J=5.46 Hz, 2 H) 2.03 - 2.19 (m, 3 H) 1.59 - 1.74 (m, 3 H).
Step D
4-{[6-bromo-1-methyl-4-(trifluoromethyl)-1 H-benz imidazol-2-yl]carbonyl}-1 -cyclobutyl-2- piperazinone
[00146] Methyl 6-bromo-1-methyl-4-(trifluoromethyl)-1 -/-benzimidazole-2-carboxylate (200 mg, 0.59 mmol) was dissolved in tetrahydrofuran (4 mL) and sodium hydroxide (1 M) (1.2 mL, 1.2 mmol) in water (4 mL) was added. The mixture was stirred for 15 minutes and concentrated. The residue was dissolved in 6 mL of Ν,Ν-dimethylformamide and then split into 3 equal 2 mL aliquots. To one of the 2 mL aliquots was added 1-cyclobutyl-2-piperazinone hydrochloride, /V,/V-diisopropylethylamine (0.124 mL, 0.712 mmol), and N-[(dimethylamino)(3H- [1 ,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylidene]-N-methylmethanaminium hexafluorophosphate (HATU) (90 mg, 0.24 mmol). The mixture was stirred overnight at room temperature and diluted with ethyl acetate before being washed with brine, washed with 5% lithium chloride, dried over sodium sulfate, and concentrated. The residue was purified by reverse phase HPLC to give the title compound (45 mg; 49%). LCMS: m/z 459, 461 (M+1). 1H NMR (DMSO-c/6) δ ppm 8.34 (d, 1 H), 7.75 (d, 1 H), 4.81 (d, 1 H), 4.34 (s, 1 H), 4.20 (s, 1 H), 3.94 (t, 1 H), 3.84 - 3.91 (m, 4 H), 3.38 - 3.49 (m, 2 H), 2.04 - 2.23 (m, 2 H), 1.86 - 2.01 (m, 2 H), 1.49 - 1.67 (m, 2 H).
Example 6
4-{[ 6-cyclopropyl- 1-m ethyl-4- ( trifluoromethyl) - 1H-benzimidazol-2-yl]carbonyl}- 1 -(trans-4- hydroxycyclohexyl)-2-piperazinone
Figure imgf000065_0001
OH
Step A methyl 6-cyclopropyl-1-methyl-4-(trifluoromethyl)-1H-benzimidazo
[00147] Methyl 6-bromo-1-methyl-4-(trifluoromethyl)-1 Ay-benzimidazole-2-carboxylate (88 mg, 0.26 mmol), potassium phosphate tribasic (166 mg, 0.783 mmol), cyclopropylboronic acid (22.4 mg, 0.261 mmol), and PdCI2(dppf)-dichloromethane adduct (10.7 mg, 0.013 mmol) in 1 ,4- dioxane (2 mL) were heated to 90 °C for 4 hours. Additional potassium phosphate tribasic (166 mg, 0.783 mmol), cyclopropylboronic acid (22.4 mg, 0.261 mmol), and PdCI2(dppf)- dichloromethane adduct (10.7 mg, 0.013 mmol) were added and the mixture heated to 90 °C. The reaction was complete after 2 hours. The mixture was diluted with ethyl acetate, washed with water, washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by silica chromatography eluting with a gradient of 0% to 6% ethyl acetate in dichloromethane to give the title compound (47 mg, 60%). LCMS: m/z 299 (M+1). H NMR (CHLOROFORM-c ) δ ppm 7.40 (s, 1 H), 7.33 (s, 1 H), 4.18 (s, 3 H), 4.05 (s, 3 H), 2.13 (s, 1 H), 1.07 - 1.18 (m, 2 H), 0.75 - 0.88 (m, 2 H).
Step B
methyl N-{[( 1, 1 -dimethyl ethyl)oxy]carbonyl}-N-2-propen-1-ylglycinate
[00148] N-Boc-glycine methyl ester (1.758 mL, 11.89 mmol) in N,N-dimethylformamide (30 mL) was cooled to 5 °C then allyl bromide (1.544 mL, 17.84 mmol) was added followed by sodium hydride (0.713 g, 17.84 mmol) . The mixture was stirred for 2 hours, quenched with saturated ammonium chloride and extracted 2 times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated. The product was purified by silica chromatography eluting with a gradient of 0% to 50% ethyl acetate in hexanes to give the title compound (1.57 g, 57%). 1H NMR (CHLOROFORM-c/) δ ppm 5.63 - 5.90 (m, 1 H), 4.99 - 5.25 (m, 2 H), 3.94 (br. s., 2 H), 3.87 (d, 1 H), 3.83 (s, 1 H), 1.43 (d, 9 H).
Step C
methyl N-{[( 1, 1 -dimethyl ethyl)oxy]carbonyl}-N-(2-oxoethyl)glycinate
[00149] A solution of methyl Λ/-{[(1 ,1-dimethylethyl)oxy]carbonyl}-/V-2-propen-1- ylgiycinate (12 g, 52.3 mmol) in methanol (374 mL) was cooled to -78 °C. Ozone was bubbled in until the reaction mixture turned blue and TLC indicated consumption of the starting material. Nitrogen was bubbled into the reaction mixture until the blue solution became colorless, and then bubbled with nitrogen for 25 more minutes. Dimethyl sulfide (19.36 mL, 262 mmol) was added slowly and the mixture was allowed to slowly come to room temperature as the cold-bath warmed overnight. The mixture was concentrated and the residue was taken up in ethyl acetate (750 mL). The organic phase was washed with water (250 mL), washed with brine (250 mL), dried over sodium sulfate, and concentrated to give the title compound (12.7 g, 99%). 1H NMR (CHLOROFORM-d) δ ppm 9.59 - 9.77 (m, 1 H), 4.13 (s, 1 H), 4.05 (s, 1 H), 4.00 (s, 1 H), 3.90 (s, 1 H), 3.72 - 3.80 (m, 3 H), 1.39 - 1.54 (m, 9 H). Spectral data matches that reported previously in the literature: Bioorg. Med. Chem., 2007 (15), 2092-2105.
Step D
1, 1 -dimethyl ethyl 4-(trans-4-hydroxycyclohexyl)-3-oxo-1 -piper azinecarboxylate
[00150] To a solution of methyl Λ/-{[(1 ,1-dimethylethyl)oxy]carbonyl}-/V-(2- oxoethyl)glycinate (12.7 g, 52.2 mmol) in methanol (200 mL) was added sodium sulfate (46.3 g, 326 mmol) followed by ira/?s-4-aminocyclohexanol hydrochloride (9.49 g, 62.6 mmol) and N,N- diisopropylethylamine (10.93 mL, 62.6 mmol). The mixture was stirred for 60 minutes before sodium borohydride (2.369 g, 62.6 mmol) was added portionwise in order to control effervescence. A mild exotherm was observed. After 2 hours, LC-MS showed the uncyclized amine/ester. Sodium hydride (60% in mineral oil) (3.99 g, 100 mmol) was added portionwise in order to control effervescence. The reaction appeared to be complete after 1 hour. The reaction was stirred for an additional hour and was concentrated. The mixture was quenched with 30% citric acid trisodium salt. 1 HCI was added until pH~7, and then solid citric acid was added until pH~5. The mixture was extracted three times with ethyl acetate and the combined organic layers were washed with brine. The organic phase was dried over sodium sulfate and concentrated. Solids precipitated while concentrating. Once the volume reached ~100-150 mL, hexanes were added (400 mL). Solids were collected by filtration, washed with hexanes, and dried under vacuum to give the title compound (10.65 g, 68%). ES-LCMS: m/z 299 (M+1 ).
Step E
1-(trans-4-hydroxycyclohexyl)-2-pip erazinone hydrochloride
[00151] To a solution of 1 ,1-dimethylethyl 4-(trans-4-hydroxycyclohexyl)-3-oxo-1- piperazinecarboxylate (10.65 g, 35.7 mmol) in dichloromethane (DCM) (100 mL) was added a solution of 4M HCI in 1 ,4-dioxane (89 mL, 357 mmol). After 6 hours, the solvent was removed under reduced pressure to give 1 -(frans-4-hydroxycyclohexyl)-2-piperazinone hydrochloride (9.7 g) as a white solid. The compound contained -0.23 eq DCM and -0.16 eq of 1 ,4-dioxane. MS (ESI): m/z 199 (M+1).
Step F 4-{[6-cyclopropyl-1-methyl-4-(trifluoromethyl)-1H-benzim^
hydroxycyclohexyl)-2-piperazinone
[00152] Methyl 6-cyclopropyl-1-methyl-4-(trifluoromethyl)-1 -benzimidazole-2- carboxylate (45 mg, 0.15 mmol) was dissolved in tetrahydrofuran (2 mL). Water (2 mL) was added followed by 1 M sodium hydroxide (0.302 mL, 0.302 mmol) and the mixture was stirred at room temperature for 15 minutes, concentrated, and the residue co-evaporated 1 time with toluene. N,N-dimethylformamide (2 mL), N.N-diisopropylethylamine (0.105 mL, 0.603 mmol), and 1-(fra/7s-4-hydroxycyclohexyl)-2-piperazinone hydrochloride (42.5 mg, 0.181 mmol) were added to the residue before N-[(dimethylamino)(3H-[1 ,2,3]triazolo[4,5-b]pyridin-3- yloxy)methylidene]-N-methylmethanaminium hexafluorophosphate (HATU) (68.8 mg, 0.181 mmol) was added in one portion. The mixture was stirred for 2 hours and diluted with ethyl acetate. The organic layer was washed with brine, washed with 5% lithium chloride, dried over sodium sulfate, and concentrated. The residue was purified by silica chromatography eluting with a gradient of 0% to 5% methanol in dichloromethane to give the title compound (59 mg; 84%). LCMS: m/z 465 (M+1). 1H NMR (DMSO-cfe) δ ppm 7.66 (s, 1 H), 7.30 - 7.52 (m, 1 H), 4.52 - 4.71 (m, 1 H), 4.42 (s, 1 H), 4.23 (s, 2 H), 3.94 - 4.01 (m, 1 H), 3.91 (s, 2 H), 3.81 - 3.87 (m, 1 H), 3.36 (d, 2 H), 2.12 - 2.25 (m, 1 H), 1.78 - 1.98 (m, 2 H), 1.43 - 1.63 (m, 4 H), 1.24 (br. s., 3 H), 1.04 (dd, 2 H), 0.77 - 0.90 (m, 3 H).
Example 7
trans-4-(4-{[6-cyclopropyM-methyl-4-(trifluoromethyl)-1H-benzimidazo
oxo-1-piperazinyl)cyclohexyl dihydrogen phosphate
H
Figure imgf000068_0001
[00153] A stirred suspension of 4-{[6-cyclopropyl-1-methyl-4-(trifluoromethyl)-1 H- benzimidazol-2-yl]carbonyl}-1-(trans-4-hydroxycyclohexyl)-2-piperazinone (500 mg, 1.076 mmol) in trimethyl phosphate (7 mL) was cooled in an ice water bath and treated with POCI3 (0.304 mL, 3.23 mmol) dropwise. The resulting mixture was stirred for 3 hours. Cooled in an ice water bath, the solution was treated with a solution of sodium bicarbonate (723 mg, 8.61 mmol) in water (9 mL) dropwise. A cloudy solution was produced, which was stirred at room temperature for 4 h, the fine precipitate was collected by vacuum filtration on a medium frit and washed with water twice, dried to afford trans-4-(4-{[6-cyclopropyl-1-methyl-4-(trifluoromethyl)- 1 H-benzimidazol-2-yl]carbonyl}-2-oxo-1-piperazinyl)cyclohexyl dihydrogen phosphate (570 mg, 97% yield) as a white solid. 1H NMR (400 MHz, CD3OD) δ ppm 7.56 (s, 1 H), 7.39 (s, 1 H), 4.55 (s, 1 H), 4.45-4.30 (m, 2 H), 4.25-4.10 (m, 1 H), 4.10-3.97 (m, 2 H), 3.96 (s, 3 H), 3.50 (bs, 2 H), 2.30 - 2.10 (m, 3 H), 1.80 - 1.50 (m, 6 H), 1.15 - 1.05 (m, 2 H), 0.90 - 0.80 (m, 2 H). ES-LCMS m/z: 545 (M+1).
Example 8
1-[(trans)-bicyclo[3.1.0]hex-3-yl]-4-{[6-cyclopropyl-1-methyl-4-(triflu
benzimidazol-2-yl]carbonyl}-2-piperazinone
(Compound 8)
Figure imgf000069_0001
Step A
2-[(trans)-bicyclo[3.1.0]hex-3-yl]- 1H-isoindole- 1, 3(2H)-dione
[00154] DIAD (8.11 mL, 41.7 mmol) was added to a solution of (cis)-bicyclo[3.1.0]hexan- 3-ol (3.15 g, 32.1 mmol), 1 H-isoindole-1 ,3(2H)-dione (6.14 g, 41.7 mmol), and
triphenylphosphine (10.94 g, 41.7 mmol) in THF (300 mL) at 0 °C. After 1 hour at 0 °C, the starting alcohol appeared to be gone by TLC. The reaction was warmed to RT and stirred overnight. Water (25 mL) and EtOAc (50 mL) were added. The organic layer was separated, washed with brine, dried over MgS04, filtered and concentrated to give a yellow solid. The material was purified on silica gel (hexanes/EtOAc) to give 2-[(trans)-bicyclo[3.1.0]hex-3-yl]-1 H- isoindole-1 ,3(2H)-dione (5.5 g, 24.20 mmol, 75 % yield) as a white solid.
Step B
(trans)-bicyclo[3.1.0]hexan-3- amine hydrochloride
[00155] Hydrazine monohydrate (5.50 mL, 112 mmol) was added to a suspension of 2- [(trans)-bicyclo[3.1.0]hex-3-yl]-1 H-isoindole-1 ,3(2H)-dione (5.1 g, 22.44 mmol) in EtOH (200 mL) and the mixture was heated at reflux for 16 hours. The mixture was cooled to RT and Et20 (50 mL) was added. The solid was filtered off and the filtrate was concentrated (note: amine appears to be volatile). Et20 (30 mL) was added and again the solid was filtered off. The filtrate was concentrated then EtOH (20 mL) and Et20 (20 mL) were added. The solvents were again removed under vacuum in an attempt to remove excess hydrazine and HCI in dioxane (4N, 5mL) was added. The mixture was concentrated to dryness and used as is in the next step.
Step C
1, 1 -dimethyl ethyl 4-[(trans)-bicyclo[3.1.0]hex-3-yl]-3-oxo-1-piperazinecarboxylate
[00156] A mixture of (trans)-bicyclo[3.1 ,0]hex-3-ylamine hydrochloride (1.098 g, 8.22 mmol), methyl N-{[(1 ,1-dimethylethyl)oxy]carbonyl}-N-(2-oxoethyl)glycinate (1.9 g, 8.22 mmol), Hunig's base (1.579 mL, 9.04 mmol), and sodium sulfate (7.00 g, 49.3 mmol) was stirred in MeOH (30 mL) for 2 hours, then NaBH4 (0.342 g, 9.04 mmol) was added in portions over ca. 10 minutes. The mixture was stirred for 2 hours then 60% NaH dispersion in oil (0.624 g, 15.61 mmol) was added in portions over ca. 0 min. After 2 hours TLC and LCMS shows what appears to product. Aqueous citric acid (30% by wt., 50 mL) was added slowly and the mixture was filtered thru Celite and washed with MeOH. The filtrate was concentrated under reduced pressure to remove the MeOH and the remaining aqueous layer was extracted with ethyl acetate (2 x 150 mL). The organic layers were combined, washed with saturated aqueous NaHC03 solution, brine, dried over Na2S04, filtered and concentrated. The product was purified on silica gel (hexanes/ethyl acetate) to give 1 ,1-dimethylethyl 4-[(trans)-bicyclo[3.1.0]hex-3-yl]-3- oxo-1-piperazinecarboxylate (1.67 g, 5.96 mmol, 72.5 % yield) as a white solid.
Step D
1 -[(trans)-bicyclo[3.1.0]hex-3-yl]-2- iperazinone hydrochloride
[00157] To a solution of 1 ,1-dimethylethyl 4-[(trans)-bicyclo[3.1.0]hex-3-yl]-3-oxo-1- piperazinecarboxylate (1.67 g, 5.96 mmol) in DCM (30 mL) was added 4M HCI in dioxane (14.89 mL, 59.6 mmol). The solution was stirred for 16 h then the solvent was removed under reduced pressure to give the title compound as a white solid that was used without further purification.
Step E
1-[(trans)-bicyclo[3.1.0]hex-3-yl]-4-{[6-cyclopropyl-1-me^
2-yl]carbonyl}-2- piperazinone
[00158] Methyl 6-bromo-1-methyl-4-(trifluoromethyl)-1 V-benzimidazole-2-carboxylate (111 mg, 0.372 mmol) was dissolved in tetrahydrofuran (2 mL). Water (2 mL) was added followed by 1 M sodium hydroxide (0.744 mL, 0.744 mmol) and the mixture stirred at room temperature for 15 minutes. The mixture was concentrated. DMF (2 mL), N,N- diisopropylethylamine (0.325 mL, 1.861 mmol), and 1-[(trans)-bicyclo[3.1.0]hex-3-yl]-2- piperazinone hydrochloride (81 mg, 0.37 mmol) were added to the residue before 1- propanephosphonic acid cyclic anhydride (50 wt. % solution in ethyl acetate) (0.332 mL, 0.558 mmol) was added. The mixture was stirred for 2 hours and diluted with water. White solids precipitated and were collected by filtration. The filter cake was washed with water and air dried to give the title compound ( 00 mg; 41 %). LCMS: m/z 447 (M+1). 1H NMR (DMSO-c/6) δ ppm 7.61 - 7.76 (m, 1 H), 7.37 - 7.49 (m, 1 H), 4.48 - 4.66 (m, 1 H), 4.37 - 4.45 (m, 1 H), 4.24 (s, 1 H), 3.94 - 4.00 (m, 1 H), 3.90 (s, 3 H), 3.81 - 3.87 (m, 1 H), 3.35 - 3.41 (m, 2 H), 2.13 - 2.25 (m, 1 H), 1.76 - 1.93 (m, 2 H), 1.65 - 1.76 (m, 2 H), 1.12 - 1.36 (m, 2 H), 0.97 - 1.10 (m, 2 H), 0.76 - 0.89 (m, 2 H), 0.31 - 0.41 (m, 1 H), 0.19 - 0.30 (m, 1 H).
Example 9
1-(cyclobutylmethyl)-4-{[6-cyclopropyl-1-methy 4-(trifluoromethyl)-1H-benzim
yl]carbonyl}-2-piperazinon e
Figure imgf000071_0001
Step A
(cyclobutylmethyl)amine hydrochloride
[00159] Borane-tetrahydrofuran complex (1 M in tetrahydrofuran) (68.8 mL, 68.8 mmol) was added slowly dropwise over 15 minutes to a solution of cyclobutanecarbonitrile (4.65 g, 57.3 mmol) in tetrahydrofuran (15 mL). The mixture was heated at reflux for 16 hours and then cooled to room temperature. Methanol (75 mL) was added slowly dropwise over 15 minutes. The mixture was cooled to 5 °C in an ice bath before gaseous hydrogen chloride was bubbled in for 30 minutes. The mixture was allowed to warm to room temperature and then refluxed for 90 minutes. The mixture was allowed to cool to room temperature and concentrated. The residue was co-evaporated 2 times with methanol and concentrated. Ethyl ether was added and solids collected by filtration. The solids were taken up in hot isopropanol, filtered, and hot acetonitrile added to the filtrate. Solids formed upon cooling and were collected by filtration. The product was dried under vacuum to give the title compound (1.1g, 16%). H NMR (DMSO-cfe) δ ppm 8.08 (br. s., 3 H), 2.79 (d, 2 H), 2.51 - 2.61 (m, 1 H), 1.94 - 2.07 (m, 2 H), 1.65 - 1.89 (m, 4 H).
Step B
1, 1 -dimethyl ethyl 4-(cyclobutylmethyl)-3-oxo- 1- piperazinecarboxylate
[00160] To a solution of methyl Λ/-{[(1 ,1-dimethylethyl)oxy]carbonyl}-/V-(2- oxoethyl)glycinate (1.36 g, 5.88 mmol) in methanol (25 ml) was added sodium sulfate (5.22 g, 36.8 mmol) followed by (cyclobutylmethyl)amine hydrochloride (0.787 g, 6.47 mmol) and N,N- diisopropylethylamine (1.130 ml, 6.47 mmol). The mixture was stirred for 20 minutes before sodium borohydride (0.267 g, 7.06 mmol) was added portionwise to control frothing. The mixture was stirred for 2 hours. LC-MS showed conversion to the cyclized product, but some of the uncyclized amine remained. The mixture was stirred at room temperature for 16 hours, quenched with saturated sodium bicarbonate, extracted with ethyl acetate, washed with brine, dried over sodium sulfate, and concentrated to give the title compound (1.35 g, 86%). LCMS: m/z 269 (M+1 ).
Step C
1 -(cyclobutylmethyl)-2-piperazinone hydrochloride
[00161] 1 ,1-dimethylethyl 4-(cyclobutylmethyl)-3-oxo-1-piperazinecarboxylate (1.3 g, 4.84 mmol) was dissolved in tetrahydrofuran (10 mL) before hydrogen chloride (4M in dioxane) (9.69 mL, 38.8 mmol) was added. The mixture was stirred for 2 hours, concentrated, and dried under vacuum. NMR showed that deprotection was not complete. The residue was dissolved in hydrogen chloride (4M in dioxane) (9.69 mL, 38.8 mmol) and stirred overnight at room temperature. The mixture was concentrated and the residue dried under vacuum to give the title compound (1.0 g, >99%). 1H NMR (DMSO-cfe) δ ppm 9.89 (br. s., 2 H), 3.59 - 3.69 (m, 2 H), 3.44 - 3.53 (m, 2 H), 3.38 (d, 2 H), 3.27 - 3.35 (m, 2 H), 2.51 - 2.59 (m, 1 H), 1.91 - 2.06 (m, 2 H), 1.61 - 1.89 (m, 4 H).
Step D
1-(cyclobutylmethyl)-4-{[6-cyclopropyl-1-methyl-4-(trifluorome
yl]carbonyl}-2-piperaz inone
[00162] Methyl 6-cyclopropyl-1-methyl-4-(trifluoromethyl)-1f -benzimidazole-2- carboxylate (149 mg, 0.355 mmol) was dissolved in tetrahydrofuran (4 mL) before sodium hydroxide (1 M) (0.709 mL, 0.709 mmol) was added. The mixture was stirred for 10 minutes and immediately concentrated to dryness. The residue was slurried in N,N-dimethylformamide (4.00 mL) before N,N-diisopropylethylamine (0.248 mL, 1.419 mmol), 1-(cyclobutylmethyl)-2- piperazinone hydrochloride (87 mg, 0.426 mmol), and N-[(dimethylamino)(3H-[1 ,2,3]triazolo[4,5- b]pyridin-3-yloxy)methylidene]-N-methylmethanaminium hexafluorophosphate (HATU) (162 mg, 0.426 mmol) were added sequentially. The mixture was stirred for 2 hours, quenched with brine, and extracted 2 times with ethyl acetate. The combined organic layers were washed with brine, washed with 5% lithium chloride, and filtered through a hydrophobic frit for drying. The mixture was concentrated and the residue purified by silica chromatography eluting with a gradient of 0% to 50% ethyl acetate in dichloromethane. After concentrating appropriate fractions, the product was recrystallized from ethyl acetate / ethyl ether to give the title compound (40 mg; 26%) as white solids. LCMS: m/z 435 (M+ ). 1H NMR (DMSO-d6) δ ppm 7.66 (s, 1 H), 7.43 (s, 1 H), 4.42 (s, 1 H), 4.25 (s, 1 H), 3.98 (t, 1 H), 3.84 - 3.94 (m, 4 H), 3.36 - 3.51 (m, 4 H), 2.54 (d, 1 H), 2.19 (s, 1 H), 1.92 - 2.04 (m, 2 H), 1.80 (dd, 2 H), 1.63 - 1.76 (m, 2 H), 1.00 - 1.07 (m, 2 H), 0.84 (d, 2 H).
Example 10
4-{[6-cyclopropyl-1-methyl-4-(trifluoromethyl)-1H-benzimidazol-2-yl]ca^
3-hydroxycyclopentyl]-2-piperazinone
(Compound 10)
Figure imgf000074_0001
Step A
1, 1 -dimethyl ethyl 4-[( 1 R, 3R)-3-hydroxycyclopentyl]-3-oxo- 1-piperazinecarboxylate
[00163] A solution methyl N-{[(1 ,1-dimethylethyl)oxy]carbonyl}-N-(2-oxoethyl)glycinate (4.5 g, 19.46 mmol) in MeOH (70.5 ml) was treated with sodium sulfate (17.28 g, 122 mmol) followed by (1 R, 3R)-3-aminocyclopentanol (2.36 g, 23.35 mmol). The mixture was stirred for 1.5 hour. The reaction was then treated by the portion wise addition of NaBH4 (0.883 g, 23.35 mmol). After stirring for 2.5 hours, the reaction was treated by the portion wise addition of 60% NaH (1.49 g, 37.2 mmol). The reaction was then allowed to stir for 1.5 hours. The reaction was then quenched by the addition of 30% citric acid to bring the pH to ~5. The organic solvent was removed under reduced pressure and the residue was taken up in water and extracted with EtOAc (3x). The combined organics were washed with brine. The organic phase was then dried over Na2S04, filtered, and concentrated to an oily crude residue. The residue was purified by silica gel chromatography (1-5% MeOH/DCM) to give the title compound (3.29 g, 60%). ES- LCMS: 285.3 (M+1).
Step B
(1R, 3R)-3-( 2-oxo- 1-piperazinyl)cyclopentyl trifluoroacetate
[00164] A solution of 1 ,1-dimethylethyl 4-[(1 R,3R)-3-hydroxycyclopentyl]-3-oxo-1- piperazinecarboxylate (3.07 g, 10.80 mmol) in DCM (45.7 mi) was treated with TFA (8.32 ml, 108 mmol) and stirred at room temperature for 3 hours. The reaction was concentrated but was found to be incomplete. The residue was treated with DCM and TFA and stirred an additional 2 hours. The reaction was then concentrated under reduced pressure to give the title compound (4.96 g, 99%). ES-LCMS: 282.1 (M+1).
Step C
4-{[6-cyclopropyl-1-methyl-4-(trifluoromethyl)-1H-benzimM^ hydroxycyclopentyl]-2-piperazinone
[00165] A solution of methyl 6-cyclopropyl-1-methyl-4-(trifluoromethyl)-1 H-benzimidazole- 2-carboxylate (0.056 g, 0.19 mmol) in THF (0.85 ml) was treated with water followed by 1 M NaOH (0.38 ml, 0.38 mmol). The reaction was stirred for 15 minutes. The reaction was concentrated and the crude residue was treated with DMF (0.85 ml), (1 R,3R)-3-(2-oxo-1- piperazinyl)cyclopentyl trifluoroacetate (0.078 g, 0.17 mmol), HATU (0.079 g, 0.21 mmol), and DIEA (0.098 ml, 0.56 mmol). The reaction was stirred at room temperature overnight. The mixture was diluted with EtOAc, washed with 5% LiCI solution, saturated NaHC03, brine, dried over MgS04, filtered, and concentrated. The crude residue was purified by silica gel chromatography (0-4% MeOH/DCM) to give the title compound. 1H NMR (CDCI3) δ ppm 7.34 (s, 1 H), 7.29 (s, 1 H), 5.12-5.25 (m, 1 H), 4.70 (s, 1 H), 4.44 (bs,1 H), 4.40 (s, 1 H), 4.28 - 4.38 (m, 1 H), 4.01 (s, 1 H), 3.93 - 3.99 (m, 2H), 3.49 (t, J = 5.2 Hz, 1 H), 3.45 - 3.36 (m, 1 H), 2.05 - 2.17 (m, 3H), 1.77 - 1.97 (m, 3H), 1.53 - 1.74 (m, 2H), 1.25 (t, J = 7.1 Hz, 1 H), 1.04 - 1.15 (m, 2H), 0.76 - 0.84 (m, 2H). ES-LCMS: 450.8 (M+1).
Example 11
3-(1-{[6-brom o- 1 -methyl-4-( trifluoro ethyl)- 1H-benzimidazol- 2-yl]carbonyl}-4-piperidinyl)-
1, 3-oxazolidin-2-on e
(Compound 11)
Figure imgf000075_0001
3-(1-{[6-bromo-1 -methyl -4-(trifluoromethyl)- 1 H-benzimidazol-2-yl]carbonyl}-4-piperidinyl)- 1, 3- oxazolidin-2-one
[00166] Methyl 6-bromo-1-methyl-4-(trifluoromethyl)-1 H-benzimidazole-2-carboxylate (200 mg, 0.593 mmol) was dissolved in tetrahydrofuran (4 mL) and sodium hydroxide (1 M) (1.19 mL, 1.19 mmol) in water (4 mL) added. The mixture was stirred for 15 minutes, concentrated, and dried under vacuum. The residue was dissolved in N,N-dimethylformamide (6 mL) and then split into three equal 2 mL aliquots. To one of the 2 mL aliquots was added 3-(4- piperidinyl)-1 ,3-oxazolidin-2-one (40.4 mg, 0.237 mmol) , /V-ethyl-/V-(1-methylethyl)-2- propanamine (0.124 mL, 0.712 mmol), and N-[(dimethylamino)(3H-[1 ,2,3]triazolo[4,5-b]pyridin- 3-yloxy)methylidene]-N-methylmethanaminium hexafluorophosphate (HATU) (90 mg, 0.237 mmol). The mixture was stirred overnight at room temperature. The mixture was diluted with ethyl acetate, washed with brine, washed with 5% lithium chloride, dried over sodium sulfate, and concentrated. The residue was subject to reverse phase HPLC. The product was recrystallized from dichloromethane/hexanes to give the title compound (33 mg; 35%). LCMS: m/z 475, 477 (M+1). 1H NMR (DMSO-d6) δ ppm 8.32 (s, 1 H), 7.73 (s, 1 H), 4.52 - 4.67 (m, 1 H), 4.21 (t, 2 H), 3.91 - 4.06 (m, 1 H), 3.85 (s, 3 H), 3.73 - 3.83 (m, 1 H), 3.47 (dd, 2 H), 3.15 - 3.25 (m, 1 H), 2.88 - 3.00 (m, 1 H), 1.73 - 1.85 (m, 1 H), .54 - 1.73 (m, 3 H).
Example 12
3-(1-{[6-bromo-1-methyl-4-(trifluoromethyl)-1 W-benzimidazol-2-yl]carbonyl}-4-piperidinyl)-
1,3-oxazolidine-2,4-dione
(Compound 12)
Figure imgf000076_0001
Step A
sodium 6-brom o- 1-methyl-4-(trifluoromethyl)-1H-benz imidazole-2-carboxylate
[00167] To a solution of methyl 6-bromo-1-methyl-4-(trifluoromethyl)-1 H-benzimidazole-2- carboxylate (500 mg; 1.48 mmol) in tetrahydrofuran (10 mL) and water (10 mL) was added sodium hydroxide (1 M) (3.0 mL; 3.0 mmol). The mixture was stirred at room temperature for 15 minutes, concentrated, and dried under vacuum to give the title compound (500 mg; 98%). LCMS: m/z 323, 325 (M+1).
Step B
3-(1 -{[6-bromo-1 -methyl -4-(trifluoromethyl)-1H-benzimidazol-2-yl]carbon
oxazolidine-2, 4-dione [00168] To sodium 6-bromo-1-methyl-4-(trifluoromethyl)-1f/-benzimidazole-2-carboxylate (200 mg; 0.58 mmol) in N,N-dimethylformamide (5 mL) was added 3-(4-piperidinyl)-1 ,3- oxazolidine-2,4-dione (150 mg; 0.70 mmol), A/-ethyl-A/-(1-methylethyl)-2-propanamine (224 mg; 1.74 mmol), and N-[(dimethylamino)(3H-[1 ,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylidene]-N- methylmethanaminium hexafluorophosphate (HATU) (265 mg; 0.70 mmol). The mixture was stirred for 2 hours at room temperature and then diluted with ethyl acetate, washed with brine, washed with 1 M hydrochloric acid, dried over sodium sulfate, and concentrated. The residue was purified by silica chromatography eluting with ethyl acetate/petroleum ether to give the title compound (200 mg; 71 %). 1 H NMR (300MHz, CDCI3) δ ppm 7.78(s, 1 H), 7.72(s, 1 H), 4.89(m, 2H), 4.67(s, 2H), 4.26(q, 1 H), 4.00(s, 3H), 3.30 (dt,1 H), 2.88(dt, 1 H), 2.45(m, 2H), 1.84(dd, 2H). LCMS: m/z 489 (M+1).
Example 13
3-(1-{[6-cyclopropyl-1-methyl-4-(trifluoromethyl)-1W-benzimidazol-2-yl]carbonyl}-4- pi e
Figure imgf000077_0001
Step A
sodium 6-cyclopropyl-1-methyl-4-(trifluoromethyl)-1H-benzimidazo
[00169] To a solution of methyl 6-cyclopropyl-1-methyl-4-(trifluoromethyl)-1 7- benzimidazole-2-carboxylate (66 mg; 0.22 mmol) in tetrahydrofuran (4 mL) and water (4 mL) was added 1M sodium hydroxide (0.44 mL, 0.44 mmol). The mixture was stirred at room temperature for 2 hours. The mixture was concentrated and the residue co-evaporated 3 times with methanol to give the title compound (67 mg; 99%). LCMS: m/z 285 (M+1).
Step B
3-(1-{[6-cyclopropyl-1-methyl-4-(trifluoromethyl)-1H-benzw
1, 3-oxazolidin-2-one [00170] To a mixture of sodium 6-cyclopropyl-1-methyl-4-(trifluoromethyl)-1 H- benzimidazole-2-carboxylate (70 mg, 0.22 mmol) in DMF was added 3-(4-piperidinyl)-1 ,3- oxazolidin-2-one hydrochloride (56.6 mg, 0.275 mmol), /V-ethyl-/V-(1-methylethyl)-2- propanamine (88.6 mg, 0.687 mmol), and N-[(dimethylamino)(3H-[1 ,2,3]triazolo[4,5-b]pyridin-3- yloxy)methylidene]-N-methylmethanaminium hexafluorophosphate (HATU) (105 mg, 0.0.275 mmol). The mixture was stirred at room temperature for 2 hours, diluted with water, and extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by silica chromatography eluting with a gradient from 1 :1 to 1 :4 petroleum ether/ethyl acetate to give the title compound (45 mg; 44%) as a white solid. 1 H NMR (300MHz, CDCI3) δ ppm 7.33 (s, 1 H), 7.27 (s, 1 H), 4.83 (d, 1 H), 4.68 (d,1 H), 4.35 (t, 2H), 4.15 (m, 1 H) 3.99 (m, 3H), 3.54(t, 2H), 3.15(t, 1 H), 2.87(m, 1 H), 2.23- 1.73(m, 5H), 1.07(m, 2H), 0.78(m, 2H). LCMS: m/z 437 (M+1).
Example 14
3-( 1-{[ 6-cyclop ropyl- 1 -methyl- 4-( trifluoromethyl) - 1 H-ben zimidazol-2-yl]carbonyl}-4- piperidinyl)-1,3-oxazolidine-2,4-dione
(Compound 14)
Figure imgf000078_0001
[00171] To a mixture of sodium 6-cyclopropyl-1-methyl-4-(trif!uoromethyl)-1 H- benzimidazole-2-carboxylate (500 mg; 1.63 mmol), 3-(4-piperidinyl)-1 ,3-oxazolidine-2,4-dione hydrochloride (428 mg, 1.96 mmol) and A/-ethyl-/V-(1-methylethyl)-2-propanamine (631 mg, 4.89 mmol) in DMF was added N-[(dimethylamino)(3H-[1 ,2,3]triazolo[4,5-b]pyridin-3- yloxy)methylidene]-N-methylmethanaminium hexafluorophosphate (HATU) (745 mg, 1.96 mmol). The mixture was stirred at room temperature for 3 hours, diluted with water, and extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by silica chromatography to give the title compound (100 mg; 14%) as a white solid. 1 H NMR (300MHz, CDCI3) δ ppm 7.34 (s, 1 H), 7.29 (s, 1 H), 4.94 (m, 2H), 4.66(s, 2H), 4.23(m, 1 H), 3.98 (s,3H), 3.29 (t,1 H), 2.81 (t, 1 H), 2.39- 2.16(m, 2H), 2.06(m, 1 H), 1.90-1.75(dd, 2H), 1.09(m, 2H), 0.78(m, 2H). LCMS: m/z 451 (M+1).
Example 15
3-(1-{[6-(3-furanyl)-1-methyl-4-(tnJluoromethyl)-1H-benzimidazol-2-yl]
piperidinyl)-1,3-oxazolidin-2-one
(Compound 15)
Figure imgf000079_0001
3-(1-{[6-(3-furanyl)-1-methyl-4-(trifluoromethyl)-1H-benzimM^
1, 3-oxaz olidin-2-one
[00172] To a mixture of 3-(1-{[6-bromo-1-methyl-4-(trifluoromethyl)-1 y-benzimidazol-2- yl]carbonyl}-4-piperidinyl)-1 ,3-oxazolidin-2-one (67 mg; 0.14 mmol) and 3-furanylboronic acid in 1 ,4-dioxane (10 mL) was added potassium carbonate (58 mg; 0.42 mmol), and
tetrakis(triphenylphosphine)palladium(0) (8 mg; 0.007 mmol). The mixture was heated to 105 °C overnight, cooled to room temperature, diluted with ethyl acetate, and the mixture filtered through a celite pad. The filtrate was concentrated and the residue purified by silica chromatography eluting with a gradient of 1 :1 to 1 :4 petroleum ether/ethyl acetate to give the title compound (45 mg; 69%). 1 H NMR (300MHz, CDCI3) δ ppm 7.84 (s, 1 H), 7.74 (s, 1 H), 7.65 (s, 1 H), 7.61 (s, 1 H), 6.78(s, 1 H), 4.90 (d,1 H), 4.79 (d,1 H), 4.33 (t, 2H), 4.14-4.03(m, 1 H), 4.01 (t, 3H), 3.63-3.56(m, 2H), 3.19-3.15(m, 1 H), 2.95-2.86(m, 1 H), 2.05-1.76(m, 4H). LCMS: m/z 463 (M+1).
Example 16
4-[(4-bromo-6-cyclopropyl-1-methyl-1H-benzimidazol-2-yl)carbonyl]-1-(tran
dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2-piperazinone
(Compound 16)
Figure imgf000080_0001
Step A
(4-cyclopropyl-2-nitrophenyl)amine
[00173] A suspension of 4-bromo-2-nitroaniline (25 g, 115 mmol), cyclopropylboronic acid (19.79 g, 230 mmol), palladium(ll) acetate (0.129 g, 0.576 mmol), potassium phosphate tribasic (73.4 g, 346 mmol), cataCXium A (0.413 g, 1.152 mmol) in toluene (230 ml) and water (99 ml) was heated in a under nitrogen at 90 °C overnight. The mixture was cooled to room
temperature and transferred to a separatory funnel. The aqueous was extracted with EtOAc and the combined organic phases were washed with saturated NaHC03, brine, dried Na2S04, filtered, and concentrated. The reddish orange oil was passed through a plug of silica eluting with DCM to give the title compound as an orange liquid (20.68 g, 100%). ES-LCMS: 179.2 (M+1).
Step B
(2-bromo-4-cyclopropyl-6-nitrophenyl)amine
[00174] A solution of (4-cyclopropyl-2-nitrophenyl)amine (20.68 g, 116 mmol) in acetic acid (387 ml) was cooled in ice bath and was then treated by the portion-wise addition of NBS (21.69 g, 122 mmol). The reaction was stirred at room temperature for 90 minutes. The reaction was then treated with water and extracted with Et20. The combined organics were washed with water (2x), poured into stirring saturated NaHC03 (2x), washed with brine, dried Na2S04, filtered, and concentrated to give the title compound as a reddish orange solid (29.44 g, 99%). ES-LCMS: 258.2, 259.0 (M+1 ).
Step C
(2-amino-3-bromo-5-cycl opropylphenyl)ami ne [00175] A solution of (2-bromo-4-cyclopropyl-6-nitrophenyl)amine (29.44 g, 115 mmol) in THF (471 ml) was treated by the drop-wise addition of sodium dithionite (sodium hydrosulfite) (80 g, 458 mmol) in water (235 ml). The reaction was stirred at room temperature for 48 hours. The reaction was transferred to separately funnel and the water layer was separated from the organics and discarded. Additional sodium dithionite (sodium hydrosulfite) (80 g, 458 mmol) in water (235 ml) was added drop-wise. The reaction mixture was stirred for 48 hours. The reaction was then treated by the addition of sodium dithionite (40 g) in water (150 mL) and stirred for an additional 48 hours. The mixture was diluted with EtOAc and the combined organic layers were washed with saturated NH4CI (2x), brine, dried Na2S04, filtered, and concentrated to give a brownish oily solid. The residue was concentrated from toluene then taken up in EtOAc and water. The combined organics were washed with saturated NaHC03, brine, dried Na2S04, filtered, and concentrated to give a brownish oil with solids. The residue was taken up in DCM (300 mL) and treated by the drop-wise addition of 4N in dioxanes HCI (57.3 ml, 229 mmol). The solution was cooled to 0 °C and stirred for 15 minutes. The light brown solid was filtered rinsing with Et20 to give the title product. (20.58 g, 68.2%). ES-LCMS: 227.1 , 229.1 (M+1 ).
Step D
4-bromo- 6-cyclopropyl-2-(trichlorom ethyl)- 1 H-benz imidazole
[00176] A suspension of (2-amino-3-bromo-5-cyclopropylphenyl)amine (11 .16 g, 42.3 mmol) in acetic acid (123 ml) followed by the drop-wise addition of methyl 2,2,2- trichloroethanimidoate (6.42 ml, 50.8 mmol). The mixture was stirred at room temperature overnight. The suspension was treated by additional methyl 2,2,2,-trichloroethanimidoate (3.0 mL) and stirred for 2 hours. The mixture was diluted with Et20 and treated with water and the layers were separated. The aqueous layer was extracted with Et20 (3x) and then the combined organic phase was washed with water (2 x), brine (2x), dried Na2S04, filtered, and concentrated. The residue was co-evaporated with toluene (2x) to give a brownish-black residue. The residue was triturated with Et20 and then solids were filtered and discarded. The filtrate was concentrated and then co-evaporated from toluene (2x) to give the title compound (8.44 g, 46.7%). ES-LCMS: 355.0, 357.0 (M+1 ).
Step E
4-[(4-bromo-6-cyclopropyl-1H-benzimidazol-2-yl)carbonyl]-1- (trans-4-hydroxycyclohex piperazinone
[00177] A solution of 4-bromo-6-cyclopropyl-2-(trichloromethyl)-1 H-benzimidazole (1.2 g, 2.81 mmol) in ACN (6.32 ml) and water (2.107 ml) was treated by the addition of 1-(trans-4- hydroxycyclohexyl)-2-piperazinone HCI (0.726 g, 3.09 mmol), then by the drop-wise addition of 4M K2C03 (2.81 ml, 11.24 mmol). The mixture was stirred at room temperature overnight. The reaction was quenched by the addition of water, then brine, and extracted with 7:1 DCM:iPrOH. The combined organics were washed with brine, dried MgS04, filtered, and concentrated to give the title compound as yellow solid (1.24 g, 81 %). ES-LCMS: 461.0, 463.2 (M+1).
Step F
4-[(4-bromo-6-cyclopropyl-1-methyl-1H-benzimidazol-2-yl)carbonyl]-1-(trans-4- hydroxycyclohexyl)-2-piperazinone
[00178] A solution of 4-[(4-bromo-6-cyclopropyl-1 H-benzimidazol-2-yl)carbonyl]-1-(trans- 4-hydroxycyclohexyl)-2-piperazinone (1.24 g, 2.285 mmol) in DMF (12.90 ml) was treated by K2CO3 (0.947 g, 6.85 mmol) and then treated by the addition of Mel (0.157 ml, 2.51 mmol). The reaction was stirred for 1 hour, and then diluted with water and extracted with EtOAc. The combined extracts were washed with 5% LiCI (3x), brine, dried MgS0 , filtered, and
concentrated. The oil was concentrated from Et20. The residue was taken up in Et20 and a seed crystal was added and the solvents were removed under reduced pressure to give the title compound (1.06 g, 98%). ES-LCMS: 475.0, 477.0 (M+1).
Step G
4-[(4-bromo-6-cyclopropyl-1-methyl-1H-benz imidazol-2-yl)carbonyl]-1-(trans-4-{[( 1, 1- dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2-piperazinone and 4-[(7-bromo-5-cyclopropyl-1- methyl- 1 H-benz imidazol-2-yl)carbonyl]- 1-(trans-4-{[( 1, 1- dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2-piperazinone
[00179] A 0 °C solution of 4-[(4-bromo-6-cyclopropyl-1-methyl-1 H-benzimidazol-2- yl)carbonyl]-1-(trans-4-hydroxycyclohexyl)-2-piperazinone (1.06 g, 2.230 mmol) in DCM (7.43 ml) was treated with DMAP (0.027 g, 0.223 mmol) and TEA (0.699 ml, 5.02 mmol). The reaction mixture was then treated with TBSCI (0.403 g, 2.68 mmol) in one portion. The bath was removed and the reaction was allowed to stir with warming to room temperature overnight. The mixture was then transferred to a separatory funnel and the reaction mixture was washed with water. The aqueous phase was extracted with DCM (3x) and the combine organics were washed with saturated NaHC03, brine, dried MgS04, filtered, and concentrated. The residue was treated with DMF (10 mL) and cooled to 0 °C. The reaction was treated with imidazole (0.304 g, 4.46 mmol) then by the addition of TBSCI (0.403 g, 2.68 mmol). The reaction was stirred at room temperature for 2 hours and diluted with water and extracted with EtOAc. The combined organics were washed with LiCI (3x), saturated NaHC03, brine, dried MgS0 , filtered, and concentrated. The crude yellow oil was purified by silica gel chromatography (30-50% EtOAc/hexanes) to give 4-[(7-bromo-5-cyclopropyl-1-methyl-1 H-benzimidazol-2-yl)carbonyl]-1- (trans-4-{[(1 ,1-dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2-piperazinone (0.089 g, 7%) ES- LCMS: 589.1 , 591.1 (M+1) and 4-[(4-bromo-6-cyciopropyl-1-methyl-1 H-benzimidazol-2- yl)carbonyl]-1-(trans-4-{[(1 ,1-dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2-piperazinone (0.316 g, 24%) ES-LCMS: 589.1 , 591.0 (M+1). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.28 (br. s., 1 H), 7.05 - 7.10 (m, 1 H), 4.75 (s, 1 H), 4.30 - 4.53 (m, 3 H), 3.96 (d, .7=11.71 Hz, 4 H), 3.36 - 3.58 (m, 3 H), 1.99 - 2.10 (m, 1 H), 1.89 - 1.98 (m, 2 H), 1.68 - 1.79 (m, 2 H), 1.45 - 1.55 (m, 4 H), 1.01 - 1.10 (m, 2 H), 0.89 (s, 9 H), 0.74 - 0.81 (m, 2 H), 0.06 (s, 6 H).
Example 17
4-[(4-bromo-6-cyclopropyl-1-methyl-1H-benzimidazol-2-yl)carbonyl]-1-(trans-4- hydroxycyclohexyl)-2-piperazinone
(Compound 17)
Figure imgf000083_0001
[00180] A solution of 4-[(4-bromo-6-cyclopropyl-1 -methyl- 1 H-benzimidazol-2-yl)carbonyl]- 1-(trans-4-{[(1 ,1-dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2-piperazinone (.050 g, 0.085 mmol) in DCM (2.0 ml) was treated by the addition of 4N in dioxanes HCI (0.509 ml, 2.035 mmol). The reaction was stirred at room temperature for 2 hours and concentrated under reduced pressure. The residue was triturated with Et20 to give the title compound as a yellow solid. ES-LCMS: 475.0, 477.0 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.37 (s, 1 H), 7.31 (s, 1 H), 4.47 (s, 1 H), 4.13 - 4.26 (m, 2 H), 3.95 - 4.03 (m, 1 H), 3.80 - 3.90 (m, 4 H), 3.30 - 3.41 (m, 4 H), 2.04 - 2.14 (m, 1 H), 1.80 - 1.93 (m, 2 H), 1.47 - 1.61 (m, 4 H), 1.16 - 1.31 (m, 2 H), 1.00 (dd, J=8.40, 2.15 Hz, 2 H), 0.75 - 0.84 (m, 2 H).
Example 18
4-[(7-bromo-5-cyclopropyl-1-methyl-1H-benzimidazol-2-yl)carbonyl]-1-(trans-4- hydroxycyclohexyl)-2-piperazinone
Figure imgf000084_0001
[00181] A solution of 4-[(7-bromo-5-cyclopropyl-1 -methyl- 1 H-benzimidazol-2-yl)carbonyl]- 1-(trans-4-{[(1 ,1-dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2-piperazinone (.050 g, 0.085 mmol) in DCM (2.0 ml) was treated by the addition of 4N in dioxanes HCI (0.509 ml, 2.035 mmol). The reaction was stirred at room temperature for 2 hours and concentrated under reduced pressure. The residue was triturated with Et20 to give the title compound as a yellow solid. ES-LCMS: 475.0, 477.0 (M+1). 1H NMR (400 MHz, DMSO- 6) δ ppm 7.40 (d, J=7.62 Hz, 1 H), 7.33 (s, 1 H), 4.31 (s, 1 H), 4.23 (s, 2 H), 4.05 (br. s., 3 H), 3.76 - 3.88 (m, 2 H), 3.29 - 3.41 (m, 4 H), 1.99 - 2.10 (m, 1 H), 1.82 - 1.92 (m, 2 H), 1.52 (br. s., 4 H), 1.15 - 1.30 (m, 2 H), 0.96 (d, J=7.82 Hz, 2 H), 0.74 (br. s„ 2 H).
Example 19
4-[(4, 6-dicyclopropyl- 1 -m ethyl- 1 H- benzimidazol-2-yl)carbonyl]- 1 -(trans-4- hydroxycyclohexyl)-2-piperazinone
(Compound 19)
Figure imgf000085_0001
Step A
4-1(4, 6-dicyclopropyl-1-methyl-1H-benzimidazol-2-yl)carbonyl]-1 -(trans- 4-{[(1, 1- dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2-piperazinone
[00182] A suspension of 4-[(4-bromo-6-cyclopropyl-1-methyl-1 H-benzimidazol-2- yl)carbonyl]-1-(trans-4-{[(1 ,1-dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2-piperazinone (.090 g, 0.153 mmol) in 1 ,4-dioxane (0.453 ml) was treated with potassium phosphate tribasic (0.097 g, 0.458 mmol), cyclopropylboronic acid (0.026 g, 0.305 mmol), and PdCI2(dppf)-CH2Cl2 adduct (6.23 mg, 7.63 pmol). The mixture was heated to 90 °C for about 5 hours and the mixture was cooled to room temperature and the mixture was diluted with water. The mixture was extracted with EtOAc and the combined organics were washed with saturated NaHC03, brine, dried MgS04, filtered, and concentrated. The crude yellow/brown oil was purified by silica gel chromatography (0-4% MeOH/DCM) to give the title compound (0.058 g, 69.0%). ES-LCMS: 551.4 (M+1).
Step B
4-[(4,6-dicyclopropyl-1-methyl-1H-benzimidazol-2-yl)carbonyl]-1-(tran
piperazinone
[00183] A suspension of 4-[(4,6-dicyclopropyl-1-methyl-1 H-benzimidazol-2-yl)carbonyl]-1- (trans-4-{[(1 ,1-dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2-piperazinone (.058 g, 0.105 mmol) in DCM (2.0 ml) was treated by the addition of 4M in dioxanes HCI (0.500 ml, 2.001 mmol). The reaction was stirred at room temperature for 2 hours and concentrated. The residue was triturated with Et20 to give the title compound as a yellow solid. ES-LCMS: 437.4 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.08 (br. s„ 1 H), 6.67 (d, J=6.83 Hz, 1 H), 4.50 (br. s., 1 H), 4.22 (br. s., 2 H), 4.02 (br. s., 2 H), 3.84 (br. s., 4 H), 3.37 (br. s., 3 H), 2.02 (br. s., 1 H), 1.86 (d, J=10.15 Hz, 2 H), 1.53 (br. s., 4 H), 1.17 - 1.30 (m, 2 H), 0.92 - 1.11 (m, 6 H), 0.74 (br. s., 2 H), 0.26 - 0.46 (m, 1 H). Example 20
6-cyclopropyl-2-{[4-(trans-4-hydroxycyclohexy^)-3-oxo-1-piperazinyl]carbonyl}^1^methyl·
1H-benzimidazole-4-carbonitrile
(Compound 20)
Figure imgf000086_0001
Step A
6-cyclopropyl-2-{[4-(trans-4-{[(1, 1-dimethylethyl)(dimethyl)silyl]oxy}cyd^
piperazinyljcarbonyl}- 1 -methyl-1 H-benz imidazole-4-carbonitrile
[00184] A solution of 4-[(4-bromo-6-cyclopropyl-1 -methyl-1 H-benzimidazol-2-yl)carbonyl]- 1-(trans-4-{[(1 ,1-dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2-piperazinone (.075 g, 0.127 mmol) in DMF (1.0 ml) was treated with palladium tetrakis (0.029 g, 0.025 mmol) and zinc cyanide (0.018 g, 0.153 mmol) and purged with nitrogen and heated to 90 °C for 3.5 hours. The reaction was cooled to room temperature and diluted with EtOAc and water. The combined organics were washed with LiCI (3x), saturated NaHC03, brine, dried MgS04, filtered, and concentrated. The crude residue was purified by silica gel chromatography (0-3% MeOH/DCM) to give the title compound as a pale yellow solid (0.059 g, 87%). ES-LCMS: 536.1 (M+1).
Step B
6-cyclopropyl-2-{[4- (trans-4-hydroxycyc lohexyl)-3-oxo- 1 -piperazinyl]carbonyl}-1 -methyl-1 H- benzimidazole-4-carbo nit rile
[00185] A solution of 6-cyclopropyl-2-{[4-(trans-4-{[(1 ,1- dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-3-oxo-1-piperazinyl]carbonyl}-1-methyl-1 H- benzimidazole-4-carbonitrile (.059 g, 0.110 mmol) in DCM (2.0 mL) was treated by the addition of 4M ίη dioxanes HCI (0.502 mL, 16.52 mmol). The reaction was stirred at room temperature for 3 hours and concentrated under reduced pressure. The crude residue was triturated with Et20 to give the title compound as a pale yellow solid (0.044 g, 95%). ES-LCMS: 422.3 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.76 (s, 1 H), 7.52 - 7.58 (m, 1 H), 4.44 (s, 1 H), 4.24 (s, 2 H), 3.94 - 3.99 (m, 1 H), 3.90 (s, 3 H), 3.83 - 3.87 (m, 1 H), 3.33 - 3.51 (m, 4 H), 2.11 - 2.19 (m, 1 H), 1.83 - 1.90 (m, 2 H), 1.54 (br. s., 3 H), 1.23 (br. s., 2 H), 1.01 - 1.06 (m, 2 H), 0.82 - 0.87 (m, 3 H).
Example 21
4-[(6-cyclopropyl-1-methyl-1H-benzimidazol-2-yl)carbonyl]-1-(trans-4-hy
2-piperazinone
(Compound 21)
Figure imgf000087_0001
Step A
4-[(6-cyclopropyl-1-methyl-1H-benzimidazol-2-yl)carbonyl]-1-(trans-4-{[(1, 1- dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2-piperazinone and 4-[( 6-cyclopropyl-4-ethyl- 1- methyl- 1H-benz imidazol-2-yl)carbonyl]- 1 - (trans-4-{[( 1, 1- dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2-piperazinone
[00186] A solution of 4-[(4-bromo-6-cyclopropyl-1-methyl-1 H-benzimidazol-2-yl)carbonyl]- 1-(trans-4-{[(1 ,1-dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2-piperazinone (.075 g, 0.127 mmol) in THF (1.441 ml) was treated with palladium tetrakis (0.147 g, 0.127 mmol) and 1.0 M in hexanes diethylzinc (0.130 ml, 0.130 mmol). The reaction was heated to 60 °C and stirred for 90 minutes. The reaction was cooled to room temperature and diluted with EtOAc and water. The layers were separated and combined organics were washed with brine, dried MgS04, filtered, and concentrated. The crude residue was purified by silica gel chromatography (0-3% MeOH/DCM). The fractions containing the product were pooled and purified by reverse phase chromatography (10-90% ACN/Water + formic acid) to give 4-[(6-cyclopropyl-1-methyl-1 H- benzimidazol-2-yl)carbonyl]-1-(trans-4-{[(1 ,1-dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2- piperazinone (0.017 g, 26.2%) ES-LCMS: 511.2 (M+1) and 4-[(6-cyclopropyl-4-ethyl-1-methyl- 1 H-benzimidazol-2-yl)carbonyl]-1-(trans-4-{[(1 ,1-dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2- piperazinone (0.01 g, 16.1 %) ES-LCMS: 540.2 (M+1). Step B
4-[(6-cyclopropyl-1-methyl-1H-benzimidazol-2-yl)carbonyl]-1-(trans-4-h^
piperazinone
[00187] A solution of 4-[(6-cyclopropyl-1-methyl-1 H-benzimidazol-2-yl)carbonyl]-1-(trans- 4-{[(1 ,1-dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2-piperazinone (.017 g, 0.033 mmol) in DCM (2.0 ml) was treated with 4N in dioxanes HCI (0.499 ml, 1.997 mmol). The reaction was stirred at room temperature for 2 hours. The reaction was concentrated under reduced pressure and the residue was triturated with Et20 to give the title compound as a white solid (0.014 g, 100%). ES-LCMS: 397.4 (M+1). H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.02 (d, J=8.59 Hz, 1 H), 7.93 (d, =8.59 Hz, 1 H), 7.34 (d, J=8.59 Hz, 1 H), 4.64 (br. s., 1 H), 4.35 - 4.53 (m, 2 H), 4.06 (s, 4 H), 3.92 - 3.98 (m, 1 H), 3.50 - 3.69 (m, 4 H), 2.01 - 2.16 (m, 3 H), 1.72 - 1.80 (m, 2 H), 1.40 - 1.60 (m, 4 H), 1.11 - 1.18 (m, 2 H), 0.83 (d, 2 H).
Example 22
4-[(6-cyclopropyl-4-ethyl-1- ethyl-1H-benzimidazol-2-yl)carbonyl]-1-(trans-4- hydroxycyclohexyl)-2-piperazinone
(Compound 22)
Figure imgf000088_0001
[00188] A solution of 4-[(6-cyclopropyl-4-ethyl-1-methyl-1 H-benzimidazol-2-yl)carbonyl]- 1-(trans-4-{[(1 ,1-dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2-piperazinone (.011 g, 0.020 mmol) in DCM (2.0 ml) was treated by the addition of 4N in dioxanes HCI (0.496 ml, 16.33 mmol). The reaction was stirred at room temperature for 2 hours and concentrated under reduced pressure. The residue was triturated with Et20 to give the title compound (0.008 g, 92%). ES-LCMS: 425.2 (M+1). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.10 - 7.17 (m, 1 H), 7.01 - 7.05 (m, 1 H), 4.46 (s, 1 H), 4.36 - 4.45 (m, 1 H), 4.06 - 4.12 (m, 1 H), 3.93 - 4.02 (m, 3 H), 3.63 - 3.68 (m, 4 H), 3.52 - 3.57 (m, 2 H), 3.20 (q, J=7.42 Hz, 2 H), 2.01 - 2.11 (m, 3 H), 1.71 - 1.81 (m, 2 H), 1.42 - 1.56 (m, 4 H), 1.36 - 1 .42 (m, 3 H), 1.06 - .15 (m, 2 H), 0.77 - 0.83 (m, 2 H).
Example 23
4-{[6-cyclopropyl-1-methyl-4-(1-methylethenyl)-1H-benzi idazol-2-yl]carbon
hydroxycyclohexyl)-2-piperazinone
(Compound 23)
Figure imgf000089_0001
Step A
4-{[6-cyclopropyl-1-methyl-4-(1 -methyl ethenyl)-1 H-benzimidazol-2-yl]carbonyl}-1-(trans-4-{[(1, 1- dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2-piperazinone
[00189] A solution of 4-[(4-bromo-6-cyclopropyl-1 -methyl-1 H-benzimidazol-2-yl)carbonyl]- 1-(trans-4-{[(1 ,1-dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2-piperazinone (.110 g, 0.187 mmol) in propanol (0.703 ml) was treated with potassium isopropenyltrifluoroborate (0.028 g, 0.187 mmol), TEA (0.130 ml, 0.933 mmol), and PdCI2(dppf)-CH2Cl2 adduct (7.62 mg, 9.33 pmol) and heated to 100 °C for 3 hours. The reaction was cooled to room temperature and treated with EtOAc and water. The combined organics were washed with saturated NaHC03, brine, dried MgS04, filtered, and concentrated. The crude residue was purified by silica gel chromatography (0-3% MeOH/DCM) to give the title compound as a yellow solid (0.080 g, 78%). ES-LCMS: 551 .4 (M+1 ).
Step B
4-{[6-cyclopropyl- 1 -methyl-4-( 1-methylethenyl )- 1 H-benzimidazol-2-yl]carbonyl}- 1-(trans-4- hydroxycyclohexyl)-2-piperazinone
[00190] A solution of 4-{[6-cyclopropyl-1-methyl-4-(1-methylethenyl)-1 H-benzimidazol-2- yl]carbonyl}-1-(trans-4-{[(1 , 1-dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2-piperazinone (.014 g, 0.025 mmol) in DCM (2.0 ml) was treated with 4N in dioxanes HCI (0.508 ml, 2.033 mmol) and stirred at room temperature for 2 hours. The reaction was concentrated and triturated with Et20 to yield the title product as a yellow solid. ES-LCMS: 437.2 (M+1). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.13 (dd, J=12.89, 1.17 Hz, 1 H), 7.00 - 7.06 (m, 1 H), 5.82 - 5.99 (m, 1 H), 5.37 - 5.52 (m, 1 H), 4.65 - 4.74 (m, 1 H), 4.38 - 4.56 (m, 2 H), 4.27 - 4.34 (m, 1 H), 3.93 - 4.03 (m, 4 H), 3.62 - 3.69 (m, 2 H), 3.43 - 3.51 (m, 2 H), 2.33 (d, J=3.52 Hz, 3 H), 2.01 - 2.12 (m, 3 H), 1.76 (br. s., 2 H), 1.40 - 1.61 (m, 4 H), 1.01 - 1.11 (m, 2 H), 0.75 - 0.94 (m, 2 H).
Example 24
4-[(6-cyclopropyl-1- ethyl-4^henyl-1H-benzimidazol-2-yl)carbonyl]-1-(tran
hydroxycyclohexyl)-2-piperazinone
(Compound 24)
Figure imgf000090_0001
Step A
4-[(6-cyclopropyl-1 -methyl -4-phenyl-1 H-benz imidazol-2-yl)carbonyl]-1-(trans-4-{[(1, 1- dimethylethyl)(dimethyl)silylJoxy}cyclohexyl)-2-piperazinone
[00191] A suspension of 4-[(4-bromo-6-cyclopropyl-1-methyl-1 H-benzimidazol-2- yl)carbonyl]-1-(trans-4-{[(1 ,1-dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2-piperazinone (.063 g, 0.107 mmol) in 1 ,4-dioxane (0.317 ml) was treated with potassium phosphate tribasic (0.068 g, 0.321 mmol), phenylboronic acid (0.026 g, 0.214 mmol), and PdCI2(dppf)-CH2Cl2 adduct (4.36 mg, 5.34 pmol). The mixture was heated to 90 °C overnight and the mixture was cooled to room temperature and the mixture was diluted with water. The mixture was extracted with EtOAc and the combined organics were washed with saturated NaHC03, brine, dried MgS04, filtered, and concentrated. The crude yellow/brown oil was purified by silica gel chromatography (0-4% MeOH/DCM). The fractions containing the product were combined and concentrated. The residue was purified by reverse phase chromatography (10-90% ACN/Water + 0.1 % formic acid) to give the title compound as a pale yellow solid (0.028 g, 44.7%). ES-LCMS: 587.1 (M+1). Step B
4-[(6-cyclopropyl-1-methyl-4-phenyl-1H-benzimidazol-2-yl)carbonyl]-1-(trans-4- hydroxycyclohexyl)-2-piperazinone
[00192] A solution of 4-[(6-cyclopropyl-1-methyl-4-phenyl-1 H-benzimidazol-2-yl)carbonyl]- 1-(trans-4-{[(1 ,1-dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2-piperazinone (0.028 g, 0.048 mmol) in DCM (2.0 mL) was treated by the addition of 4M in dioxanes HCI (0.507 mL, 16.70 mmol). The reaction was stirred at room temperature for 2 hours then concentrated under reduced pressure. The residue was triturated with Et20 to give the title compound as a light yellow solid (0.029 g, 100%). ES-LCMS: 473.3 (M+1). 1H NMR (400 MHz, CHLOROFORM- ) δ ppm 7.92 (d, J=7.61 Hz, 1 H), 7.83 (d, J=7.41 Hz, 1 H), 7.48 - 7.59 (m, 2 H), 7.40 - 7.47 (m, 1 H), 7.32 (d, J=14.83 Hz, 1 H), 7.11 - 7.20 (m, 1 H), 4.59 (br. s., 1 H), 4.35 - 4.53 (m, 2 H), 4.17 - 4.25 (m, 1 H), 4.02 (s, 3 H), 3.97 (br. s., 1 H), 3.65 (br. s., 2 H), 3.43 - 3.52 (m, 2 H), 2.10 - 2.21 (m, 1 H), 2.01 - 2.10 (m, 2 H), 1.74 (br. s., 2 H), 1.39 - 1.59 (m, 4 H), 1.06 - 1.16 (m, 2 H), 0.81 - 0.93 (m, 2 H).
Example 25
4-[(6-cyclopropyM,4-dimethyl-1H-benzimidazol-2-yl)carbonyl]-1-(trans-4- hydroxycyclohexyl)-2-piperazinone
Figure imgf000091_0001
Step A
4-[(6-cyclopropyl- 1, 4-dim ethyl-1 H-benz imidazol-2-yl)carbonyl]- 1 - (trans-4-{[( 1, 1- dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2-piperazinone
[00193] A solution of 4-[(4-bromo-6-cyclopropyl-1-methyl-1 H-benzimidazol-2-yl)carbonyl]- 1-(trans-4-{[(1 ,1-dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2-piperazinone (.080 g, 0.136 mmol) in THF (1.539 ml) was treated with palladium tetrakis (0.016 g, 0.014 mmol) and 1.0 M in heptanes dimethylzinc (0.136 ml, 0.136 mmol). The reaction was heated to 60 °C. The reaction was cooled to room temperature and diluted with EtOAc and water. The layers were separated and combined organics were washed with brine, dried MgS04, filtered, and concentrated. The crude residue was purified by silica gel chromatography (0-3% MeOH/DCM). The fractions containing the product were pooled and purified by reverse phase chromatography (10-90% ACN/Water + fromic acid) to give the title compound as a white solid (0.020 g, 28.1 %). ES- LCMS: 526.1 (M+1).
Step B
4-[(6-cyclopropyl-1,4-dimethyl-1H-benzimidazol-2-yl)carbonyl]-1 -(trans- 4-hydroxycyclohexyl)-2- piperazinone
[00194] A solution of 4-[(6-cyclopropyl-1 ,4-dimethyl-1 H-benzimidazol-2-yl)carbonyl]-1- (trans-4-{[(1 ,1-dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2-piperazinone (.020 g, 0.038 mmol) in DCM (2.0 ml) was treated by the addition of 4M in dioxanes HCI (0.494 ml, 16.27 mmol). The reaction was stirred at room temperature then concentrated under reduced pressure. The solids were triturated with Et20 to give the title compound (0.015 g, 96%). ES-LCMS: 411.3 (M+1). 1H NMR (400 MHz, CHLOROFORM-cf) δ ppm 7.02 - 7.13 (m, 2 H), 4.36 - 4.54 (m, 2 H), 4.08 - 4.16 (m, 1 H), 3.94 - 4.03 (m, 4 H), 3.63 - 3.68 (m, 3 H), 3.51 - 3.58 (m, 2 H), 2.75 - 2.81 (m, 3 H), 2.01 - 2.11 (m, 3 H), 1.73 - 1.81 (m, 2 H), 1.42 - 1.58 (m, 4 H), 1.06 - 1.14 (m, 2 H), 0.76 - 0.83 (m, 2 H).
Example 26
4-{[6-cyclopropyl-1-methyl-4-(1-methylethyl)-1H-benzimidazol-2-yl]cart
hydroxycyclo hexyl)- 2-piperazinon e
(Compound 26)
Figure imgf000092_0001
Step A
4-{[6-cyclopropyl-1-methyl-4-(1-methylethyl)-1H-benzimidazol-2-yl]carbon dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2-piperazinone
[00195] A solution of 4-{[6-cyclopropyl-1-methyl-4-(1-methylethenyl)-1 H-benzimidazol-2- yl]carbonyl}-1-(trans-4-{[(1 ,1-dimethylethyl)(dimetriyl)silyl]oxy}cyclohexyl)-2-piperazinone (.063 g, 0.114 mmol) in was treated with 10% Degussa Pd/C (5 mg, 4.70 prnol). The reaction was purged with nitrogen and treated with a hydrogen double balloon. The reaction was stirred at room temperature overnight. The catalyst was filtered and the solvents were evaporated under reduced pressure. The crude residue was purified by reverse phase chromatography (10-90% ACN/Water + formic acid) to give the title product as a solid (0.033 g, 52.2%). ES-LCMS: 553.4 (M+1).
Step B
4-{[6-cyclopropyl-1-methyl-4-(1-methylethyl)-1H-benzimidazol-2-yl]carbon
hydroxycyclohexyl)-2-piperazinone
[00196] A solution 4-{[6-cyclopropyl-1-methyl-4-(1-methylethyl)-1 H-benzimidazol-2- yl]carbonyl}-1-(trans-4-{[(1 ,1-dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2-piperazinone (.033 g, 0.060 mmol) in DCM (2.0 mL) was treated by the addition of 4N in dioxanes HCI (0.507 tnL, 2.030 mmol). The reaction was stirred at room temperature for 90 minutes and concentrated. The crude residue was triturated with Et20 to give the title compound as a solid (0.026 g, 100%). ES-LCMS: 439.4 (M+1). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.15 - 7.24 (m, 1 H), 6.99 - 7.06 (m, 1 H), 4.35 - 4.55 (m, 2 H), 3.94 - 4.02 (m, 4 H), 3.83 - 3.93 (m, 1 H), 3.63 - 3.68 (m, 4 H), 3.51 - 3.58 (m, 2 H), 2.00 - 2.14 (m, 3 H), 1.75 (br. s., 2 H), 1.43 - 1.58 (m, 4 H), 1.41 (d, J=6.83 Hz, 6 H), 1.06 - 1.15 (m, 2 H), 0.76 - 0.84 (m, 2 H).
Example 27
4-[(6-cyclopropy 4-hydroxy-1-methyl-1H-benzimidazol-2-yl)carbonyl]-1-(trans-4- hydroxycyclohexyl)-2-piperazinone
(Compound 27)
Figure imgf000093_0001
Step A
4~{[6-cyclopropyl- 1-met yl-4-(4, 4, 5, 5-tetramethyl- 1, 3, 2-dioxabor olan-2-yl)-1 H-benz imidazol-2- yl]carbonyl}-1-(trans-4-{[(1, 1-dimethylethyl)(dimethyl)silyl]oxy}cyclo^
[00197] A solution of 4-f(4-bromo-6-cyclopropyl-1 -methyl- 1 H-benzimidazol-2-yl)carbonyl]- 1-(trans-4-{[(1 ,1-dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2-piperazinone (0.250 g, 0.424 mmol) in 1 ,4-dioxane (5.65 ml) was treated with potassium acetate (0.125 g, 1.272 mmol), bis(pinacolato)diboron (0.269 g, 1.060 mmol), and PdCI2(dppf)-CH2Cl2 adduct (0.017 g, 0.021 mmol) and heated to 100 °C overnight. The reaction was treated by the addition of potassium acetate (0.125 g, 1.272 mmol), bis(pinacolato)diboron (0.269 g, 1.060 mmol), and PdCI2(dppf)- CH2CI2 adduct (0.017 g, 0.021 mmol) and was continued to be heated for 8 hours, then stirred at room temperature overnight. The solids were filtered, rinsing with EtOAc and concentrated onto celite. The residue was purified by silica gel chromatography to give the title compound (0.293 g, 100%). ES-LCMS: 555.3 (M+1- pinacol).
Step B
4-[(6-cyclopropyl-4-hydroxy-1-methyl-1 H-benz imidazol-2-yl)carbonyl]-1-(trans-4-{[(1, 1- dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2-piperazinone
[00198] A solution of 4-{[6-cyclopropyl-1-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-1 H-benzimidazol-2-yl]carbonyl}-1-(trans-4-{[(1 ,1- dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2-piperazinone (0.293 g, 0.460 mmol) in MeOH (1.514 ml) was treated with 4N solution of NaOH (0.552 ml, 2.209 mmol), cooled to 0 °C and treated by the addition of 30% H202 (0.235 ml, 2.301 mmol). The mixture was stirred with warming to room temperature overnight. The reaction mixture was poured into 10% Na2S203 and Et20 and stirred for 30 minutes. The aqueous was extracted with Et20 and the combine organics were washed with 10% Na2S203, brine, dried MgS04, filtered, and concentrated to give the title compound (0.111 g, 45.8%). ES-LCMS: 527.4 (M+1).
Step C
4-[(6-cyclopropyl-4-hydroxy-1-methyl-1 H-benz imidazol-2-yl)carbonyl]-1-(trans-4- hydroxycyclohexyl)-2-piperazinone
[00199] A solution of 4-[(6-cyclopropyl-4-hydroxy-1-methyl-1 H-benzimidazol-2- yl)carbonyl]-1-(trans-4-{[(1 ,1-dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2-piperazinone (0.028 g, 0.053 mmol) in DCM (2.0 mL) was treated by the addition of 4M in dioxanes HCI (0.5 ml, 2.000 mmol). The reaction was stirred at room temperature for 1 hour then concentrated under reduced pressure. The crude residue was purified by reverse phase chromatography (10-90% ACN/ H20 + formic acid) to give the title compound as a white solid (0.005 g, 22.8%). ES- LCMS: 413.3 (M+1). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 6.66 - 6.75 (m, 1 H), 6.54 (d, J=6.25 Hz, 1 H), 4.86 (s, 1 H), 4.33 - 4.56 (m, 2 H), 4.20 - 4.27 (m, 1 H), 3.91 - 4.02 (m, 4 H), 3.53 - 3.67 (m, 1 H), 3.35 - 3.47 (m, 2 H), 1.95 - 2.11 (m, 3 H), 1.40 - 1.77 (m, 6 H), 0.96 - 1.07 (m, 2 H), 0.71 - 0.83 (m, 2 H).
Example 28
4-(4-cyclobutyl-6-cyctopropyl-1-methyl-1H-benzo[d]imidazole-2-carbonyl)-1-(
hydroxycyclo hexyl)piperazin-2-on e
(Compound 28)
Figure imgf000095_0001
Step A
1-((1r, 4r)-4-((tert-butyldim ethylsilyl)oxy)cyclohexyl)-4- (4-cyclobutyl~6-cyclopropyl-1-methyl -1H- benzo[d]imidazole-2-carbonyl)piperazin-2-one
[00200] A solution of 4-[(4-bromo-6-cyclopropyl-1-methyl-1 H-benzimidazol-2-yl)carbonyl]-
1-(trans-4-{[(1 ,1-dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2-piperazinone (0.200 g, 0.339 mmol) in THF (1.932 ml) was treated by the addition of PdCI2(dppf)-CH2CI2 adduct (0.028 g, 0.034 mmol). The reaction was then treated by the drop-wise (1 drop every 3-5 second) addition of 0.5M in THF bromo(cyclobutyl)zinc (1.018 ml, 0.509 mmol). The reaction was stirred at room temperature for 48 hours. The residue was treated with copper(l) iodide (0.019 g, 0.102 mmol), PdCI2(dppf)-CH2CI2 adduct (0.028 g, 0.034 mmol) and then with 0.5 M in THF
bromo(cyclobutyl)zinc (1.018 ml, 0.509 mmol). The reaction was stirred at room temperature for 1 hour. The reaction was diluted with H20 and extacted with EtOAc. The combine organics were washed with saturated NaHC03, brine, dried MgS04, filtered, and concentrated to give the title compound (0.229 g, 100%). ES-LCMS: 565.4 (M+1). Step B
4-(4-cyclobutyl-6-cyclopropyl-1-methyl-1H-benzo[d]imidazole-2-carbon
hydroxycyclohexyl)piperazin-2-one
[00201] A solution of 1-((1 r,4r)-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)-4-(4-cyclobutyl- 6-cyclopropyl-1-methyl-1 H-benzo[d]imidazole-2-carbonyl)piperazin-2-one (.229 g, 0.405 mmol) in DCM (2.0 mL) was treated by the addition of 4N in dioxanes HCI (0.5 mL, 2.000 mmol). The reaction was stirred at room temperature for 90 minutes then concentrated under reduced pressure. The crude reddish residue was purified by reverse phase chromatography (10-90% ACN/ H20 + formic acid) to give the title compound as a solid (0.053 g, 29%). ES-LCMS: 451.4 (M+1). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 6.88 - 7.01 (m, 2 H), 4.85 (s, 1 H), 4.40 - 4.58 (m, 2 H), 4.36 (t, J=4.69 Hz, 1 H), 4.02 - 4.19 (m, 1 H), 3.97 (d, J=2.35 Hz, 4 H), 3.60 (br. s., 1 H), 3.49 (br. s., 1 H), 3.40 (br. s., 1 H), 2.31 - 2.55 (m, 4 H), 2.03 - 2.20 (m, 4 H), 1.89 - 2.00 (m, 1 H), 1.72 - .84 (m, 2 H), 1.37 - 1.71 (m, 5 H), 0.96 - 1.09 (m, 2 H), 0.71 - 0.82 (m, 2 H).
Example 29
4-[(4-cyclopentyl-6-cyclopropyl-1-methyl-1H-benzimidazol-2-yl)carbonyl]-^
hydroxycyclohexyl)-2-piperazinone
(Compound 29)
Figure imgf000096_0001
Step A
4-[(4-cyclopentyl-6-cyclopropyl-1-methyl-1 H-benzimidazol-2-yl)carbonyl]-1-(trans-4-{[(1 ,1- dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2-piperazinone
[00202] A solution of 4-[(4-bromo-6-cyclopropyl-1 -methyl- H-benzimidazol-2-yl)carbonyl]- 1-(trans-4-{[(1 ,1-dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2-piperazinone (0.200 g, 0.339 mmol) in THF (1.932 ml) was treated by the addition of PdCl2(dppf)-CH2Cl2 adduct (0.028 g, 0.034 mmol) and copper(l) iodide (0.019 g, 0.102 mmol). The reaction was then treated by the drop-wise (1 drop every 3-5 second) addition of 0.5M in THF bromo(cyclopentyl)zinc (1.018 ml, 0.509 mmol) . The reaction was stirred at room temperature for the 48 hours. The reaction was treated with additional copper(l) iodide (0.019 g, 0.102 mmol), PdCI2(dppf)-CH2CI2 adduct (0.028 g, 0.034 mmol) and then with 0.5 M in THF bromo(cyclopentyl)zinc (1.018 ml, 0.509 mmol). The reaction was stirred for an additional 90 minutes. The reaction was treated by the drop- wise addition of 0.5M in THF bromo(cylcopentyl)zinc (3 mL) and stirred for 90 minutes. The reaction was quenched by the addition of water and EtOAc. The combined organics were washed with saturated NaHC03, brine, dried MgS04, and filtered through GF/F. The solvents were removed under reduced pressure to give the title compound (0.251 g, 100%). ES-LCMS: 579.5 (M+1).
Step B
4-[(4-cyclopentyl-6-cyclopropyl-1-methyl-1H-benzimidazol-2-yl)carbon
hydroxycyclohexyl)-2-piperazinone
[00203] A solution of 4-[(4-cyclopentyl-6-cyclopropyl-1 -methyl- 1 H-benzimidazol-2- yl)carbonyl]-1-(trans-4-{[(1 ,1-dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2-piperazinone (.251 g, 0.434 mmol) in DCM (2.0 mL) was treated with 4N in dioxanes HCI (0.5 mL, 2.000 mmol). The reaction was stirred at room temperature for 90 minutes and the reaction was concentrated. The crude residue was purified by reverse phase chromatography (10-90% ACN/ H20 + formic acid) to give the title product as a solid (0.086g, 42.7%). ES-LCMS: 465.0 (M+1). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 6.97 (s, 1 H), 6.92 (d, J=10.36 Hz, 1 H), 4.83 (s, 1 H), 4.41 - 4.56 (m, 2 H), 4.31 - 4.37 (m, 1 H), 3.93 - 4.00 (m, 4 H), 3.65 - 3.69 (m, 1 H), 3.54 - 3.65 (m, 2 H), 3.45 - 3.49 (m, 1 H), 3.38 - 3.43 (m, 1 H), 2.12 - 2.23 (m, 2 H), 2.02 - 2.12 (m, 3 H), 1.43 - 1.94 (m, 12 H), 0.99 - 1.06 (m, 2 H), 0.74 - 0.81 (m, 2 H).
Example 30
4-{[6-cyclopropyl-4-(3-fluoroph enyl)- 1 -m ethyl-1H- benzimidazol-2-yl]carbonyl}- 1- (trans-4- hydroxycyclohexyl)-2-piperazinone
(Compound 30)
Figure imgf000098_0001
[00204] A suspension of 4-[(4-bromo-6-cyclopropyl-1-methyl-1 H-benzimidazol-2- yl)carbonyl]-1-(trans-4-hydroxycyclohexyl)-2-piperazinone (0.050 g, 0.105 mmol)in 1 ,4-dioxane (0.312 ml) was treated with potassium phosphate tribasic (0.067 g, 0.316 mmol), 3- fluorobenzeneboronic acid (0.029 g, 0.210 mmol), and PdCI2(dppf)-CH2CI2 adduct (4.29 mg, 5.26 mol). The mixture was heated to 90 °C for the 48 hours and the mixture was cooled to room temperature and the mixture was diluted with water. The mixture was extracted with EtOAc and the combined organics were washed with saturated NaHC03, brine, dried MgS04, filtered, and concentrated. The crude yellow/brown oil was purified by silica gel chromatography (1-5% MeOH/DCM) to give the title compound as a light beige solid (0.035 g, 67.8%). ES- LCMS: 491.1 (M+1 ). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.88 - 7.98 (m, 1 H), 7.68 - 7.81 (m, 1 H), 7.39 - 7.51 (m, 1 H), 7.22 - 7.33 (m, 1 H), 7.04 - 7.16 (m, 2 H), 4.80 (s, 1 H), 4.40 - 4.57 (m, 2 H), 4.32 (br. s., 1 H), 3.90 - 4.07 (m, 4 H), 3.53 (br. s., 3 H), 3.41 (br. s., 1 H), 2.06 - 2.17 (m, 3 H), 1.41 - 1.84 (m, 6 H), 1.03 - 1.12 (m, 2 H), 0.78 - 0.87 (m, 2 H).
Example 31
4-{[6-cyc lopropyl~4-(4-fluoroph enyl)- 1 -methyl- 1 H-benzimidazol-2-yl]carbonyl}- 1- (trans-4- hydroxycyclo hexyl)-2-piperazinon e
(Compound 31)
Figure imgf000099_0001
4-{[6-cyclopropyl-4-(4-fluorophenyl)- 1 -methyl- 1H-benz imidazol-2-yl]carbonyl}- 1- (trans-4- hydroxycyclohexyl)-2-piperazinone
[00205] A suspension of 4-[(4-bromo-6-cyciopropyl-1 -methyl-1 H-benzimidazol-2- yl)carbonyl]-1-(trans-4-hydroxycyclohexyl)-2-piperazinone (0.050 g, 0.105 mmol) in 1 ,4-dioxane (0.312 ml) was treated with potassium phosphate tribasic (0.067 g, 0.316 mmol), 4- fluorophenylboronic acid (0.029 g, 0.210 mmol), and PdCI2(dppf)-CH2Cl2 adduct (4.29 mg, 5.26 Mmol). The mixture was heated to 90 °C for the 48 hours and the mixture was cooled to room temperature and the mixture was diluted with water. The mixture was extracted with EtOAc and the combined organics were washed with saturated NaHC03, brine, dried MgS04, filtered, and concentrated. The crude yellow/brown oil was purified by silica gel chromatography (1-5% MeOH/DCM) to give the title compound as a yellow solid (0.024 g, 46.5%). ES-LCMS: 491.4 (M+1). 1H NMR (400 MHz, CHLOROFORM-cQ δ ppm 7.90 - 7.97 (m, 2 H), 7.13 - 7.22 (m, 3 H), 7.06 - 7.11 (m, 1 H), 4.80 (s, 1 H), 4.39 - 4.53 (m, 2 H), 4.28 - 4.33 (m, 1 H), 4.01 (d, J=5.08 Hz, 3 H), 3.94 (t, J=5.47 Hz, 1 H), 3.63 - 3.68 (m, 1 H), 3.56 - 3.62 (m, 1 H), 3.41 (dt, .7=13.04, 5.39 Hz, 2 H), 2.05 - 2.15 (m, 3 H), 1.74 (d, 2 H), 1.43 - 1.58 (m, 4 H), 1.02 - 1.10 (m, 2 H), 0.78 - 0.85 (m, 2 H).
Example 32
4-{[6-cyclo propyl-4-(3, 5-dlfluoroph enyl)- 1 -methyl- 1H-ben zimidazol-2-yl]carbonyl}- 1- (trans-4-hydroxycyclohexyl)-2-piperazinone
(Compound 32)
Figure imgf000100_0001
Step A
4-{[6-cyclopropyl-4-(3, 5-difluorophenyl)-1-methyl-1H-benz imidazol-2-yl]carbonyl}- 1 -( trans-4- hydroxycyclohexyl)-2-piperazinone
[00206] A suspension of 4-[(4-bromo-6-cyclopropyl-1-methyl-1 H-benzimidazol-2- yl)carbonyl]-1-(trans-4-hydroxycyclohexyl)-2-piperazinone (0.050 g, 0.105 mmol) in ,4-dioxane (0.312 ml) was treated with potassium phosphate tribasic (0.067 g, 0.316 mmol), 3,5- difluorophenylboronic acid (0.033 g, 0.210 mmol), and PdCI2(dppf)-CH2CI2 adduct (4.29 mg, 5.26 μιηοΙ). The mixture was heated to 90 °C for the 48 hours and the mixture was cooled to room temperature and the mixture was diluted with water. The mixture was extracted with EtOAc and the combined organics were washed with saturated NaHC03, brine, dried MgS04, filtered, and concentrated. The crude yellow/brown oil was purified by silica gel chromatography eluting (1-5% MeOH/DCM) to give the title compound as a light yellow solid (0.028 g, 52.3%). ES-LCMS: 509.3 (M+1). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.54 - 7.69 (m, 2 H), 7.22 - 7.31 (m, 1 H), 7.10 - 7.15 (m, 1 H), 6.77 - 6.87 (m, 1 H), 4.76 (s, 1 H), 4.39 - 4.55 (m, 2 H), 4.28 - 4.33 (m, 1 H), 3.92 - 4.05 (m, 4 H), 3.53 - 3.68 (m, 3 H), 3.38 - 3.44 (m, 1 H), 2.05 - 2.16 (m, 3 H), 1.41 - 1.82 (m, 6 H), 1.04 - 1.12 (m, 2 H), 0.79 - 0.85 (m, 2 H).
Example 33
4-{[6-cyclopropyl-1-methyl-4-(methyloxy)-1H-benzimidazol-2-yl]carbonyl}-1-(trans-4- hydroxycyclohexyl)-2-piperazinone
(Compound 33)
Figure imgf000101_0001
Step A
4-{[6-cyclopropyl-1 -methyl-4-(methyloxy)-1 H-benzimidazol-2-yl]carbonyl}-1 -(trans-4-{[(1 , 1 - dimethylethyl)(dimethyl)silyl]oxy}cyclohexyi)-2-piperazinone
[00207] A solution of 4-[(6-cyclopropyl-4-hydroxy-1 -methyl- 1 H-benzimidazol-2- yl)carbonyl]-1-(trans-4-{[(1 ,1-dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2-piperazinone (0.100 g, 0.190 mmol) in DMF (0.935 ml) was treated with K2C03 (0.052 g, 0.380 mmol) and Mel (0.014 ml, 0.228 mmol). The reaction was stirred at room temperature for 2 hours then was diluted with EtOAc and water. The combined organics were washed with LiCI (3x), brine, dried MgS04, filtered, and concentrated to give the title compound (0.075 g, 73.1 %). ES-LCMS: 541.4 (M+1).
Step B
4-{[6-cyclopropyl-1-methyl-4-(methyloxy)- 1 H-benzimidazol-2-yl]carbonyl}- 1-(trans-4- hydroxycyclohexyl)-2-piperazinone
[00208] A solution of 4-{[6-cyclopropyl-1-methyl-4-(methyloxy)-1 H-benzimidazol-2- yl]carbonyl}-1-(trans-4-{[(1 ,1-dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2-piperazinone (.075 g, 0.139 mmol) in DCM (2.0 ml.) was treated by the addition of 4N in dioxanes HCI (0.5 ml_, 2.000 mmol). The reaction was stirred at room temperature for 2 hours and concentrated under reduced pressure. The crude residue was purified by reverse phase chromatography (10-90% ACN/ H20 + formic acid) to give the title compound as a solid (0.023 g, 38.9%). ES-LCMS: 427.2 (M+1). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 6.65 - 6.78 (m, 1 H), 6.38 - 6.56 (m, 1 H), 4.79 (s, 1 H), 4.27 - 4.62 (m, 3 H), 3.89 - 4.22 (m, 8 H), 3.52 - 3.68 (m, 1 H), 3.31 - 3.49 (m, 2 H), 2.01 - 2.16 (m, 3 H), 1.40 - 1.83 (m, 6 H), 0.96 - 1.13 (m, 2 H), 0.67 - 0.87 (m, 2 H).
Example 34
4-({6-cyclopropyl-4-[(difluoromethyl)oxyJ-1-methyl-1H-benzimidazol-2-yl}carbon
(trans-4-hydroxycyclohexyl)-2-piperazinone (Compound 34)
Figure imgf000102_0001
Step A
4-({6-cyclopropyl-4-[(difluoromethyl)oxy]-1~methyl- 1H-benzimidazol-2-yl}carbonyl)- 1 -(trans-4- {[(1, 1-dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2-piperazinone
[00209] A solution of 4-[(6-cyclopropyl-4-hydroxy-1-methyl-1 H-benzimidazol-2- yl)carbonyl]-1-(trans-4-{[(1 ,1-dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2-piperazinone (0.100 g, 0.190 mmol), chlorodifluoroacetic acid sodium salt (0.067 g, 0.437 mmol), and Cs2C03 (0.087 g, 0.266 mmol) in DMF (5.27 ml) was stirred 90 °C overnight. The reaction was treated by additional Cs2C03 (0.087 g, 0.266 mmol) and chlorodifluoroacetic acid sodium salt (0.067 g, 0.437 mmol) the reaction was then heated for an additional 24 hours. The reaction was then diluted with EtOAc, washed with 5% LiCI (2x), brine, dried MgS04, filtered, and concentrated to give the title compound (0.134 g, 100%). ES-LCMS: 577.4 (M+1).
Step B
4-({6-cyclopropyl-4-[(difluoromethyl)oxy]-1-methyl-1H-benzimida
hydroxycyclohexyl)-2-piperazinone
[00210] A solution of 4-({6-cyclopropyl-4-[(difluoromethyl)oxy]-1 -methyl-1 H-benzimidazol- 2-yl}carbonyl)-1 -(trans-4-{[(1 , 1 -dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2-piperazinone (0.134 g, 0.232 mmol) in DCM (2.0 mL) was treated by the addition of 4N in dioxanes HCI (0.5 mL, 2.000 mmol). The reaction was stirred at room temperature for 1 hour then concentrated under reduced pressure. The crude residue was purified by reverse phase chromatography (10-90% ACN/ H20 + formic acid) to give the title compound as a solid (0.010 g, 9.31 %). ES- LCMS: 463.1 (M+1). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.52 - 7.54 (m, 0.25 H), 7.31 - 7.36 (m, 0.50 H), 7.15 - 7.16 (m, 0.25 H), 6.93 - 7.00 (m, 1 H), 6.79 (s, 1 H), 4.73 (s, 1 H), 4.38 - 4.57 (m, 2 H), 4.28 (t, J=5.08 Hz, 1 H), 3.91 - 4.02 (m, 4 H), 3.54 - 3.65 (m, 1 H), 3.46 (t, J=5.18 Hz, 1 H), 3.40 (t, J=5.37 Hz, 1 H), 2.02 - 2.12 (m, 3 H), 1.37 - 1.84 (m, 10 H), 1.00 - 1.10 (m, 2 H), 0.71 - 0.80 (m, 2 H).
Example 35
4-{[6-cyclopropyl-4-(ethyloxy)-1-methyl-1H-benzimidazol-2-yl]carbony
hydroxycyclohexyl)-2-piperazinone
Figure imgf000103_0001
Step A
4-{[6-cyclopropyl-4-(ethyloxy)- 1 -methyl- 1H-benz imidazol-2-yl]carbonyl}- 1-(trans-4-{[( 1, 1- dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2-piperazinone
[00211] A solution of 4-[(6-cyclopropyl-4-hydroxy-1 -methyl-1 H-benzimidazol-2- yl)carbonyl]-1-(trans-4-{[(1 ,1-dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2-piperazinone (0.090 g, 0.171 mmol) in DMF (0.838 ml) was treated with K2C03 (0.047 g, 0.342 mmol) and ethyl iodide (0.017 ml, 0.205 mmol). The reaction was stirred at room temperature overnight then was diluted with EtOAc and water. The combined organics were washed with LiCI (3x), brine, dried MgS04, filtered, and concentrated to give the title compound (0.058 g, 61.2%). ES-LCMS: 555.4 (M+1).
Step B
4-{[6-cyclopropyl-4-(ethyloxy)-1 -methyl-1 H-benz imidazol-2-yl]carbonyl}-1 -(trans-4- hydroxycyclohexyl)-2-piperazinone
[00212] A solution of 4-{[6-cyclopropyl-4-(ethyloxy)-1-methyl-1 H-benzimidazol-2- yl]carbonyl}-1-(trans-4-{[(1 ,1-dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2-piperazinone (0.058 g, 0.105 mmol) in DCM (2.0 ml) was treated by the addition of 4N in dioxanes HCI (0.5 ml, 2.000 mmol). The reaction was stirred at room temperature for 90 minutes then concentrated under reduced pressure. The crude residue was purified by reverse phase chromatography (10-90% ACN/ H20 + formic acid) to give the title compound as a solid (0.014 g, 30.4%). ES-LCMS: 441.2 (M+1).
Example 36
4-({6-cyclopropyt-1-methyl-4-[(1-methylethyl)oxy]-1H-benzimidazol-2-yl}carbonyl)-1- (trans-4-hydroxycyclohexyl)-2-piperazinone
Figure imgf000104_0001
Step A
4-({6-cyclopropyl-1-methyl-4-[(1-methylethyl)oxy]-1H-benzimidazol-2-yl}carbon 1-(trans-4- {[( 1, 1-dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2-piperazinone
[00213] A solution of 4-[(6-cyclopropyl-4-hydroxy-1-methyl-1 H-benzimidazol-2- yl)carbonyl]-1-(trans-4-{[(1 ,1-dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2-piperazinone (0.090 g, 0.171 mmol) in DMF (0.834 ml) was treated with K2C03 (0.047 g, 0.342 mmol) and 2- iodopropane (0.021 ml, 0.205 mmol). The reaction was stirred at room temperature overnight then was diluted with EtOAc and water. The combined organics were washed with LiCI (3x), brine, dried MgS04, filtered, and concentrated to give the title compound (0.056 g, 57.6%). ES- LCMS: 569.5 (M+1).
Step B
4-({6-cyclopropyl- 1-methyl-4-[( 1-methylethyl)oxy]-1H-benzimidazol-2-yl}carbonyl)- 1-(trans-4- hydroxycyclohexyl)-2-piperazinone
[00214] A solution of 4-({6-cyclopropyl-1-methyl-4-[(1-methylethyl)oxy]-1 H-benzimidazol- 2-yl}carbonyl)-1-(trans-4-{t(1 ,1-dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2-piperazinone (0.056 g, 0.098 mmol) in DCM (2.0 mL)was treated by the addition of 4N in dioxanes HCI (0.5 ml, 2.000 mmol). The reaction was stirred at room temperature for 90 minutes then
concentrated under reduced pressure. The crude residue was purified by reverse phase chromatography (10-90% ACN/ H20 + formic acid) to give the title compound as a white solid (0.022 g, 49.2%). ES-LCMS: 455.4 (M+1). 1H NMR (400 MHz, CHLOROFORM-cQ δ ppm 6.68 (d, J=12.69 Hz, 1 H), 6.50 (d, J=9.96 Hz, 1 H), 4.95 - 5.06 (m, 1 H), 4.79 (s, 1 H), 4.38 - 4.55 (m, 2 H), 4.28 - 4.33 (m, 1 H), 3.90 - 3.97 (m, 4 H), 3.54 - 3.64 (m, 1 H), 3.34 - 3.45 (m, 2 H), 1.97 - 2.11 (m, 3 H), 1.71 - 1.80 (m, 2 H), 1.48 - 1.64 (m, 4 H), 1.44 (dd, =5.96, 4.59 Hz, 6 H), 0.97 - 1.04 (m, 2 H), 0.72 - 0.78 (m, 2 H).
Example 37
4-[(4-cyclohexyl-6-cyclopropyl-1- ethyl-1H-benzimidazol-2-yl)carbonyl]-1-(trans-4- hydroxycyclo hexyl)-2-piperazinon e
Figure imgf000105_0001
Step A
4-[(4-cyclohexyl-6-cyclopropyl-1-methyl-1 H -benzimidazol-2-yl)carbonyl]~1-(trans-4-{[(1 , 1- dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2-piperazinone
[00215] A solution of 4-[(4-bromo-6-cyclopropyl-1-methyl-1 H-benzimidazol-2-yl)carbonyl]- 1-(trans-4-{[(1 ,1-dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2-piperazinone (0.157 g, 0.266 mmol) in THF (1.517 ml) was treated by the addition of PdCI2(dppf)-CH2Cl2 adduct (0.022 g, 0.027 mmol) and copper(l) iodide (0.015 g, 0.080 mmol). The reaction was then treated by the drop-wise (1 drop every 3-5 second) addition of 0.5M in THF bromo(cyclohexyl)zinc (0.799 ml, 0.399 mmol) . The reaction was stirred at room temperature overnight. The reaction was treated with additional copper(l) iodide (0.015 g, 0.080 mmol) and 0.5 M in THF
bromo(cyclohexyl)zinc (0.799 ml, 0.399 mmol). The reaction was stirred overnight. The reaction was then treated with additional copper(l) iodide (0.015 g, 0.080 mmol), PdCI2(dppf)- CH2CI2 adduct (0.022 g, 0.027 mmol), and bromo(cyclohexyl)zinc (0.799 ml, 0.399 mmol) and stirred overnight. The reaction then treated by the addition of 2.0 mL of bromocyclohexylzinc and stirred at room temperature for 2 hours. The reaction was treated by the addition of water and EtOAc. The combined organics were washed with saturated NaHC03, brine, dried gS04, filtered and concentrated to give the title compound (0.225 g, 100%). ES-LCMS: 593.5 (M+1).
Step B
44-[(4-cyclohexyl-6-cyclopropyl-1-methyl-1H-benzimidazol-2~yl)carbo
hydroxycyclohexyl)-2-piperazinone
[00216] A solution of 4-[(4-cyclohexyl-6-cyclopropyl-1-methyl-1 H-benzimidazol-2- yl)carbonyl]-1-(trans-4-{[(1 ,1-dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2-piperazinone (0.225 g, 0.379 mmol) in DCM (4.0 mL) was treated by the addition of 4N in dioxanes HCI (1.0 ml_, 4.00 mmol). The reaction was stirred at room temperature for 90 minutes and concentrated under reduced pressure. The crude residue was purified by reverse phase chromatography ( 0-90% ACN- H20 + formic acid) to give the title compound as a white solid (0.049 g, 27.0%). ES-LCMS: 479.4 (M+1). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 6.87 - 6.95 (m, 2 H), 4.79 (s, 1 H), 4.39 - 4.57 (m, 2 H), 4.28 - 4.34 (m, 1 H), 3.91 - 3.98 (m, 4 H), 3.55 - 3.64 (m, 1 H), 3.45 - 3.52 (m, 1 H), 3.38 - 3.43 (m, 1 H), 3.13 - 3.32 (m, 1 H), 2.02 - 2.11 (m, 3 H), 1.96 (br. s., 2 H), 1.70 - 1.91 (m, 6 H), 1.42 - 1.69 (m, 8 H), 1.26 - 1.39 (m, 1 H), 0.98 - 1.06 (m, 2 H), 0.71 - 0.81 (m, 2 H).
Example 38
4-{[6-cyclopropyl-1-methyl-4-(1^yrrolidinyl)-1H-benzimidazol-2- hydroxycyclohexyl)-2-piperazinone
Figure imgf000106_0001
[00217] A solution of 4-[(4-bromo-6-cyclopropyl-1-methyl-1 H-benzimidazol-2-yl)carbonyl]- 1-(trans-4-hydroxycyclohexyl)-2-piperazinone (0.090 g, 0.189 mmol) in toluene (1.876 ml) was treated by the addition of pyrrolidine (0.017 ml, 0.208 mmol), Pd2(dba)3 (8.67 mg, 9.47 pmol), NaOtBu (0.038 g, 0.398 mmol), and johnphos (8.47 mg, 0.028 mmol). The reaction was purged with nitrogen and then heated to 90 °C overnight. The reaction was cooled to room temperature and diluted with EtOAc and water. The combined organics were washed with 1 N NaOH, brine, dried MgS04, filtered, and combined with the test reaction and concentrated. The crude residue was purified by reverse phase chromatography (10-90% ACN/ H20 + formic acid) to give the title compound as a yellow solid (0.010 g, 11.3%). ES-LCMS: 466.3 ( +1). H NMR (400 MHz, CHLOROFORM-d) δ ppm 6.34 (d, J=15.82 Hz, 1 H), 6.05 (d, =11.72 Hz, 1 H), 4.89 (s, 1 H), 4.39 - 4.58 (m, 2 H), 4.36 (t, J=4.98 Hz, 1 H), 3.88 - 4.00 (m, 4 H), 3.68 - 3.79 (m, 4 H), 3.59 (br. s., 1 H), 3.34 - 3.47 (m, 2 H), 1.93 - 2.11 (m, 7 H), 1.38 - 1.83 (m, 6 H), 0.97 (d, J=7.62 Hz, 2 H), 0.71 - 0.81 (m, 2 H).
Example 39
methyl 6-cyclopropyl-2-{t4-(trans-4-hyd roxycyclohexyl)-3-oxo-1-piperazinyl]carbonyl}-1- methyl-1H-benzimidazole-4-carboxylate
Figure imgf000107_0001
Step A
methyl 6-cyclopropyl-2-{[4-(trans-4-{[(1, 1-dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-3-oxo-1- piperazinyl]carbonyl}-1-methyl-1H-benzimidazole-4-carboxylate
[00218] A flask containing the solid reagents including 4-[(4-bromo-6-cyclopropyl-1- methyl-1 H-benzimidazol-2-yl)carbonyl]-1-(trans-4-{[(1 ,1- dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2-piperazinone (0.150 g, 0.254 mmol), PdOAc2 (1.142 mg, 5.09 pmol), Xantphos (5.89 mg, 10.18 μηηοΙ), was purged with nitrogen. To the flask was added the liquid reagents, including TEA (0.496 ml, 3.56 mmol) and MeOH (0.103 ml, 2.54 mmol). The reaction was purged with nitrogen then purged with carbon monoxide using a double balloon. The reaction vessel was then submerged into a preheated oil bath at 70 °C and stirred for 15 hours. The reaction was then cooled to room temperature, diluted with MeOH, and filtered through a filter disc and concentrated to give the title compound (0.188 g, 100%). ES-LCMS: 569.4 (M+1). Step B
methyl 6-cyclopropyl-2-(l4-(trans-4-hydroxycyclohexyl)-3-oxo-1^iperazinyl]carbonyl}-1-
1H-benzimidazole-4-carboxylate
[00219] A solution of methyl 6-cyclopropyl-2-{[4-(trans-4-{[(1 , 1 - dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-3-oxo-1-piperazinyl]carbonyl}-1-methyl-1 H- benzimidazole-4-carboxylate (0.188 g, 0.331 mmol) in DCM (2.0 mL) was treated by the addition of 4M in dioxanes HCI (0.5 mL, 2.000 mmol). The reaction was stirred at room temperature for 1 hour and concentrated under reduced pressure. The crude residue was taken up in DCM and MeOH and treated by the addition of 2M in MeOH NH4. The solvents were removed under reduced pressure and the residue was purified by reverse phase
chromatography (10-90% ACN/ H20 + formic acid) to give the title compound as solid (0.044 g, 29.3%). ES-LCMS: 455.3 (M+1). 1H NMR (400 MHz, CHLOROFORM-c/) δ ppm 7.76 - 7.79 (m, 1 H), 7.31 - 7.34 (m, 1 H), 4.85 (s, 1 H), 4.42 (s, 3 H), 3.92 - 4.04 (m, 7 H), 3.54 - 3.63 (m, 1 H), 3.47 - 3.52 (m, 1 H), 3.38 - 3.43 (m, 1 H), 2.03 - 2.15 (m, 3 H), 1.72 - 1.81 (m, 2 H), 1.42 - 1.65 (m, 4 H), 1.04 - 1.11 (m, 2 H), 0.81 (d, J=5.08 Hz, 2 H).
Example 40
4-{[6-cyclopropyl-1-methyl-4-(1-piperidinylcarbonyl)-1H-benzimidazol-2-ylJcarbon
(trans-4-hydroxycyclohexyl)-2-piperazinone
Figure imgf000108_0001
4-{[6-cyclopropyl-1-methyl-4-(1^iperidinylcarbonyl)-1H-benzimida
{[(1, 1-dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2-piperazinone
[00220] A flask containing 4-[(4-bromo-6-cyclopropyl-1 -methyl-1 H-benzimidazol-2- yl)carbonyl]-1-(trans-4-{[(1 ,1-dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2-piperazinone (0.1 g, 0.170 mmol), Na2C03 (0.018 g, 0.170 mmol), Xantphos (1.963 mg, 3.39 pmol), and PdOAc2 (0.038 g, 0.170 mmol) and piperidine (0.025 ml, 0.254 mmol) was purged with nitrogen. To the flask was added toluene (0.144 ml). The reaction was purged with nitrogen, the purged with carbon monoxide using a double balloon. The reaction vessel was then submerged into a preheated oil bath at 80 °C and stirred for 15 hours. The reaction was then cooled to room temperature and diluted with EtOAc. The reaction was filtered using a filter disc and concentrated under reduced pressure to give the title compound (0.119 g, 100%). ES-LCMS: 622.5 (M+1).
Step B
4-{[6-cyclopropyl-1-methyl-4-(1^iperidinylcarbonyl)-1H-benzimid^
hydroxycyclohexyl)-2-piperazinone
[00221] A solution of 4-{[6-cyclopropyl-1-methyl-4-(1-piperidinylcarbonyl)-1 H- benzimidazol-2-yl]carbonyl}-1-(trans-4-{[(1 ,1-dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2- piperazinone (0.119 g, 0.191 mmol) in DCM (2.0 mL) was treated by the addition of 4M in dioxanes HCI (0.5 ml, 2.000 mmol). The reaction was stirred at room temperature for 1 hour and concentrated under reduced pressure. The crude residue was taken up in DCM and MeOH and treated by the addition of 2M in MeOH NH4. The solvents were removed under reduced pressure and the residue was purified by reverse phase chromatography (10-90% ACN/ H20 + formic acid) to give the title compound as solid (0.032 g, 32.9%). ES-LCMS: 508.4 (M+1). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.05 - 7.16 (m, 2 H), 4.78 - 4.84 (m, 1 H), 4.37 - 4.54 (m, 3 H), 4.20 - 4.33 (m, 1 H), 3.92 - 4.00 (m, 4 H), 3.78 - 3.85 (m, 2 H), 3.54 - 3.64 (m, 1 H), 3.36 - 3.47 (m, 2 H), 3.23 - 3.29 (m, 1 H), 3.14 - 3.20 (m, 1 H), 2.01 - 2.11 (m, 4 H), 1.39 - 1.79 (m, 11 H), 0.99 - 1.08 (m, 2 H), 0.75 - 0.84 (m, 2 H).
Example 41
4-{[6-cyclopropyl-1-methyl-4-(2-methylpropyl)-1H-benzimidazol-2-yl]carbonyl}-^
hydroxycyclohexyl)-2-piperazinone
(Compound 41)
Figure imgf000110_0001
Step A
4-{[6-cyclopropyl-1-methyl-4-(2-methylpropyl)-1H-benzimi^azol-2-yl]ca 1- dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2-piperazinone
[00222] A solution of 4-[(4-bromo-6-cyclopropyl-1 -methyl-1 H-benzimidazol-2-yl)carbonyl]- 1-(trans-4-{[(1 ,1-dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2-piperazinone (0.123 g, 0.209 mmol) in THF (1.188 ml) was treated by the addition PdCI2(dppf)-CH2Cl2 adduct (0.017 g, 0.021 mmol) and copper(l) iodide (0.012 g, 0.063 mmol). The reaction was then treated by the drop- wise (1 drop every 3-5 second) addition of 0.5M in THF isobutylzinc bromide (0.626 ml, 0.313 mmol). The reaction was stirred at room temperature for 48 hours. The reaction was treated with copper(l) iodide (0.012 g, 0.063 mmol), PdCI2(dppf)-CH2Cl2 adduct (0.017 g, 0.021 mmol) and then treated by the addition of isobutylzinc bromide (3.0 mL). The reaction was stirred at room temperature for 1 hour and then was diluted with H20 and extracted with EtOAc. The combine organics were washed with saturated NaHC03, water, brine, dried MgS04, filtered, and concentrated to give the title compound (0.136 g, 100%). ES-LCMS: 567.5 (M+1).
Step B
4-{[6-cyclopropyl-1-methyl-4-(2-methylpropyl)-1H-benzimidazol-2-yl]carbon
hydroxycyclohexyl)-2-piperazinone
[00223] A solution of 4-{[6-cyclopropyl-1 -methyl-4-(2-methylpropyl)-1 H-benzimidazol-2- yl]carbonyl}-1 -(trans-4-{[(1 , 1 -dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2-piperazinone (0.136 g, 0.240 mmol) in DCM (2.0 mL) was treated by the addition of 4N in dioxanes HCI (.5 mL, 2.000 mmol). The reaction was stirred at room temperature for 2 hours and concentrated under reduced pressure. The crude residue was purified by reverse phase chromatography (10-90% ACN/ H20 + formic acid) to give the title compound as a solid (0.041 g, 37.8%). ES-LCMS: 453.4 (M+1). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 6.91 - 6.96 (m, 1 H), 6.85 (br. s., 1 H), 4.79 (s, 1 H), 4.39 - 4.55 (m, 2 H), 4.28 - 4.33 (m, 1 H), 3.93 - 3.99 (m, 4 H), 3.56 - 3.65 (m, 1 H), 3.44 - 3.49 (m, 1 H), 3.38 - 3.42 (m, 1 H), 2.81 - 2.89 (m, 2 H), 1.99 - 2.20 (m, 4 H), 1.41 - 1.83 (m, 6 H), 0.99 - 1.06 (m, 2 H), 0.91 - 0.97 (m, 6 H), 0.73 - 0.79 (m, 2 H).
Example 42
4-{[4-(cyclohexylmethyl)-6-cyclopropyl-1-methyl-1H-benzimidazol-2-yl]carbonyl}-1-(tra^
4-hydroxycyclohexyl) -2-pip erazinone
Figure imgf000111_0001
Step A
4-{[4-(cyclohexylmethyl)-6-cyclopropyl-1-methyl-1H-benz imidazol-2-yl]carbonyl}-1-(trans-4- {[(1, 1-dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2-piperazinone
[00224] A solution of 4-[(4-bromo-6-cyclopropyl-1-methyl-1 H-benzimidazol-2-yl)carbonyl]- 1-(trans-4-{[(1 ,1-dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2-piperazinone (0.123 g, 0.209 mmol) in THF (1.188 ml) was treated by the addition PdCI2(dppf)-CH2Cl2 adduct (0.017 g, 0.021 mmol) and copper(l) iodide (0.012 g, 0.063 mmol). The reaction was then treated by the drop- wise (1 drop every 3-5 second) addition of 0.5M in THF (cyclohexylmethyl)zinc bromide (0.626 ml, 0.313 mmol). The reaction was stirred at room temperature for 48 hours. The reaction was treated with copper(l) iodide (0.012 g, 0.063 mmol), PdCI2(dppf)-CH2CI2 adduct (0.017 g, 0.021 mmol) and (cyclohexylmethyl)zinc bromide (3.0 ml_). The reaction was stirred at room temperature for 1 hour and then was diluted with H20 and extracted with EtOAc. The combine organics were washed with saturated NaHC03, water, brine, dried MgS04l filtered, and concentrated to give the title compound (0.185 g, 100%). ES-LCMS: 607.6 (M+1).
Step B
4-{[4- (cyclohexylmethyl)-6-cyclopropyl- 1 -methyl- 1 H-benz imidazol-2-yl]carbonyl}- 1 -( trans-4- hydroxycyclohexyl)-2-piperazinone [00225] A solution of 4-{[4-(cyclohexylmethyl)-6-cyclopropyl-1 -methyl-1 H-benzimidazol-2- yl]carbonyl}-1-(trans-4-{[(1 ,1 -dimethyl^ (.185 g, 0.305 mmol) in DCM (2.0 mL) was treated by the addition of 4N in dioxanes HCI (0.5 mL, 2.000 mmol). The reaction was stirred at room temperature for 2 hours and concentrated under reduced pressure. The crude residue was purified by reverse phase chromatography (10-90% ACN/ H20 + formic acid) to give the title compound as a solid (0.048 g, 32%). ES-LCMS: 493.4 (M+1). 1H NMR (400 MHz, CHLOROFORM-cQ δ ppm 6.88 - 6.96 (m, 1 H), 6.84 (s, 1 H), 4.80 (s, 1 H), 4.39 - 4.61 (m, 2 H), 4.26 - 4.37 (m, 1 H), 3.92 - 4.01 (m, 4 H), 3.60 (br. s., 1 H), 3.46 - 3.50 (m, 1 H), 3.38 - 3.42 (m, 1 H), 2.81 - 2.89 (m, 2 H), 1.99 - 2.12 (m, 3 H), 1.42 - 1.85 (m, 12 H), 1.13 - 1.27 (m, 3 H), 0.96 - 1.08 (m, 4 H), 0.73 - 0.80 (m, 2 H).
Example 43
4-({6-cyclopropyl-1-methyl-4-[(phenylmethyl)amino]-1H-benzimidazol-2-yl}carb
(trans-4-hydroxycyclohexyl)-2-piperazinone
Figure imgf000112_0001
Step A
4-({6-cyclopropyl-1-methyl-4-[(phenylmethyl)amino]-1H-benz imidazol-2-yl}carbonyl)-1-(trans-4-
{[(1, 1-dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2-piperazinon
[00226] A mixture of 4-[(4-bromo-6-cyclopropyl-1 -methyl-1 H-benzimidazol-2-yl)carbonyl]- 1-(trans-4-{[(1 ,1-dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2-piperazinone (0.120 g, 0.204 mmol), N,N-diethylsalicylamide (7.87 mg, 0.041 mmol), and potassium phosphate tribasic (0.086 g, 0.407 mmol) were added to a vial. The vial was purged with nitrogen, followed by the addition of DMF (0.5 ml) and benzylamine (0.033 ml, 0.305 mmol). The solution was purged with nitrogen and was heated to 90 °C overnight. N,N-diethylsalicylamide (7.87 mg, 0.041 mmol), potassium phosphate tribasic (0.086 g, 0.407 mmol), and benzylamine (0.033 ml, 0.305 mmol) was added and flask was purged with nitrogen and was heated to 105 °C. The reaction was cooled to room temperature and diluted with H20 and EtOAc and treated by the addition of NH4OH (-.5 mL). The combined organics were washed with LiCI (3x), brine, dried MgS04, filtered, and concentrated to give the title compound (0.164 g, 100%). ES-LCMS: 616.5 (M+1).
Step B
4-({6-cyclopropyl-1-methyl-4-[(phenylmethyl)amino]-1H-benzim
hydroxycyclohexyl)-2-piperazinone
[00227] A solution of 4-({6-cyclopropyl-1 -methyl-4-[(phenylmethyl)amino]-1 H- benzimidazol-2-yl}carbonyl)-1-(trans-4-{[(1 ,1-dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2- piperazinone (0.164 g, 0.266 mmol) in DCM (2.0 mL) was treated by the addition of 4N in dioxanes HCI (0.5 mL, 2.000 mmol). The reaction was stirred at room temperature for 60 minutes then concentrated under reduced pressure. The crude residue was taken up in DCM and MeOH and treated by the addition of 2N in MeOH NH4. The reaction was concentrated. The residue was taken up in DCM, filtered, and then concentrated. The residue was purified by reverse phase chromatography (10-90% ACN/ H20 + formic acid) to give the title compound as a solid (0.025 g, 18.7%). ES-LCMS: 502.4 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.34 - 7.41 (m, 2 H), 7.27 - 7.33 (m, 2 H), 7.17 - 7.24 (m, 1 H), 6.46 (br. s., 1 H), 6.36 - 6.43 (m, 1 H), 5.96 - 6.02 (m, 1 H), 4.45 - 4.63 (m, 4 H), 4.15 - 4.27 (m, 2 H), 4.06 - 4.12 (m, 1 H), 3.80 - 3.86 (m, 1 H), 3.77 (s, 3 H), 3.34 (s, 3H), 1.78 - 1.91 (m, 3H), 1.47 - 1.58 (m, 4 H), 1.17 - 1.30 (m, 2 H), 0.80 - 0.89 (m, 2 H), 0.50 - 0.60 (m, 2 H).
Example 44
4-[(6-cyclopropyl-1-methyl-4-{[2-( ethyloxy)ethyl]amino}-1H-benzi ida
1-(trans-4-hydroxycyclohexyl)-2-piperazinone
(Compound 44)
Figure imgf000113_0001
Step A
4-[(6-cyclopropyl-1-methyl-4-{[2-( methyloxy)ethyl]amino}- 1 H-benz imidazol-2-yl)carbonyl]- 1- (trans-4- {[( 1, 1-dimethylethyl) (dimethyl)silyl]oxy}cyclohexyl)-2-piperazinone
[00228] A mixture of 4-[(4-bromo-6-cyclopropyl-1-methyl-1 H-benzimidazol-2-yl)carbonyl]- 1-(trans-4-{[(1 ,1-dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2-piperazinone (0,120 g, 0.204 mmol), N,N-diethylsalicylamide (7.87 mg, 0.041 mmol), and potassium phosphate tribasic (0.407 mmol) were added to a vial. The vial was purged with nitrogen, followed by the addition of DMF (0.5 ml) and 2-(methyloxy)ethanamine (0.026 ml, 0.305 mmol). The solution was purged with nitrogen and was heated to 90 °C overnight. The reaction was treated with N,N- diethylsalicylamide (7.87 mg, 0.041 mmol), potassium phosphate tribasic (0.407 mmol) (.5 ml), and 2-(methyloxy)ethanamine (0.026 ml, 0.305 mmol) and the temperature was increased to 105 °C. The reaction was cooled to room temperature and diluted with H20 and EtOAc and treated by the addition of NH4OH (-0.5 mL). The combined organics were washed with LiCI (3x), brine, dried MgS04, filtered, and concentrated to give the title compound (0.095 g, 80%). ES-LCMS: 584.5 (M+1).
Step B
4-[(6-cyclopropyl-1-methyl-4-{[2-( methyloxy)ethyl]amino}-1 H-benz imidazol-2-yl)carbonyl]-1-
(trans-4-hydroxycyclohexyl)-2-piperazinone
[00229] A solution of 4-[(6-cyclopropyl-1 -methyl-4-{[2-(methyloxy)ethyl]amino}-1 H- benzimidazol-2-yl)carbonyl]-1-(trans-4-{[(1 ,1-dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2- piperazinone (.095 g, 0.163 mmol) in DCM (2.0 mL) was treated by the addition of 4N in dioxanes HCI (0.5 mL, 2.000 mmol). The reaction was stirred at room temperature for 60 minutes then concentrated under reduced pressure. The crude residue was taken up in DCM and MeOH and treated by the addition of 2N in MeOH NH4. The reaction was concentrated. The residue was taken up in DCM, filtered, and then concentrated. The residue was purified by reverse phase chromatography (10-90% ACN/ H20 + formic acid) to give the title compound as a solid (0.012 g, 15.7%). ES-LCMS: 470.4 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 6.48 (s, 1 H), 6.12 - 6.16 (m, 1 H), 5.47 - 5.57 (m, 1 H), 4.58 - 4.61 (m, 1 H), 4.53 (s, 1 H), 4.14 - 4.28 (m, 2 H), 4.04 - 4.09 (m, 1 H), 3.76 - 3.84 (m, 4 H), 3.52 - 3.58 (m, 2 H), 3.40 - 3.47 (m, 2 H), 3.34 - 3.39 (m, 3 H), 3.29 (s, 3 H), 1.91 - 1.99 (m, 1 H), 1.83 - 1.90 (m, 2 H), 1.49 - 1.58 (m, 4 H), 1.18 - 1.30 (m, 2 H), 0.89 - 0.95 (m, 2 H), 0.67 - 0.73 (m, 2 H).
Example 45 4-{[6-cyclo propyl-1-methyl-4-( 1H-p yrrol-2-yl) - 1 H-benzimidazol-2-yl]carbonyl}-1 -(trans-4- hydroxycyclohexyl)-2-piperazinone
Figure imgf000115_0001
Step A
1, 1 -dimethyl ethyl 2-(6-cyclopropyl-2-{[4-(trans-4-{[(1, 1- dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-3-oxo-1-piperaz inyl]carbonyl}- 1-methyl-1H- benzimidazol-4-yl)-1H-pyrrole- 1-carboxylate
[00230] A flask containing 4-[(4-bromo-6-cyclopropyl-1-methyl-1 H-benzimidazol-2- yl)carbonyl]-1-(trans-4-{[(1 ,1-dimethylethyl)(dimethyl)sN^ (0.1 g,
0.170 mmol), K2C03 (0.094 g, 0.678 mmol), PdCI2(dppf)-CH2Ci2 adduct (0.014 g, 0.017 mmol), in 1 ,4-dioxane (1.542 ml) was treated with 1-boc-pyrrole-2-boronic acid (0.054 g, 0.254 mmol) and heated to 85 °C. The reaction was stirred at room temperature and then treated with K2CO- (0.094 g, 0.678 mmol), PdCI2(dppf)-CH2CI2 adduct (0.014 g, 0.017 mmol), 1 ,4-dioxane (1.542 ml), and 1-boc-pyrrole-2-boronic acid (0.054 g, 0.254 mmol). The reaction was then heated under nitrogen overnight. The reaction was cooled to room temperature and diluted with EtOAc and water. The combine organics were washed with saturated NaHC03, brine, dried MgS04, filtered, and concentrated. The crude residue was purified by reverse phase chromatography (10-90% ACN/ H20 + formic acid) to give the title compound as a solid (0.040 g, 34.5%). ES- LCMS: 676.5 (M+1).
Step B
4-{[6-cyclopropyl-1-methyl-4-(1H-pyrrol-2-yl)- 1H-benzimidazol-2-yl]carbonyl}-1-(trans-4- hydroxycyclohexyl)-2-piperazinone
[00231] A solution of 1 , 1 -dimethylethyl 2-(6-cyclopropyl-2-{[4-(trans-4-{[(1 , 1 - dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-3-oxo-1-piperazinyl]carbonyl}-1-methyl-1 H- benzimidazol-4-yl)- H-pyrrole-1-carboxylate (.040 g, 0.059 mmol) in DCM (2.0 mL) was treated by the addition of 4M in dioxanes HCI (0.5 mL, 2.000 mmol). The reaction was stirred at room temperature for 5 hours and then concentrated under reduced pressure. The residue was triturated with Et20 to give the title compound as greenish solid (0.027 g, 100%). ES-LCMS: 462.4 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 11 ,29 - 11.38 (m, 1 H), 7.35 (s, 1 H), 7.11 - 7.15 (m, 1 H), 7.02 - 7.08 (m, 1 H), 6.94 (br. s., 1 H), 6.17 (br. s., 1 H), 4.60 (s, 1 H), 4.25 (s, 2 H), 4.07 (br. s., 1 H), 3.87 (d, J=4.10 Hz, 5 H), 3.33 - 3.45 (m, 3 H), 2.03 - 2.12 (m, 1 H), 1.83 - .91 (m, 2 H), 1.51 - 1.59 (m, 3 H), 1.20 - 1.28 (m, 3 H), 0.97 - 1.03 (m, 2 H), 0.80 - 0.86 (m, 2 H).
Example 46
4-{[6-cyclopropyl-1-methyl-4-(trifluoromethyl)-1H-benzimidazol-2-yl]
hydroxycyclohexyl)-2-piperazinone
Figure imgf000116_0001
H
[00232] To a mixture of methyl 6-cyclopropyl-1-methyl-4-(trifluoromethyl)-1 H- benzimidazole-2-carboxylate (100 mg, 0.228 mmol) in tetrahydrofuran (1 mL) was added 1 M sodium hydroxide (0.46 mL, 0.46 mmol). The mixture was stirred for 10 minutes and concentrated. To the residue was added Ν,Ν-dimethylformamide followed by N-ethyl-N-(1- methylethyl)-2-propanamine (0.20 mL, 1.1 mmol), and N-[(dimethylamino)(3H- [1 ,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylidene]-N-methylmethanaminium hexafluorophosphate (HATU) (104 mg, 0.274 mmol). The reaction was stirred for 2 hours and diluted with ethyl acetate. The organic phase was washed with brine, washed with 5% lithium chloride, dried over sodium sulfate, and concentrated. The residue was purified by silica chromatography to give the title compound (58 mg, 55%). LCMS: m/z 465 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.66 (s, 1 H), 7.42 (d, 1 H), 4.35 - 4.47 (m, 2 H), 4.24 (s, 2 H), 3.83 - 4.01 (m, 5 H), 3.80 (br. s., 1 H), 3.38 (q, 2 H), 2.14 - 2.25 (m, 1 H), 1.82 (d, 2 H), 1.70 (br. s., 2 H), 1.47 (br. s., 2 H), 1.20 - 1.35 (m, 2 H), 1.00 - 1.08 (m, 2 H), 0.77 - 0.89 (m, 2 H). Example 47
4-{[6-cyclopropyl-1-methyl-4-(trifluoromethyl)-1H-benzimidazol-2-yl]carbon
{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2-piperazinone
Figure imgf000117_0001
Step A
N-[4-bromo-2-( trifluorom ethyl)phenyl]acetami de
[00233] 4-bromo-2-(trifluoromethyl)aniline (553 g, 2.30 mol) was dissolved in acetic anhydride (1087 ml, 11.5 mol) and stirred at room temperature overnight. A thick white solid had formed and was slurried in a mixture of 200 mL of ethyl ether and 400 mL of hexanes. The solids were triturated thoroughly and collected by filtration. The filter cake was washed with a mixture of 200 mL of ethyl ether and 400 mL of hexanes, and was thoroughly air dried to give the title compound (528 g; 81 %) as a white solid. LCMS: m/z 282, 284 (M+1).
Step B
4-bromo-2-nitro-6-(trifluoromethyl)aniline
[00234] Sulfuric acid (350 ml) was cooled to 5 °C in an ice-bath before V-[4-bromo-2- (trifluoromethyl)phenyl]acetamide (100 g, 355 mmol) was added portion-wise. The observed internal temperature increased from 5 °C to 10 °C. After the solids dissolved and temperature decreased to 5 °C, nitric acid (70%) (43.8 ml) was added slowly drop-wise at such a rate that the internal temperature did not increase above 10 °C. The temperature was carefully controlled between 8 °C and 12 °C until the reaction was complete. The cold dark solution was carefully poured into stirring ice water (2L, mostly ice). The tan precipitate was collected by filtration and the filter cake washed with 1 L of cold water before being air dried. The tan powder was slurried in methanol (500 mL) in a 3L 3-neck flask, and concentrated hydrochloric acid (37%) (750 mL, 9130 mmol) was added and the mixture heated with a heating mantel to 100 °C. Excessive frothing occurred. 10OmL of 1 ,4-dioxane and 200mL of tetrahydrofuran were added to help the frothing subside. Frothing did not subside. The reaction temperature was brought down to 80 °C and heated overnight. The mixture was much more manageable and frothing was better controlled. The mixture was slowly heated to 95 °C and was stirred for 72 hours. The mixture was cooled to room temperature and extracted 3 times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated to give the title compound (101 g, 99%). 1H NMR (400 MHz, DMSO-tf6) δ ppm 8.40 (d, 1 H), 7.96 (d, 1 H), 7.44 (br. s„ 2 H).
Step C
4-cyclopropyl-2-nitro-6-( tr!fluoromethyl )aniline
[00235] 4-bromo-2-nitro-6-(trifluoromethyl)aniline (101 g, 354 mmol) was dissolved in 1 ,4- dioxane (886 mL). Potassium phosphate tribasic (226 g, 1060 mmol), cyciopropylboronic acid (45.7 g, 532 mmol), and PdCI2(dppf)-CH2CI2 adduct (8.68 g, 10.6 mmol) were added and the mixture heated to 100 °C for 3 hours. Additional cyciopropylboronic acid ( 5.2 g, 177 mmol) and PdCI2(dppf)-CH2CI2 adduct (5.79 g, 7.09 mmol) were added and the reaction continued to stir at 100 °C for 1 hour. The mixture was allowed to cool to room temperature, diluted with water, and extracted 3 times with ethyl acetate. The combined organic layers were passed through a large silica plug that was flushed with ethyl acetate. The filtrate was concentrated to leave 137 g of crude material. 40 g of the crude material (63% pure) was harvested and carried forward without further purification. The remaining 97 g of crude material was dissolved in
dichloromethane and passed through a large plug of silica eluting with dichloromethane.
Fractions were concentrated to give the title compound (54.7 g; 63%). 1H NMR (400 MHz, DMSO-de)□ ppm 7.98 (d, 1 H), 7.59 (d, 1 H), 7.16 (s, 2 H), 1.99 (tt, 1 H), 0.83 - 1.04 (m, 2 H), 0.59 - 0.80 (m, 2 H).
Step D
5-cyclopropyl-3-(trifluoromethyl)~ 1, 2-benz enediamine
[00236] 4-cyclopropyl-2-nitro-6-(trifluoromethyl)aniline (40 g (63% pure by weight), 102 mmol) was dissolved in tetrahydrofuran (500 ml). Triethylamine (57.1 ml, 409 mmol) and 10% Pd/C (degussa) (1.09 g, 1.02 mmol) were added followed by drop-wise addition of formic acid (12.4 ml, 307 mmol). The mixture was heated at 65 °C for 16 hours, cooled to room temperature, and filtered through celite. The filtrate was diluted with ethyl acetate, washed with saturated sodium bicarbonate, dried over sodium sulfate, and concentrated. The residue was co-evaporated 1 time with hexanes and dried briefly under mild vacuum. The residue was taken up in dichloromethane and passed through a silica plug with dichloromethane. Fractions were concentrated to give the title compound (11.6 g; 45%). LCMS: m/z 217 (M+1).
Step E
5-cyclopropyl-2-(trichloromethyl)-7-(tri†luoromethyl)-1H
[00237] 5-cyclopropyl-3-(trifluoromethyl)-1 ,2-benzenediamine (15.5 g, 61.3 mmol) was dissolved in acetic acid (200 ml) before methyl 2,2,2-trichloromethylacetimidatate (9.30 ml, 73.6 mmol) was added drop-wise. The mixture was stirred at room temperature until the reaction was complete (~3 hours). The mixture was diluted with ethyl ether before water was added, and the mixture shaken in a separatory funnel. The layers were separated and the organic phase washed with brine, dried over sodium sulfate, and concentrated. The residue was co- evaporated 1 time with hexanes. The solids were co-evaporated with toluene 2 times to help get rid of acetic acid. Final concentration afforded the title compound (22.4 g; 99%) as an orange solid. LCMS: m/z 343, 345 (M+1).
Step F
4-{[5-cyclopropyl-7-(trifluoromethyl)-1 H-benz imidazol-2-yl]carbonyl}-1-(trans-4- hydroxycyclohexyl)-2-piperazinone
[00238] To a mixture of 5-cyclopropyl-2-(trichloromethyl)-7-(trifluoromethyl)-1 H- benzimidazole (22.4 g, 61.3 mmol) in acetonitrile (138 ml) and water (46 ml) was added 1- (trans-4-hydroxycyclohexyl)-2-piperazinone hydrochloride (21.58 g, 92 mmol) followed by drop- wise addition of potassium carbonate (4M in water) (61.3 ml, 245 mmol). The mixture was stirred overnight at room temperature. The reaction was quenched with water and extracted 2 times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by silica chromatography eluting with a gradient of 0% to 5% methanol in dichloromethane. A set of clean fractions were concentrated to leave the title compound (17.3 g; 63%) as a pale yellow foam. LCMS: m/z 451 (M+1). A second set of fractions was concentrated to give additional title compound (2.85 g) that was 95% pure. LCMS: m/z 451 (M+1).
Step G 4-{[6-cyclopropyl-1-methyl-4-(trifluoromethyl)-1H-benzimida
hydroxycyclohexyl)-2-piperazinone and 4-{[5-cyclopropyl-1-methyl-7-(trifluoromethyl)-1 H- benzimidazol-2-yl]carbonyl}-1- (trans-4-hydroxycyclohexyl)-2-piperazinone (mixture of regioisomers)
[00239] 4-{[5-cyclopropyl-7-(trifluoromethyl)-1 Y-benzimidazol-2-yl]carbonyl}-1 -(trans-4- hydroxycyclohexyl)-2-piperazinone (15.8 g, 35.1 mmol) was dissolved in N,N- dimethylformamide (200 ml) before potassium carbonate (14.54 g, 105 mmol) and methyl iodide (2.63 ml, 42.1 mmol) were added. The mixture was stirred for 1 hour, diluted with water, and extracted 2 times with ethyl acetate. The combined organic layers were washed with brine, washed with 5% lithium chloride, dried over sodium sulfate, and concentrated. Seed crystals were added to the oil and the material concentrated further via vacuum rotovap for 2 hours. A hard solid remained. Ethyl acetate (~250 mL) was added and the solids were triturated for 16 hours with a stir bar. Diethyl ether (~300 mL) was added and the mixture cooled in an ice bath. White solids were collected by filtration, washed with cold diethyl ether, and dried under vacuum to give pure 4-{[6-cyclopropyl-1-methyl-4-(trifluoromethyl)-1H-benzimidazol-2-yl]carbonyl}-1- (fra 7s-4-hydroxycyclohexyl)-2-piperazinone (8.3g, 51 %). LCMS: m/z 451 (M+1). The filtrate was concentrated to give a 7:3 mixture of the regioisomers 4-{[6-cyclopropyl-1-methyl-4- (trifluoromethyl)-1H-benzimidazol-2-yl]carbonyl}-1-(fra/?s-4-hydroxycyclohexyl)-2-piperazinone and 4-{[5-cyclopropyl-1-methyl-7-(trifluoromethyl)-1 /- -benzimidazol-2-yl]carbonyl}-1-(fra/7s-4- hydroxycyclohexyl)-2-piperazinone respectively (6.2 g: 38%). LCMS: m/z 465 (M+1).
Step H
4-{[6-cyclopropyl-1-methyl-4-(trifluoromethyl)-1H-benzimidazol-2^
dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2-piperazinone
[00240] A mixture of the regioisomers 4-{[6-cyclopropyl-1 -methyl-4-(trifluoromethyl)-1 H- benzimidazol-2-yl]carbonyl}-1 -(fra/7s-4-hydroxycyclohexyl)-2-piperazinone and 4-{[5-cyclopropyl- 1 -methyl-7-(trifluoromethyl)-1 H-benzimidazol-2-yl]carbonyl}-1 -(fra/7S-4-hydroxycyclohexyl)-2- piperazinone (5.2 g, 11 mmol) was dissolved in N,N-dimethylformamide (50 mL). Imidazole (1.52 g, 22.4 mmol) was added and the mixture cooled in an ice bath before tert- butyldimethylchlorosilane (2.53 g, 16.8 mmol) was added. Sodium iodide (10 mg) was added and the reaction was allowed to warm to room temperature overnight. The reaction mixture was quenched with water and extracted 2 times with ethyl acetate. The combined organic layers were washed with brine, washed with 5% lithium chloride, dried over sodium sulfate, and concentrated. The regioisomers were separated and purified by silica chromatography eluting with a gradient of 50% to 100% ethyl acetate in hexanes. One set of fractions was concentrated to give the title compound (3.9 g, 60%). LCMS: m/z 579 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.66 (s, 1 H), 7.42 (br. s., 1 H), 4.43 (s, 1 H), 4.23 (s, 2 H), 3.95 - 4.01 (m, 1 H), 3.91 (s, 3 H), 3.81 - 3.87 (m, 1 H), 3.52 - 3.63 (m, 1 H), 3.37 (br. s., 2 H), 2.10 - 2.30 (m, 1 H), 1.76 - 1.91 (m, 2 H), 1.55 (br. s., 4 H), 1.22 - 1.39 (m, 2 H), 1.04 (dd, 2 H), 0.85 (d, 11 H), 0.03 (d, 6 H)2 H), 0.85 (d, 11 H), 0.03 (d, 6 H).
Example 48
4-{[5-cyclopropyl-1- ethyl-7-(trifluoromethyl)-1H-benzi idazol-2-yl]car^
{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2-piperazinone
Figure imgf000121_0001
[00241] A second set of fractions was concentrated from the chromatographic separation in the previous example to give the title compound (1.5 g, 23%). LCMS: m/z 579 (M+1). 1H NMR (400 MHz, DMSO-de) δ ppm 7.68 - 7.83 (m, 1 H), 7.55 (s, 1 H), 4.31 (s, 1 H), 4.24 (s, 2 H), 3.86 (s, 4 H), 3.77 - 3.84 (m, 1 H), 3.48 - 3.65 (m, 1 H), 3.36 - 3.41 (m, 2 H), 2.10 - 2.22 (m, 1 H), 1.77 - 1.92 (m, 2 H), 1.56 (br. s., 4 H), 1.21 - 1.41 (m, 2 H), 1.00 (d, 2 H), 0.74 - 0.89 (m, 11 H), 0.04 (d, 6 H).
Example 49
4-{[5-cyclopropyl-1-methyl-7-(trifluoromethyl)-1H-benzimidazol-2-yl]carbo
hydroxycyclohexyl)-2-piperazinone
(Compound 49)
Figure imgf000122_0001
[00242] 4-{[5-cyclopropyl-1-methyl-7-(trifluorom
(frans-4-{[(1 ,1-dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2-piperaz (1.5 g, 2.6 mmol) was dissolved in ethanol (50 mL) before hydrochloric acid (37%) (0.85 mL, 10 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours and concentrated. The residue was slurried in saturated sodium bicarbonate and the mixture extracted with ethyl acetate. The organic phase was washed with brine, dried by passing through a hydrophobic frit, and concentrated to give the title compound (1.2 g, 98%) as a white powder. LCMS: m/z 465 (M+1). 1H NMR (400 MHz, DMSO-cfe) § ppm 7.72 (d, 1 H), 7.55 (s, 1 H), 4.59 (dd, 1 H), 4.31 (s, 1 H), 4.08 - 4.29 (m, 2 H), 3.86 (s, 4 H), 3.77 - 3.83 (m, 1 H), 3.29 - 3.41 (m, 3 H), 2.16 (m, 1 H), 1.86 (d, 2 H), 1.41 - 1.63 (m, 4 H), 1.18 - 1.32 (m, 2 H), 0.94 - 1.05 (m, 2 H), 0.73 - 0.83 (m, 2 H).
Example 50
4-{[4-bromo-6-(1,1-dimethylethyl)-1-methyl-1H-benzimidazol-2-yl]carbon
hydroxycyclohexyl)-2-piperazinone
(Compound 50)
Figure imgf000122_0002
Step A
3-bromo-5-( 1, 1-dimethylethyl)-1,2-benzenediamine [00243] To a mixture of 4-tert-butyl-2-nitroaniline (5.0 g, 26 mmol) in acetic acid (100 mL) was added N-bromosuccinimide (4.81 g, 27.0 mmol) portion-wise. The mixture was stirred for 4 hours at room temperature, quenched with aqueous sodium thiosulfate, and extracted 2 times with ethyl acetate. The combined organic layers were washed with water, washed with brine, dried over sodium sulfate, and concentrated to give 2-bromo-4-(1 ,1-dimethylethyl)-6-nitroaniline (8.5 g). A portion of the 2-bromo-4-(1 ,1-dimethylethyl)-6-nitroaniline (4.0 g, 14.65 mmol) was dissolved in acetic acid (50 mL) before zinc (2.87 g, 43.9 mmol) was added portion-wise at room temperature. One drop of concentrated hydrochloric acid was added. After 2 hours at room temperature the reaction was heated to 60 °C for 1 hour. The reaction mixture was allowed to cool to room temperature before hydrochloric acid (37%) (3.61 mL, 43.9 mmol) was added. The mixture was heated to 60 °C for 2 hours, cooled to room temperature, worked-up, and purified by chromatography to give the title compound (3.15 g, 88%). LCMS: m/z 243, 245 (M+1).
Step B
4-bromo-6-( 1, 1-dimethylethyl)-2-(trichloromethyl)- 1H-benzimidazole
[00244] 3-bromo-5-(1 ,1-dimethylethyl)-1 ,2-benzenediamine (1.2 g, 4.9 mmol) was dissolved in acetic acid (25 mL) and methyl 2,2,2-trichloromethylacetimidatate (0.94 mL, 7.4 mmol) was added drop-wise. The reaction was stirred for 3 hours. The mixture was diluted with ethyl ether and washed with water. The aqueous layer was extracted again with ether. The combined organic layers were washed with water, washed with brine, dried over sodium sulfate, and concentrated to give the title compound (0.91 g, 50%). LCMS: m/z 369, 371 , 373 (M+1).
Step C
4-bromo-6-( 1, 1-dimethylethyl)-1H-benzimidazole-2-carboxylic acid
[00245] 4-bromo-6-(1 ,1-dimethylethyl)-2-(trichloromethyl)-1 H-benzimidazole (0.91 g, 2.5 mmol) was slurried in cold sodium hydroxide (27 ml, 27 mmol). The slurry was allowed to warm to room temperature and stirred for 2 hours. Tetrahydrofuran (10 mL) was added to help dissolve solids. The reaction mixture was stirred for 20 minutes. The mixture was neutralized to pH = 4-5 with 1 hydrogen chloride before being diluted with a 10% citric acid solution. The mixture was extracted 3 times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated to give the title compound (0.71 g, 46% purity, 45%). LCMS: m/z 297, 299 (M+1).
Step D 4-{[4-bromo-6-(1, 1-dimethylethyl)-1H-benzimidazol-2-yl]carbonyl}-1- (tran
hydroxycyclohexyl)-2-piperazinone
[00246] 4-bromo-6-(1 ,1-dimethylethyl)-1 H-benzimidazole-2-carboxylic acid (0.71 g, 1.1 mmol), 1 -(frans-4-hydroxycyclohexyl)-2-piperazinone hydrochloride (0.62 g, 2.64 mmol), and N,N-diisopropylethylamine (1.68 mL, 9.59 mmol) were added to N,N-dimethylformamide (10 mL) at room temperature. N-[(dimethylamino)(3H-[1 ,2,3]triazolo[4,5-b]pyridin-3- yloxy)methylidene]-N-methylmethanaminium hexafluorophosphate (HATU) (1.1 g, 2.9 mmol) was added and the mixture stirred for 3 hours. The mixture was diluted with water and extracted 2 times with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by silica chromatography eluting with a gradient of 0% to 5% methanol in dichioromethane. Fractions were concentrated to give the title compounds (270 mg, 51 %). LCMS: m/z 477, 479 (M+1 ).
Step E
4-{[4-bromo-6-(1 , 1-dimethylethyl)-1-methyl-1H-benzimidazol-2-yl]carbonyl}-1-(trans-4-{[(1, ^ dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2-piperazinone
[00247] To a solution of 4-{[4-bromo-6-(1 , 1 -dimethylethyl)-1 H-benzimidazol-2- yl]carbonyl}-1-(trans-4-hydroxycyclohexyl)-2-piperazinone (270 mg, 0.566 mmol) in N,N- dimethylformamide (3 mL) was added imidazole (77 mg, 1.1 mmol), and tert- butyldimethylchlorosilane (128 mg, 0.848 mmol). The mixture was heated to 35 °C before a catalytic amount (2 mg) of sodium iodide was added, followed by imidazole (77 mg, 1.1 mmol), and tert-butyldimethylchlorosilane ( 28 mg, 0.848 mmol). The mixture was again cooled to room temperature before imidazole (77 mg, 1.1 mmol) was added followed by drop-wise addition of (1 ,1 -dimethylethyl)(dimethyl)silyl trifluoromethanesulfonate (0.13 mL, 0.57 mmol). The reaction mixture was allowed to stir at room temperature overnight. The mixture was diluted with water and extracted 2 times with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated. The residue was dissolved in N,N- dimethylformamide (DMF) (5 mL) before potassium carbonate (391 mg, 2.83 mmol) and methyl iodide (0.071 mL, 1.1 mmol) were added. The mixture was stirred for 3 hours, diluted with water, and extracted 2 times with ethyl acetate. The combined organic layers were washed with 5% lithium chloride, dried over sodium sulfate, and concentrated. The residue was dissolved in dichioromethane and cooled to 5 °C in an ice bath before 2,6-lutidine (0.20 mL, 1.7 mmol) was added followed by drop-wise addition of (1 ,1-dimethylethyl)(dimethyl)silyl
trifluoromethanesulfonate (0.195 mL, 0.848 mmol). The mixture was stirred for 30 minutes and quenched with water. The mixture was extracted 2 times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by silica chromatography eluting with a gradient of 50% to 100% ethyl acetate in hexanes. Fractions from the first eluting peak were concentrated to give 4-{[7-bromo- 5-(1 , 1 -dimethylethyl)-1 -methyl- 1 H-benzimidazol-2-yl]carbonyl}-1 -(trans-4-{[(1 , 1 - dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2-piperazinone (80 mg). Fractions from the second eluting peak were concentrated to give the title compound (170 mg, 50%). LCMS: m/z 605, 607 (M+1).
Step F
4-{[4-bromo-6-( 1, 1 -dimethylethyl)- 1- methyl- 1 H-benz imidazol-2-yl]carbonyl}-1-(trans- 4- hydroxycyclohexyl)-2-piperazinone
[00248] 4-{[4-bromo-6-(1 ,1-dimethylethyl)-1-methyl-1 H-benzimidazol-2-yl]carbonyl}-1- (trans-4-{[(1 ,1-dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2-piperazinone (38 mg, 0.063 mmol) was dissolved in dichloromethane (2 mL) and 4M hydrogen chloride in dioxane (1 mL) added. The mixture was stirred for 30 minutes and concentrated. The residue was slurried in hexanes, concentrated, and dried under vacuum to give the title compound (32 mg, 99%) as a white solid. LCMS: m/z 491 , 493 (M+1). 1H NMR (DMSO-d6) δ ppm 7.59 (2 H, s), 4.47 (4 H, s), 4.24 (2 H, s), 3.94 - 4.03 (1 H, m), 3.80 - 3.87 (1 H, m), 3.37 (3 H, d), 1.79 - 1.94 (2 H, m), 1.54 (4 H, br. s.), 1 -37 (9 H, s), 1.13 - 1.30 (3 H, m).
Example 51
4-{[4-cyclopropyl-6-(1,1-dimethylethyl)-1-methyl-1H-benzimidazol-2-yQ
4-hydroxycyclohexyl)-2-piperazinone
Figure imgf000125_0001
Step A 4-{[4-cyclopropyl-6-( 1, 1-dimethylethyl)-1 -methyl- 1H-benz imidazol-2-yl]carbonyl}-1-( trans-4- {1(1, 1-dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2-piperazinone
[00249] 4-{[4-bromo-6-(1 ,1-dimethylethyl)-1 -methyl- 1 H-benzimidazol-2-yl]carbonyl}-1- (trans-4-{[(1 ,1-dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2-piperazinone (130 mg, 0.215 mmol) was dissolved in 1 ,4-dioxane (1.5 ml_). Potassium phosphate tribasic (137 mg, 0.644 mmol), cyclopropylboronic acid (37 mg, 0.43 mmol), and PdCI2(dppf)-CH2CI2 adduct (18 mg, 0.021 mmol) were added and the mixture heated to 90 °C for 4 hours. The reaction was allowed to cool to room temperature and quenched with water. The mixture was extracted 2 times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by silica chromatography eluting with a gradient of 0% to 100% ethyl acetate in dichloromethane. Fractions were concentrated to give the title compound (60 mg; 49%). LCMS: m/z 567 (M+1 ).
Step B
4-{[4-cyclopropyl-6-( 1, 1-dimethylethyl)-1 -methyl- 1 H-benz imidazol-2-ylJcarbonyl}- 1 -( trans-4- hydroxycyclohexyl)-2-piperazinone
[00250] 4-{[4-cyclopropyl-6-(1 ,1-dimethylethyl)-1-methyl-1 H-benzimidazol-2-yl]carbonyl}- 1 -(trans-4-{[(1 ,1-dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2-piperazinone (55 mg, 0.097 mmol) was dissolved in dichloromethane (2 mL) and 4M hydrogen chloride in dioxane (1 mL) added. The mixture was stirred for 30 minutes and concentrated. The residue was dissolved in dichloromethane before hexanes were added. A precipitate formed and solids were collected by filtration. The product was washed with hexanes and air dried to give the title compound (25 mg, 57%) as a white solid. LCMS: m/z 453 (M+1 ). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.33 (s, 1 H), 6.94 - 7.06 (m, 1 H), 5.23 - 5.29 (m, 2 H), 4.49 (s, 1 H), 4.23 (s, 2 H), 3.96 - 4.07 (m, 1 H), 3.87 (d, 4 H), 3.38 (br. s., 2 H), 2.25 - 2.43 (m, 1 H), 1.79 - 1.95 (m, 2 H), 1.53 (br. s., 4 H), 1.34 (s, 9 H), 1.17 - 1.30 (m, 2 H), 1.08 - 1.17 (m, 2 H), 0.98 - 1.06 (m, 2 H).
Example 52
4-{[6-bromo-4-( 1, 1-dimethylethyl)-1-methyl-1H-b enzimidazol-2-yl]carbonyl}-1-( trans-4- hydroxycyclohexyl)-2-piperazinone
(Compound 52)
Figure imgf000127_0001
Step A
4-bromo-2-( 1, 1-dimethylethyl)aniline
[00251] 2-(1 ,1-dimethylethyl)aniline (5.22 ml_, 33.5 mmol) in tetrahydrofuran (100 ml_) was cooled to 5 °C before tetrabutylammonium tribromide (16.2 g, 33.5 mmol) was added portion-wise at a rate such that temperature did not rise significantly. The ice-water bath was removed and the reaction was allowed to warm to room temperature. The mixture was stirred for 0 minutes, was diluted with water, and was extracted 2 times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by silica chromatography eluting with 25% dichloromethane in hexanes. A significant portion of the material was accidentally spilled while loading the column. Fractions were concentrated to give the title compound (3.42 g, 45%) as an oil. LCMS: m/z 228, 230 (M+1 ).
Step B
[00252] 4-bromo-2-(1 ,1-dimethylethyl)aniline (3.4 g, 15 mmol) was dissolved in dichloromethane (100 mL) and N-chlorosuccinimide (2.0 g, 15 mmol) added portion-wise. The mixture was stirred for 3 hours at room temperature. 3Acetonitrile (100 mL) was added and the reaction flask heated in an oil bath at 80 °C. No reflux condenser was added so that the dichloromethane could slowly evaporate. The internal temperature reached about 65 °C and a reflux condenser was attached. The mixture was heated for 2 more hours. An additional 1 g of N-chlorosuccinimide was added slowly portion-wise at temperature and the mixture continued to heat overnight. The reaction was allowed to cool to room temperature and was concentrated to 75 mL of solvent. Brine was added and the mixture extracted 2 times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. The residue was purified by silica chromatography eluting with 35% dichloromethane in hexanes. Fractions were concentrated to give the title compound (3.13 g, 65% purity, 52%) as a redish oil. LCMS: m/z 262, 264, 266 (M+1).
Step C
5-bromo- 1-chloro- 3-(1, 1-dimethylethyl )-2-nitrobe nzene
[00253] 4-bromo-2-chloro-6-(1 ,1-dimethylethyl)aniline (2.4 g (65% by weight), 5.94 mmol) was dissolved in 1 ,2-dichloroethane (50 mL) and 3-chloroperoxybenzoic acid (3.99 g, 17.8 mmol) was added. The mixture was stirred at room temperature for 20 minutes and then heated at 50 °C for 20 minutes. The mixture was allowed to cool to room temperature, quenched with water, and extracted 2 times with dichloromethane. The combined organic layers were washed with saturated sodium bicarbonate, washed with aqueous sodium thiosulfate, washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by silica chromatography and fractions concentrated to give the title compound (2.4 g, 72% by weight, 99%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.71 (d, 1 H), 7.34 - 7.46 (m, 1 H), 1.50 - 1.61 (m, 9 H).
Step D
5-bromo-3- ( 1, 1-dimethylethyl)-N-methyl-2-nitroan iline
[00254] 5-bromo-1-chloro-3-(1 ,1-dimethylethyl)-2-nitrobenzene (2.4 g, 5.9 mmol) was dissolved in methylamine (2M in tetrahydrofuran) (15 ml, 30 mmol) and stirred at room temperature for 3 hours. The mixture was concentrated, the residue dissolved in
dichloromethane, and the solution passed through a silica plug eluting with dichloromethane. Fractions were concentrated to give the title compound (1.77 g, 99%). H NMR (400 MHz, CHLOROFORM-d) δ ppm 12.28 - 12.53 (m, 1 H), 6.95 (s, 1 H), 6.90 (d, 1 H), 2.87 (d, 3 H), 1.49 - 1.65 (m, 9 H).
Step E
[2-amino-5-bromo-3-( 1, 1 -dimethyl ethyl)phenyl]methylamine
[00255] A solution of 5-bromo-3-(1 ,1-dimethylethyl)-N-methyl-2-nitroaniline (810 mg, 2.82 mmol) in tetrahydrofuran (30 mL) was maintained with stirring at room temperature while sodium dithionate (5.81 g, 28.2 mmol) in water (30.0 mL) was added drop-wise by addition funnel. The mixture was maintained with vigorous stirring for 3 hours. The mixture was heated to 60 °C and solid sodium dithionate (5.81 g, 28.2 mmol) was added portion-wise. The reaction mixture was heated for 3 hours. The mixture was allowed to cool and was diluted with water before being extracted 3 times with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated to give the title compound (680 mg, 75%). LCMS: m/z 257, 259 (M+1).
Step F
[6-bromo-4-( 1, 1-dimethylethyl)-1-methyl-1H-benzimidazol-2-yl]methanol
[00256] [2-amino-5-bromo-3-(1 ,1-dimethylethyl)phenyl]methylamine (680 mg, 2.64 mmol) and glycolic acid (2.01 g, 26.4 mmol) were mixed and heated neat to 130 °C for 2 hours. The mixture was allowed to cool to room temperature and the solids triturated in a mixture of ethyl acetate and saturated sodium bicarbonate. Solids were filtered off. The filtrate was extracted 3 times with ethyl acetate. The combined organic layers were washed with saturated sodium bicarbonate, washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by silica chromatography eluting with a gradient of 0% to 10% methanol in
dichloromethane. Fractions were concentrated and the residue purified by reverse phase HPLC. Fractions were concentrated to give the title compound (150 mg, 19%). LCMS: m/z 297, 299 (M+1).
Step G
4-{[6-bromo-4-( 1, 1-dimethylethyl)-1-methyl-1H-benz imidazol-2-yl]carbonyl}- 1-(trans-4- hydroxycyclohexyl)-2-piperazinone
[00257] Sodium cyanide (124 mg, 2.52 mmol) and manganese dioxide (585 mg, 5.05 mmol) were added to methanol (3 mL) and the mixture cooled to 5 °C in an ice-bath. A solution of [6-bromo-4-(1 ,1-dimethylethyl)-1-methyl-1 H-benzimidazol-2-yl]methanol (150 mg, 0.505 mmol) in methanol (3 mL) was added quickly drop-wise. The reaction was allowed to warm to room temperature and stirred over the weekend. LC-MS showed ~7% starting material, 77% carboxylic acid, and 15% of the methyl ester. The reaction mixture was filtered through Celite®, the celite pad washed with methanol, and the filtrate concentrated. The residue was dissolved in N,N-dimethylformamide (3 mL) before 2,6-lutidine (1.2 mL, 10 mmol) and N,N- diisopropylethylamine (0.35 mL, 2.0 mmol) were added. 1-(frans-4-hydroxycyclohexyl)-2- piperazinone hydrochloride (130 mg, 0.55 mmol) was added followed by N- [(dimethylamino)(3H-[1 ,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylidene]-N-methylmethanaminium hexafluorophosphate (HATU) (230 mg, 0.606 mmol). The reaction mixture was stirred for 50 minutes and quenched with saturated sodium bicarbonate. The mixture was extracted 3 times with ethyl acetate. The combined organic layers were washed with saturated sodium bicarbonate, dried over sodium sulfate, and concentrated. The residue was purified by silica chromatography eluting with a gradient of 0% to 5% methanol in dichloromethane. Fractions were concentrated and the residue dissolved in dichloromethane. Hexanes were added and the mixture was concentrated. White solids were dried under vacuum to give the title compound (170 mg, 68%). LCMS: m/z 491 , 493 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.84 (dd, 1 H), 7.20 (d, 1 H), 4.58 (d, 1 H), 4.48 (s, 1 H), 4.25 (s, 1 H), 4.11 - 4.23 (m, 1 H), 4.03 (s, 2 H), 3.81 - 3.90 (m, 4 H), 3.35 - 3.44 (m, 2 H), 1.85 (br. s., 2 H), 1.43 - 1.59 (m, 13 H), 1.12 - 1.32 (m, 2 H).
Example 53
4-{[6-cyclopropyl-4-(1,1-dimethylethyl)-1-methyl-1H-benzimid^
4-hydroxycyclohexyl)-2-piperazinone
[00258] 4-{[6~bromo-4-(1 , 1 -dimethylethyl)-1 -methyl-1 H-benzimidazol-2-yl]carbonyl}-1 -
(trans-4-hydroxycyclohexyl)-2-piperazinone (48 mg, 0.098 mmol) was dissolved in 1 ,4-dioxane (1 ml_). Potassium phosphate tribasic (62.2 mg, 0.293 mmol), cyclopropylboronic acid (24 mg, 0.28 mmol), and PdCI2(dppf)-dichloromethane adduct (7.98 mg, 9.77 pmol) were added and the mixture heated to 90 °C for 2 hours. The reaction mixture was allowed to cool to room temperature, quenched with water, and extracted 3 times with ethyl acetate. The combined organic layers were washed with brine and concentrated. The residue was purified by reverse phase HPLC. Fractions were concentrated to give the title compound (29 mg, 66%). LCMS: m/z 453 (M+1). 1H NMR (DMSO- /6) δ ppm 7.12 (1 H, s), 6.92 (1 H, d), 4.59 (1 H, d), 4.53 (1 H, s), 4.23 (2 H, s), 4.08 (1 H, br. s.), 3.84 (4 H, s), 3.39 (3 H, d), 1.99 - 2.13 (1 H, m), 1.84 (2 H, br. s.), 1.43 - 1.58 (13 H, m), 1.24 (2 H, br. s.), 0.91 - .02 (2 H, m), 0.75 (2 H, d).
Example 54 4-[(4,6-dicyclopropyl-1,5-dimethyl-1H-benzimidazol-2-yl)carbonyl]-1-(trans-4- hydroxycyclohexyl)-2-piperazinone
Figure imgf000131_0001
Step A
(2,4-dibromo-3-methylphenyl)amine and (2,4-dibro mo-5-methylphenyl)amine (mixture of regioisomers)
[00259] To a mixture of 4-bromo-3-methylaniline (4.5 g, 24 mmol) in acetic acid (100 mL) at 5 °C was added N-bromosuccinimide (4.30 g, 24.19 mmol) portion-wise. The reaction mixture solidified after about half of the N-bromosuccinimide was added, so the mixture was allowed to warm to room temperature. The reaction mixture still contained solids, but the reaction mixture was much less viscous and stirred well. The remaining N-bromosuccinimide was added portion- wise and stirred at room temperature for 2 hours. The mixture was diluted with water and extracted 2 times with ether. The combined ether layers were washed with water, dried over sodium sulfate, and concentrated. The residue was purified by silica chromatography to give the title compounds (4.54 g, 71 %) as a mixture of regioisomers. LCMS: m/z 264, 266, 268 (M+1).
Step B
N-(2, 4-dibrom o-3-methyl phenyl) acetamide and N-(2, 4- dibromo-5-methylphenyl)acetamide
(mixture of regioisomers)
[00260] (mixture of regioisomers) (4.5 g, 17 mmol) was dissolved in acetic anhydride (30 ml, 320 mmol) and the mixture stirred at room temperature for 4 hours. White solids precipitated. Ethyl ether (100 mL) was added to the flask and solids were broken up with a spatula before being triturated for 30 minutes with a stir bar. Solids were collected by filtration, washed with ethyl ether, and air dried. Recovery was low, so the solids were combined with the filtrate and the filtrated concentrated to leave white solids. The solids were dried under vacuum to give the title compounds (5.2 g, 99%) as a mixture of regioisomers. LCMS: m/z 306, 308, 310 (M+1).
Step C
N-(2,4-dibromo-3-methyl-6-nitrophenyl)acetamide and N-(4,6-dibromo- 3-methyl-2- nitrophenyl )acetamide
[00261] Sulfuric acid (20 ml) was cooled to 5 °C before being added to N-(2,4-dibromo-3- methylphenyl)acetamide and N-(2,4-dibromo-5-methylphenyl)acetamide (mixture of regioisomers) (5.2 g, 17 mmol). The mixture was allowed to warm to room temperature in order to facilitate solvation. The mixture was cooled to 5 °C in an ice bath and nitric acid (70%) (2.5 ml) was added slowly drop-wise. The mixture was stirred at 5 °C for 1 hour and poured into ice. The ice mixture was diluted with water and the ice was allowed to melt. Solids were collected by filtration and washed with water. The residue was adsorbed onto silica gel by dissolving the residue in dichloromethane, adding silica gel, and concentrating. The adsorbed material was eluted onto a silica column that was eluted with a gradient of 30% to 50% ethyl acetate in hexanes. One set of fractions was concentrated to give pure /V-(4,6-dibromo-3-methyl-2- nitrophenyl)acetamide (1.0 g, 17%). LCMS: m/z 351 , 353, 355 (M+1). A second set of fractions was concentrated to give N-(2,4-dibromo-3-methyl-6-nitrophenyl)acetamide and N-(4,6- dibromo-3-methyl-2-nitrophenyl)acetamide (mixture of regioisomers) (1.07 g, 18%). LCMS: m/z 351 , 353, 355 (M+1). A third set of fractions contained a slight impurity and was concentrated to give additional N-(2,4-dibromo-3-methyl-6-nitrophenyl)acetamide and N-(4,6-dibromo-3-methyl- 2-nitrophenyl)acetamide (mixture of regioisomers) (0.90 g, 15%). LCMS: m/z 351 , 353, 355 (M+1).
Step D
(2,4-dibromo-3~methyl-6-nitrophenyl)amine
[00262] N-(2,4-dibromo-3-methyl-6-nitrophenyl)acetamide and N-(4,6-dibromo-3-methyl- 2-nitrophenyl)acetamide (mixture of regioisomers) (1.97 g, 5.60 mmol) were dissolved in sulfuric acid (8.95 ml, 168 mmol) and the solution heated to 100 °C for 3hour. The reaction was allowed to cool to room temperature and 1 mL of water was added carefully. The reaction was re-heated to 100 °C for 3 hours. The reaction was allowed to cool to room temperature before being poured into ice. The mixture was extracted 2 times with ethyl acetate and the combined organic layers washed with saturated sodium bicarbonate, washed with brine, and concentrated. The residue was purified by silica chromatography eluting with 35% dichloromethane in hexanes. One set of fractions was concentrated to give (4,6-dibromo-3-methyl-2-nitrophenyl)amine (0.37 g, 21 %). Confirmed by NMR. A second set of fractions was concentrated to give the title compound (590 mg, 34%). 1H NMR (400 MHz, DMSO-cfe)□ ppm 8.26 (s, 1 H), 7.34 (br. s., 2 H), 2.57 (s, 3 H).
Step E
2,4-dicyclopropyl-3-methyl-6-nitroaniline
[00263] (2,4-dibromo-3-methyl-6-nitrophenyl)amine (580 mg, 1.87 mmol) was dissolved in 1 ,4-dioxane (10 mL). Potassium phosphate tribasic (2.38 g, 11.2 mmol), cyclopropylboronic acid (643 mg, 7.49 mmol), and PdCI2(dppf)-CH2Cl2 adduct (306 mg, 0.374 mmol) were added and the mixture heated to 90 °C for 4 hours. The mixture was allowed to cool to room
temperature, quenched with water, and extracted 2 times with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by silica chromatography eluting with 50% dichloromethane in hexanes. Fractions were
concentrated to give the title compound (425 mg, 98%). LCMS: m/z 233 (M+1 ).
Step F
2-amino-3, 5-dicy clopropyl-4-methyl 'phenyl) amine
[00264] A solution of 2,4-dicyclopropyl-3-methyl-6-nitroaniline (425 mg, 1.83 mmol) in tetrahydrofuran (10 mL) was maintained with stirring at room temperature while sodium dithionate (3.77 g, 18.3 mmol) in water (10 mL) was added drop-wise by addition funnel. The mixture was maintained with vigorous stirring for several hours. No reaction was observed. The reaction vessel was heated to 65 °C and addtional sodium dithionate (3.77 g, 18.3 mmol) was added slowly portion-wise. The reaction mixture was heated for 16 hours. LC-MS showed minimal conversion. The mixture was allowed to cool to room temperature, quenched with water, and extracted 3 times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated. The residue was dissolved in acetic acid (10 mL) and hydrochloric acid (37%) (0.142 mL, 4.66 mmol) was added. The mixture was warmed to 60 °C and zinc powder (325 mg, 4.97 mmol) was carefully and slowly added portion-wise. The reaction mixture was stirred at temperature for 30 minutes and allowed to cool to room temperature. Excess zinc was filtered off over celite and the celite pad washed with ethanol. The filtrate was concentrated. Saturated sodium bicarbonate and ethyl acetate were added to the residue and mixed thoroughly with stirring. The mixture was extracted 3 times with ethyl acetate. The combined organic layers were washed with saturated sodium bicarbonate, washed with brine, dried over sodium sulfate, and concentrated to give the title compound (310 mg, 84% purity, 83%). LCMS: m/z 203 (M+1).
Step G
(4, 6-dicyclopropyl-5-methyl -1 H-benzimidazol-2-yl)methanol
[00265] Hydrochloric acid (6N, 3.1 mL) and water (2.1 mL) were added to (2-amino-3,5- dicyclopropyl-4-methylphenyl)amine (320 mg, 1.58 mmol). Glycolic acid (602 mg, 7.91 mmol) was added and the mixture heated at reflux for 3 hours. The reaction was allowed to cool to room temperature and carefully quenched with saturated sodium bicarbonate. The mixture was extracted 3 times with ethyl acetate and the combined organic layers washed with brine, dried over sodium sulfate, and concentrated to give the title compound (270 mg, 70%). LCMS: m/z 243 (M+1).
Step H
methyl 4,6-dicyclopropyl-5-methyl-1H-benzimidazole-2-carboxylate
[00266] Sodium cyanide (263 mg, 5.36 mmol) and manganese dioxide (1240 mg, 10.7 mmol) were added to methanol (5 mL) and the mixture cooled to 5 °C in an ice-bath. A solution of (4,6-dicyclopropyl-5-methyl-1 H-benzimidazol-2-yl)methanol (260 mg, 1.07 mmol) in methanol (10 mL) was added quickly drop-wise. The reaction was allowed to warm to room temperature and stirred overnight. The reaction mixture was filtered through Celite® and the filtrate concentrated. Water was added and the mixture extracted 3 times with ethyl acetate. The combined organic layers were washed with saturated sodium bicarbonate, washed with brine, dried over sodium sulfate, and concentrated to give the title compound (200 mg, 69%). LCMS: m/z 271 (M+1).
Step I
4-[(4, 6- dicyclopropyl-5-m ethyl- 1 H-benz imidazol-2-yl) carbon yl]- 1-( trans-4-hydroxycyclohexyl)-2- piperazinone
[00267] Methyl 4,6-dicyclopropyl-5-methyl-1 H-benzimidazole-2-carboxylate (200 mg, 0.74 mmol) was dissolved in tetrahydrofuran (5 mL) before water (5 mL) and 1 M sodium hydroxide (1.48 mL, 1.48 mmol) were added. The mixture was stirred for 1 hour and concentrated. The residue was dissolved in N,N-dimethylformamide (5 mL) before N,N- diisopropylethylamine (0.517 mL, 2.96 mmol) and 1-(fra/7s-4-hydroxycyclohexyl)-2-piperazinone hydrochloride (208 mg, 0.888 mmol) were added, followed by N-[(dimethylamino)(3H- [1 ,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylidene]-N-methylmethanaminium hexafluorophosphate (HATU) (309 mg, 0.814 mmol). The reaction was stirred for 2 hours and was quenched with water. The mixture was extracted 2 times with ethyl acetate. The combined organic layers were washed with 5% lithium chloride, washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by silica chromatography eluting with a gradient of 0% to 10% methanol in dichloromethane. Fractions were concentrated to give the title compound (167 mg, 45%) as a white powder. LCMS: m/z 437 (M+1).
Step J
4-[(4,6-dicyclopropyl-1,5-dimethyl-1H-benzimidazol-2-yl)carbonyl]-1-(trans-4- hydroxycyclohexyl)-2-piperazinone
[00268] 4-[(4,6-dicyclopropyl-5-methyl-1 H-benzimidazol-2-yl)carbonyl]-1-(trans-4- hydroxycyclohexyl)-2-piperazinone (167 mg, 0.383 mmol) was dissolved in N,N- dimethylformamide (5 mL) before potassium carbonate (159 mg, 1.15 mmol) was added followed by methyl iodide (0.048 mL, 0.77 mmol). The mixture was stirred at room temperature for 2 hours, quenched with water, and extracted 2 times with ethyl acetate. The combined organic layers were concentrated and the residue purified by silica chromatography eluting with a gradient of 0% to 5% methanol in dichloromethane. Fractions were concentrated. The residue was purified by reverse phase HPLC. Fractions were concentrated to give the title compound (90 mg, 52%). LCMS: m/z 451 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.05 - 7.18 (m, 1 H), 4.57 (d, 1 H), 4.52 (s, 1 H), 4.22 (s, 2 H), 4.05 (t, 1 H), 3.82 (s, 4 H), 3.34 - 3.44 (m, 3 H), 2.58 (s, 3 H), 1.97 - 2.10 (m, 2 H), 1.87 (d, 2 H), 1.48 - 1.62 (m, 4 H), 1.17 - 1.32 (m, 4 H), 0.91 - 1.05 (m, 4 H), 0.60 - 0.72 (m, 2 H)
Example 55
4-({6-cyclopropyl-1 -m ethyl-4-[(1 £)-1 -methyl-1 -propen-1 -y l]-1 H-benzimidazol-2- yl}carbonyl)-1-(ira/is-4-hydroxycyclohexyl)-2-piperazinone
(Compound 55)
Figure imgf000136_0001
Step A
tributyl[1-methyl~1-propen-1-yl]stannane (mixture of E and Z isomers)
[00269] Tributyl(chloro)stannane (2.89 ml, 10.7 mmol) was added to bromo[(1 E)-1- methyl-1-propen-1-yl]magnesium (0.5M in THF) (53.8 ml, 26.9 mmol) and the mixture stirred at reflux for 5 hours. The mixture was cooled to room temperature and quenched with saturated ammonium chloride. The organic phase was separated, washed with saturated sodium bicarbonate, washed with brine, dried over sodium sulfate, and concentrated. The residue was dissolved and passed through a silica plug eluting with ethyl ether. The filtrate was concentrated to give the title compound as a mixture of E and Z isomers. 1H NMR (CHLOROFORM-d) δ ppm 6.01 - 6.17 (m, 0.7 H (major isomer)), 5.55 - 5.67 (m, 0.3 H (minor isomer)), 1.78 - 1.93 (m, 3 H), 1.60 - 1.72 (m, 3 H), 1.37 - 1.56 (m, 6 H), 1.20 - 1.38 (m, 7 H), 0.77 - 0.96 (m, 14 H).
Step B
4-({6-cyclopropyl-1-methyl-4-[(1 E)-1-methyl-1- propen-1-yl]-1 H-benz imidazol-2-yl}carbonyl)-1- (trans-4-{[(1 , 1-dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2-piperazinone
[00270] 4-[(4-bromo-6-cyclopropyl-1-methyl-1 H-benzimidazol-2-yl)carbonyl]-1-(frans-4- {[(1 ,1-dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2-piperazinone (500 mg, 0.848 mmol), tributyl[1-methyl-1-propen-1-yl]stannane (mixture of E and Z isomers) (644 mg, 1.87 mmol), copper(l) bromide (12 mg, 0.085 mmol), and trans- benzyl(chloro)bis(triphenylphosphine)palladium (II) (64 mg, 0.085 mmol) in N,N- dimethylformamide (5 mL) were purged with nitrogen for 5 minutes and then heated to 100 °C for 16 hours. Additional trans-benzyl(chloro)bis(triphenylphosphine)palladium (II) (64 mg, 0.085 mmol) was added followed by tributyl[1-methyl-1-propen-1-yl]stannane (mixture of E and Z isomers) (644 mg, 1.87 mmol). The mixture was heated to 110 °C for 5 hours. The mixture was cooled to room temperature, quenched with brine, and extracted 2 times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by silica chromatography eluting with a gradient of 50% to 100% ethyl acetate in hexanes. Fractions were concentrated. The residue was purified and regioisomers separated by reverse phase HPLC. Fractions corresponding to the first eluting peak were concentrated to give the title compound (140 mg, 29%) as a white solid. LCMS: m/z 565 (M+1).
Step C
4-({6-cyclopropyl-1-methyl-4-[( 1E)-1 -methyl- 1- propen- 1-yl]- 1 H-benzimidazol-2-yl}carbonyl)- 1-
(trans-4-hydroxycyclohexyl)-2-piperazinone
[00271] 4-({6-cyclopropyl-1-methyl-4-[(1 E)-1-methyl-1-propen-1-yl]-1 H-benzimidazol-2- yl}carbonyl)-1-(trans-4-{[(1 ,1-dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2-piperazinone (75 mg, 0.13 mmol) was dissolved in 4M hydrogen chloride in dioxane (664 μΙ, 2.66 mmol) and stirred at room temperature for 15 minutes. The reaction was concentrated and the residue purified by silica chromatography. Fractions were concentrated. The residue was dissolved in 2 mL of dichloromethane. Hexanes were added slowly until crystals formed. The mixture was concentrated to 3 mL. 10 mL of hexanes were added and the mixture cooled to 5 °C in an ice bath. Solids were collected by filtration, washed with cold hexanes, and dried to give the title compound (40 mg, 67%). LCMS: m/z 451 (M+1). H NMR (400 MHz, DMSO-d6) δ ppm 7.21 (s, 1 H), 6.77 - 6.89 (m, 1 H), 5.65 (d, 1 H), 4.55 - 4.63 (m, 1 H), 4.51 (s, 1 H), 4.21 (s, 2 H), 4.03 (t, 1 H), 3.74 - 3.91 (m, 4 H), 3.33 - 3.39 (m, 3 H), 2.12 (br. s, 3 H), 2.07 (s, 1 H), 1.86 (d, 2 H), 1.45 - 1.61 (m, 7 H), 1.22 (d, 2 H), 0.94 - 1.04 (m, 2 H), 0.76 (d, 2 H).
Example 56
4-({6-cyclopropyl-1-methyl-4-[(1Z)-1-methyl-1-propen-1-yl]-1H-benzimidazol-2- yl} carbonyl)- 1 -( trans-4- hydroxycyclo hexyl)-2-pip erazinone
Figure imgf000137_0001
4-({6-cyclopropyl- 1 -methyl-4-[(1Z)- 1 -methyl- 1 -propen- 1-yl]- 1 H-benzimidazol-2-yl}carbonyl)- 1 - (trans-4-{[(1, 1-dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2-piperazinone
[00272] Fractions corresponding to the second peak in the reverse phase HPLC purification of step B in the example above were concentrated to give the title compound (83 mg, 17%). LCMS: m/z 565 (M+1).
Step B
4-({6-cyclopropyl-1-methyl-4-[( 1Z)- 1 -methyl- 1 -propen- 1-yl]- 1 H-benzimidazol-2-yl}carbonyl)- 1-
(trans-4-hydroxycyclohexyl)-2-piperazinone
[00273] 4-({6-cyclopropyl-1-methyl-4-[(1Z)-1-methyl-1-propen-1-y!]-1 H-benzimidazol-2- yl}carbonyl)-1-(trans-4-{t(1 ,1-dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2-piperazinone was further purified by reverse phase HPLC. Fractions were concentrated and the white solids dissolved in dichloromethane. 2M hydrogen chloride in diethyl ether (excess) was added and the mixture stirred at room temperature for 1 hour before being concentrated. The residue was purified by reverse phase HPLC. Fractions were concentrated to give the title compound (20 mg, 30%). LCMS: m/z 451 (M+1). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 6.91 - 7.08 (m, 2 H), 6.28 (d, 1 H), 4.85 (s, 1 H), 4.30 - 4.58 (m, 4 H), 3.90 - 4.05 (m, 4 H), 3.54 - 3.68 (m, 1 H), 3.48 (t, 1 H), 3.40 (t, 1 H), 2.24 (s, 3 H), 2.08 (dd, 3 H), 1.89 (d, 3 H), 1.78 (br. s., 2 H), 1.38 - 1.67 (m, 4 H), 0.96 - 1.09 (m, 2 H), 0.72 - 0.83 (m, 2 H).
Example 57
4-[(5 -dicyclopropyl-1,4-dimethyl-1H-benzimidazol-2-yl)carbonyl]-1-(trans-4- hydroxycyclohexyl)-2-piperazinone
Figure imgf000138_0001
Step A
N-(4, 6-dibrom o-3-methyl-2-nitrophenyl)acetamide [00274] Sulfuric acid (20 ml) was cooled to 5 °C before being added to N-(2,4-dibromo-3- methylphenyl)acetamide and N-(2,4-dibromo-5-methylphenyl)acetamide (mixture of regioisomers) (5.2 g, 17 mmol). The mixture was allowed to warm to room temperature in order to facilitate solvation. The mixture was cooled to 5 °C in an ice bath and nitric acid (70%) (2.5 ml) was added slowly drop-wise. The mixture was stirred at 5 °C for 1 hour and poured into ice. The ice mixture was diluted with water and the ice was allowed to melt. Solids were collected by filtration and washed with water. The residue was adsorbed onto silica gel by dissolving the residue in dichloromethane, adding silica gel, and concentrating. The adsorbed material was then eluted onto a silica column, which was then eluted with a gradient of 30% to 50% ethyl acetate in hexanes. One set of fractions was concentrated to give pure A/-(4,6-dibromo-3- methyl-2-nitrophenyl)acetamide (1.0 g, 17%). LCMS: m/z 351 , 353, 355 (M+1).
Step B
4, 6-dibromo-3-methyl-2-nitroanil ine
[00275] N-(4,6-dibromo-3-methyl-2-nitrophenyl)acetamide (1 g, 2.84 mmol) was dissolved in sulfuric acid (4.5 ml, 85 mmol) and the solution heated to 100 °C for 1 hour. The reaction was allowed to cool to room temperature, poured into ice, and a yellow solid precipitated. Water was added and the mixture extracted 2 times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated to give the title comound (725 mg, 82%). H NMR (400 MHz, DMSO-cfe) δ ppm 7.88 (s, 1 H), 6.01 (8, 2 H), 2.19 (s, 3 H).
Step C
(4, 6-dicyclopropyl-3-methyl -2-nitrophenyl)amine
[00276] 4,6-dibromo-3-methyl-2-nitroaniline (0.72 g, 2.3 mmol) was dissolved in 1 ,4- dioxane (2 ml_). Potassium phosphate tribasic (2.97 g, 14.0 mmol), cyclopropylboronic acid (0.80 g, 9.3 mmol), and PdCI2(dppf)- dichloromethane adduct (0.19 g, 0.23 mmol) were added and the mixture heated to 90 °C for 2 hours. The reaction was allowed to cool to room temperature and quenched with water. The mixture was extracted 2 times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by silica chromatography eluting with 40%
dichloromethane in hexanes. Fractions were concentrated to give the title compound (500 mg, 92%). LCMS: m/z 233 (M+1). Step D
4, 6-dicyclopropyl-3-methyl- 1, 2-benzenediamine
[00277] (4,6-dicyclopropyl-3-methyl-2-nitrophenyl)amine (500 mg, 2.15 mmol) was dissolved in tetrahydrofuran (10 ml). Triethylamine (1.2 ml, 8.6 mmol) and 10% palladium on carbon (degussa) (57 mg, 0.054 mmol) were added followed by drop-wise addition of formic acid (0.261 ml, 6.46 mmol). The mixture was heated at 65 °C for 16 hours, cooled to room temperature, and filtered through celite. The filtrate was diluted with ethyl acetate, washed with saturated sodium bicarbonate, dried over sodium sulfate, and concentrated to give the title compound (430 mg, 91%). LCMS: m/z 203 (M+1 ).
Step E
4-[(4, 6- dicyclopropyl- 7-m ethyl- 1 H-benz imidazol-2-yl)carbon yl]-1-(trans-4- hydroxycyclohexyl)-2- piperazinone
[00278] 4, 6-dicyclopropyl-3-methyl-1 , 2-benzenediamine (167 mg, 0.826 mmol) was dissolved in acetic acid (10 ml) before methyl 2,2,2-trichloromethylacetimidatate (0.146 ml, 1.16 mmol) was added drop-wise. The mixture was stirred at room temperature until the reaction was complete (~3 hours). The reaction was diluted with ethyl ether and then water added. The mixture was extracted 2 times with ethyl ether. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated. The residue was dissolved in acetonitrile (5 ml) before water (1.7 ml) was added. 1-(trans-4-hydroxycyclohexyl)-2-piperazinone
hydrochloride (370 mg, 1.58 mmol) was added followed by drop-wise addition of potassium carbonate (4M) (0.789 ml, 3.15 mmol). The mixture was stirred for 1 hour. LC-MS showed none of the amide product, but the 2-carboxylic acid was observed. The reaction was concentrated and N,N-dimethylformamide (3 mL) added to the residue. N,N- diisopropylethylamine (0.551 ml, 3.15 mmol) was added followed by N-[(dimethylamino)(3H- [1 ,2,3]triazolot4,5-b]pyridin-3-yloxy)methylidene]-N-methylmethanaminium hexafluorophosphate (HATU) (360 mg, 0.946 mmol). The mixture was stirred for 2 hours and quenched with brine. The mixture was extracted 3 times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by silica chromatography eluting with a gradient of 0% to 10% methanol in dichloromethane.
Fractions were concentrated to leave the title compound (62 mg, 18%) as a white solid. LCMS: m/z 437 (M+1).
Step F 4-[(5, 7-dicyclopropyl- 1, 4- dimethyl-1H-benz imidazol-2-yl)carbonyl]-1-(trans- 4- hydroxycyclohexyl)-2-piperazinone
[00279] 4-[(4,6-dicyclopropyl-7-methyl-1 H-benzimidazol-2-yl)carbonyl]-1 -(trans-4- hydroxycyclohexyl)-2-piperazinone (62 mg, 0.142 mmol) was dissolved in N,N- dimethylformamide (1 ml) before potassium carbonate (58.9 mg, 0.426 mmol) was added followed by methyl iodide (0.018 ml, 0.28 mmol). The mixture was stirred at room temperature for 2 hours, quenched with water, and extracted 2 times with ethyl acetate. The combined organic layers were concentrated and the residue purified by silica chromatography eluting with a gradient of 0% to 5% methanol in dichloromethane. Fractions were concentrated. The residue was purified by reverse phase HPLC to separate the regioisomers. Fractions were
concentrated to give the title compound (10 mg, 14%). LCMS: m/z 451 (M+1).
Example 58
4-[(4,6-dicyclopropyl-1 -dimethyl-1H-benzimidazol-2-yl)carbony!J-1-(trans-4- hydroxycyclohexyl)-2-piperazinone
Figure imgf000141_0001
[00280] Fractions corresponding to a second peak in the reverse phase HPLC purification of step F in Example 57 were concentrated to give the title compound (17 mg, 24%). LCMS: m/z 451 (M+1 ).
Example 59
4-[(4-amino-6-cyclopropyl-1-methyl-1H-benzimidazol-2-yf)carbonyl]-1-(trans-4- hydroxycyclohexyl)-2-piperazinone
(Compound 59)
Figure imgf000142_0001
[00281] 4-[(4-bromo-6-cyclopropyl-1 -methyl-1 H-benzimidazol-2-yl)carbonyl]-1 -(trans-4- {[(1 ,1-dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2-piperazinone (200 mg, 0.339 mmol) was dissolved in toluene (2 mL) and the reaction vessel purged with nitrogen before benzophenone imine (0.142 mL, 0.848 mmol), sodium tert-butoxide (52 mg, 0.54 mmol), BINAP (21 mg, 0.034 mmol), and tris(dibenzylideneacetone)dipalladium(0) (16 mg, 0.017 mmol) were added sequentially. The reaction vial was lowered into an oil bath that was pre-heated to 1 10 °C. The reaction was heated for 2 hours. The mixture was allowed to cool to room temperature, diluted with water, and extracted 2 times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium suflate, and concentrated. The residue was subject to a 1 :1 mixture of tetrahydrofuran / 1 hydrochloric acid and stirred at room temperature for 30 minutes. The reaction mixture was quenched with saturated sodium bicarbonate and extracted 2 times with ethyl acetate. The combined organic layers were washed with brine and concentrated. The residue was purified by silica chromatography eluting with a gradient of 0% to 10% methanol in dichloromethane. Fractions were concentrated to give the title compound (60 mg, 43%). LCMS: m/z 412 (M+1 ). H NMR (DMSO-d6) δ ppm 6.46 (1 H, d), 6.18 (1 H, d), 5.36 (2 H, d), 4.46 - 4.65 (2 H, m), 4.20 (2 H, s), 4.08 (1 H, br. s.), 3.80 - 3.86 (1 H, m), 3.28 - 3.43 (6 H, m), 1.88 (3 H, dd), 1.54 (4 H, br. s.), 1.24 (2 H, br. s.), 0.87 - 0.98 (2 H, m), 0.65 (2 H, dd).
Example 60
4-{[6-cyclopropyl-4-(dimethylamino)-1-methyl-1H-benzimidazol-2-yl]carbon
hydroxycyclohexyl)-2-piperazinone
(Compound 60)
Figure imgf000143_0001
Step A
4-{[6-cyclopropyl-4-(dimethylamino)- 1 -methyl- 1 H-benzimidazol-2-yl]carbonyl}- 1-(trans-4-{[( 1, 1- dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2-piperazinone
[00282] A solution of 4-[(4-bromo-6-cyclopropyl-1 -methyl- 1 H-benzimidazol-2-yl)carbonyl]- 1-(fra is-4-{[(1 ,1-dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2-piperazinone (83 mg, 0.14 mmol) in toluene (2 mL) was treated with dimethylamine (2M in tetrahydrofuran) (0.28 mL, 0.56 mmol), Pd2(dba)3 (13 mg, 0.014 mmol), cesium carbonate (92 mg, 0.28 mmol), and xantphos (12 mg, 0.021 mmol). The reaction was purged with nitrogen and then heated to 75 °C for 5 hours. An additional portion of dimethylamine (2M in tetrahydrofuran) (0.28 mL, 0.56 mmol) was added and the mixture allowed to heat overnight. Additional Pd2(dba)3 (13 mg, 0.014 mmol), xantphos (12 mg, 0.021 mmol), and dimethylamine (2M in tetrahydrofuran) (0.28 mL, 0.56 mmol) were added and the reaction continued to heat at 75 °C overnight. The mixture was allowed to cool to room temperature and was diluted with water. The mixture was extracted 3 times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by reverse phase HPLC. Fractions were concentrated to give the title compound (12 mg, 15%). LCMS: m/z 554 (M+1).
Step B
4-{[6-cyclopropyl-4-(dimethylamino)- 1 -methyl- 1 H -benzimidazol-2-yl]carbonyl}- 1 -(trans-4- hydroxycyclohexyl)-2-piperazinone
[00283] 4-{[6-cyclopropyl-4-(dimethylamino)-1 -methyl-1 H-benzimidazol-2-yl]carbonyl}-1 - (trans-4-{[(1 ,1-dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2-piperazinone (12 mg, 0.022 mmol) was dissolved in 1 M hydrogen chloride in ethyl ether (433 μΙ, 0.433 mmol) and stirred at room temperature for 15 minutes. The reaction was concentrated and dried under vacuum. The residue was purified by reverse phase HPLC. Fractions were concentrated to give the title compound (4 mg, 42%). LCMS: m/z 440 (M+1). H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.94 - 8.14 (m, 1 H), 6.53 (d, 1 H), 6.30 (d, 1 H), 4.91 (s, 1 H), 4.31 - 4.57 (m, 3 H), 3.89 - 4.05 (m, 4 H), 3.60 (br. s., 1 H), 3.32 - 3.53 (m, 2 H), 3.23 (d, 6 H), 1.97 - 2.13 (m, 3 H), 1.77 (br. s., 2 H), 1.36 - 1.66 (m, 4 H), 0.92 - 1.07 (m, 2 H), 0.71 - 0.83 (m, 2 H).
Example 61
1-cyclobutyl-4-{[6-cyclopropyM-methyl-4-(trifluoromethyl)-1H-benzto
yl]carbonyl}-5-ethyl-2-piperazinone
Figure imgf000144_0001
Step A
1, 1 -dimethyl ethyl {1-[(cyclobutylamino)carbonyl ]propyl}carbamate
[00284] To a solution of 2-({[(1 ,1-dimethylethyl)oxy]carbonyl}amino)butanoic acid (4.0 g, 20 mmol) in N,N-dimethylformamide (100 mL) was added cyclobutylamine (1.9 mL, 22 mmol), N,N-diisopropylethylamine (10.3 mL, 59.0 mmol), and N-[(dimethylamino)(3H-[1 ,2,3]triazolo[4,5- b]pyridin-3-yloxy)methylidene]-N-methylmethanaminium hexafluorophosphate (HATU) (8.23 g, 21.7 mmol). The mixture was stirred for 2 hours, quenched with water, and extracted 2 times with ethyl acetate. The combined organic layers were washed with brine, washed with 5% lithium chloride, dried over sodium sulfate and concentrated. The residue was slurried in ethyl ether, stirred for 30 minutes, and the solids collected by filtration. The product was purified by passing through a silica gel plug, eluting with 25% ethyl acetate in dichloromethane. Fractions were concentrated to give the title compound (3.1 g; 62%). 1H NMR (400 MHz, CHLOROFORM- d) 5 ppm 6.00 - 6.39 (m, 1 H), 4.85 - 5.19 (m, 1 H), 4.27 - 4.53 (m, 1 H), 3.78 - 4.03 (m, 1 H), 2.26 - 2.46 (m, 2 H), 1.78 - 1.96 (m, 3 H), 1.52 - 1.78 (m, 3 H), 1.45 (s, 9 H), 0.94 (t, 3 H).
Step B
1, 1 -dimethyl ethyl {1-[(cyclobutylamino)methyl]propyl}carbama te
[00285] To a 5 °C slurry of 1 ,1-dimethylethyl {1-[(cyclobutylamino)
carbonyl]propyl}carbamate (3.12 g, 12.17 mmol) in tetrahydrofuran (30.4 ml) and toluene (30.4 ml) was added Red-AI (11.1 ml, 36.5 mmol) slowly drop-wise. The mixture was allowed to warm to room temperature and then heated to 35 °C for 16 hours. The mixture was cooled in an ice-bath and carefully quenched with 5M sodium hydroxide, which was added at such a rate to keep internal temperature below 20 °C. The mixture was stirred for 20 minutes at room temperature before 30 mL of toluene was added. The layers were separated and the organic phase washed 2 times with 10 mL of 5M sodium hydroxide. The organic phase was dried over sodium sulfate and concentrated. The residue was purified by silica chromatography eluting with a gradient of 0% to 10% 2M ammonia/isopropanol in dichloromethane. Fractions were concentrated to give the title compound (1.7 g, 59%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 4.51 - 4.79 (m, 1 H), 3.94 - 4.16 (m, 1 H), 3.44 - 3.64 (m, 1 H), 3.14 - 3.32 (m, 1 H), 2.57 (d, 2 H), 2.20 (d, 2 H), 1.56 - 1.75 (m, 4 H), 1.47 - 1.56 (m, 2 H), 1.21 (d, 9 H), 0.92 (t, 3 H).
Step C
1, 1-dimethylethyl (1-{[(chloroacetyl)(cyclobutyl)amino]methyl}propyl)carbamate
[00286] A solution of 1 ,1-dimethylethyl {1-[(cyclobutylamino)methyl]propyl}carbamate (440 mg, 1.82 mmol) in ethyl acetate (5.0 mL) and 1 M sodium bicarbonate (5.0 mL, 5.0 mmol) was cooled to 5 °C in an ice bath before chloroacetyl chloride (0.22 mL, 2.7 mmol) was added. The mixture was slowly allowed to warm to room temperature, stirred for 3 hours, and then extracted 2 times with ethyl acetate. The combined organic layers were washed with saturated sodium bicarbonate, washed with brine, dried over sodium sulfate, and concentrated to give the title compound (530 mg, 92%) as a clear oil. MS (ESI) m/z = 319, 321 (MH+).
Step D
1, 1 -dimethyl ethyl 4-cyclobutyl-2-ethyl-5-oxo-1-piperazinecarboxylate
[00287] ,1-dimethylethyl (1-{[(chloroacetyl)(cyclobutyl)amino]methyl}propyl)carbamate (530 mg, 1.7 mmol) was dissolved in N,N-dimethylformamide (10 mL) and cooled to 5 °C in an ice bath before cesium carbonate (1.1 g, 3.3 mmol) was added. The mixture was allowed to warm to room temperature and stirred overnight. The mixture was quenched with water and extracted 3 times with ethyl acetate. The combined organic layers were washed with 5% lithium chloride, washed with brine, dried over sodium sulfate, and concentrated to give the title compound (430 mg, 91 %). MS (ESI) m/z = 283 (MH+).
Step E
1-cyclobutyl-5-ethyl-2-piperazinone trifluoroacetate T U 2011/023763
[00288] 1 ,1-dimethylethyl 4-cyclobutyl-2-ethyl-5-oxo-1-piperazinecarboxylate (430 mg, 1.52 mmol) was dissolved in dichloromethane (5 mL) before trifluoroacetic acid (5.00 mL) was added. The mixture was stirred for 3 hours and concentrated. The residue was co-evaporated 2 times with toluene to help remove any remaining trifluoroacetic acid. Concentration gave the title compound (490 mg, >99%). 1H N R (400 MHz, DMSO- /6) δ ppm 9.07 - 9.49 (m, 2 H), 4.71 - 4.94 (m, 1 H), 3.74 (s, 2 H), 3.63 (dd, 1 H), 3.39 - 3.55 (m, 1 H), 3.25 (dd, 1 H), 2.22 (dt, 2 H), 1.90 - 2.04 (m, 2 H), 1.56 - 1.80 (m, 4 H), 0.99 (t, 3 H).
Step F
1-cyclobutyl-4-{[6-cyclopropyl-1-methyl-4-(trifluoromethyl)-1H-benz imidazol-2-yl]carbonyl}-5- ethyl-2-piperaz inone
[00289] Methyl 6-cyclopropyl-1-methyl-4-(trifluoromethyl)-1H-benzimidazole-2- carboxylate (75 mg, 0.251 mmol) was dissolved in tetrahydrofuran (1 mL) before water (1 mL) and 1 M sodium hydroxide (0.302 mL, 0.302 mmol) were added. The mixture was stirred for 1 hour and concentrated. The residue was dissolved in N,N-dimethylformamide (1 mL) before N,N-diisopropylethylamine (0.220 mL, 1.26 mmol) and 1-cyclobutyl-5-ethyl-2-piperazinone trifluoroacetate (82 mg, 0.251 mmol) were added, followed by N-[(dimethylamino)(3H- [1 ,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylidene]-N-methylmethanaminium hexafluorophosphate (HATU) (115 mg, 0.302 mmol). The reaction mixture was stirred for 2 hours and quenched with water. The mixture was extracted 2 times with ethyl acetate. The combined organic layers were washed with 5% lithium chloride, washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by silica chromatography eluting with a gradient of 0% to 100% ethyl acetate in dichloromethane. Fractions were concentrated and the residue in a minimal amount of diethyl ether. Hexanes were added and the mixture concentrated to give the title compound (70 mg, 62%) as a white foam. LCMS: m/z 449 (M+1 ). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.67 (br. s., 1 H), 7.42 (d, 1 H), 4.82 - 5.00 (m, 1 H), 4.68 - 4.81 (m, 0.5 H), 4.45 - 4.66 (m, 1.5 H), 4.07 (d, 0.5 H), 3.89 (d, 3 H), 3.73 - 3.85 (m, 0.5 H), 3.45 - 3.61 (m, 2 H), 2.06 - 2.29 (m, 3 H), 1.91 - 2.06 (m, 2 H), 1.48 - 1.78 (m, 4 H), 1.00 - 1.08 (m, 2 H), 0.95 (t, 1 H), 0.78 - 0.91 (m, 4 H).
Example 62
(5R)-4-{[6-cyclopropyl-4-(1,1-dimethylethyl)-1-methyl-1 H-benzimidazol-2-yl]carbonyl}-1- (trans-4-hydroxycyclohexyl)-5-tnethyl-2-piperazinone
(Compound 62) 2011/023763
Figure imgf000147_0001
Step A
1, 1 -dimethyl ethyl {(1R)-2-[(trans-4-hydroxycyclohexyl)amino]-1-methyl-2-oxoethyl}carbamate
[00290] To a solution of Λ/-{[(1 ,1-dimethylethyl)oxy]carbonyl}-D-alanine (11.3 g, 59.5 mmol) in N,N-dimethylformamide (200 mL) was added trans-4-aminocyclohexanol hydrochloride (9.93 g, 65.5 mmol), N-ethyl-N-(1-methylethyl)-2-propanamine (41.6 mL, 238 mmol), and the mixture cooled to 5 °C in an ice bath. 1-propanephosphonic acid cyclic anhydride, 50 wt. % solution in ethyl acetate (53 mL, 89 mmol) was then added slowly drop-wise. The mixture was allowed to warm to room temperature and stirred overnight. The reaction was concentrated to 100 mL and diluted with saturated sodium bicarbonate. The aqueous phase was saturated with sodium chloride, extracted 2 times with ethyl acetate, and extracted 2 times with
dichloromethane. The combined organic layers were concentrated. The residue was slurried in dichloromethane (100 mL). White solids precipitated and were collected by filtration. Air drying gave the title compound (3.8 g, 22%). LCMS: m/z 287 (M+1). The filtrate was added to a silica column that was eluted with a gradient of 0% to 10% ethanol in dichloromethane. Fractions were concentrated to give additional title compound (3.8 g, 22%). LCMS: m/z 287. A second set of fractions were concentrated to give additional title compound (2.1 g, 12%). LCMS: m/z 287 (M+1)..
Step B
N1-(trans-4-{[(1, 1-dimethylethyl)(dimethyl)silyl]oxy}c^^ 1- dimethylethyl)oxy]carbonyl}-D-alaninamide
[00291] To a mixture of 1 ,1-dimethylethyl {(1 R)-2-[(trans-4-hydroxycyclohexyl)amino]-1- methyl-2-oxoethyr}carbamate (7.59 g, 26.5 mmol), imidazole (3.61 g, 53.0 mmol), and N,N- dimethyl-4-pyridinamine (0.324 g, 2.65 mmol) was added tert-butyldimethylchlorosilane (4.79 g, 31.8 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was quenched with saturated sodium bicarbonate and extracted 3 times with ethyl acetate. The 1 023763
combined organic layers were washed with 10% citric acid, washed with brine, dried over sodium sulfate, and concentrated to give the title compound (10.6 g, 99%). H NMR (DMSO-d6) δ ppm 7.43 - 7.65 (1 H, m), 6.64 - 6.90 (1 H, m), 3.81 - 3.95 (1 H, m), 3.53 - 3.65 (1 H, m), 3.39 - 3.52 (1 H, m), 1.65 - 1.86 (4 H, m), 1 .36 (9 H, s), 1 .15 - 1 .30 (4 H, m), 1.12 (3 H, d), 0.81 - 0.88 (9 H, m), 0.03 (6 H, s).
Step C
1, 1-dimethylethyl {(1R)-2-[(trans-4-{[(1, 1-dime thylethyl)(dimethyl)silyl]oxy}cyclohexyl)amino]- 1- methylethyl}carbamate
[00292] To a 5 °C slurry of N -(trans-4-{[(1 ,1-dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)- N2-{[(1 ,1-dimethylethyl)oxy]carbonyl}-D-alaninamide (10.62 g, 26.5 mmol) in tetrahydrofuran (65 ml) and toluene (65 ml) was added Red-AI (65% wt in toluene) (8.08 ml, 26.5 mmol) slowly drop-wise. The mixture was allowed to warm to room temperature and then heated to 40 °C for 16 hours. The mixture was cooled in an ice-bath and carefully quenched with 5M sodium hydroxide at such a rate as to keep the internal temperature below 20 °C. The mixture was stirred for 20 minutes at room temperature before 200 ml. of toluene was added. Layers were separated and the organic phase washed 2 times with 100 mL of 5M sodium hydroxide. The organic layer was dried over sodium sulfate and concentrated. The residue was purified by silica chromatography eluting with a gradient of 0% to 5% methanol in dichloromethane. Mixed fractions eluted first and were concentrated to give the title compound (3.9 g, 75% purity, 29%). A second set of fractions was concentrated to give additional title compound (2.6 g, 25%).
LCMS: m/z 387 (M+1 ).
Step D
1, 1-dimethylethyl (2R)-4-(trans-4-{[(1, 1-dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2-m
oxo- 1 -plperazinecarboxylate
[00293] A solution of 1 , 1-dimethylethyl {(1 R)-2-[(trans-4-{[(1 , 1- dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)amino]-1-methylethyl}carbamate (2.57 g, 6.65 mmol) in ethyl acetate (20 mL) and sodium bicarbonate (saturated) (20 mL) was cooled to 5 °C in an ice bath before chloroacetyl chloride (0.80 mL, 10 mmol) was added. The mixture was slowly allowed to warm to room temperature, stirred for 3 hours, and then extracted 2 times with ethyl acetate. The combined organic layers were washed with saturated sodium bicarbonate, washed with brine, dried over sodium sulfate, and concentrated to give a clear oil. The oil was dissolved in N,N-dimethylformamide (20 mL) and cooled 5 °C before cesium carbonate (4.33 g, 13.3 mmol) was added. The mixture was allowed to warm to room temperature and stirred overnight. Additional cesium carbonate (4.33 g, 13.3 mmol) was added and the mixture heated to 45 °C for 2 hours. The mixture was allowed to cool to room temperature and was quenched with water. The mixture was extracted 2 times with ethyl acetate and the combined organic layers dried over sodium sulfate before being concentrated to give the title compound (2.3 g, 85% purity, 70%) as a white solid. LC S: m/z 427 (M+1).
Step E
(5R)-1-(trans-4-hydroxycycl ohexyl)-5-methyl-2-piperaz inone hydrochloride
[00294] Hydrogen chloride (4M in dioxane) (20 mL, 80 mmol) was added to 1 ,1- dimethylethyl (2R)-4-(trans-4-{[(1 ,1-dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2-methyl-5-oxo- 1-piperazinecarboxylate (2.2 g, 5.2 mmol), which dissolved completely before white solids precipitated after a few minutes of stirring. Methanol was added until solids dissolved. The mixture was stirred for 1 hour, concentrated, and dried to give (5Ry -(trans-4- hydroxycyclohexyl)-5-methyl-2-piperazinone hydrochloride (1.78 g, 70% purity, 97%).
Step F
(5R)-4-{[6-cyclopropyl-4-(1 , 1-dimethylethyl)-1-methyl-1H-benzimidazol-2-yl]carbonyl}-1- (trans-4^ hydroxycyclohexyl)-5-methyl-2-piperazinone
[00295] Methyl 6-cyclopropyl-4-( ,1-dimethylethyl)-1-methyl-1 H-benzimidazole-2- carboxylate (56.4 mg, 0.197 mmol) was dissolved in tetrahydrofuran (1 mL). Water (1 mL) was added followed by 1 M sodium hydroxide (0.236 mL, 0.236 mmol). The mixture was stirred for 30 minutes at room temperature and concentrated. The residue was co-evaporated 1 time with toluene and slurried in N,N-dimethylformamide (2 mL). N,N-diisopropylethylamine (0.172 mL, 0.985 mmol), (5R)-1-(fraA?s-4-hydroxycyclohexyl)-5-methyl-2-piperazinone hydrochloride (70 mg, 70% purity, 0.197 mmol), and N-[(dimethylamino)(3H-[1 ,2,3]triazolo[4,5-b]pyridin-3- yloxy)methylidene]-N-methylmethanaminium hexafluorophosphate (HATU) (90 mg, 0.236 mmol) were added sequentially. The mixture was stirred for 2 hours, quenched with brine, and extracted 3 times with ethyl acetate. The combined organic layers were washed with 5% lithium chloride, washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by silica chromatography eluting with a gradient 0% to 10% ethanol in dichloromethane. Fractions were concentrated and the residue purified by reverse phase HPLC. Fractions were concentrated to give the title compound (25 mg, 25%). LCMS: m/z 467 (M+1). 1H NMR (400 MHz, DMSO-c/6) δ ppm 7.12 (s, 1 H), 6.93 (d, 1 H), 4.73 - 4.91 (m, 1 H), 4.44 - 4.73 (m, 2 H), 4.10 - 4.36 (m, 2 H), 3.76 - 3.93 (m, 4 H), 3.41 - 3.56 (m, 1 H), 3.16 - 3.30 (m, 1 H), 1.99 - 2.13 (m, 1 H), 1.78 - 1.94 (m, 2 H), 1.51 (s, 13 H), 1.15 - 1.37 (m, 5 H), 0.97 (dd, 2 H), 0.75 (d, 2 H).
Example 63
(5R)-4-{[6-(dim ethylamino) -1-m ethyl-4-(trifluo romethyl)-1H-ben zimidazol-2-yl]carbonyl}-1- (trans-4-hydroxycyclohexyl)-5-methyl-2-piperazinone
(Compound 63)
Figure imgf000150_0001
Step A
4-bromo-2-chloro-6-(trifluoromethyl)aniline
[00296] 4-bromo-2-(trifluoromethyl)aniline (12.2 g, 50.8 mmol) was dissolved in acetonitrile (200 mL) before N-chlorosuccinimide (7.47 g, 55.9 mmol) was added and the mixture heated to 80 °C. The reaction was stirred for 2 hours and allowed to cool to room temperature. The reaction mixture was quenched with water and extracted 3 times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated. The residue passed through a silica plug eluting with dichloromethane. The filtrate was concentrated to give the title compound (13.1 g, 94%) as a liquid. H NMR (400 MHz, DMSO- /6) δ ppm 7.78 (d, 1 H), 7.52 (d, 1 H), 5.92 (s, 2 H).
Step B
5-bromo-1-chloro-2-nitro-3-(trifluoromethyl)benzene
[00297] 4-bromo-2-chloro-6-(trifluoromethyl)aniline (1 1 .5 g, 41.9 mmol) was dissolved in 1 ,2-dichloroethane (DCE) (300 mL) and 3-chloroperoxybenzoic acid (28.2 g, 126 mmol) was added. The mixture was stirred at room temperature for 20 minutes and then heated at 50 °C overnight. The mixture was allowed to cool to room temperature, quenched with water, and extracted 2 times with dichloromethane. The combined organic layers were washed with saturated sodium bicarbonate, washed with aqueous sodium thiosulfate, washed with brine, dried over sodium sulfate, and concentrated. The residue was passed through a silica plug with dichloromethane. Fractions were concentrated to give the title compound (10.5 g, 61 %). 1H NMR (400 MHz, DMSO-tf6) δ ppm 8.47 (d, 1 H), 8.32 (d, 1 H).
Step C
5-bromo-N-methyl-2-nitro-3-(trifluoromethyl)aniline
[00298] 5-bromo-1-chloro-2-nitro-3-(trifluoromethyl)benzene (10.3 g, 24.9 mmol) was dissolved in tetrahydrofuran (100 mL) and methylamine (2M in tetrahydrofuran) (27.4 mL, 54.8 mmol) was added. The mixture was stirred at room temperature until LC-MS indicated a complete reaction. The mixture was diluted with water and extracted 2 times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by silica chromatography eluting with 50%
dichloromethane and hexanes. Fractions were concentrated to give the title compound (3.8 g, 51 %). 1H NMR (400 MHz, DMSO-c/6) δ ppm 11.56 (br. s., 1 H), 7.69 (d, 1 H), 7.39 (d, 1 H), 2.92 (d, 3 H).
Step D
[5-(dimethylamino)-2-nitro-3-(trifluoromethyl)phenyl]m
[00299] 5-bromo-N-methyl-2-nitro-3-(trifluoromethyl)aniline (820 mg, 2.74 mmol) was dissolved in tetrahydrofuran (5 mL) and 2M dimethylamine in tetrahydrofuran (4.11 mL, 8.23 mmol) was added. The mixture was stirred for 4 hours. Additional 2 M dimethylamine in tetrahydrofuran (4.11 mL, 8.23 mmol) was added and the reaction stirred overnight at room temperature. The mixture was quenched with saturated sodium bicarbonate and extracted 3 times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated to give the title compound (760 mg, 99%). 1H NMR (400 MHz, DMSO-c¾) δ ppm 11.58 - 11.82 (m, 1 H), 6.87 (d, 1 H), 5.69 (d, 1 H), 3.20 (s, 6 H), 2.85 (d, 3 H).
Step E
[2-amino-5-(dimethylamino)-3-(trifluoromethyl)phenyl]methylam
[00300] [5-(dimethylamino)-2-nitro-3-(trifluoromethyl)phenyl]methylamine (300 mg, 1.08 mmol) was dissolved in tetrahydrofuran (5 ml). Triethylamine (0.604 ml, 4.33 mmol) and 10% palladium on carbon (degussa) (30 mg, 0.028 mmol) were added followed by drop-wise addition of formic acid (0.131 ml, 3.25 mmol). The mixture was heated at 65 °C for 3 hours. The mixture was allowed to cool before being filtered through Celite®. The filtrate was concentrated to give the title compound (250 mg, 99%). LCMS: m/z 234 (M+1).
Step F
methyl 6-(dimethylamino)-1-methyl-4-(trifluoromethyl)-1H-benz imidazole^
[00301] [2-amino-5-(dimethylamino)-3-(trifluoromethyl)phenyl]methylamine (250 mg, 1.07 mmol) was dissolved in 1 ,2-dichloroethane (20 mL). N,N-diisopropylethylamine (1.12 mL, 6.43 mmol), methyl dichloro(methyloxy)acetate (0.41 mL, 3.2 mmol), and 4-dimethylaminopyridine (13.1 mg, 0.107 mmol) were added sequentially before the mixture heated to 75 °C overnight. The reaction was allowed to cool to room temperature and was quenched with water. The mixture was extracted 2 times with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by silica chromatography eluting with a gradient of 0% to 5% ethyl acetate in dichloromethane. Fractions were concentrated to give the title compound (52 mg, 16%). LCMS: m/z 302 (M+1).
Step G
(5R)-4-{[6-(dimethylamino)-1-methyl-4-(tnfluoromethyl)-1H-ben
4-hydroxycyclohexyl)-5-methyl-2-piperazinone
[00302] Methyl 6-(dimethylamino)-1-methyl-4-(trifluoromethyl)-1H-benzimidazole-2- carboxylate (46 mg, 0.15 mmol) was dissolved in tetrahydrofuran (1 mL). Water (1 mL) was added followed by 1 M sodium hydroxide (0.183 mL, 0.183 mmol). The mixture was stirred for 30 minutes, concentrated, and the residue co-evaporated 1 time with toluene. The residue was slurried in N,N-dimethylformamide (2 mL). N,N-diisopropylethylamine (0.107 mL, 0.611 mmol), (5f?)-1-(fra 7s-4-hydroxycyclohexyl)-5-methyl-2-piperazinone hydrochloride (81 mg, 0.229 mmol), and N-[(dimethylamino)(3H-[1 ,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylidene]-N- methylmethanaminium hexafluorophosphate (HATU) (69.7 mg, 0.183 mmol) were added sequentially. The mixture was stirred for 2 hours, quenched with brine, and extracted 3 times with ethyl acetate. The combined organic layers were washed with 5% lithium chloride, washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by reverse phase HPLC. Fractions were concentrated to give the title compound (27 mg, 37%). LCMS: m/z 482 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.10 (d, 1 H), 6.97 - 7.07 (m, 1 H), 4.69 - T/US2011/023763
4.83 (m, 1 H), 4.40 - 4.68 (m, 1.5 H), 4.13 - 4.36 (m, 1.5 H), 3.85 (d, 3 H), 3.17 - 3.55 (m, 4 H), 3.03 (s, 6 H), 1.78 - 1.95 (m, 2 H), 1.37 - 1.65 (m, 4 H), 1.24 (dd, 5 H).
Example 64
(5R)-4-{[6-cyclopropyl-1-methyl-4-(trifluoromethyl)-1H-benzimidazol-2-yl]
(trans-4-hydroxycyclohexyl)-5-methyl-2-piperazinone
(Compound 64)
Figure imgf000153_0001
[00303] Methyl 6-cyclopropyl-1-methyl-4-(trifluoromethyl)-1 f -benzimidazole-2- carboxylate (105 mg, 0.352 mmol) was dissolved in tetrahydrofuran (2 mL). Water (2 mL) was added followed by 1M sodium hydroxide (0.422 mL, 0.422 mmol). The mixture was stirred for 30 minutes, concentrated, and the residue co-evaporated 1 time with toluene. The residue was slurried in N,N-dimethylformamide (4 mL). N,N-diisopropylethylamine (0.307 mL, 1.76 mmol), (5f?)-1-(fra/?s-4-hydroxycyclohexyl)-5-methyl-2-piperazinone hydrochloride (125 mg, 0.352 mmol), and N-[(dimethylamino)(3H-[1 ,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylidene]-N- methylmethanaminium hexafluorophosphate (HATU) (161 mg, 0.422 mmol) were added sequentially. The mixture was stirred for 2 hours, quenched with brine, and extracted 3 times with ethyl acetate. The combined organic layers were washed with 5% lithium chloride, washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by reverse phase HPLC. Fractions were concentrated to give the title compound (89 mg, 53%). LC S: m/z 479 (M+1). 1H NMR (400 MHz, DMSO-c 6) δ ppm 7.66 (s, 1 H), 7.42 (br. s., 1 H), 4.55 - 4.80 (m, 2 H), 4.43 - 4.55 (m, 1 H), 4.19 (s, 2 H), 3.81 - 3.94 (m, 4 H), 3.42 - 3.59 (m, 1 H), 3.13 - 3.29 (m, 1 H), 2.19 (s, 1 H), 1.85 (br. s., 2 H), 1.53 (br. s., 4 H), 1.24 (t, 5 H), 1.04 (dd, 2 H), 0.84 (d, 2 H).
Example 65
4-{[6-(dimethylamino)-1-methyl-4-(trifluoromethyl)-1H-benzimidazo (trans-4-hydroxycyclohexyl)-2-piperazinone
Figure imgf000154_0001
[00304] Methyl 6-(dimethylamino)-1 -methyl-4-(trifluoromethyl)-1 H-benzimidazole-2- carboxylate (60 mg, 0.119 mmol) was dissolved in tetrahydrofuran (1 mL). Water (1 mL) was added followed by 1M sodium hydroxide (0.143 mL, 0.143 mmol). The mixture was stirred for 30 minutes, concentrated, and the residue co-evaporated 1 time with toluene. The residue was slurried in N,N-dimethylformamide (2 mL). N,N-diisopropylethylamine (0.083 mL, 0.478 mmol), 1-(trans-4-hydroxycyclohexyl)-2-piperazinone hydrochloride (33.7 mg, 0.143 mmol), and N- [(dimethylamino)(3H-[1 ,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylidene]-N-methylmethanaminium hexafluorophosphate (HATU) (54.5 mg, 0.143 mmol) were added sequentially. The mixture was stirred for 2 hours, quenched with brine, and extracted 3 times with ethyl acetate. The combined organic layers were washed with 5% lithium chloride, washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by reverse phase HPLC. Fractions were concentrated to give the title compound (35 mg, 63%). LCMS: m/z 468 (M+1). 1H NMR (400 MHz, DMSO-de) δ ppm 7.07 - 7.15 (m, 1 H), 6.97 - 7.07 (m, 1 H), 4.49 (s, 1 H), 4.22 (s, 2 H), 4.00 - 4.11 (m, 1 H), 3.87 (s, 3 H), 3.80 - 3.85 (m, 1 H), 3.39 - 3.57 (m, 4 H), 3.03 (s, 6 H), 1.80 - 1.91 (m, 2 H), 1.53 (br. s., 4 H), 1.14 - 1.32 (m, 2 H).
Example 66
4-{[6-cyclo propyl- 1-methyl-4-( 1, 3-oxazo l-5-yl)- 1H-ben zimidazol-2-yl]carbonyl}- 1-( trans-4- hydroxycyclohexyl)- 2-piperazinon e
(Compound 66)
Figure imgf000155_0001
Step A
4-({6-cyclopropyl-1-methyl-4-[(1E/Z)-1^ropen-1-yl]-1H-benzimid^^
{[(1, 1-dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2-piperazinone
[00305] 4-[(4-bromo-6-cyclopropyl-1-methyl-1W-benzimidazol-2-yl)carbonyl]-1-(irans-4- {[(1 ,1-dimethylethyl)(dimethy!)silyl]oxy}cyclohexyl)-2-piperazinone (460 mg, 0.78 mmol), tributyl[(1Z)-1-propen-1-yl]stannane (387 mg, 1.17 mmol) and copper(l) iodide (8.9 mg, 0.047 mmol) in toluene (5 mL) were degassed with nitrogen for 5 minutes.
Bis(triphenylphosphine)palladium(ll) chloride (27 mg, 0.039 mmol) was added and the mixture heated to 100 °C overnight. Additional tributyl[(1Z)-1-propen-1-yl]stannane (387 mg, 1.17 mmol), copper(l) iodide (8.9 mg, 0.047 mmol), and bis(triphenylphosphine)palladium(ll) chloride (27 mg, 0.039 mmol) were added and the reaction mixture continued to heat overnight. The reaction was allowed to cool to room temperature and was filtered through a pad of celite. The filtrate was concentrated and the residue purified by silica chromatography eluting with a gradient of 0% to 5% ethanol in dichloromethane. Fractions were concentrated to give the title compound (365 mg, 70%). LCMS: m/z 551 (M+1).
Step B
6-cyclopropyl-2-{[4~(trans-4-{[(1, 1-dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-3-oxo-1- piperazinyl]carbonyl}-1-methyl-1H-benzimidazole-4-carbaldehyde
[00306] To a stirring mixture of 4-({6-cyclopropyl-1-methyl-4-[(1 E/Z)-1-propen-1-yl]-1 H- benzimidazol-2-yl}carbonyl)-1 -(trans-4-{[(1 , 1 -dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2- piperazinone (130 mg, 0.24 mmol) in tetrahydrofuran (1 mL) and water (1.000 mL) was added osmium tetroxide (0.059 mL, 4.7 pmol) followed by sodium periodate (126 mg, 0.590 mmol). The mixture was stirred for 6 hours, diluted with water, and extracted 2 times with ethyl acetate. The combined organic layers were washed with water, washed with brine, dried over sodium sulfate, and concentrated to give the title compound. Yield not recorded and entire sample carried into the next step. LCMS: m/z 539 (M+1).
Step C
4-{[6-cyclopropyl-1-methyl-4-(1,3-oxazol-5-yl)-1H-benzimidazo
hydroxycyclohexyl)-2-piperazinone
[00307] 6-cyclopropyl-2-{[4-(trans-4-{[(1 , 1 -dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-3- oxo-1-piperazinyl]carbonyl}-1-methyl-1 H-benzimidazole-4-carbaldehyde (127 mg, 0.236 mmol) was dissolved in methanol (3 mL) before potassium carbonate (48.9 mg, 0.354 mmol) and isocyanomethyl 4-methylphenyl sulfone (TOSMIC) (50.6 mg, 0.259 mmol) were added. The mixture was stirred for 1 hour, concentrated to 1 mL, and diluted with dichloromethane. The organic phase was washed 2 times with water, washed 2 times with brine, dried over sodium sulfate, and concentrated. The residue was dissolved in 4 mL of dichloromethane and 4 mL of trifluoroacetic acid was added. The mixture was stirred for 2 hours and concentrated. The residue was purified by reverse phase HPLC. Fractions were concentrated to give the title compound (25 mg, 23%). LCMS: m/z 464 (M+1). 1H NMR (400 MHz, DMSO-cfe) δ ppm 8.53 (s, 1 H), 7.92 - 8.09 (m, 1 H), 7.31 - 7.51 (m, 2 H), 4.54 - 4.70 (m, 2 H), 4.25 (s, 2 H), 4.11 (t, 1 H), 3.92 (d, 3 H), 3.86 (t, 1 H), 3.36 - 3.48 (m, 3 H), 2.12 - 2.25 (m, 1 H), 1.80 - 1.96 (m, 2 H), 1.45 - 1.63 (m, 4 H), 1.18 - 1.32 (m, 2 H), 0.99 - 1.09 (m, 2 H), 0.77 - 0.90 (m, 2 H).
Example 67
1-cyclobutyl-4-{[6-(3 uranyl)-1- ethyl-4-(trifluoromethyl)-1H-benzimidazol-2^
2-piperazinone
Figure imgf000156_0001
Step A
1, 1 -dimethyl ethyl (2-bromoethyl)carbamate
[00308] A solution of (2-bromoethyl)amine hydrobromide (30.0 g 0.146 mol), (Boc)20 (32.0 g, 0.146 mol), and triethylamine (61.0 mL, 0.439 mol) in THF (200 mL) was stirred at room temperature overnight. After removal of the organic solvent, H20 (200 mL) was added and the mixture extracted with ethyl acetate (200 mL x 3). The combined organic solutions were washed with 1 N aq. HCI (100 mL), brine (200 mL x 2), H20 (200 mL x 2) and then dried over anhydrous Na2S0 . Removal of the solvent gave the title compound (30 g, 91%).
Step B
1, 1 -dimethyl ethyl [2-(cyclobutylamino)ethyl] 'carbamate
[00309] A solution of cyclobutanamine (5.4 mL, 0.064 mol), 1 ,1-dimethylethyl (2- bromoethyl)carbamate (12 g, 0.054 mol) and potassium carbonate (14.8 g, 0.107 mol) in DMF (120 mL) was heated at 100 °C for 1 nr. The reaction mixture was diluted with ethyl acetate (500 mL) and then washed with brine (200 mL x 2) and H20 (200 mL x 2). The organic solution was dried over anhydrous Na2S04. After the removal of the solvent, the crude product purified with silica chromatography eluting with a gradient of 1 :1 ethyl acetate/petroleum ether to ethyl acetate to give the title compound (3.6 g, 31 %). LCMS: m/z 215 (M+1).
Step C
1 , 1 -dimethyl ethyl {2-[(chloroacetyl)(cyclobuty l)amino]ethyl}carbamate
[00310] To a solution of 1 ,1-dimethylethyl [2-(cyclobutylamino)ethyl]carbamate (400 mg, 1.87 mmol) and triethylamine (285 mg, 2.80 mmol) in dichloromethane (5 mL) was added chloroacetyl chloride (232 mg; 2.05 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 30 min. After the addition of H20 (20 mL), the solution was extracted with ethyl acetate (20 mL x 3). The combined organic solutions were washed with brine (20 mL x 2), H20 (20 mL x 2) and then dried over anhydrous Na2S04. After the removal of the solvent, the crude product was purified with silica chromatography eluting with a gradient of 1 :5 to 1 :3 ethyl acetate/petroleum ether to give the title compound (342 mg; 63%). LCMS: m/z 291 (100%), 293 (32%) (M+1).
Step D
1, 1 -dimethyl ethyl 4-cyclobutyl-3-oxo- 1-piperazinecarboxylate
[00311] To a solution of 1 ,1-dimethylethyl {2-[(chloroacetyl)(cyclobutyl)amino] ethyljcarbamate (4.3 g, 0.015mol) in DMF (50 mL) was added NaH (60% in mineral oil, 1.1 g, 0.044 mol) at 0 °C. The reaction mixture was stirred at room temperature for 30 min. The reaction mixture was poured into ice/water (100 mL) and then extracted with ethyl acetate (150 mL x 3). The combined organic solutions were washed with brine (200 mL x 2), H20 (200 mL x 2) and then dried over anhydrous Na2S04. After the removal of the solvent, the crude product was purified with silica chromatography eluting with 1 :2 ethyl acetate/petroleum ether to give the title compound (2.8 g, 76%). LCMS: m/z 255 (M+1 ).
Step E
1 -cyclobutyl-2-piperaz inone
[00312] To a solution of 1 ,1-dimethylethyl 4-cyclobutyl-3-oxo-1-piperazinecarboxylate (1.5 g, 7.9 mmol) in dioxane (200 mL) was added 2N HCI in dioxane solution (20 mL) at room temperature. The reaction solution was stirred at room temperature for 3 hr. After the addition of sat. NaHC03 (aq. 100 mL), the organic solvent was removed under vacuum. The aqueous solution was extracted with ethyl acetate ( 50 mL x 2). The combined organic solutions were washed with brine (100 mL x 2), H20 (100 mL x 2) and then dried over anhydrous Na2S04. Removal of solvent, gave the title compound (0.80 g, 66%). LCMS: m/z 154 (M+1 ).
Step F
N-[4-bromo-2-(tri†luoromethyl)phenyl]acetamide
[00313] To a solution of 4-bromo-2-(trifluoromethyl)aniline (5.00 g, 20.8 mmol) in chloroform (60 mL) was added acetyl chloride (2.45 g, 31 .2 mmol) dropwise at 0 °C. The mixture was stirred at room temperature overnight. The reaction solution was quenched with sat. NaHC03 (80 mL) and then extracted with dichloromethane (100 mL x 2). The combined organic solutions were washed with brine (100 mL x 2), H20 (100 mL x 2) and then dried over anhydrous Na2S0 . Removal of the solvent gave the title compound (5.68 g, 97%). LCMS; m/z 282, 284 (M+1 ).
Step G
N-[4-bromo-2-nitro-6- (trifluoromethyl)phenyl ]acetamide
[00314] To a solution of A/-[4-bromo-2-(trifluoromethyl)phenyl]acetamide (15.0 g, 53.1 mmol) in cone. H2S04 (65 mL) was added cone. HN03 (7.5 mL) dropwise at 0 °C. The reaction mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into ice water (100 mL) and the precipitate was filtered off. The solid was washed with diethyl ether (300 mL) and dried under vacuum to give the title compound (10.2 g, 59%). LCMS: m/z 327, 329 (M+1 ).
Step H 4-bromo-2-nitro-6-(trifluoromethyl)aniline
[00315] A solution of /V-(4-bromo-2-nitro-6-(trifluoromethyl)phenyl)acetamide (7.30 g, 22.5 mmol) in cone. HCI (100 mL) was heated at 110 °C overnight. The reaction mixture was basified with sat. NaHC03 (aq.) to pH=10 and then extracted with ethyl acetate (300 mL x 3). The combined organic solutions were washed with brine (300 mL x 2), H20 (300 mL x 2) and then dried over anhydrous Na2S04. Removal of solvent afforded the title compound (6.0 g, 94%). LCMS: m/z 285, 287 ( +1).
Step I
[2-amino-4-bromo-6-(trifluoromethyl)phenyl]ami ne
[00316] A solution of 4-bromo-2-nitro-6-(trifluoromethyl)aniline (5.50 g, 19.3 mmol) and tin (II) chloride dihydrate ( 23.5 g, 104 mmol) in ethyl acetate/ethanol (50 mL/25 mL) was heated at 70 °C for 2 hr. After the reaction solution was cooled to room temperature, it was poured into ice water (200 mL). The aqueous solution was basified with sat. NaHC03 (aq.) to pH=10 and then extracted with ethyl acetate (200 mL x 4). The combined organic solutions were washed with brine (300 mL x 2), H20 (300 mL x 2) and then dried over anhydrous Na2S04. Removal of the solvent gave the title compound (4.98 g, quantitative). LCMS: m/z 255, 257 (M+1).
Step J
5-bromo-2-(trichloromethyl)-7-(trifluoromethyl)-1H-benzi
[00317] A solution of [2-amino-4-bromo-6-(trifluoromethyl)phenyl]amine (4.98 g, 19.5 mmol) and methyl 2,2,2-trichloroacetimidate (4.13 g, 23.4 mmol) in AcOH (60 mL) was stirred at room temperature for 2 hr. After addition of H20 (150 mL), the solution was extracted with ethyl acetate (100 mL x 3). The combined organic solutions were washed with brine (100 mL x 2), H20 (100 mL x 2) and then dried over anhydrous Na2S04. Removal of the solvent gave the title compound (7.3 g, 99%). LCMS: m/z 381 (52%), 383 (100%), 385 (64%) (M+1).
Step K
5-bromo-7-(trifluoromethyl)-2-[tris(methyloxy)methyl]-1H-ben
[00318] A mixture of 5-bromo-2-(trichloromethyl)-7-(trifluoromethyl)-1 H-benzimidazole (7.30 g, 19.0 mmol) and sodium carbonate (3.03 g, 28.6 mmol) in MeOH (100 mL) was heated under reflux for 2 hr. After removal of the solvent, the residue was suspended in H20 (200 mL) and extracted with ethyl acetate (100 mL x 2). The combined organic solutions were dried over anhydrous Na2S04. Concentration at reduced pressure afforded the title compound (7.0 g, quantitative). LCMS: m/z 369, 371 (M+1 ).
Step L
methyl 5-brom o- 7-(trifluoromethyl )-1 H-benz imidazole-2-carb oxylate
[00319] A solution of 5-bromo-7-(trifluoromethyl)-2-[tris(methyloxy)methyl]-1 H- benzimidazole (7.00 g, 19.0 mmol) and para-toluenesulfonic acid (16.3 g, 9.50 mmol) in acetone (100 mL) was heated under reflux for 2 hr. After removal of the solvent, the residue was dissolved in ethyl acetate (200 mL). The organic solution was washed with brine (50 mL x 2), H20 (50 mL x 2) and then dried over anhydrous Na2S04. After concentration under vacuum, the crude product was purified with silica chromatography eluting with 1 :4 ethyl acetate/petroleum ether to give the title compound (3.8 g, 51 %). LCMS: m/z 323, 325 (M+1 ).
Step M
methyl 6-bromo-1-methyl-4-(trifluoromethyl)-1H-benzimidazole-2-carboxylate
[00320] To a mixture of methyl 5-bromo-7-(trifluoromethyl)-1 H-benzimidazole-2- carboxylate (3.70 g, 1 1.5 mmol) and cesium carbonate (5.58 g, 17.2 mmol) in DMF (70 mL) was added methyl iodide (6.50 g, 45.8 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 2 hr. After addition of H20 (150 mL), the solution was extracted with ethyl acetate (100 mL x 2). The combined organic solutions were washed with brine (100 mL x 2), H20 (100 mL x 2) and then dried over anhydrous Na2S04. Removal of the solvent at reduced pressure afforded the title compound (2.5 g; 65%). LCMS: m/z 337, 339 (M+1 ).
Step
sodium 6-bromo-1-methyl-4-(trifluoromethyl)-1 H-benz imidazole-2-carboxyl ate
[00321] A solution of methyl 6-bromo-1-methyl-4-(trifluoromethyl)-1 H-benzo[d]imidazole- 2-carboxylate (500 mg, 1.50 mmol) and 1 aqueous NaOH (3 mL) in THF/H20 (10 mL/10 mL) was stirred at room temperature for 15 min. The reaction mixture was concentrated under vacuum to afford the title compound (530 mg, quantitative). LCMS: m/z 323, 325 (M+1).
Step O
4-{[6-bromo-1-methyl-4-(trifluoromethyl)-1 H-benz imidazol-2-yl]carbonyl }- 1-cyclobutyl-2- piperazinone
[00322] To a solution of sodium 6-bromo-1 -methyl-4-(trifluoromethyl)-1 H-benzimidazole- 2-carboxylate (100 mg, 0.29 mmol) and 1-cyclobutyl-2-piperazinone (54 mg, 0.35 mmol) in DMF (5 mL) at RT was added DIPEA (112 mg; 0.870 mmol) followed by HATU (133 mg, 0.350 mmol). The mixture was stirred at room temperature for 0.5 hr. The reaction mixture was diluted with ethyl acetate (20 mL) and the phases separated. The organic solution was washed with brine (10 mL x 2), H20 (10 mL x 2) and then dried over anhydrous Na2S04. Concentration of the solution at reduced pressure gave the crude product which was purified with silica chromatography eluting with ethyl acetate to give the title compound (100 mg; 75%).
Step P
1-cyclobutyl-4-{[6-(3-†uranyl)-1- ethyl-4-(trifluoromethyl)-1H-benz
piperazinone
[00323] A solution of 4-{[6-bromo-1 -methyl-4-(trifluoromethyl)-1 H-benzimidazol-2- yl]carbonyl}-1-cyclobutyl-2-piperazinone (98 mg, 0.21 mmol), furan-3-boronic acid (48 mg, 0.42 mmol), palladium (II) acetate (3 mg, 0.01 mmol), tricyclohexylphosphine (6 mg, 0.02 mmol) and K3PO4 heptahydrate (213 mg; 0.630 mmol) in toluene (5 mL) was heated at 100 °C under a nitrogen atmosphere for 0.5 hr. After removal of the solvent, the residue was dissolved in ethyl acetate (20 mL). The organic solution was washed with brine (10 mL x 2), H20 (10 mL x 2) and then dried over anhydrous Na2S04. After concentrating the solution at reduced pressure, the crude product was purified with silica chromatography eluting with ethyl acetate to give the title compound (70 mg, 74%). 1 H N R (300MHz, CDCI3) δ ppm 7.84(s, 1 H), 7.75 (s, 1 H), 7.66 (d, 1 H), 7.55 (t, 1 H), 6.79 (s, 1 H), 5.04 (q, 1 H), 4.72 (s, 0.8H), 4.72 (s, 1.2H), 4.37 (t, 1.2H), 4.07 (d, 3H), 4.03 (m, 0.8H), 3.64 (t,1.2H), 3.55 (t, 08H), 2.14-2.05 (m, 4H), 1.79-1.70 (m, 2H). LCMS: m/z 447 (M+1).
Example 68
1-cyclobutyl-4-{[6-cyclo propyl-1-methyl-4-(trifluoromethyl)-1H-b enzimidazol-2- yl]carbonyl}-2-piperazinon e
Figure imgf000161_0001
[00324] A solution of 4-{[6-bromo-1-methyl-4-(trifluoromethyl)-1 H-benzimidazol-2- yl]carbonyl}-1-cyclobutyl-2-piperazinone (148 mg, 0.320 mmol), cyclopropylboronic acid (55 mg, 0.64 mmol), palladium (II) acetate (3.4 mg, 0.015 mmol), tricyclohexylphosphine (8 mg, 0.03 mmol) and K3P04 heptahydrate (325 mg, 0.960 mmol) in toluene (5 mL) was heated at 100 °C under nitrogen atmosphere for 3 hr. After removal of the solvent, the residue was dissolved in ethyl acetate (20 mL). The organic solution was washed with brine (10 mL x 2), H20 (10 mL x 2) and then dried over anhydrous Na2S04. After concentration of the solution at reduced pressure, the crude product was purified with silica chromatography eluting with ethyl acetate to give the title compound (100 mg, 74%). 1 H NMR (300MHz, CDCI3) δ ppm 7.33 (d, 1 H), 7.27 (d, 1 H), 5.02 (m, 1 H), 4.67 (s, 0.8H), 4.38 (s, 1.2H), 4.34 (t, 1.2H), 4.00 (d, 3H), 3.97 (m, 0.8H), 3.59 (t,1.2H), 3.51 (t, 08H), 2.17-2.02 (m, 5H), 1.79-1.72 (q, 2H), 1.08 (m, 2H), 0.77 (m, 2H). LCMS: m/z 421 (M+1).
Example 69
3-(1-{[ 6-(3- furanyl)- 1 -methyl- 4-(trifluoromethyl)- 1H-b enzimidazol-2-yl]carbonyl}-4- piperidinyl)-1,3-oxazolidine-2,4-dione
Figure imgf000162_0001
Step A
1, 1-Dimethylethyl 4-[(hydroxyacetyl)amino]-1-piperidinecarboxylate
[00325] To a solution of glycolic acid (18.1 g, 0.240 mol) in DMF (98 mL) was added
TBTU (80.3 g; 0.250 mol). After stirring at room temperature for 1 hr, 1 ,1-dimethylethyl 4- amino-1-piperidinecarboxylate (50.1 g, 0.250 mol) and DIPEA (98 mL, 0.60 mol ) were added and the reaction mixture was stirred at room temperature for 2 hr. After the addition of brine (200 mL), the solution was extracted with ethyl acetate (200 mL x 3). The combined organic solutions were washed with brine (200 mL x 2), H20 (200 mL x 2) and then dried over anhydrous Na2S04. After removal of the solvent, the crude product was purified with silica chromatography eluting with ethyl acetate to give the title compound (35.0 g, 54%). T/US2011/023763
Step B
1, 1-Dimethylethyl 4-(2, 4-dioxo-1, 3-oxazolidin-3-yl)- 1 -piperidinecarboxylate
[00326] To a solution of 1 ,1-dimethylethyl 4-[(hydroxyacetyl)amino]-1- piperidinecarboxylate (38.8 g, 0.150 mol) in D F (200 mL) was added CDI (26.2 g, 0.140 mol). The reaction solution was stirred at room temperature for 1 hr and then heated at 90 °C for 5 hr. After removal of the organic solvent at reduced pressure, the crude product was recrystallized from MeOH/petroleum ether to give the title compound (30.2 g, 71 %).
Step C
3-(4-Piperidinyl)-1,3-oxazolidine-2,4-dione hydrochloride
[00327] To a solution of 1 ,1-dimethylethyl 4-(2,4-dioxo-1 ,3-oxazolidin-3-yl)-1- piperidinecarboxylate (37.0 g, 0.130 mol) in dioxane (200 mL) was added 4N HCI in dioxane (160 mL) at room temperature. The reaction solution was stirred at room temperature overnight. After removal of the solvent, the crude product was recrystallized with diethyl ether to give the title compound (28.0 g, 80%). 1 H NMR (300MHz, c/6-DMSO) δ ppm 9.32 (br, 1 H), 8.63 (br, 1 H), 4.76 (s, 2H), 4.11 (m, 1 H), 3.45(t, 2H), 2.98 (q,2H), 2.36 (dq,2H), 1.85 (d, 2H). LCMS: m/z 185 (M+1).
Step D
3-(1-{[6-Bro o-1-methyl-4-(trifluoromethyl)-1H-benzimida
oxazolidine-2, 4-dione
[00328] To a solution of sodium 6-bromo-1 -methyl-4-(trifluoromethyl)-1 H-benzimidazole- 2-carboxylate (200 mg, 0.58 mmol) and 3-(4-piperidinyl)-1 ,3-oxazolidine-2,4-dione hydrochloride (154 mg, 0.70 mmol) in DMF (10 mL) at RT was added DIPEA (224 mg, 1.74 mmol). This was followed by addition of a solution of HATU (266 mg, 0.70 mmol) in DMF (15 mL) in one portion. The mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate (20 mL). The organic solution was washed with brine (10 mL x 2), H20 (10 mL x 2) and then dried over anhydrous Na2S0 . After concentration under vacuum, the crude product was purified with silica chromatography eluting with 1 :2 ethyl acetate/petroleum ether to give the title compound (200 mg, 70%).
Step E
3-(1-{[6-(3-Furanyl)-1-methyl-4-(trifluoromethyl)-1H-benzimid^^
1, 3-oxazolidine-2, 4-dione [00329] A solution of 3-(1-{[6-bromo-1 -methyl-4-(trifluoromethyl)-1 H-benzimidazol-2- yl]carbonyl}-4-piperidinyl)-1 ,3-oxazolidine-2,4-dione (180 mg, 0.370 mmol), furan-3-boronic acid (82 mg, 0.74 mmol), palladium (II) acetate (4.1 mg, 0.02 mmol), tricyclohexylphosphine (10 mg, 0.04 mmol) and K3P04 heptahydrate (373 mg, 1.10 mmol) in toluene (10 mL) was heated at 100 °C under a nitrogen atmosphere for 6 hr. After removal of the solvent, the residue was dissolved in ethyl acetate (40 mL). The organic solution was washed with brine (10 mL x 2), H20 (10 mL x 2) and then dried over anhydrous Na2S04. After concentration under vacuum, the crude product was purified with silica chromatography eluting with 1 :1 ethyl acetate/petroleum ether to give the title compound (50 mg, 29%). 1 H NMR (300MHz, CDCI3) δ ppm 7.81 (s, H), 7.70 (s, 1 H), 7.63 (s, 1 H), 7.51 (t, 1 H), 6.76 (s, 1 H), 4.87 (dt, 2H), 4.64 (s, 2H), 4.22 (m, 1 H), 4.01 (s, 3H), 3.27 (dt, 1 H), 2.85 (m, 1 H), 2.44 (m, 2H), 1.82 (dd, 2H). LCMS: m/z 477 (M+1 ).
Example 70
3-(1-{[6-cyclopropyl-4-(1,1-dimethylethyl)-1-methyl-1H-benzimidazo
piperidinyl)-1,3-oxazolidin-2-one
Figure imgf000164_0001
Step A
[4-bromo-2-( 1, 1-dimethylethyl)phenyl]amine
[00330] To a solution of 2-tert-butylaniline (52.2 mL, 335 mmol) in THF (618 mL) at 5 °C (ice-water bath) was added tetrabutylammonium tribromide (146 g, 303 mmol) in THF (200 mL) dropwise over 45 minutes. After 30 minutes, the mixture was quenched with water (100 mL) and stirred for 15 minutes. The mixture was diluted with diethyl ether (1 L) and washed with saturated aqueous NaHC03 (400 mL), then brine (400 mL), dried (Na2S04), filtered and concentrated to give [4-bromo-2-(1 ,1-dimethylethyl)phenyl]amine (78.40 g, 344 mmol, quantitative yield) as brown oil. This was used for next step. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.30 (s, 9 H), 4.98 (s, 2 H), 6.57 - 6.62 (m, 1 H), 7.02 (dd, J=8.5, 2.3 Hz, 1 H), 7.09 (d, J=2.3 Hz, 1 H); MS(ESI) m/z: 228.1 , 230.2 (MH+). Step B
5-bromo-1-(tert-butyl)-3-chloro-2-nitrobenzene
[00331] A solution of [4-bromo-2-(1 , 1-dimethylethyl)phenyl]amine (77.9 g, 341 mmol) and NCS (50.2 g, 376 mmol) was heated to 60 °C in 1 ,2-dichloroethane (683 mL). After 45 minutes, the mixture was cooled to room temperature. The mixture was washed with water (200 mL), 5% aqueous sodium bisulfite solution (200 mL), water (200 mL), dried (Na2S0 ), filtered into a 2 L E-flask. To a solution of crude f4-bromo-2-chloro-6-(1 , 1 -dimethylethyl)phenyl]amine in 1 ,2- dichloroethane (800 mL) in a water bath (internal temperature = 15 °C) was added 3- chloroperoxybenzoic acid (214 g, 955 mmol) in 3 portions over 30 minutes. After addition of 160 g, temperature raised to 45 °C. The mixture was cooled with more ice to keep temperature below 30 °C. The mixture was then allowed to stir at room temperature. After 30 minutes, the suspension was filtered through a pad of Celite® and washed with DCM (100 mL). The filtrate was washed with saturated aqueous NaHC03 (200 mL), water (200 mL), 10% aqueous sodium bisulfite (200 mL, heat generated with this wash), saturated aqueous NaHCO3 (200 mL), water (200 mL), brine (200 mL), dried (Na2S04), filtered and concentrated to give 92.44 g brown oil. The crude material was used for next step. LCMS showed 50% purity (UV254).
Step C
5-bromo-3- (1, 1 -dimethylethyl)-N-methyl-2-nitroan iline
[00332] To a solution of crude 5-bromo-1-chloro-3-(1 ,1-dimethylethyl)-2-nitrobenzene (91 .7 g, 313 mmol) in THF (200 mL) cooled in an ice-water bath was added a solution of methylamine (2M, 313 mL, 627 mmol) in THF in one portion. After 15 minutes, the ice-water bath was removed. After 3 hours, the mixture was washed with water (200 mL) and brine (25 mL)] twice. The second aqueous wash was back-extracted with diethyl ether (100 mL). The combined organic phase was dried (Na2S04), filtered and concentrated to give about 94 g brown solid (crude). The crude was crystallized from EtOH (350 mL) and water (~150 mL) and left overnight. The dark crystals were filtered and rinsed with water/EtOH (200 mL, 6:1 v/v)] to give 5-bromo-3-(1 ,1-dimethylethyl)-N-methyl-2-nitroaniline (65.35 g, 228 mmol, 72.6 % yield). MS(ESI) m/z: 271.3, 273.3 (MH+ - O).
Step D
[2-amino-5-bromo-3-( 1, 1 -dimethyl ethyl)phenyl Jmethylamine U 2011/023763
[00333] To a stirred solution of 5-bromo-3-(1 ,1 -dimethylethyl)-N-methyl-2-nitroaniline (15.25 g, 53.1 mmol) in THF (45 mL), and EtOH (90 mL) equipped with a water bath was added a solution of sodium dithionate (76 g, 313 mmol) in water (180 mL) (dissolved with heating at 70 °C) while keeping internal temperature less than 45 °C. After 20 minutes, the suspension was filtered through a sintered glass funnel and washed with diethyl ether (300 mL). The aqueous phase was separated and extracted with diethyl ether (200 mL). The combined ethereal layer was washed with brine (200 mL), dried (Na2S04), filtered and concentrated. The crude was purified by silica gel chromatography (0-15% EtOAc in hexanes) to give [2-amino-5-bromo-3- (1 ,1 -dimethylethyl)phenyl]methylamine (6.67 g, 25.95 mmol, 52.1 % yield) as red oil. 1H NMR (400 MHz, DMSO-de) δ ppm 1.32 (s, 9 H), 2.67 (d, J=4.9 Hz, 3 H), 4.23 (s, 2 H), 4.88 (d, J=4.8
Hz, 1 H), 6.41 (d, J=2.0 Hz, 1 H), 6.61 (t, J=2.1 Hz, 1 H); MS(ESI) m/z: 257.2, 259.2 (MH+).
Step E
6-bromo-4-( 1, 1 -dimethylethyl)-1-methyl-1H-benz imidazole-2-carboxylate
[00334] To a solution of [2-amino-5-bromo-3-(1 ,1-dimethylethyl)phenyl]methylamine (4.7 g, 18.28 mmol) in ,2-dichloroethane (34.8 mL) was added DIPEA (19.15 mL, 1 10 mmol), DMAP (0.223 g, 1.828 mmol) followed by methyl 2,2-dichloro-2-methoxyacetate (6.97 mL, 54.8 mmol) at room temperature. The mixture was heated to 70 °C. After 1 hour 50 minutes, the mixture was cooled, diluted with DCM (65 mL), and washed with 1 N HCI (2 x 30 mL), brine (30 mL), dried (Na2S04), filtered and concentrated. The crude was purified by silica gel
chromatography [0-10% EtOAc in hexanes] to give methyl 6-bromo-4-(1 ,1 -dimethylethyl)-1- methyl-1 H-benzimidazole-2-carboxylate (4.09 g, 12.58 mmol, 68.8 % yield) as beige solid. H NMR (400 MHz, DMSO-c/6) δ ppm 1.48 - 1.57 (m, 9 H), 3.95 (s, 3 H), 4.05 (s, 3 H), 7.22 (d, J=1.8 Hz, 1 H), 7.90 (d, J=1.8 Hz, 1 H); MS(ESI) m/z: 325.2, 327.2 (MH+).
Step F
methyl 6-cyclopropyl-4-(1 , 1-dimethylethyl)-1-methyl-1H-benzimidazole-2-carboxylate
[00335] A suspension of methyl 6-bromo-4-(1 ,1 -dimethylethyl)-1-methyl-1 H- benzimidazole-2-carboxylate (800 mg, 2.460 mmol), cyclopropylboronic acid (634 mg, 7.38 mmol), palladium(ll) acetate (27.6 mg, 0.123 mmol), potassium phosphate tribasic (1462 mg, 6.89 mmol), and cataCXium® A (88 mg, 0.246 mmol) was heated to110 °C in toluene (5.74 mL) and water (2.46 mL). After 3 hours, the mixture was cooled, filtered through 45 urn disc, diluted with EtOAc (60 mL), washed with brine (15 mL), dried (Na2S04), filtered and concentrated. The crude was absorbed on silica gel and purified by column chromatography [0-10% EtOAc in hexanes] to give methyl 6-cyclopropyl-4-(1 ,1-dimethylethyl)-1-methyl-1 H-benzimidazole-2- carboxylate (551.7 mg, 1.927 mmol, 78 % yield) as light yellow solid. 1H NMR (400 MHz, OMSO-de) δ ppm 0.73 - 0.82 (m, 2 H), 0.94 - 1.03 (m, 2 H), 1.44 - 1.59 (m, 9 H), 2.07 (tt, J=8.4, 5.1 Hz, 1 H), 3.90 - 3.97 (m, 3 H), 4.00 - 4.07 (m, 3 H), 6.94 (d, .7=1.4 Hz, 1 H), 7.16 (d, J=1.4 Hz, 1 H); MS(ESI) m/z: 287.3 (MH+).
Step G
potassium 6-cyclopropyl-4-( 1, 1-dimethylethyl)-1-methyl-1H-benzimidazole-2-carboxylate
[00336] To a solution of methyl 6-cyclopropyl-4-(1 ,1-dimethylethyl)-1 -methyl- 1 H- benzimidazole-2-carboxylate (697.4 mg, 2.435 mmol) in THF (21.4 mL) at 0 °C (ice-water bath) was added potassium trimethylsilanolate (375 mg, 2.92 mmol) in one portion. After 4 hours, the precipitate was filtered through a fritted filter funnel, rinsed with chilled THF (5 mL), and dried under high vacuum to give potassium 6-cyclopropyl-4-(1 ,1-dimethylethyl)-1-methyl-1 H- benzimidazole-2-carboxylate (674.5 mg, 2.166 mmol, 89 % yield) as white solid. 1H NMR (400 MHz, DMSO-c/6) δ ppm 0.63 - 0.74 (m, 2 H), 0.87 - 0.97 (m, 2 H), 1.49 (s, 9 H), 2.00 (tt, J=8.4, 5.1 Hz, 1 H), 3.87 (s, 3 H), 6.76 (d, J=1.4 Hz, 1 H), 6.90 (d, J = 1.4 Hz, 1 H); MS(ESI) m/z: 273.4 (MH+).
Step H
3-(1-{[6-cyclopropyl-4-(1, 1-dimethylethyl)-1-methyl-1H-benz imida
piperidinyl)- 1, 3-oxazolidin~2-one
[00337] To a suspension of potassium 6-cyclopropyl-4-(1 ,1-dimethylethyl)-1-methyl-1 H- benzimidazole-2-carboxylate (60 mg, 0.193 mmol), 3-(4-piperidinyl)-1 ,3-oxazolidin-2-one (49.2 mg, 0.289 mmol), N,N-diisopropylethylamine (168 μΙ, 0.963 mmol) in DMF (646 μΙ) at 0 °C was added 1-propanephosphoric acid cyclic anhydride, 50% wt in EtOAc (149 μΙ, 0.250 mmol). After 30 minutes, DMSO (65 uL) was added. After 3.5 hours, the mixture was cooled with ice-water bath and 0.5 eq of T3P (57 uL) was added. After 6 hours, the mixture was diluted with EtOAc (20 mL) and washed with saturated aqueous NaHC03 (8 mL), brine (8 mL), dried (Na2S04), filtered and concentrated. The crude was absorbed on silica gel and purified by column chromatography [40-100% EtOAc in hexanes] to give 3-(1-{[6-cyclopropyl-4-(1 ,1-dimethylethyl)- 1-methyl- H-benzimidazol-2-yl]carbonyl}-4-piperidinyl)-1 ,3-oxazolidin-2-one (39.6 mg, 0.092 mmol, 47.9 % yield) as white powder. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.70 - 0.77 (m, 2 H), 0.94 - 1.02 (m, 2 H), 1.50 (s, 9 H), 1.60 - 1.86 (m, 4 H), 2.01 - 2.10 (m, 1 H), 2.87 - 3.01 (m, 1 H), 3.19 - 3.29 (m, 1 H), 3.48 (q, J=8.3 Hz, 1 H), 3.55 (q, J=8.2 Hz, 1 H), 3.80 (s, 3 H), 3.81 - 3.91 (m, 1 H), 4.26 (t, J=8.2 Hz, 2 H), 4.32 - 4.42 (m, 1 H), 4.61 (br. s., 1 H), 6.91 (d, J=1.2 Hz, 1 H), 7.10 (d, J=1.1 Hz, 1 H); MS(ESI) m/z: 425.3 (MH+).
Example 71
3-(1-{[6-cyclopropyl-4-(1,1-dimethylethyl)-1-methyl-1H-benzimidazol-2-yl]carbo^
piperidinyl)-1,3-oxazolidine-2,4-dione
Figure imgf000168_0001
[00338] To a suspension of potassium 6-cyclopropyl-4-(1 ,1-dimethylethyl)-1-methy!-1 H- benzimidazole-2-carboxylate (60 mg, 0.193 mmol), 3-(4-piperidinyl)-1 ,3-oxazolidine-2,4-dione hydrochloride (63.8 mg, 0.289 mmol), N,N-diisopropylethylamine (168 μΙ, 0.963 mmol) in DMF (795 μΙ) at room temperature was added HATU (88 mg, 0.231 mmol) . After 30 minutes, the mixture was diluted with EtOAc (20 mL) and washed with saturated aqueous NaHC03 (8 ml_), brine (8 mL), dried (Na2S04), filtered and concentrated. The crude was absorbed on silica gel and purified by column chromatography [0-55% EtOAc in hexanes] to give 3-(1-{[6-cyclopropyl- 4-(1 , 1 -dimethylethyl)-1 -methyl- 1 H-benzimidazol-2-yl]carbonyl}-4-piperidinyl)-1 ,3-oxazolidine- 2,4-dione (63.5 mg, 0.143 mmol, 74.4 % yield) as white powder. 1H NMR (400 MHz, DMSO-cfe) δ ppm 0.71 - 0.79 (m, 2 H), 0.92 - 1.02 (m, 2 H), 1.49 (s, 9 H), 1.74 (d, J=10.7 Hz, 1 H), 1.87 (br. s., 1 H), 2.01 - 2.23 (m, 2 H), 2.33 (qd, J=12.5, 4.2 Hz, 1 H), 2.95 (td, J=13.0, 2.4 Hz, 1 H), 3.16 - 3.28 (m, 1 H), 3.77 - 3.84 (m, 3 H), 4.18 (tt, J=12.1 , 4.0 Hz, 1 H), 4.41 (d, J=13.5 Hz, 1 H), 4.66 (d, J=13.3 Hz, 1 H), 4.77 (s, 2 H), 6.91 (d, J=1.3 Hz, 1 H), 7.11 (d, J=1.1 Hz, 1 H); MS(ESI) m/z: 439.3 (MH+).
Example 72
4-{[6-cyclopropyl-4-(2-fluorophenyl)-1-methyl-1H-benzimidazol-2-yl]carbonyl}-^
hydroxycyclohexyl)-2-piperazinone
(Compound 72)
Figure imgf000169_0001
[00339] A mixture of 4-[(4-bromo-6-cyclopropyl-1 -methyl- 1 -/-benzimidazoi-2-yl)carbonyl]- 1-(fra/7s-4-{[(1 ,1-dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2-piperazinone (50 mg, 0.085 mmol), (2-fluorophenyl)boronic acid (24 mg, 0.17 mmol), potassium phosphate (54 mg, 0.25 mmol) and bis(tricyclohexylphosphine)palladium(ll) dichloride (6.3 mg, 0.0085 mmol) in 10:1 1 ,4-dioxane/water (2.75 mL) was heated in a microwave at 120 °C for 10 min. The reaction mixture was diluted with water and extracted with dichloromethane (2x). The combined organic layers were filtered through a phase-separating tube and concentrated. The residue was dissolved in dichloromethane (2 mL) and treated with 4 N HCI in dioxane (0.5 mL). After stirring for 1 hour, the reaction mixture was concentrated. The residue was purified by reverse phase HPLC and lyophilized to afford a white powder. This solid was treated with 2 M NH3 in MeOH and stirred for 30 min. The mixture was diluted with water and extracted with ethyl acetate (2x). The organic layers were removed by pipette and concentrated to give the title compound (11 mg, 27%). LCMS: m/z 491 (M+1). 1H NMR (METHANOL-d4) δ: 7.68 - 7.63 (m, 1 H), 7.36 - 7.46 (m, 1 H), 7.32 (s, 1 H), 7.17 - 7.30 (m, 2H), 7.15 (s, 1 H), 4.21 - 4.57 (m, 3H), 3.98 - 4.06 (m, 1 H), 3.88 - 3.98 (m, 4H), 3.37 - 3.60 (m, 3H), 2.09 - 2.18 (m, 1 H), 1.96 - 2.07 (m, 3H), 1.51 - 1.77 (m, 4H), 1.31 - 1.47 (m, 2H), 0.98 - 1.09 (m, 2H), 0.73 - 0.88 (m, 2H)
Example 73
4-{[ 6-cyclo propyl-4- (2,4-difluoroph enyl)- 1-methyl-1 H-ben zimidazol-2-yl]carb>
(trans-4-hydroxycyclohexyl)-2-piperazinone
(Compound 73)
Figure imgf000170_0001
[00340] A mixture of 4-[(4-bromo-6-cyclopropyl-1-methyl-1H-benzimidazol-2-yl)carbonyl]- 1-(fra 7s-4-{[(1 ,1-dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2-piperazinone (50 mg, 0.085 mmol), (2,4-difluorophenyl)boronic acid (27 mg, 0.17 mmol), potassium phosphate (54 mg, 0.25 mmol) and bis(tricyclohexylphosphine)palladium(ll) dichloride (6.3 mg, 0.0085 mmol) in 10:1 1 ,4-dioxane/water (2.75 mL) was heated in a microwave at 120 °C for 10 min. The reaction mixture was diluted with water and extracted with dichloromethane (2x). The combined organic layers were filtered through a phase-separating tube and concentrated. The residue was dissolved in dichloromethane (2 mL) and treated with 4 N HCI in dioxane (0.5 mL). After stirring for 1 hour, the reaction mixture was concentrated. The residue was purified by reverse phase HPLC and lyophilized to afford a white powder. This solid was treated with 2 M NH3 in MeOH and stirred for 30 min, then concentrated to give the title compound (23 mg, 53%). LCMS: m/z 509 (M+1). 1H NMR (METHANOL-d4) δ: 7.63 - 7.75 (m, 1 H), 7.32 (s, 1 H), 7.13 (d, 1 H), 7.01 - 7.11 (m, 2H), 4.21 - 4.58 (m, 3H), 3.98 - 4.08 (m, 1 H), 3.86 - 3.98 (m, 4H), 3.37 - 3.60 (m, 3H), 2.06 - 2.20 (m, 1 H), 2.00 (d, 2H), 1.52 - 1.74 (m, 4H), 1.28 - 1.47 (m, 2H), 0.98 - 1.11 (m, 2H), 0.74 - 0.87 (m, 2H).
Example 74
4-{[6-cyclopropyl-4-(2,5-difluorophenyl)-1-methyl-1H-benzimidazol-2-yl]carbo
(trans-4-hydroxycycIohexyl)-2-piperazinone
(Compound 74)
Figure imgf000171_0001
[00341] A mixture of 4-[(4-bromo-6-cyclopropyl-1 -methyl-1 V-benzimidazol-2-yl)carbonyl]- 1-(fraA7s-4-{[(1 ,1-dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2-piperazinone (50 mg, 0.085 mmol), (2,5-difluorophenyl)boronic acid (27 mg, 0.17 mmol), potassium phosphate (54 mg, 0.25 mmol) and bis(tricyclohexylphosphine)palladium(ll) dichloride (6.3 mg, 0.0085 mmol) in 10:1 1 ,4-dioxane/water (2.75 mL) was heated in a microwave at 120 °C for 10 min. The reaction mixture was diluted with water and extracted with dichloromethane (2x). The combined organic layers were filtered through a phase-separating tube and concentrated. The residue was dissolved in dichloromethane (2 mL) and treated with 4 N HCI in dioxane (0.5 mL). After stirring for 1 hour, the reaction mixture was concentrated. The residue was purified by reverse phase HPLC and lyophilized to afford a white powder. This solid was treated with 2 M NH3 in MeOH and stirred for 30 min, then concentrated to give the title compound (17 mg, 39%). LCMS: m/z 509 (M+1). 1H NMR (METHANOL-d4) δ: 7.41 - 7.57 (m, 1 H), 7.34 (s, 1 H), 7.08 - 7.28 (m, 3H), 4.21 - 4.56 (m, 3H), 4.03 (t, 1 H), 3.88 - 3.99 (m, 4H), 3.39 - 3.59 (m, 3H), 2.06 - 2.21 (m, 1 H), 2.00 (d, 2H), 1.49 - 1.77 (m, 4H), 1.27 - 1.49 (m, 2H), 0.99 - 1.14 (m, 2H), 0.72 - 0.89 (m, 2H).
Example 75
4-{[6-cyclopropyl-1-methyl-4-(2-pyridinyl)-1H-benzi idazol-2-yl]carbon
hydroxycyclohexyl)-2-piperazinone
(Compound 75)
Figure imgf000172_0001
[00342] A mixture of 4-[(4-bromo-6-cyclopropyl-1-methyl-1H-benzimidazol-2-yl)carbonyl]- 1-(irans-4-{[(1 ,1-dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2-piperazinone (50 mg, 0.085 mmol), 2-(tributylstannanyl)pyridine (33 pL, 0.10 mmol), copper(l) bromide (1.2 mg, 0.0085 mmol) and bis(tri-o-tolylphosphine)palladium(ll) dichloride (6.7 mg, 0.0085 mmol) in acetonitrile (2.0 ml_) was heated in a microwave at 130 °C for 30 min. The reaction mixture was treated with additional 2-(tributylstannanyl)pyridine (33 μΙ_, 0.10 mmol) and bis(tri-o- tolylphosphine)palladium(ll) dichloride (6.7 mg, 0.0085 mmol) and reheated in the microwave at 130 °C for 10 min. The reaction mixture was concentrated, then partitioned between dichloromethane and saturated aqueous potassium fluoride. After stirring 30 min, the organic layer was removed by pipette, filtered through a phase-separating tube and concentrated. The residue was dissolved in dichloromethane (0.5 ml_) and treated with 4 N HCI in dioxane (0.1 mL). After stirring for 30 min, the reaction mixture was concentrated. The residue was purified by reverse phase HPLC and lyophilized to afford a white powder. This solid was treated with 2 M NH3 in MeOH and stirred for 30 min, then concentrated to give the title compound (13 mg, 31 %). LCMS: m/z 474 (M+1). H NMR (METHANOL-d4) δ: 8.50 - 8.80 (m, 2H), 7.91 - 8.07 (m, 1 H), 7.66 - 7.79 (m, 1 H), 7.34 - 7.52 (m, 2H), 4.69 (s, 1 H), 4.23 - 4.44 (m, 2H), 4.13 (t, 1 H), 3.91 - 4.05 (m, 4H), 3.42 - 3.60 (m, 3H), 2.09 - 2.25 (m, 1 H), 2.02 (d, 2H), 1.53 - 1.78 (m, 4H), 1.30 - 1.51 (m, 2H), 0.99 - 1.16 (m, 2H), 0.81 - 0.94 (m, 2H).
Example 76
4-{[6-cyctopropyl-1-methyl-4-(3^yridinyl)-1H-benzimidazol-2-yl]carbonyl}- hydroxycyclohexyl)-2-piperazinone
(Compound 76)
Figure imgf000173_0001
OH
[00343] A mixture of 4-[(4-bromo-6-cyclopropyl-1-methyl-1 -/-benzimidazol-2-yl)carbonyl]- 1-(fra ?s-4-{[(1 ,1-dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2-piperazinone (50 mg, 0.085 mmol), 3-(tributylstannanyl)pyridine (27 pL, 0.085 mmol), copper(l) bromide (1.2 mg, 0.0085 mmol) and bis(tri-o-tolylphosphine)palladium(ll) dichloride (6.7 mg, 0.0085 mmol) in acetonitrile (2.0 mL) was heated in a microwave at 130 °C for 30 min. The reaction mixture was treated with additional 2-(tributylstannanyl)pyridine (27 μΙ_, 0.085 mmol) and bis(tri-o- tolylphosphine)palladium(ll) dichloride (6.7 mg, 0.0085 mmol) and reheated in the microwave at 130 °C for 10 min. The reaction mixture was concentrated, then partitioned between dichloromethane and saturated aqueous potassium fluoride. After stirring 30 min, the organic layer was removed by pipette, filtered through a phase-separating tube and concentrated. The residue was dissolved in dichloromethane (0.5 mL) and treated with 4 N HCI in dioxane (0.1 mL). After stirring for 30 min, the reaction mixture was concentrated. The residue was purified by reverse phase HPLC and lyophilized to afford a white powder. This solid was treated with 2 M NH3 in MeOH and stirred for 30 min, then concentrated to give the title compound (15 mg, 37%). LCMS: m/z 474 (M+1). 1H NMR (METHANOL-d4) δ: 9.07 - 9.43 (m, 1 H), 8.31 - 8.73 (m, 2H), 7.50 - 7.72 (m, 1 H), 7.28 - 7.41 (m, 2H), 4.62 (s, 1 H), 4.22 - 4.44 (m, 2H), 4.14 (t, 1 H), 3.89 - 4.03 (m, 4H), 3.40 - 3.63 (m, 3H), 2.09 - 2.24 (m, 1 H), 2.01 (d, 2H), 1.55 - 1.76 (m, 4H), 1.28 - 1.49 (m, 2H), 0.99 - 1.17 (m, 2H), 0.78 - 0.92 (m, 2H).
Example 77
4-{[6-cyclopropyl-1-methyl-4-(4-pyridinyl)-1H-benzimidazol-2-yl]carbonyl^
hydroxycyclohexyl)-2-piperazinone
(Compound 77)
Figure imgf000174_0001
[00344] A mixture of 4-[(4-bromo-6-cyclopropyl-1-methyl-1 -/-benzimidazol-2-yl)carbonyl]- 1-(irans-4-{[(1 ,1-dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2-piperazinone (50 mg, 0.085 mmol), 4-(tributylstannanyl)pyridine (34 μΐ_, 0.10 mmol), copper(l) bromide (1.2 mg, 0.0085 mmol) and bis(tri-o-tolylphosphine)palladium(ll) dichloride (6.7 mg, 0.0085 mmol) in acetonitrile (2.0 ml_) was heated in a microwave at 130 °C for 30 min. The reaction mixture was treated with additional 4-(tributylstannanyl)pyridine (34 μΙ_, 0.10 mmol) and bis(tri-o- tolylphosphine)palladium(ll) dichloride (6.7 mg, 0.0085 mmol) and reheated in the microwave at 130 °C for 20 min. The reaction mixture was then treated with copper (I) bromide (10 mg, 0.068 mmol) and reheated in the microwave at 130° for 20 min. The reaction mixture was
concentrated, then partitioned between dichloromethane and saturated aqueous potassium fluoride. After stirring 30 min, the organic layer was removed by pipette, filtered through a phase-separating tube and concentrated. The residue was dissolved in dichloromethane (0.5 mL) and treated with 4 N HCI in dioxane (0.1 ml_), After stirring for 30 min, the reaction mixture was concentrated. The residue was purified by reverse phase HPLC and lyophilized to afford a white powder. This solid was treated with 2 M NH3 in MeOH and stirred for 30 min, then concentrated to give the title compound (4.4 mg, 11 %). LCMS: m/z 474 (M+1). 1H NMR (METHANOLS) δ: 8.64 (m, 2H), 8.12 - 8.31 (m, 2H), 7.48 (dd, 1 H), 7.41 (s, 1 H), 4.68 (s, 1 H), 4.25 - 4.45 (m, 2H), 4.07 - 4.20 (m, 1 H), 3.90 - 4.06 (m, 4H), 3.39 - 3.61 (m, 3H), 2.11 - 2.24 (m, 1 H), 2.02 (d, 2H), 1.54 - 1.81 (m, 4H), 1.31 - 1.49 (m, 2H), 1.01 - 1.18 (m, 2H), 0.87 (m, 2H).
Example 78
4-({4-bromo-1-methyl-6-[(trifluoro ethyl)oxy]-1H-benzi idazol-2-yl}carbon
hydroxycyclohexyl)-2-piperazinone
(Compound 78) 11 023763
Figure imgf000175_0001
Step A
{2-amino-3-bromo-5-[(trifluoromethyl)oxy]p enyl}amine
[00345] A solution of {2-bromo-6-nitro-4-[(trifluoromethyl)oxy]phenyl}amine (5.00 g, 16.6 mmol, Matrix Scientific) in ethanol (100 mL) was treated with a solution of sodium dithionite (11.6 g, 66.4 mmol) in water (50 mL) and allowed to stir at rt overnight. A second portion of sodium dithionite (5.80 g, 33.2 mmol) was added as a solution in water and the reaction was stirred for an additional 2 h. The reaction mixture was concentrated to remove some of the ethanol, then diluted with water and extracted with ethyl acetate (2x). The combined organic layers were washed with saturated aqueous ammonium chloride (2x), 10% aqueous sodium carbonate (1x) and brine (1x). After drying over sodium sulfate, the solution was concentrated to a brown oil. This was slurried in diethyl ether and treated with 4 N HCI in dioxane. The mixture was filtered and the solids rinsed with diethyl ether to afford the title compound as the HCI salt (2.08 g, 41 %).
Step B
4-bromo-2-(trichloromethyl)-6-[(trifluoromethyl)oxy]-1H-benzim
[00346] A suspension of {2-amino-3-bromo-5-[(trifluoromethyl)oxy]phenyl}amine (2.08 g, 6.76 mmol) in acetic acid (35 mL) was treated with methyl 2,2,2-trichloroacetimidate (1.14 mL, 9.21 mmol), added dropwise via syringe. After stirring at rt overnight, the reaction mixture was diluted with water and extracted with diethyl ether (3x). The combined organic layers were washed with water (2x) and brine (1x), then dried over sodium sulfate and concentrated.
Toluene was added and the mixture was concentrated under reduced pressure, then dried under vacuum to afford the title compound (2.54 g, 94%). LCMS: m/z 399 (M+1).
Step C
4-({4-bromo-6~[(trifluoromethyl)oxy]-1H-benzimidazol-2-yl}carbon
hydroxycyclohexyl)-2-piperazinone [00347] A suspension of 4-bromo-2-(trichloromethyl)-6-[(trifluoromethyl)oxy]-1 H- benzimidazole (3.99 g, 10.0 mmol) in acetonitrile (48 mL) and water (8 mL) was treated with 1- (frans-4-hydroxycyclohexyl)-2-piperazinone hydrochloride (2.38 g, 10.1 mmol) and aqueous potassium carbonate (10.0 mL, 4.0 ), added dropwise. The reaction mixture was stirred at rt for 24 h, then diluted with water and extracted with 3:1 chloroform/isopropanol (1x). The organic layer was washed with brine, dried over sodium sulfate and concentrated to give the title compound (3.89 g, 77%) as a brown foam. LCMS: m/z 505 (M+1).
Step D
4-({4-bromo~6-[(trifluoromethyl)oxy]-1H-ben zimidazol-2-yl}carbonyl)- 1-(trans-4-{[( 1, 1 - dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2-piperazinone
[00348] A solution of 4-({4-bromo-6-[(trifluoromethyl)oxy]-1 /- -benzimidazol-2-yl}carbonyl)- 1-(fra/7s-4-hydroxycyclohexyl)-2-piperazinone (3.80 g, 7.52 mmol) in Λ/,/V-dimethylformamide (40 mL) was treated with imidazole (1.02 g, 15.0 mmol) and i-butyldimethylsilyl chloride (1.70 g, 11.3 mmol). After stirring overnight at rt, additional imidazole (0.26 g, 3.75 mmol) and t- butyldimethylsilyl chloride (0.57 g, 3.77 mmol) were added. After stirring for an additional 1 h, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with 5% aqueous lithium chloride (2x), saturated aqueous sodium bicarbonate (1x) and brine, then dried over sodium sulfate and concentrated. Purification by silica gel chromatography (0 to 100% ethyl acetate in dichloromethane) afforded the title compound (2.46 g, 53%) as a pale yellow solid. LCMS: m/z 619 (M+1). 1H NMR (DMSO-d6) δ: 13.70 - 13.89 (m, 1 H), 7.58 - 7.74 (m, 1 H), 7.43 - 7.58 (m, 1 H), 5.05 (s, 1 H), 4.62 (br. s., 1 H), 4.12 - 4.32 (m, 2H), 3.87 (t, 1 H), 3.51 - 3.67 (m, 1 H), 3.40 - 3.51 (m, 1 H), 3.35 - 3.40 (m, 1 H), 1.76 - 1.93 (m, 2H), 1.46 - 1.75 (m, 4H), 1.24 - 1.44 (m, 2H), 0.79 - 0.89 (m, 9H), -0.03 - 0.07 (m, 6H).
Step E
4-({4-bromo-1-methyl-6-[(trifluoromethyl)oxy]-1H-benzimida
dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2-piperazinone
[00349] A partial solution of 4-({4-bromo-6-[(trifluoromethyl)oxy]-1 W-benzimidazol-2- yl}carbonyl)-1-(frans-4-{[(1 ,1-dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2-piperazinone (2.46 g, 3.97 mmol) in /V,/V-dimethylformamide (25 mL) was treated with potassium carbonate (0.55 g, 3.97 mmol) and methyl iodide (0.25 mL, 3.97 mmol). After stirring at rt for 1.5 h, the reaction mixture was diluted with water and extracted with ethyl acetate (2x). The combined organic layers were washed with water (1x) and brine (1x), then dried over sodium sulfate and concentrated. Purification by silica gel chromatography (0 to 75% ethyl acetate in hexanes) afforded the title compound (1.80 g, 72%) as a pale yellow foam. LCMS: m/z 633 (M+1). 1H NMR (D SO-d6) δ: 7.91 (m, 1 H), 7.64 (m, 1 H), 4.44 (s, 1 H), 4.15 - 4.31 (m, 2H), 3.96 (m, 1 H), 3.88 - 3.94 (m, 3H), 3.86 (m, 1 H), 3.49 - 3.66 (m, 1 H), 3.37 (m, 2H), 1.85 (d, 2H), 1.45 - 1.69 (m, 4H), 1.23 - 1.44 (m, 2H), 0.78 - 0.93 (m, 9H), 0.04 (d, 6H).
Step F
4-({4-bromo-1-methyl-6-[(trifluoromethyl)oxy]-1H-benzi idazo 1-(trans-4- hydroxycyclohexyl)-2-piperazinone
[00350] A solution of 4-({4-bromo-1 -methyl-6-[(trifluoromethyl)oxy]-1 /-/-benzimidazol-2- yl}carbonyl)-1-(fra 7S-4-{[(1 ,1-dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2-piperazinone (100 mg, 0.16 mmol) in dichloromethane (3 ml_) was treated with 4 N HCI in dioxane (0.5 mL) and stirred at rt for 1 h. The reaction mixture was concentrated and purified twice by reverse phase HPLC followed by lyophilization to afford the title compound (45 mg, 55%) as a fluffy white solid. LCMS: m/z 519 (M+1). 1H NMR (DMSO-d6) δ: 7.91 (dd, 1 H), 7.65 (d, 1 H), 4.60 (dd, 1 H), 4.44 (s, 1 H), 4.06 - 4.29 (m, 2H), 3.93 - 4.02 (m, 1 H), 3.88 - 3.93 (m, 3H), 3.78 - 3.88 (m, 1 H), 3.35 - 3.41 (m, 2H), 3.16 (d, 1 H), 1.76 - 1.97 (m, 2H), 1.42 - 1.63 (m, 4H), 1.10 - 1.33 (m, 2H).
Example 79
4-({4-(3-fluorophenyl)-1-methyl-6-[(trifluoromethy0oxy]-1H-benzimM^
(trans-4-hydroxycyclohexyl)-2-piperazinone
Figure imgf000177_0001
H
[00351] A mixture of 4-({4-bromo-1-methyl-6-[(trifluoromethyl)oxy]-1 W-benzimidazol-2- yl}carbonyl)-1-(fraA7S-4-{[(1 ,1-dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2-piperazinone (100 mg, 0.16 mmol), (3-fluorophenyl)boronic acid (44 mg, 0.32 mmol), potassium phosphate (101 mg, 0.47 mmol) and bis(tricyclohexylphosphine)palladium(ll) dichloride (11.7 mg, 0.016 mmol) in 10:1 1 ,4-dioxane/water (2.75 mL) was heated in a microwave at 120 °C for 10 min. The reaction mixture was concentrated to remove most of the dioxane, then diluted with water and extracted with dichloromethane (2x). The combined organic layers were filtered through a phase-separating tube and concentrated. The residue was purified by silica gel
chromatography (0 to 100% ethyl acetate in hexanes). This residue was dissolved in dichloromethane (3 mL) and treated with 4 N HCI in dioxane (0.5 mL). After stirring for 1 h, the reaction mixture was treated with 2 M NH3 in MeOH (1.5 mL) and concentrated. The residue was slurried in water and extracted with dichloromethane containing several drops of methanol (2x). The combined organic extracts were filtered through a phase-separating tube and concentrated. Purification by silica gel chromatography (0 to 10% ethanol in dichloromethane) to afford the title compound (63 mg, 75%) as a colorless oil which solidified. LCMS: m/z 535 (M+1 ). 1H NMR (DMSO-d6) δ: 7.90 - 8.12 (m, 2H), 7.80 - 7.90 (m, 1 H), 7.61 - 7.69 (m, 1 H), 7.50 - 7.61 (m, 1 H), 7.23 - 7.34 (m, 1 H), 4.56 - 4.64 (m, 1 H), 4.09 - 4.47 (m, 3H), 3.80 - 4.03 (m, 5H), 3.36 - 3.48 (m, 2H), 1.86 (d, 2H), 1.46 - 1.61 (m, 4H), 1.14 - 1.34 (m, 2H).
Example 80
4-({4-cyclopropyl-1-methyl-6-[(tnJluoromethyl)oxy]-1H-benzimidazol-2-yl}carb^
(trans-4-hydroxycyclohexyl)-2-piperazinone
Compound 80)
Figure imgf000178_0001
[00352] A mixture of 4-({4-bromo-1 -methyl-6-[(trifluoromethyl)oxy]-1 W-benzimidazol-2- yl}carbonyl)-1-(irans-4-{[(1 ,1-dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2-piperazinone (100 mg, 0.16 mmol), cyclopropylboronic acid (27 mg, 0.32 mmol), potassium phosphate (101 mg, 0.47 mmol) and bis(tricyclohexylphosphine)palladium(ll) dichloride (11.7 mg, 0.016 mmol) in 10:1 1 ,4-dioxane/water (2.75 mL) was heated in a microwave at 120 °C for 10 min. Additional cyclopropylboronic acid (27 mg, 0.32 mmol) was added and the mixture was reheated in the microwave at 140° for 20 min. Again, additional cyclopropylboronic acid (27 mg, 0.32 mmol) was added and the mixture was reheated in the microwave at 140 °C for 20 min. The reaction mixture was concentrated to remove most of the dioxane, then diluted with water and extracted with dichloromethane (2x). The combined organic layers were filtered through a phase- separating tube and concentrated. The residue was purified by silica gel chromatography (0 to 40% ethyl acetate in dichloromethane). This residue was dissolved in dichloromethane (5 ml_) and treated with 4 N HCI in dioxane (0.5 mL). After stirring for 1 h, the reaction mixture was treated with 2 M NH3 in MeOH (1.5 mL) and concentrated. The residue was slurried in water and extracted with dichloromethane containing several drops of methanol (2x). The combined organic extracts were filtered through a phase-separating tube and concentrated. Purification by silica gel chromatography (0 to 10% ethanol in dichloromethane) followed by a second purification by reverse phase HPLC and lyopyhilization afforded the title compound (30 mg, 40%) as a fluffy white solid. LCMS: m/z 481 (M+1). 1H NMR (DMSO-d6) δ: 7.51 (m, 1 H), 6.87 (m, 1H), 4.59 (dd, 1 H), 4.47 (s, 1 H), 3.96 - 4.28 (m, 3H), 3.79 - 3.92 (m, 4H), 3.35 - 3.43 (m, 3H), 1.78 - 1.94 (m, 2H), 1.44 - 1.62 (m, 4H), 1.01 - 1.32 (m, 6H).
EXAMPLE 81
4-{[6-cyclopropyl-1-methyl-4-(trifluoro ethyl)-1H-benzimidazol-2-yl]carbo
2-hydroxy-3-cyclopenten-1-yl]-2-piperazinone
(Compound 81)
Figure imgf000179_0001
Step A
4-{[5-cyclopropyl-7-(trifluoromethyl)-1H-benzi idazol-2^
dimethylethyl)(dimethyl)silyl]oxy}-3-cyclopenten- 1-yl)-2^iperazinon
[00353] DIPEA (4.19 mL, 24.0 mmol) was added to a mixture of 5-cyclopropyl-7- (trifluoromethyl)-1 H-benzimidazole-2-carboxylic acid (2.70 g, 8.80 mmol) and 1-((1S,2S)-2- {[(1 ,1-dimethylethyl)(dimethyl)silyl]oxy}-3-cyclopenten-1-yl)-2-piperazinone (2.372 g, 8.0 mmol) in tetrahydrofuran (80 mL) at room temperature under N2. The mixture was stirred for 30 minutes at room temperature and was then cooled to 0 °C, 2,4,6-tripropyl-1 ,3,5,2,4,6- trioxatriphosphorinane 2,4,6-trioxide (7.14 mL, 12.0 mmol) was added. The mixture was allowed to warm up to room temperature and stirred for 1 hour. Saturated NaHC03 was then added to the mixture. It was extracted with EtOAc and the extracts were dried over Na2S04. After concentration, the residue was purified by silica gel chromatography (0-50 % EtOAc in hexane) to give the desired product (3.71 g, 85 %) as an off-white solid. 1H NMR (400 MHz,
CHLOROFORM-d) δ ppm 10.46 (br. s., 1 H) 7.70 (br. s., 1 H) 7.41 (br. s„ 1 H) 5.86 - 5.94 (m, 1 H) 5.68 - 5.77 (m, 1 H) 5.02 - 5.51 (m, 2 H) 4.37 - 4.95 (m, 3 H) 3.88 - 4.24 (m, 1 H) 3.40 - 3.60 (m, 2 H) 2.63 - 2.81 (m, 1 H) 2.47 (ddd, J=16.78, 4.00, 1.85 Hz, 1 H) 2.03 - 2.17 (m, 1 H) 1.03 - 1.12 (m, 2 H) 0.83 - 0.91 (m, 9 H) 0.78 (q, J=5.27 Hz, 2 H) 0.00 - 0.11 (m, 6 H). LC/MS. m/z 549.37 (M + 1).
Step B
4-{[6-cyclopropyl-1-methyl-4-(trifluoromethyl)-1H-benzimidazol-2-yl]ca^
{[(1, 1-dimethylethyl)(dimethyl)silyl]oxy}-3-cyclopenten-1-yl)-2^iperazinone
[00354] Mel (0.632 mL, 10.12 mmol) was added to a mixture of 4-{[5-cyclopropyl-7- (trifluoromethyl)-l H-benzimidazol-2-yl]carbonyl}-1 -((1 S ,2S)-2-{[(1 , 1 - dimethylethyl)(dimethyl)silyl]oxy}-3-cyclopenten-1-yl)-2-piperazinone (3.7 g, 6.7 mmol) and K2C03 (2.80 g, 20.23 mmol) in N,N-dimethylformamide (60 mL) at room temperature under N2. The reaction mixture was stirred for 2 h, and then diluted with water and extracted with EtOAc. The combined extracts were washed with 5 % LiCI, dried over Na2S04. After concentration, the crude residue was purified by silica gel chromatography eluting with 0-60 % EtOAc in hexane to give the desired product (3.0 g, 79 %) as white foam. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.35 (s, 1 H) 7.28 - 7.33 (m, 1 H) 5.89 (d, J=2.93 Hz, 1 H) 5.71 (dt, J=6.05, 2.05 Hz, 1 H) 5.01 - 5.14 (m, 1 H) 4.22 - 4.75 (m, 4 H) 3.90 - 4.06 (m, 4 H) 3.43 - 3.67 (m, 2 H) 2.62 - 2.77 (m, 1 H) 2.37 - 2.54 (m, 1 H) 2.06 - 2.17 (m, 1 H) 1.05 - 1.14 (m, 2 H) 0.87 (s, 9 H) 0.77 - 0.83 (m, 2 H) 0.03 - 0.09 (m, 6 H). LC/MS. m/z 563.39 (M + 1 ).
Step C
4-{[6-cyclopropyl-1~methyl-4-(trifluoromethyl)-1H-benzimidazol-2-yl]carbon
hydroxy-3-cycl openten- 1-yl]-2-piperazinone
[00355] 1.0 M TBAF /THF (10.66 mL, 10.66 mmol) was added to a solution of 4-{[6- cyclopropyl-1-methyl-4-(trifluoromethyl)-1 H-benzimidazol-2-yl]carbonyl}-1-((1S,2S)-2-{[(1 ,1- dimethylethyl)(dimethyl)silyl]oxy}-3-cyclopenten-1-yl)-2-piperazinone (3.00 g, 5.33 mmol) in tetrahydrofuran (60 mL) at room temperature under N2. The mixture was stirred for 1 h, and it was then concentrated to remove most of the THF. EtOAc (100 mL) and 10 % NaHC03 (100mL) were added. The organic layer was separated and the water layer was extracted with EtOAc (3x50 mL). The combined extracts were dried over Na2S04. After concentration, the crude residue was purified by silica gel chromatography eluting with 20-90 % EtOAc (containing 5 % MeOH) in hexane to give the title compound (2.18 g, 91 %) as white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.36 (s, 1 H) 7.29 - 7.33 (m, 1 H) 5.91 - 5.97 (m, 1 H) 5.84 (dd, J=5.85, 1.76 Hz, 1 H) 4.74 - 4.95 (m, 3 H) 4.26 - 4.58 (m, 3 H) 3.94 - 4.09 (m, 4 H) 3.45 - 3.68 (m, 2 H) 2.70 - 2.81 (m, 1 H) 2.41 - 2.58 (m, 1 H) 2.08 - 2.17 (m, 1 H) 1.06 - 1.13 (m, 2 H) 0.78 - 0.84 (m, 2 H). LC/MS. m/z 449.31 (M + 1).
Example 82
4-{[6-cyclopropyl- 1-methyl-4-(trifluoromethyl) -1H-benzimidazol-2-yl]carbonyl}- 1- [(1SR,3SR,5SR)-2,2-difluorobicyclo[3.1.0]hex-3-yl]-2-piperazinone
(Compound 82)
Figure imgf000181_0001
Step A
1, 1 -dimethyl ethyl ((1RS)-1-{[methyl(methyloxy)amino]carbonyl}-3-buten-1-yl)carbamate
[00356] A solution of (2RS)-2-({[(1 ,1-dimethylethyl)oxy]carbonyl}amino)-4-pentenoic acid (30.0 g, 139 mmol) in THF (137 mL) and DCM (540 mL) was cooled to -20°C and treated with /V-methylpiperidine (16.9 mL, 139 mmol). To this solution was slowly added methyl
chloroformate (10.7 mL, 139 mmol). This was followed by slow addition of a chilled solution of dimethylhydroxylamine hydrochloride (13.6 g, 139 mmol) and /V-methylpiperidine (16.9 mL, 139 mmol) in DCM (71 mL). The mixture was allowed to warm to RT with stirring. After 2 hours the mixture was cooled to 5°C, washed with 0.2 N aqueous HCI (2x150 mL), 0.5 N aqueous NaOH (2x150 mL), brine (1x), dried over magnesium sulfate and concentrated to dryness at reduced pressure to afford the title compound as a tan solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 5.66 - 5.78 (m, 1 H) 5.03 - 5.22 (m, 3 H) 4.68 - 4.78 (m, 1 H) 3.75 (s, 3 H) 3.18 (s, 3 H) 2.40 - 2.52 (m, 1 H) 2.26 - 2.40 (m, 1 H) 1.40 (s, 9 H).
Step B
1, 1 -dimethyl ethyl [( 1RS)-2-oxo* 1-(2-propen- 1-yl)-3-buten- 1-yl]carbamate
[00357] A stirred solution of 1 , 1 -dimethylethyl (( 1 RS)-1 -
{[methyl(methyloxy)amino]carbonyl}-3-buten-1-yl)carbamate (10.0 g, 38.8 mmol) in THF (50 mL) was cooled to -78°C and treated with 1 vinylmagnesium bromide/THF (136 mL, 136 mmol). The resulting solution was slowly warmed to 15°C. The reaction mixture was then cooled in an ice water bath and added to 100 mL of chilled 3N aqueous HCI over a 5 minute period. This was followed by addition of EtOAc (40 mL). After stirring for several minutes the phases were separated. The EtOAc solution was washed with 1 :1 3N aqueous HCI/13% aqueous NaCI (1x), 13% aqueous NaCI (1x), dried over sodium sulfate and concentrated to dryness at reduced pressure to give the title compound (8.50 g, 97%) as a yellow oil. H NMR (400 MHz,
CHLOROFORM-cQ δ ppm 6.31 - 6.55 (m, 2 H) 5.87 (d, J=10.3 Hz, 1 H) 5.56 - 5.70 (m, 1 H) 5.28 (s, 1 H) 5.02 - 5.15 (m, 2 H) 4.61 - 4.72 (m, 1 H) 2.54 - 2.67 (m, 1 H) 2.29 - 2.42 (m, 1 H) 1.42 (s, 9 H).
Step C
bis( 1, 1-dime thylethyl) [( 1 RS)-2-oxo-3-cyclopenten-1-yl]imidodicarbonate
[00358] To a stirred solution of 1 ,1 -dimethylethyl [(ifiS)-2-oxo-1-(2-propen-1-yl)-3-buten- 1-yl]carbamate (8.73 g, 38.8 mmol) in DCM (87 mL) under nitrogen was added Hoveyda- Grubbs 2nd generation catalyst (0.44 g, 0.70 mmol) and the solution stirred at RT. After 45 minutes the solution was treated with an additional portion of catalyst (87 mg, 0.10 mmol). After 18 hours a third portion of catalyst was added (87 mg, 0.10 mmol). After an additional 2 hours the solution was concentrated to dryness at reduced pressure. The residue was dissolved in MeCN (76 mL) and the solution treated with dimethylaminopyridine (0.48 g, 3.9 mmol) followed by Boc-anhydride (12.7 g, 58.2 mmol). The resulting solution was stirred at RT. After 1 hour the solution was treated with an additional portion of Boc-anhydride (4.78 g, 21.9 mmol). After stirring at RT for 2 days the solvent was removed by rotary evaporation and the residue dissolved in EtOAc (100 mL). The solution was washed with saturated aqueous ammonium chloride (2x25 mL), brine (1x25 mL), and concentrated to dryness at reduced pressure. The crude residue was subjected to flash chromatography (silica gel, gradient from heptane to 8:2 heptane/EtOAc) to afford the title compound (7.66 g, 67%) as a solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.54 - 7.59 (m, 1 H) 6.21 - 6.27 (m, 1 H) 4.74 (dd, J=7.0, 3.7 Hz, 1 H) 2.93 - 3.05 (m, 1 H) 2.68 - 2.79 (m, 1 H) 1.38 - 1.51 (m, 18 H).
Step D
bis(1, 1-dimethylethyl) [(1 RS,3RS,5RS)-2-oxobicyclo[3.1.0]hex-3-yl]imidodicarbonate
[00359] To 95% sodium hydride (0.391 g, 16.3 mmol) was added anhydrous DMSO (33 mL). To this was added trimethylsulfoxonium iodide (3.91 g, 17.8 mmol) and the resulting mixture was stirred at RT for 20 minutes to give the ylide solution. To a separate vessel was added bis(1 , 1-dimethylethyl) [(1/?S)-2-oxo-3-cyclopenten-1 -yljimidodicarbonate (2.20 g, 7.4 mmol) followed by anhydrous DMSO (15.4 mL). The mixture was heated to 50°C and treated with 20 mL of the ylide solution. Additional smaller aliquots of the ylide solution were added periodically until the reaction was determined to be complete by HPLC. The mixture was cooled to RT and poured into a mixture of water (60 mL) and MTBE (100 mL). After separating the phases, the MTBE solution was washed with water (1x30 mL) and concentrated to dryness at reduced pressure. The crude material was purified by flash chromatography (silica gel, 9:1 hexane/EtOAc) to afford the title compound (1.4 g, 61 %) as a tan solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 4.55 (t, J=8.7 Hz, 1 H) 2.33 (dd, J=8.7, 2.9 Hz, 2 H) 1.98 - 2.09 (m, 1 H) 1.79 - 1.91 (m, 1 H) 1.32 - 1.55 (m, 18 H) 1.12 - 1.25 (m, 1 H) 0.85 - 0.96 (m, 1 H).
Step E
1, 1-dimethylethyl [(1 RS,3RS,5RS)-2-oxobicyclo[3.1.0]hex-3-yl]carbamate
[00360] A solution of bis(1 , 1-dimethylethyl) [(1 ftS,3RS,5RS)-2-oxobicyclo[3.1.0]hex-3- yl]imidodicarbonate (0.366 g, 1.18 mmol) in MeCN (5 mL) was treated with CeCI3-7H20 (0.438 g, 1.18 mmol) followed by sodium iodide (0.176 g, 1.18 mmol) and the resulting mixture was stirred at RT. After 16 hours the mixture was diluted with water and extracted with EtOAc (3x). The combined EtOAc extracts were dried over sodium sulfate and concentrated to dryness at reduced pressure. The crude product was subjected to flash chromatography (silica gel, gradient from hexane to EtOAc, cerric ammonium molybdate stain) to afford the title compound (0.216 g, 87%) as a light tan solid. H NMR (400 MHz, CHLOROFORM-d) δ ppm 4.82 (br. s., 1 H) 3.90 - 4.03 (m, 1 H) 2.69 (dd, J=12.5, 8.1 Hz, 1 H) 2.04 - 2.16 (m, 1 H) 1.80 - 1.94 (m, 2 H) 1.38 - 1.49 (m, 9 H) 1.19 - .34 (m, 2 H).
Step F 1, 1 -dimethyl ethyl [(1RS,3RS,5RS)-2,2-difluorobicyclo[3. 1.0]hex-3-yl) 'carbamate
[00361] A solution of 1 , 1-dimethylethyl [(1f?S,3/?S,5flS)-2-oxobicyclo[3.1.0]hex-3- yljcarbamate (210 mg, 0.994 mmol) in 1 ,2-dichloroethane (6 mL) in a screw cap polyethylene vessel was treated with diethylaminosulfur trifluoride (0.53 mL, 4.0 mmol). The resulting solution was heated to 60°C with stirring. After 18 hours the solution was cooled to RT and slowly added to a rapidly stirred mixture EtOAc and 5% aqueous sodium bicarbonate. After separating the phases the EtOAc solution was washed with water (2x), brine (1x), dried over sodium sulfate and concentrated to dryness at reduced pressure. The crude product was purified by flash chromatography (silica gel, gradient from hexane to 1 :1 hexane/EtOAc) to give the title compound (147 mg, 63%) as a tan solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 4.59 - 4.73 (m, 1 H) 3.87 - 4.08 (m, 1 H) 2.25 (dd, J=12.6, 7.7 Hz, 1 H) 1.62 - 1.79 (m, 2 H) 1.37 - 1.60 (m, 10 H) 0.71 - 0.86 (m, 2 H).
Step G
[(1RS,3RS, 5RS)-2,2-difluorobicyclo[3.1.0]hex-3-yl]amine hydrochloride
[00362] A solution of 1 ,1-dimethylethyl [(1 RS,3RS,5RS)-2,2-difluorobicyclo[3.1.0]hex-3- yljcarbamate (140 mg, 0.60 mmol) in EtOAc (4 mL) was treated with 4N HCI/dioxane (1.5 mL) and the resulting solution stirred at RT. After 6 hours the solution was concentrated to dryness at reduced pressure to afford the title compound in quantitative yield as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.76 (br. s., 3 H) 3.58 - 3.77 (m, 1 H) 2.20 (dd, J=12.8, 7.7 Hz, 1 H) 1.81 - 2.04 (m, 2 H) 1.60 - 1.74 (m, 1 H) 0.89 - 0.98 (m, 1 H) 0.74 - 0.86 (m, 1 H).
Step H
N1-[(1RS,3RS,5RS)-2,2-difluorobicyclo[3 .0]hex-3-yl]^2-[(4-nitroph
[00363] A solution of [(1 RS,3ftS,5RS)-2,2-difluorobicyclo[3.1 .0]hex-3-yl]amine hydrochloride (100 mg, 0.590 mmol), /V-[(4-nitrophenyl)sulfonyl]glycine (153 mg, 0.590 mmol), HOBt (96 mg, 0.71 mmol), and DIEA (0.31 mL, 1.8 mmol) in DMF (5 mL) was treated with EDC (136 mg, 0.708 mmol) and the resulting solution stirred at RT. After 18 hours the solution was diluted with EtOAc, washed with 5% aqueous citric acid (2x), saturated aqueous sodium bicarbonate (3x), brine (1x), dried over sodium sulfate and concentrated to dryness at reduced pressure to give the title compound (209 mg, 94%) as a tan solid. 1H NMR (400 MHz, DMSO- d6) δ ppm 8.34 - 8.45 (m, 3 H) 7.96 - 8.07 (m, 3 H) 3.98 - 4.16 (m, 1 H) 3.56 - 3.68 (m, 2 H) 1.92 (dd, J=12.5, 7.9 Hz, 1 H) 1 .62 - 1 .78 (m, 2 H) 1 .49 - 1.60 (m, 1 H) 0.68 - 0.83 (m, 2 H). Step I
RS, 3R S, 5RS)-2, 2-difluorobicyclo[3.1.0]hex-3-yl]-4-[(4-nitrophenyl)sulfonyl]-2-pip erazinone [00364] A mixture of N1-[(1 ftS,3ftS,5RS)-2,2-difluorobicyclo[3.1.0]hex-3-yl]-N2-[(4- nitrophenyl)sulfonyl]glycinamide (204 mg, 0.543 mmol), 1 ,2-dibromoethane (0.38 mL, 4.4 mmol), and Cs2C03 (708 mg, 2.17 mmol) in DMF (4 mL) was stirred at RT. After 1.5 hours the mixture was heated to 45°C. After stirring at 45°C for 18 hours the mixture was cooled to RT, diluted with EtOAc, washed with water (3x), brine (1x), dried over sodium sulfate, and concentrated to dryness at reduced pressure. The crude residue was subjected to flash chromatography (silica gel, gradient from hexane to EtOAc) to afford the title compound (125 mg, 57%) as a light yellow solid. 1H NMR (400 MHz, CHLOROFORM-cf) δ ppm 8.43 (d, =8.9 Hz, 2 H) 8.00 (d, J=8.9 Hz, 2 H) 4.94 (m, J=19.2, 11.4, 8.1 , 8.1 Hz, 1 H) 4.04 (d, .7=16.8 Hz, 1 H) 3.74 (d, J=16.8 Hz, 1 H) 3.57 - 3.70 (m, 2 H) 3.41 - 3.51 (m, 1 H) 3.20 (ddd, .7=11.6, 8.9, 2.9 Hz, 1 H) 2.12 - 2.23 (m, 1 H) 1.94 (dd, .7=12.6, 8.1 Hz, 1 H) 1.53 - 1.75 (m, 2 H) 0.79 - 0.89 (m,
2 H). ES-LCMS m/z: 402 (M+1).
Step J
1-[(1 RS, 3R S, 5RS)-2, 2-difluorobicyclo[3.1.0]hex-3-yl]~2-piperazinone
[00365] A mixture of 1-[(1 RS,3RS,5RS)-2,2-difluorobicyclo[3.1.0]hex-3-yl]-4-[(4- nitrophenyl)sulfonyl]-2-piperazinone (132 mg, 0.329 mmol), potassium carbonate (182 mg, 1.32 mmol) and thiophenol (102 pL, 0.987 mmol) in acetonitrile (5 mL) was stirred at RT. After 3 hours the mixture was filtered through a medium frit to remove solids and the filtrate concentrated to dryness at reduced pressure. The residue was subjected to flash
chromatography (silica gel, gradient from dichloromethane to 8:2 dichloromethane/EtOH) to afford 60 mg of the title compound as a tan solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 5.11 (m, .7=19.7, 11.7, 8.1 , 8.1 Hz, 1 H) 3.47 - 3.70 (m, 3 H) 3.31 (ddd, .7=11.8, 7.5, 4.4 Hz, 1 H) 3.02 - 3.16 (m, 2 H) 2.27 (td, .7=12.1 , 4.8 Hz, 1 H) 1.92 (dd, .7=12.5, 8.0 Hz, 1 H) 1.59 - 1.78 (m,
3 H) 0.92 (td, .7=3.8, 2.2 Hz, 1 H) 0.79 - 0.87 (m, 1 H).
Step K
4-{[6-cyclopropyl-1-methyl-4-(trifluoromethyl)-1H-benzimidazol-2-yl]car^
[(1SR.3SR, 5SR)-2,2-difluorobicyclo[3.1.0]hex-3- yl]-2-piperazinone
[00366] A solution of methyl 6-cyclopropyl-1 -methyl-4-(trifluoromethyl)-1 W-benzimidazole- 2-carboxylate (62.0 mg, 0.208 mmol) in THF (3 mL) was treated with 1 N aqueous NaOH (170 pL , 0.17 mmol) followed by water (2 mL). After 45 minutes the solution was treated with an additional 30 μΙ_ portion of 1 aqueous NaOH. After another 30 minutes the solution was concentrated to dryness at reduced pressure and the residue dissolved in DMF (4 ml_). The resulting solution was treated with 1-[( f?S,3RS,5 ?S)-2,2-difluorobicyclo[3.1.0]hex-3-yl]-2- piperazinone (30.0 mg, 0.139 mmol), /V,/V-diisopropylethylamine (97 pL, 0.56 mmol) and HATU (79.0 mg, 0.208 mmol) and stirred at RT. After 3 hours, the solution was diluted with EtOAc. The solution was then washed with water (3x), brine (1x), dried over sodium sulfate and concentrated to dryness at reduced pressure. The crude product was subjected to reverse phase HPLC purification (C18, MeCN/water with a 0.1 % formic acid modifier) followed by lyophilization to afford the racemic title compound (51 mg, 76%) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.17 - 7.44 (m, 2 H) 4.93 - 5.20 (m, 1 H) 4.24 - 4.91 (m, 3 H) 3.95 - 4.19 (m, 4 H) 3.47 - 3.94 (m, 2 H) 1.92 - 2.36 (m, 3 H) 1.52 - 1.83 (m, 2 H) 1.00 - 1.15 (m, 2 H) 0.69 - 0.98 (m, 4 H). ES-LCMS m/z: 483 (M+1).
Example 83
1-(3-cyclopenten-1-yl)-4-{[6-cyclopropyl-1-methyl-4-(trifluoromethy
yl]carbonyl}-2-piperazinon e
(Compound 83)
Figure imgf000186_0001
Step A
1 , 1 -dimethyl ethyl 4-(3-cyclopenten-1- yl)-3-oxo-1-piperazinecarboxylate
[00367] A mixture of 1-amino-3-cyclopentene hydrochloride (2.98 g, 24.39 mmol), methyl N-{[(1 ,1-dimethylethyl)oxy]carbonyl}-N-(2-oxoethyl)glycinate (5 g, 20.32 mmol), DIPEA (4.26 mL, 24.39 mmol) and sodium sulfate (17.32 g, 122 mmol) was stirred in MeOH (80 mL) for 2 hours, then NaBH4 (0.932 g, 24.39 mmol) was added in portions. The mixture was stirred for 2 hours then 60% NaH dispersion in oil (1.626 g, 40.6 mmol) was added in portions. After 2 hours, aqueous citric acid (10% by wt.) was added slowly to adjust pH to about 5. The mixture was extracted with EtOAc. The combined EtOAc extract was washed with brine, dried over Na2S04, filtered, concentrated and purified by silica gel chromatography (0-45 % EtOAc/Hexanes) to give 1 ,1 -dimethylethyl 4-(3-cyclopenten-1 -yl)-3-oxo-1-piperazinecarboxylate (3.21 g, 59%) as an off- white solid.
Step B
1-(3-cyclopenten- 1-yl)-2-piperazinone hydrochloride
[00368] AM HCI in 1 ,4-dioxane (20 ml_, 80 mmol) was added to a solution of 1 , 1 - dimethylethyl 4-(3-cyclopenten-1 -yl)-3-oxo-1-piperazinecarboxylate (1.6 g, 6.01 mmol) in 1 ,4- dioxane (25 mL) at room temperature. The mixture was stirred at room temperature overnight and then evaporated under reduced pressure to give 1-(3-cyclopenten-1 -yl)-2-piperazinone hydrochloride (1.3 g, 100 %) as a brown solid with some brown oil, which contained some 1 ,4- dioxane. The material was used without further purification.
Step C
1-(3-cyclopenten~1-yl)-4-{[5-cyclopropyl-7-(trifluoromethyl)-1H-benz imidazol-2-yl]carbonyl}-2- piperazinone
[00369] To a stirred solution of 5-cyclopropyl-7-(trifluoromethyl)-1 H-benzimidazole-2- carboxylic acid (3.49 g , 12.9 mmol) and 1 -(3-cyclopenten-1 -yl)-2-piperazinone hydrochloride (1.95 g, 9.64 mmol) in DMF (50 mL) was added Λ/,/V-diisopropylethylamine (8.20 mL, 46.9 mmol). After 15 minutes the solution was cooled to 0°C and 50% 1-propanephosphonic acid cyclic anhydride/EtOAc (6.98 mL, 11.7 mmol) was added dropwise. The solution was allowed to warm to RT with stirring. After 18 hours the solution was poured into water (600 mL). The resulting mixture was stirred vigorously for 15 minutes and then diluted with EtOAc (500 mL). The mixture was basified by addition of saturated aqueous sodium bicarbonate, stirred for several minutes, and the phases separated. The EtOAc solution was washed with water, brine, dried over magnesium sulfate. The original aqueous layer was extracted again with EtOAc and the organic layer separated. The EtOAc solution was washed with water, brine, dried over magnesium sulfate, and combined with the original EtOAc solution. The resulting solution was concentrated to dryness at reduced pressure. The crude material was purified by silica gel flash chromatography to give the title compound (3.55 g, 88%) as an off-white solid. ES-LCMS m/z: 419 (M+1 ).
Step D
1-(3-cyclopenten-1-yl)-4-{[6-cyclopropyl-1- ethyl -(trifluoromethyl)-1H
yl]carbonyl}-2-piperaz inone [00370] A mixture of 1-(3-cyclopenten-1-yl)-4-{[5-cyclopropyl-7-(trifluoromethyl)-1 H- benzimidazol-2-yl]carbonyl}-2-piperazinone (3.45 g, 8.25 mmol) , potassium carbonate (3.42 g, 24.7 mmol), and methyl iodide (0.619 mL, 9.89 mmol) in DMF (30 mL) was stirred at RT. After 4 hours the reaction mixture was diluted with water (500 mL) followed by EtOAc (300 mL). After stirring briefly, the EtOAc solution was separated, washed with water (2x), brine (1x), dried over magnesium sulfate, and concentrated to dryness at reduced pressure. The crude product was purified by flash chromatography (silica gel, gradient from hexane/EtOAc to 9:1 EtOAc/MeOH) to afford the title compound (2.85 g, 80%) as a white solid. H NMR (400 MHz, DMSO-d6) δ ppm 7.66 (s, 1 H) 7.42 (s, 1 H) 5.69 - 5.82 (m, 2 H) 5.19 - 5.34 (m, 1 H) 4.45 (s, 1 H) 4.26 (s, 1 H) 3.79 - 4.07 (m, 5 H) 3.20 - 3.32 (m, 2 H) 2.46 - 2.61 (m, 2 H) 2.26 - 2.38 (m, 2 H) 2.11 - 2.25 (m, 1 H) 0.96 - 1.09 (m, 2 H) 0.74 - 0.91 (m, 2 H) ES-LCMS m/z: 433 (M+1).
Examples 84 and 85
4-{[6^cyclopropyl·1-methyl■4-(trifluoromethyl)-1H-benzimidazol-2-yl]carbony^}-1- [(1R,2R,3R,5R)-2-hydroxybicyclo[3.1.0]hex-3-yl]-2-piperazinone and 4-{[6-cyclopropyl-1- methyl-4-(trifluoromethyl)- 1H-benzimidazol-2-yl]carbonyl}-1-[(1S,2S,3S,5S)-2- hydroxybicyclo[3.1.0]hex-3-yl]-2-piperazinone
(Compounds 84 and 85)
Figure imgf000188_0001
Step A
4-{[6-cyclopropyl-1-methyl-4- (trifluoromethyl)- 1H-benz imidazol-2-yl]carbonyl}-1-[(1RS, 2RS)-2- hydroxy-3-cyclopenten- 1-yl]-2-piperazinone
[00371] A mixture of 1 -(3-cyclopenten-1 -yl)-4-{[6-cyclopropyl-1 -methyl-4-(trifluoromethyl)- 1/-/-benzimidazol-2-yl]carbonyl}-2-piperazinone (0.720 g, 1.67 mmol) and selenium dioxide (0.369 g, 3.33 mmol) in 450:10:1 dioxane/water/pyridine (150 mL) in a sealed vessel was heated to 100°C with stirring. After 7 hours the solution was cooled to RT, stirred for an additional 0 hours, diluted with EtOAc and filtered through celite to remove solids. The filtrate was concentrated to dryness at reduced pressure. The residue was dissolved in EtOAc. The solution was washed with 10% aqueous citric acid (2x), saturated aqueous sodium bicarbonate (2x), dried over sodium sulfate and concentrated to dryness at reduced pressure to afford a yellow-brown residue. This material was subjected to flash chromatography (silica gel, gradient from DCM to 9:1 DCM/EtOH) to afford the racemic title compound (0.671 g, 90%) as a yellow foam. ES-LCMS m/z: 449 (M+1).
Step B
4-{[6-cyclopropyl-1-methyl-4-(trifluoromethyl)-1H-benzim^^
2-hydroxybicyclo[3.1.0]hex-3-yl]-2-piperazinone and 4-{[6-cyclopropyl-1-methyl-4- (trifluoromethyl)-1H-benzimidazol-2-yl]carbonyl}- 1-[( 1 S, 2S, 3S, 5S)-2-hydroxybicyc lo[3.1.0]hex-3- yl]-2-piperaz inone
[00372] A solution of 4-{[6-cyclopropyl-1 -methyl-4-(trifluoromethyl)-1 H-benzimidazol-2- yl]carbonyl}-1-[(1 RS,2RS)-2-hydroxy-3-cyclopenten-1-yl]-2-piperazinone (0.600 g, 1.34 mmol) in anhydrous dichloromethane (45 mL) was cooled in an ice water bath and treated with 1 M diethylzinc/hexane (6.70 mL, 6.70 mmol) by dropwise addition over 10 minutes. After 15 minutes at 0°C, the solution was treated with a solution of diiodomethane (1.10 mL, 13.4 mmol) in dichloromethane (10 mL) by dropwise addition over 5 minutes. The solution was then stirred at 0°C for 15 minutes and allowed to warm to RT. After 3 hours the solution was diluted with saturated aqueous ammonium chloride followed by EtOAc. The mixture was stirred vigorously for several minutes and the phases separated. The EtOAc solution was washed with water (1x), brine (1x), dried over sodium sulfate and concentrated to dryness at reduced pressure. The crude residue was purified by flash chromatography (silica gel, gradient from DCM to 9:1 DCM/MeOH) to afford the racemic product (344 mg, 54%) as a light yellow foam. This material was subjected to chiral separation by supercritical fluid chromatograpy (Chiral Technologies AD- H column, MeOH/chloroform/C02 eluent, 140 bars, 40°C), to afford 103 mg of 4-{[6- cyclopropyl-1-methyl-4-(trifluoromethyl)-1H-benzimidazol-2-yl]carbonyl}-1-[(1f?,2R,3 ,5/?)-2- hydroxybicyclo[3.1.0]hex-3-yl]-2-piperazinone as the earlier eluting enantiomer (example 84) and 102 mg of 4-{[6-cyclopropyl-1-methyl-4-(trifluoromethyl)-1 -benzimidazol-2-yl]carbonyl}-1- [(1 S,2S,3S,5S)-2-hydroxybicyclo[3.1.0]hex-3-yl]-2-piperazinone as the later eluting enantiomer (example 85). Analytical data for Example 84: 1H NMR (400 MHz, METHANOL-^) δ ppm 7.57 (s, 1 H) 7.40 (s, 1 H) 4.43 - 4.68 (m, 2 H) 4.13 - 4.43 (m, 3 H) 3.78 - 4.02 (m, 4 H) 3.43 - 3.62 (m, 2 H) 2.10 - 2.23 (m, 1 H) 1.81 - 2.05 (m, 2 H) 1.45 - 1.56 (m, 1 H) 1.31 - 1.43 (m, 1 H) 1.02 - 1.18 (m, 2 H) 0.68 - 0.90 (m, 3 H) 0.40 - 0.54 (m, 1 H). ES-LCMS m/z: 463 (M+1). Analytical data for Example 85: 1H NMR (400 MHz, METHANOL-^) δ ppm 7.57 (s, 1 H) 7.39 (s, 1 H) 4.43 - 4.65 (m, 2 H) 4.10 - 4.43 (m, 3 H) 3.77 - 4.05 (m, 4 H) 3.41 - 3.62 (m, 2 H) 2.10 - 2.25 (m, 1 H) 1.81 - 2.08 (m, 2 H) 1.44 - 1.55 (m, 1 H) 1.32 - 1.44 (m, 1 H) 1.02 - 1.17 (m, 2 H) 0.68 - 0.92 (m, 3 H) 0.39 - 0.54 (m, 1 H). ES-LCMS m/z: 463 (M+1).
[00373] Alternatively, 4-{[6-cyclopropyl-1 -methyl-4-(trifluoromethyl)-1 H-benzimidazol-2- yl]carbonyl}-1-[(1 S,2S,3S,5S)-2-hydroxybicyclo[3.1.0]hex-3-yl]-2-piperazinone (Example 85) can be prepared as a single enantiomer according to the following route:
Step A
(4R)-3-(4-pentenoyl)-4-(phenylmethyl)-1,3-oxazolidin-2-one
[00374] To a solution of (4R)-4-(phenylmethyl)-1 ,3-oxazolidin-2-one (2.5 g, 13.97 mmol) in tetrahydrofuran (THF) (40 mL) under N2 at -78 °C was added drop-wise 1.6M n-butyl lithium in hexane (9.17 mL, 14.67 mmol), and the resulting mixture was stirred at -78 °C for 1 hour. A solution of 4-pentenoyl chloride (1.589 mL, 14.11 mmol) in tetrahydrofuran (THF) (10 mL) was added drop-wise. After stirring at -78 °C for 1 hour, the reaction mixture was allowed to warm up to room temperature and stirred overnight, poured into water, and the mixture was extracted with ethyl acetate (2 x 60 mL). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, concentrated and purified by silica gel chromatography (0-20 % ethyl acetate/hexanes) to give (4R)-3-(4-pentenoyl)-4-(phenylmethyl)-1 ,3-oxazolidin-2-one (3.29 g, 91 %) as a light yellow oil.
Step B
(4R)-3-[(2S, 3S, 4E)-3-hydroxy-5-phe nyl-2-(2-propen- 1-yl)-4-pentenoyl]-4-(phenyl methyl)- 1, 3- oxazolidin-2-one
[00375] A mixture of (4R)-3-(4-pentenoyl)-4-(phenylmethyl)-1 ,3-oxazolidin-2-one (3.29 g, 12.69 mmol), magnesium chloride (0.121 g, 1.269 mmol), NaSbF6 (0.985 g, 3.81 mmol), triethylamine (3.54 mL, 25.4 mmol), (fra/7s)-cinnamaldehyde (1.936 mL, 15.23 mmol) and trimethylsilyl chloride (2.43 mL, 19.0 mmol) in ethyl acetate (58 mL) was stirred at room temperature for 17 hours. The reaction mixture was diluted with ethyl acetate, and filtered through a pad of celite. The filtrate was concentrated and the residue was dissolved in 50 mL of methanol with some ethyl acetate. Trifluoroacetic acid (0.1 mL) was added, and the solution was stirred at room temperature for 1 hour, concentrated and purified by silica gel
chromatography (0-20 % ethyl acetate/Hexanes) to give (4R)-3-[(2S,3S,4E)-3-hydroxy-5- phenyl-2-(2-propen-1-yl)-4-pentenoyl]-4-(phenylmethyl)-1 ,3-oxazolidin-2-one (4.38 g, 88%) as a yellow viscous glass-like oil. ES-LCMS m/z: 374 (M+1-H20). Step C
(4R)-3-{[(1 S, 2S)-2-hydroxy-3-cyclopenten- 1- yl]carbonyl}-4-(phenylmethyl)- 1, 3-oxazolidin-2-one
[00376] A solution of (4R)-3-[(2S,3S,4E)-3-hydroxy-5-phenyl-2-(2-propen-1-yl)-4- pentenoyl]-4-(phenylmethyl)-1 ,3-oxazolidin-2-one (495 mg, 1.264 mmol) in toluene (60 mL) was degassed three times with nitrogen, then 1 ,3-Bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2- ylidene[2-(i-propoxy)-5-(N,N-dimethylaminosulfonyl)phenyl]methyleneruthenium(ll) dichloride (Zhan Catalyst-I B) (65 mg, 0.089 mmol) was added and the mixture was degassed twice and backfilled with nitrogen and stirred at room temperature overnight, concentrated and purified by silica gel chromatography (0-40 % ethyl acetate/hexanes) to give (4R)-3-{[(1 S,2S)-2-hydroxy-3- cyclopenten-1-yl]carbonyl}-4-(phenylmethyl)-1 ,3-oxazolidin-2-one (340 mg, 94%) as a dark brown oil, which solidified upon standing. ES-LCMS m/z: 270 (M+1-H20).
Step D
(4R)-3-{[(1S,2S,3S,5S)-2-hydroxybicyclo[3.1.0]hex-3-yl]carbonyl}-4-(phen
oxazolidin-2-one
[00377] A solution of (4R)-3-{[(1S,2S)-2-hydroxy-3-cyclopenten-1-yl]carbonyl}-4- (phenylmethyl)-1 ,3-oxazolidin-2-one (330 mg, 1.149 mmol) in dichloromethane (DCM) (15 mL) was cooled in an ice bath and treated with 1/W diethylzinc in hexane (5.74 mL, 5.74 mmol) drop- wise. After stirring at 0 °C for 20 minutes, diiodomethane (0.936 mL, 11.49 mmol) was added drop-wise. The resulting cloudy solution was stirred at 0 °C for 20 minutes and allowed to warm up to room temperature. After 6 hours, the reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, concentrated and purified by silica gel chromatography (0-40 % ethyl acetate/hexanes) to give (4R)-3-{[(1 S,2S,3S,5S)-2- hydroxybicyclo[3.1.0]hex-3-yl]carbonyl}-4-(phenylmethyl)-1 ,3-oxazolidin-2-one (308 mg, 89%) as a light brown viscous oil. ES-LCMS m/z: 284 (M+1-H20).
Step E
(4R)-3-[((1S,2S,3S, 5S)-2-{[(1, 1-dimethylethyl)(dimethyl)silyl]oxy}bicyclo[3.1.0]hex-3- yl)carbonyl ]-4-(phenylmethyl)-1, 3-oxaz olidin-2-one
[00378] To a stirred solution of (4R)-3-{[(1S,2S,3S,5S)-2-hydroxybicyclo[3.1.0]hex-3- yl]carbonyl}-4-(phenylmethyl)-1 ,3-oxazolidin-2-one (308 mg, 1.022 mmol) and 2,6-lutidine (0.475 mL, 4.09 mmol) in dichloromethane (DCM) (5 mL) at 0 °C was added (1 ,1- dimethylethyl)(dimethyl)silyl trifluoromethanesulfonate (0.587 mL, 2.56 mmol) under nitrogen. The resulting reaction mixture was stirred at 0 °C for 30 minutes and at room temperature for 1 hour. The reaction mixture was quenched with methanol (0.3 mL) and poured into water and extracted with ether (75 mL and 25 mL). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, concentrated, and purified by silica gel
chromatography (0-20 % ethyl acetate/hexanes) to give (4R)-3-[((1S,2S,3S,5S)-2-{[(1 ,1- dimethylethyl)(dimethyl)silyl]oxy} bicyclo[3.1.0]hex-3-yl)carbonyl]-4-(phenylmethyl)-1 ,3- oxazolidin-2-one (406 mg, 96%) as a colorless oil. ES-LCMS m/z: 416 (M+1).
Step F
(1S,2S,3S,5S)-2-{[(1, 1-dimethylethyl)(dimethyl)silyl]oxy}bicyclo[3.1.0]hexane-3-carboxylic ac id
[00379] To a solution of (4R)-3-[((1 S,2S,3S,5S)-2-{[(1 ,1-dimethylethyl)(dimethyl)silyl]oxy} bicyclo[3.1.0]hex-3-yl)carbonyl]-4-(phenylmethyl)-1 ,3-oxazolidin-2-one (405 mg, 0.974 mmol) in tetrahydrofuran (THF) (6 mL) and water (2 mL) at 0 °C was added 30% aqueous hydrogen peroxide (0.796 mL, 7.80 mmol) drop-wise, followed by addition of lithium hydroxide monohydrate (167 mg, 3.90 mmol) in water (1 mL). After stirring for 1 hour at 0 °C, the reaction mixture was stirred at room temperature overnight. The excess hydrogen peroxide was quenched by the addition of saturated aqueous sodium thiosulfate (4 mL). The reaction mixture was then adjusted to pH ~14 with 0.1 N sodium hydroxide (0.2 mL) and washed with ethyl ether (40 mL). The aqueous layer was acidified to pH ~ 3 with 1 M KHS04, and extracted with ethyl acetate (3 x 40 mL). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated to give (1 S,2S,3S,5S)-2-{[(1 ,1-dimethylethyl)
(dimethyl)silyl]oxy}bicycle[3.1.0]hexane-3-carboxylic acid (220 mg, 88%) as a colorless viscous oil.
Step G
((1S.2S.3S, 5S)-2-{[(1, 1-dimethylethyl)(dimethyl)silyl]oxy}bicyclo[3.1.0]hex-3-yl)amine
[00380] To a solution of (1S,2S,3S,5S)-2-{[(1 ,1-dimethylethyl)(dimethyl)silyl]oxy} bicyclo[3.1.0]hexane-3-carboxylic acid (10 g, 39.0 mmol) in toluene (180 mL) was added triethylamine (6.52 mL, 46.8 mmol) and diphenylphosphoryl azide (8.43 mL, 39.0 mmol). The solution was heated to 80 °C for 5 hours then cooled to 0 °C in an ice bath. To this was added potassium trimethylsilanolate (10.01 g, 78 mmol) in 90 mL of tetrahydrofuran, and the mixture was stirred at room temperature for 1 hour. 15% aqueous citric acid was added. The resulting mixture was then made basic with aqueous sodium hydroxide and extracted with ethyl ether. The organic layer was separated and the aqueous layer was evaporated to a small volume and extracted again with ethyl ether. The combined organic layers were washed with small amount of brine, dried over sodium sulfate, filtered and evaporated to afford ((1 S,2S,3S,5S)-2-{[(1 ,1- dimethylethyl)(dimethyl)silyl]oxy}bicyclo[3.1.0]hex-3-yl)amine (8.86 g, 95%) as a pale yellow oil.
Step H
N1-((1S, 2S, 3S, 5S)-2-{[(1, 1 -dimethyl ethyl) (dimethyl)silyl]oxy}bicyclo[3.1.0]hex-3-yl)-N2-[(4- nitrophenyl ) sulfonyljglycinamide
[00381] N-[(4-nitrophenyl)sulfonyl]glycine (10.14 g, 39.0 mmol), ((1S,2S,3S,5S)-2-{[(1 ,1- dimethylethyl)(dimethyl)silyl]oxy}bicyclo[3.1.0]hex-3-yl)amine (8.86 g, 39.0 mmol), 1- hydroxybenzotriazole (6.56 g, 42.9 mmol) and N-ethyl-N-(1-methylethyl)-2-propanamine (8.17 mL, 46.8 mmol) were combined in N,N-dimethylformamide (DMF) (187 ml_). To this solution was added 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (8.22 g, 42.9 mmol), and the reaction mixture was stirred for 5 hours, diluted with ethyl acetate and poured into water. The organic layer was separated and washed with saturated aqueous sodium bicarbonate, brine and dried over sodium sulfate, filtered and evaporated to dryness to yield a solid, which was triturated with Et20 to afford N1-((1S,2S,3S,5S)-2-{[(1 ,1- dimethylethyl)(dimethyl)silyl]oxy}bicyclo[3.1.0]hex-3-yl)-N2-[(4-nitrophenyl)sulfonyl]glycinamide (18.26 g, quant.), which was used without further purification. ES-LCMS m/z: 470 (M+1).
Step I
1-((1S,2S,3S,5S)-2-{[(1, 1-dimethylethyl)(dimethyl)silyl]oxy}bicyclo[3 .0]hex-3-yl)-^^ nitrophenyl)sulfonyl]-2-piperazinone
[00382] N1-((1S,2S,3S,5S)-2-{[(1 ,1-dimethylethyl)(dimethyl)silyl]oxy}bicyclo[3.1.0]hex-3- yl)-N2-[(4-nitrophenyl)sulfonyl]glycinamide (18.26 g, 38.9 mmol), 1 ,2-dibromoethane (26.8 mL, 311 mmol), and cesium carbonate (50.7 g, 156 mmol) were combined in N,N- dimethylformamide (DMF) (200 mL) and stirred at room temperature for 6 hours. The reaction mixture was diluted with ethyl acetate and washed with water, brine and dried over sodium sulfate, filtered and evaporated to dryness to give a solid, which was triturated with ethyl ether and hexanes to afford a solid. The filtrate was evaporated to an oil, which was purified by silica gel chromatography eluting with ethyl acetate and hexanes to afford a solid, which was combined with the triturated solid to yield 1-((1S,2S,3S,5S)-2-{[(1 ,1- dimethylethyl)(dimethyl)silyl]oxy}bicyclo[3.1.0]hex-3-yl)-4-[(4-nitrophenyl)sulfonyl]-2- piperazinone (15.8 g, 82%) as a yellow solid. ES-LCMS m/z: 496 (M+1). Step J
1-((1S,2S,3S,5S)-2-{[(1 -dimethylethyl)(dimethyl)silyl]oxy^
piperazinone
[00383] A solution of 1-((1S,2S,3S,5S)-2-{[(1 ,1-dimethyiethyl)(dimethyl)silyl]oxy} bicyclo[3.1.0]hex-3-yl)-4-[(4-nitrophenyl)sulfonyl]-2-piperazinone (300 mg, 0.605 mmol) in acetonitrile (6 mL) was treated with thiophenol (0.187 mL, 1.816 mmol), followed by addition of potassium carbonate (335 mg, 2.42 mmol). The reaction mixture was stirred at room temperature for 5 hours. The mixture was diluted with dichloromethane and filtered through a pad of celite. The filtrate was dried over sodium sulfate, filtered, concentrated and purified by silica gel chromatography (0-5 % 2M ammonia in methanol/dichloromethane) to give 1- ((1S,2S,3S,5S)-2-{[(1 ,1-dimethylethyl)(dimethyl)silyl]oxy} bicyclo[3.1.0]hex-3-yl)-2-piperazinone (160 mg, 85%) as a colorless oil.
Step K
4-{[6-cyclopropyl-1-methyl-4-(trifluoromethyl)-1H-benzim 1-((1 S, 2S, 3S, 5S)-
2-{[( 1, 1-dimethylethyl)(dimethyl)silyl]oxy}bicyclo[3.1.0]hex-3-yl)-2-piperazinone
[00384] Methyl 6-cyclopropyl-1-methyl-4-(trifluoromethyl)-1 f -benzimidazole-2- carboxylate (0.98 g, 3.3 mmol) was dissolved in tetrahydrofuran (10 mL). Water (10 mL) was added followed by 1 M sodium hydroxide (3.94 mL, 3.94 mmol) and the mixture stirred at room temperature for 15 minutes. The mixture was concentrated and co-evaporated 1 time with toluene. N,N-Dimethylformamide (20 mL), N,N-diisopropylethylamine (2.30 mL, 13.1 mmol), and 1-((1 S,2S,3S,5S)-2-{[(1 ,1-dimethylethyl)(dimethyl)silyl]oxy}bicyclo[3.1.0]hex-3-yl)-2- piperazinone (1.12 g, 3.61 mmol) were added to the residue before N-[(dimethylamino)(3H- [1 ,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylidene]-N-methylmethanaminium hexafluorophosphate (HATU) (1.50 g, 3.94 mmol) was added in one portion. The mixture was stirred for 2 hours and diluted with ethyl acetate. The organic layer was washed with brine, washed with 5% lithium chloride, dried over sodium sulfate, and concentrated. The residue was purified by silica chromatography eluting with 20% ethyl acetate in dichloromethane. Fractions were
concentrated to give the title compound (1.4 g, 74%). LCMS: m/z 577 (M+1). 1H NMR (DMSO- d6) δ ppm 7.66 (1 H, s), 7.43 (1 H, s), 4.58 - 4.72 (1 H, m), 4.38 - 4.50 (1 H, m), 4.02 - 4.36 (3 H, m), 3.90 (4 H, s), 3.39 - 3.53 (2 H, m), 2.13 - 2.28 (1 H, m), 1.88 - 2.08 (1 H, m), 1.63 - 1.77 (1 H, m), 1.34 - 1.44 (1 H, m), 1.21 - 1.34 (1 H, m), 0.99 - 1.11 (2 H, m), 0.84 (2 H, d), 0.81 (9 H, s), 0.55 - 0.64 (1 H, m), 0.37 - 0.47 (1 H, m), 0.03 - 0.07 (3 H, m), 0.01 (3 H, s). Step L
4-{[6-cyclopropyl-1-methyl-4-(trifluoromet yl)-1H-benz imidazol-2-yl]carbonyl}- 1-[(1S, 2S, 3S, 5S)-
2-hydroxybicyclo[3.1.0]hex-3-yl]-2-piperazinone
[00385] 4-{[6-cyclopropyl-1 -methyl-4-(trifluoromethyl)-1 H-benzimidazol-2-yl]carbonyl}-1 - ((1 S,2S,3S,5S)-2-{[(1 -dimethylethyl)(dimethyl)silyl]oxy}bicyclo[3.1.0]hex-3-yl)-2-piperazino (1.4 g, 2.4 mmol) was dissolved in tetrahydrofuran (25 mL) and cooled to 5 °C before tetrabutylammonium fluoride (TBAF) (7.28 mL, 7.28 mmol) was added drop-wise. The mixture was allowed to warm to room temperature and stirred for 2 hours. The mixture was quenched with water and extracted 3 times with ethyl acetate. The combined organic layers were washed with water, washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by silica chromatography eluting with a gradient of 0% to 10% ethanol in
dichloromethane. Fractions were concentrated. The residue was slurried in ethyl ether and triturated with a stir bar overnight. White solids were collected by filtration, washed with ether, and dried to give the title compound (750 mg, 66%). LCMS: m/z 463 (M+1). 1H NMR (DMSO-cfe) δ ppm 7.67 (1 H, s), 7.43 (1 H, d), 4.77 (1 H, dd), 4.30 - 4.58 (2 H, m), 3.97 - 4.24 (3 H, m), 3.91 (3 H, s), 3.62 - 3.86 (1 H, m), 3.35 - 3.48 (2 H, m), 2.20 (1 H, t), 1.84 (1 H, d), 1.66 - 1.77 (1 H, m), 1.37 (1 H, br. s.), 1.24 (1 H, br. s.), 1.00 - 1.08 (2 H, m), 0.79 - 0.89 (2 H, m), 0.61 (1 H, t), 0.30 - 0.44 (1 H, m).
Administration and Formulation
[00386] The chemical entities provided herein may inhibit viral replication by inhibiting the enzymes involved in replication, such as the non-structural proteins including RNA dependent RNA polymerase. They may also inhibit other enzymes utilized in the activity or proliferation of viruses in the Flaviviridae family, such as HCV. The chemical entities are administered at a therapeutically effective dosage, e.g., a dosage sufficient to provide treatment for the disease.
[00387] In another embodiment, there is provided a pharmaceutical composition comprising a pharmaceutically acceptable diluent and a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
[00388] The compounds of the present invention can also be supplied in the form of a pharmaceutically acceptable salt. The terms "pharmaceutically acceptable salt" refer to salts prepared from pharmaceutically acceptable inorganic and organic acids and bases.
[00389] Pharmaceutically acceptable inorganic bases include metallic ions. More preferred metallic ions include, but are not limited to, appropriate alkali metal salts, alkaline earth metal salts and other physiological acceptable metal ions. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like and in their usual valences. Exemplary salts include aluminum, calcium, lithium, magnesium, potassium, sodium and zinc. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts.
[00390] Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, including in part, trimethylamine, diethylamine, N, N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine; substituted amines including naturally occurring substituted amines; cyclic amines; quaternary ammonium cations; and basic ion exchange resins, such as arginine, betaine, caffeine, choline, Ν,Ν-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N- ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.
[00391] Illustrative pharmaceutically acceptable acid addition salts of the compounds of the present invention can be prepared from the following acids, including, without limitation formic, acetic, propionic, benzoic, succinic, glycolic, gluconic, lactic, maleic, malic, tartaric, citric, nitic, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, hydrochloric, hydrobromic, hydroiodic, isocitric, trifluoroacetic, pamoic, propionic, anthranilic, mesylic, oxalacetic, oleic, stearic, salicylic, p-hydroxybenzoic, nicotinic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, phosphoric, phosphonic, ethanesulfonic, benzenesulfonic, pantothenic, toluenesulfonic, 2-hydroxyethanesulfonic, sulfanilic, sulfuric, salicylic,
cyclohexylaminosulfonic, algenic, β-hydroxybutyric, galactaric and galacturonic acids. Preferred pharmaceutically acceptable salts include the salts of hydrochloric acid and trifluoroacetic acid. All of the above salts can be prepared by those skilled in the art by conventional means from the corresponding compound of the present invention. For example, the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. The salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionisation in the salt may vary from completely ionised to almost non-ionised. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p.1418, the disclosure of which is hereby incorporated by reference only with regards to the lists of suitable salts.
[00392] The compounds of the invention may exist in both unsolvated and solvated forms. The term 'solvate' is used herein to describe a molecular complex comprising the compound of the invention and one or more pharmaceutically acceptable solvent molecules, for example, ethanol. The term 'hydrate' is employed when said solvent is water. Pharmaceutically acceptable solvates include hydrates and other solvates wherein the solvent of crystallization may be isotopically substituted, e.g. D20, d6-acetone, d6-DMSO.
[00393] Compounds of formula (I) containing one or more asymmetric carbon atoms can exist as two or more stereoisomers. Where a compound of formula (I) contains an alkenyl or alkenylene group or a cycloalkyl group, geometric cis/trans (or Z/E) isomers are possible.
Where the compound contains, for example, a keto or oxime group or an aromatic moiety, tautomeric isomerism ('tautomerism') can occur. It follows that a single compound may exhibit more than one type of isomerism.
[00394] Included within the scope of the claimed compounds present invention are all stereoisomers, geometric isomers and tautomeric forms of the compounds of formula (I), including compounds exhibiting more than one type of isomerism, and mixtures of one or more thereof. Also included are acid addition or base salts wherein the counterion is optically active, for example, D-lactate or L-lysine, or racemic, for example, DL-tartrate or DL-arginine.
[00395] Cis/trans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallisation.
[00396] Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid
chromatography (HPLC).
[00397] Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound of formula (I) contains an acidic or basic moiety, an acid or base such as tartaric acid or 1- phenylethylamine. The resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to a skilled person. [00398] Chiral compounds of the invention (and chiral precursors thereof) may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on a resin with an asymmetric stationary phase and with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% isopropanol, typically from 2 to 20%, and from 0 to 5% of an alkylamine, typically 0.1 % diethylamine. Concentration of the eluate affords the enriched mixture.
[00399] Mixtures of stereoisomers may be separated by conventional techniques known to those skilled in the art. [see, for example, "Stereochemistry of Organic Compounds" by E L Eliel (Wiley, New York, 1994).]
[00400] The present invention includes all pharmaceutically acceptable isotopically- labelled compounds of formula (I) wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
[00401] Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as 2H and 3H, carbon, such as C, 13C and 14C, chlorine, such as 36CI, fluorine, such as 8F, iodine, such as 23l and 125l, nitrogen, such as 13N and 15N, oxygen, such as 150, 170 and 180, phosphorus, such as 32P, and sulphur, such as 35S.
[00402] Certain isotopically-labelled compounds of formula (I), for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, i.e. 3H, and carbon-14, i.e. 4C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
[00403] Substitution with heavier isotopes such as deuterium, i.e. 2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
[00404] Isotopically-labelled 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- labelled reagents in place of the non-labelled reagent previously employed.
[00405] The compounds of the present invention may be administered as prodrugs. Thus, certain derivatives of compounds of formula (I) which may have little or no
pharmacological activity themselves can, when administered into or onto the body, be converted into compounds of formula (I) having the desired activity, for example, by hydrolytic cleavage. Such derivatives are referred to as 'prodrugs'. [00406] Administration of the chemical entities described herein can be via any of the accepted modes of administration for agents that serve similar utilities including, but not limited to, orally, sublingually, subcutaneously, intravenously, intranasally, topically, transdermal^, intraperitoneally, intramuscularly, intrapulmonarilly, vaginally, rectally, or intraocularly. In some embodiments, oral or parenteral administration is used.
[00407] Pharmaceutical compositions or formulations include solid, semi-solid, liquid and aerosol dosage forms, such as, e.g., tablets, capsules, powders, liquids, suspensions, suppositories, aerosols or the like. The chemical entities can also be administered in sustained or controlled release dosage forms, including depot injections, osmotic pumps, pills, transdermal (including electrotransport) patches, and the like, for prolonged and/or timed, pulsed
administration at a predetermined rate. In certain embodiments, the compositions are provided in unit dosage forms suitable for single administration of a precise dose.
[00408] The chemical entities described herein can be administered either alone or more typically in combination with a conventional pharmaceutical carrier, excipient or the like (e.g., mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, sodium crosscarmellose, glucose, gelatin, sucrose, magnesium carbonate, and the like). If desired, the pharmaceutical composition can also contain minor amounts of nontoxic auxiliary substances such as wetting agents, emulsifying agents, solubilizing agents, pH buffering agents and the like (e.g., sodium acetate, sodium citrate, cyclodextrine derivatives, sorbitan monolaurate, triethanolamine acetate, triethanolamine oleate, and the like). Generally, depending on the intended mode of administration, the pharmaceutical composition will contain about 0.005% to 95%; in certain embodiments, about 0.5% to 50% by weight of a chemical entity. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania.
[00409] In certain embodiments, the compositions will take the form of a pill or tablet and thus the composition will contain, along with the active ingredient, a diluent such as lactose, sucrose, dicalcium phosphate, or the like; a lubricant such as magnesium stearate or the like; and a binder such as starch, gum acacia, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives or the like. In another solid dosage form, a powder, marume, solution or suspension (e.g., in propylene carbonate, vegetable oils or triglycerides) is encapsulated in a gelatin capsule.
[00410] Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing, etc. at least one chemical entity and optional pharmaceutical adjuvants in a carrier (e.g., water, saline, aqueous dextrose, glycerol, glycols, ethanol or the like) to form a solution or suspension. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, as emulsions, or in solid forms suitable for dissolution or suspension in liquid prior to injection. The percentage of chemical entities contained in such parenteral compositions is highly dependent on the specific nature thereof, as well as the activity of the chemical entities and the needs of the subject. However, percentages of active ingredient of 0.01 % to 10% in solution are employable, and will be higher if the composition is a solid which will be subsequently diluted to the above percentages. In certain embodiments, the composition will comprise from about 0.2 to 2% of the active agent in solution.
[00411] Pharmaceutical compositions of the chemical entities described herein may also be administered to the respiratory tract as an aerosol or solution for a nebulizer, or as a microfine powder for insufflation, alone or in combination with an inert carrier such as lactose. In such a case, the particles of the pharmaceutical composition have diameters of less than 50 microns, in certain embodiments, less than 10 microns.
[00412] In general, the chemical entities provided will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities. The actual amount of the chemical entity, i.e., the active ingredient, will depend upon numerous factors such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the chemical entity used, the route and form of administration, and other factors. The drug can be administered more than once a day, such as once or twice a day.
[00413] Therapeutically effective amounts of the chemical entities described herein may range from approximately 0.01 to 200 mg per kilogram body weight of the recipient per day; such as about 0.01-100 mg/kg/day, for example, from about 0.1 to 50 mg/kg/day. Thus, for administration to a 70 kg person, the dosage range may be about 7-3500 mg per day.
[00414] In general, the chemical entities will be administered as pharmaceutical compositions by any one of the following routes: oral, systemic (e.g., transdermal, intranasal or by suppository), or parenteral (e.g., intramuscular, intravenous or subcutaneous) administration. In certain embodiments, oral administration with a convenient daily dosage regimen that can be adjusted according to the degree of affliction may be used. Compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate compositions. Another manner for administering the provided chemical entities is inhalation.
[00415] The choice of formulation depends on various factors such as the mode of drug administration and bioavailability of the drug substance. For delivery via inhalation the chemical entity can be formulated as liquid solution, suspensions, aerosol propellants or dry powder and loaded into a suitable dispenser for administration. There are several types of pharmaceutical inhalation devices-nebulizer inhalers, metered dose inhalers (MDI) and dry powder inhalers (DPI). Nebulizer devices produce a stream of high velocity air that causes the therapeutic agents (which are formulated in a liquid form) to spray as a mist that is carried into the patient's respiratory tract. MDIs typically are formulation packaged with a compressed gas. Upon actuation, the device discharges a measured amount of therapeutic agent by compressed gas, thus affording a reliable method of administering a set amount of agent. DPI dispenses therapeutic agents in the form of a free flowing powder that can be dispersed in the patient's inspiratory air-stream during breathing by the device. In order to achieve a free flowing powder, the therapeutic agent is formulated with an excipient such as lactose. A measured amount of the therapeutic agent is stored in a capsule form and is dispensed with each actuation.
[00416] Recently, pharmaceutical compositions have been developed for drugs that show poor bioavailability based upon the principle that bioavailability can be increased by increasing the surface area i.e., decreasing particle size. For example, U.S. Patent No. 4,107,288 describes a pharmaceutical formulation having particles in the size range from 10 to 1 ,000 nm in which the active material is supported on a cross-linked matrix of macromolecules. U.S. Patent No. 5,145,684 describes the production of a pharmaceutical formulation in which the drug substance is pulverized to nanoparticles (average particle size of 400 nm) in the presence of a surface modifier and then dispersed in a liquid medium to give a pharmaceutical formulation that exhibits remarkably high bioavailability.
[00417] The compositions are comprised of, in general, at least one chemical entity described herein in combination with at least one pharmaceutically acceptable excipient.
Acceptable excipients are non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the at least one chemical entity described herein. Such excipient may be any solid, liquid, semi-solid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art.
[00418] Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like. Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc. Liquid carriers, for injectable solutions, include water, saline, aqueous dextrose, and glycols. [00419] Compressed gases may be used to disperse a chemical entity described herein in aerosol form. Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc. Other suitable pharmaceutical excipients and their formulations are described in Remington's
Pharmaceutical Sciences, edited by E. W. Martin (Mack Publishing Company, 18th ed., 1990).
[00420] The amount of the chemical entity in a composition can vary within the full range employed by those skilled in the art. Typically, the composition will contain, on a weight percent (wt%) basis, from about 0.01-99.99 wt% of at least one chemical entity described herein based on the total composition, with the balance being one or more suitable pharmaceutical excipients. In certain embodiments, the at least one chemical entity described herein is present at a level of about 1-80 wt%. Representative pharmaceutical compositions containing at least one chemical entity described herein are described below.
[00421] In another embodiment, there is provided a method for treating a viral infection in a mammal mediated at least in part by a virus in the Flaviviridae family of viruses, which method comprises administering to a mammal that has been diagnosed with said viral infection or is at risk of developing said viral infection a compound described herein. In another embodiment, the virus is hepatitis C virus.
[00422] In another embodiment, the method for treating a viral infection in a mammal mediated at least in part by a virus in the Flaviviridae family of viruses further comprises administration of a therapeutically effective amount of one or more agents active against hepatitis C virus. In another embodiment, the agent is an inhibitor of HCV protease, HCV polymerase, HCV helicase, HCV NS4B protein, HCV entry, HCV assembly, HCV egress, HCV replicase, HCV NS5A protein, or inosine 5'-monophosphate dehydrogenase. In another embodiment, the agent is interferon. In another embodiment, the agent is ribavirin. In yet another embodiment, the agent(s) is a combination of interferon and ribavirin that is
administered either simultaneously or sequentially.
[00423] In addition, the chemical entities described herein can be co-administered with, and the pharmaceutical compositions can include, other medicinal agents, pharmaceutical agents, adjuvants, and the like. Suitable medicinal and pharmaceutical agents include therapeutically effective amounts of one or more agents active against HCV. In some embodiments, the agent active against HCV is an inhibitor of HCV protease, HCV polymerase, HCV helicase, HCV NS4B protein, HCV entry, HCV assembly, HCV egress, HCV replicase, HCV NS5A protein, or inosine 5'-monophosphate dehydrogenase.
[00424] Active agents against HCV include ribavirin, levovirin, viramidine, thymosin alpha-1 , an inhibitor of NS3 serine protease, and inhibitor of inosine monophosphate dehydrogenase, interferon-alpha, either alone or in combination with ribavirin or levovirin. In some embodiments, the additional agent active against HCV is interferon-alpha or pegylated interferon-alpha alone or in combination with ribavirin or levovirin. In some embodiments, the agent active against hepatitis C virus is interferon.
[00425] The above other therapeutic agents, when employed in combination with the chemical entities described herein, may be used, for example, in those amounts indicated in the Physicians' Desk Reference (PDR) or as otherwise determined by one of ordinary skill in the art.
[00426] Additionally, the present specification is directed to a pharmaceutical composition comprising a therapeutically effective amount of at least one chemical entity described herein in combination with a therapeutically effective amount of another active agent against RNA- dependent RNA virus and, in particular, against HCV. Agents active against HCV include, but are not limited to, ribavirin, levovirin, viramidine, thymosin alpha-1 , an inhibitor of HCV NS3 serine protease, or an inhibitor of inosine monophosphate dehydrogenase, interferon-alpha pegylated interferon-alpha (peginterferon-alpha), a combination of interferon-alpha and ribavirin, a combination of peginterferon-alpha and ribavirin, a combination of interferon-alpha and levovirin, and a combination of peginterferon-alpha and levovirin. Interferon-alpha includes, but is not limited to, recombinant interferon-alpha2a (such as ROFERON interferon available from Hoffman-LaRoche, Nutley, NJ), interferon-alpha2b (such as Intron-A interferon available from Schering Corp., Kenilworth, New Jersey, USA), a consensus interferon, and a purified interferon-alpha product. For a discussion of ribavirin and its activity against HCV, see J.O. Saunders and S.A. Raybuck, "Inosine Monophosphate Dehydrogenase: Consideration of Structure, Kinetics and Therapeutic Potential," Ann. Rep. Med. Chem., 2:201-210 (2000).
[00427] The following examples serve to more fully describe the manner of making and using the above-described invention. It is understood that these examples in no way serve to limit the true scope of the invention, but rather are presented for illustrative purposes.
BIOLOGICAL EXAMPLES
EXAMPLE 98
ANTI-HEPATITIS C ACTIVITY
[00428] Compounds can exhibit anti-hepatitis C activity by inhibiting HCV polymerase, by inhibiting other enzymes needed in the replication cycle, or by other pathways. A number of assays have been published to assess these activities. A general method that assesses the gross increase of HCV virus in culture was disclosed in U.S. Patent No. 5,738,985 to Miles et al. In vitro assays have been reported in Ferrari et al. Jnl. of Vir., 73:1649-1654, (1999); Ishii et al., Hepatology, 29:1227-1235, (1999); Lohmann et al., J. Biol. Chem., 274:10807-10815, (1999); and Yamashita et al., J. Biol. Chem., 273:15479-15486, (1998).
EXAMPLE 99
REPLICON ASSAY
[00429] Compounds were assayed for activity against HCV using the genotype 1a and 1 b subgenomic replicon model systems. Stable cell lines bearing the genotype 1a and 1 b replicons were used for screening of compounds. Both replicons are bicistonic and contain the firefly luciferase gene. The ET cell line is stably transfected with RNA transcripts harboring a sgluc- ubi-neo/NS3-37ET replicon with firefly luciferase-ubiquitin-neomycin phosphotransferase fusion protein and EMCV-IRES driven NS3-5B polyprotein containing the cell culture adaptive mutations (E1202G; T1280I; K1846T) (Krieger at al , 2001 and unpublished). The genotype 1a replicon is a stable cell line licensed from Apath LLC, modified to contain the firefly luciferase gene. The cells were grown in DMEM, supplemented with 10% fetal calf serum, 2 mM
Glutamine, Penicillin (100 IU/mL)/Streptomycin (100 pg/mL), 1x nonessential amino acids, and 250-500 pg/mL G418 ("Geneticin"). They were all available through Life Technologies
(Bethesda, Md.). The cells were plated at 0.5 x 104 cells/well in 384 well plates containing compounds. The final concentration of compounds ranged between 0.03 pM to 50 pm and the final DMSO concentration of 0.5-1 %.
[00430] Luciferase activity was measured 48 hours later by adding a Steady glo
(Promega, Madison, Wis.). Percent inhibition of replication data was plotted relative to no compound control. Under the same condition, cytotoxicity of the compounds was determined using cell titer glo (Promega, Madison, Wis). IC5oS were determined from a 10 point dose response curve using 3-4-fold serial dilution for each compound, which spans a concentration range > 1000 fold. BioAssay determines the level of inhibition for each compound by normalizing cross-talk corrected plate values against the negative (low or background, cells with no compound present) and positive (high DMSO, no cells) controls to determine Percent Inhibition: 100 * (1 -(Cross-talk corrected value - Compound Positive Control Mean))
DMSO Negative Control Mean - Compound Positive Control Mean
[00431] These normalized values are exported to EC5o where they are plotted against the molar compound concentrations using the standard four parameter logistic equation:
Figure imgf000205_0001
Where:
A minimum y D= slope factor
B maximum y x = log compound concentration [M]
C log10EC5o
[00432] As shown below, the tested compounds tested were found to inhibit the activity of the replicon with EC50 values of about 10,000 nM or less. Preferably, the compounds will exhibit EC50 values of about 500 nM or less, in some embodiments about 100 or less, and in some embodiments, about 40 or less, and in some embodiments 10 or less, and in some
embodiments 5 or less, and in some embodiments, 1 or less. Further, compounds of the present disclosure, which were tested against more than one genotype of HCV replicon, were found to have similar inhibitory properties.
[00433] Percent inhibition values at a specific concentration, 10 μΜ for example, can also be derived from the equation above. In some aspects, the compounds of Formula (I) will exhibit a % inhibition of at least 80% at 10 μΜ. In other aspects, the % inhibition is at least 50% at 10 μΜ. In other aspects, the % inhibition is at least 10% at 10 μΜ.
[00434] When tested, certain compounds of Table 1 were found to have EC5o values listed in Table 3.
Table 3
Figure imgf000206_0001
Compound HCV Genotype HCV Genotype Number 1A I B
(From Table 1) Replicon Replicon
EC50 (μΜ) EC50 (μ )
27 0.1995 >0.501
28 0.0003 0.0020
29 0.0003 0.0016
30 0.0016 0.0050
31 0.0032 0.0158
32 0.0013 0.0040
33 0.0631 0.1585
34 0.0020 0.0126
35 0.0251 0.1259
36 0.0040 0.0398
37 0.0013 0.0100
38 0.0025 0.0158
39 0.0316 0.1995
40 >0.501 0.1259
41 0.0005 0.0050
42 0.0501 0.3981
43 0.1000 0.1995
44 0.1000 0.0631
45 0.0025 0.0316
46 0.0398 0.0158
47 0.0158 0.0794
48 >0.501 0.1259
49 >0.501 0.1995
50 0.1000 0.2512
51 0.0631 0.1585
52 0.0025 0.0100
53 0.0002 0.0016 Compound HCV Genotype HCV Genotype Number 1A I B
(From Table 1) Replicon Replicon
ECso (μΜ) ECso (μΜ)
54 0.0079 0.0631
55 0.0006 0.0032
56 0.0002 0.0016
57 0.0501 0.1585
58 1.2589 0.0794
59 0.0794 6.3096
60 0.0004 0.0050
61 0.1585 0.1259
62 0.0001 0.0006
63 0.0032 0.0126
64 0.0005 0.0032
65 0.0040 0.0251
66 0.0050 0.0794
67 0.0158 0.0063
68 0.0040 0.0032
69 0.0398 0.0794
70 0.0079 0.0079
71 0.0063 0.0050
72 0.0040 0.0398
73 0.0050 0.0501
74 0.0025 0.0200
75 0.0079 0.1259
76 0.0158 0.1585
77 0.0063 0.0794
78 0.0050 0.1259
79 0.0005 0.0251
80 0.0010 0.0200 Compound HCV Genotvoe HCV Genotvoe Number 1A I B
(From Table 1) Replicon Replicon
EC50 (μ ) EC50 (μΜ)
81 0.0501 0.0158
82 0.0020 0.0006
83 0.0079 0.0020
84 0.0100 0.0032
85 0.0025 0.0008
Formulation Examples
[00435] The following are representative pharmaceutical formulations containing a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
EXAMPLE 100
Tablet formulation
[00436] The following ingredients are mixed intimately and pressed into single scored tablets.
Ingredient Quantity per tablet (mg)
compound 400
cornstarch 50
croscarmellose sodium 25
lactose 120
magnesium stearate 5
EXAMPLE 101
Capsule formulation.
[00437] The following ingredients are mixed intimately and loaded into a hard-shell gelatin capsule.
Ingredient Quantity per capsule (mg)
compound 200 Lactose, spray-dried 148
magnesium stearate 2
EXAMPLE 102
Suspension formulation
The following ingredients are mixed to form a suspension for oral administration.
Ingredient Amount
compound 1.0 g
fumaric acid 0.5 g
sodium chloride 2.0 g
methyl paraben 0.15 g
propyl paraben 0.05 g
granulated sugar 25.0 g
sorbitol (70% solution) 13.00 g
Veegum K (Vanderbilt Co.) 1.0 g
flavoring 0.035 mL
colorings 0.5 mg
distilled water q.s. (quantity sufficient) to I00 mL
EXAMPLE 103
Injectable formulation
[00439] The following ingredients are mixed to form an injectable formulation.
Ingredient Amount
compound 0.2 mg-20 mg sodium acetate buffer solution, 0.4 M 2.0 mL
HCI (1 N) or NaOH (1 N) q.s. to suitable pH
water (distilled, sterile) q.s. to 20 mL
EXAMPLE 104
Suppository Formulation
[00440] A suppository of total weight 2.5 g is prepared by mixing the compound with Witepsol® H-15 (triglycerides of saturated vegetable fatty acid; Riches-Nelson, Inc., New York), and has the following composition:
Ingredient Amount compound 500 mg
Witepsol® H-15 balance
[00441] Although the invention has been shown and described above with reference to some embodiments, those skilled in the art will readily appreciate that the specific experiments detailed are only illustrative of the invention. It should be understood that various modifications can be made without departing from the spirit of the invention.
[00442] For example, for claim construction purposes, it is not intended that the claims set forth hereinafter be construed in any way narrower than the literal language thereof, and it is thus not intended that exemplary embodiments from the specification be read into the claims. Accordingly, it is to be understood that the present invention has been described by way of illustration and not limitations on the scope of the claims. Accordingly, the invention is limited only by the following claims. All publications, issued patents, patent applications, books and journal articles, cited in this application are each herein incorporated by reference in their entirety.

Claims

WHAT IS CLAIMED IS:
A compound of Formula (I):
(I)
Figure imgf000212_0001
or a pharmaceutically acceptable salt thereof, wherein:
Z is optionally a bond or (C C3)alkylene;
W is selected from CH or N;
A is selected from the group consisting of hydrogen, halo, (C C6)alkyl, (CrC6)alkoxy, (C C6)alkenyl, (C CeJalkynyl, (C3-C14)cycloalkyl, aryl, hydroxyl, -NR6R6, -NR6C(0)NR6R6, -OR6(R5)m, -OR6(R5)y, -R6(R5)m, -alkyl(R5)2R6, -S02NR6R6, -C(0)NR6R6, -OR7, -R6R7, -S02R6, -NR6C(S)NR6R6, -NR6S(0)2R6, -alkylR9R6, -NR6C(0)OR6, -NR6C(0)R6, (C2-C6)heteroaryl having 1-3 heteroatoms selected from S, N, and O, (C2-C6)heterocyclic having 1-3 heteroatoms selected from S, N and O; wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclic group is optionally substituted with one to three R10 groups;
R1 is selected from the group consisting of hydrogen, halo, cyano, hydroxyl, (CrC6)alkyl, (Ci-CeJalkoxy, (C C6)alkenyl, (C C6)alkynyl, -C(0)N(R6)2l -R9R6, -S02NR6R6, -R1 R15, -R1 (R15)2, -S02R6, -OSi, -OSi(R6)3, (C3-C14)cycloalkyl, (C3- C14)cycloalkenyl, -(C3-C1 )cycloalkenyl-R8, aryl, (C2-C6)heterocyclic having 1-3 heteroatoms selected from S, N and O, and (C2-C6)heteroaryl having 1-3 heteroatoms selected from S, N, and O; wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclic group is optionally substituted with one to three R1 groups;
R2 is independently selected from the group consisting of hydroxyl, oxo, (C C6)alkyl, (C3-Ci )cycloalkyl, -alkylR8, and aryl, or optionally two R2 alkyl groups, together with any intervening atoms, form a spiro or fused (C3-C14)cycloalkyl ring;
R2', R3, R3' and R4' are independently selected from the group consisting of hydrogen, (Ci-C6)alkyl, (C3-C14)cycloalkyl, and -alkylR8; wherein said alkyl or cycloalkyl group is optionally substituted with one to three R12 groups;
R4 is selected from the group consisting of hydrogen, hydroxyl, halo, nitrile, (CrC6)alkyl, (C C6)alkoxy, (C C6)alkenyl, (C C6)alkynyl, (C3-C14)cycloalkyl, aryl, -aryl(R12)y, -arylR12, -OR6(R5)y, -OR6(R5)m, -R6(R5)m, -alkyl(R5)yR6, -alkyl(R5)x(R6)y, -alkylR9R6, -C(0)R14, -R9R6, -R9R14, -R9R7, -NR6R6, -NR6C(0)NR6R6,
-S02NR6R6, -NR6R6R11, -C(0)NR6R6, -OR7, -R6R7, -S02R6, -NR6C(S)NR6R6, -NR6S(0)2R6, -alkylR9R6, -NR6C(0)OR6, -NR6C(0)R6, (C2-C6)heteroaryl having 1-3 heteroatoms selected from S, N, and O, and (C2-C6)heterocyclic having 1-3 heteroatoms selected from S, N and O; wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclic group is optionally substituted with one to three R10 groups;
R5 is independently selected from the group consisting of hydrogen and halo;
R6 is independently selected from the group consisting of hydrogen and (C C6)alkyl;
R7 is (C3-C14)cycloalkyl;
R8 is hydroxyl;
R9 is carboxyl;
R10 is independently selected from the group consisting of (C C6)alkyl, (d-C6)alkoxy, (CrC6)alkenyl, (CrC6)alkynyl, hydroxyl, oxo, carboxyl, cyano, halo,
-C(0)NH2, -S02NH2, -SR6, -S(0)R6, -S(0)2R6, -S(0)2NR6R6, -NR6R6, -NR6C(0)NR6R6, -NR6C(S)NR6R6, -NR6S(0)2R6 -NR6C(0)OR6, -NR6C(0)R6, -C(NR6)NR6R6, -C(0)NR6R6, -C(0)OR6, -C(0)R6, (C3-C14)cycloalkyl, aryl, (C2- C6)heterocyclic having 1-3 heteroatoms selected from S, N and O, and (C2- C6)heteroaryl having 1-3 heteroatoms selected from S, N, and O;
R11 is independently selected from the group consisting of (Ci-C6)alkyl, (C C6)alkoxy, (C C6)alkenyl, (C,-C6)alkynyl, oxo, dioxo, hydroxyl, -NR6R6, -NR6C(0)R6, -OC(0)R6, -OR6(R5)m, -OR6(R5)y, -R6(R5)m, -alkyl(R5)yR6, halo, -C(0)NR6R6, -S02NR6R6, -S02R6, -alkylR8, -alkylR9, -alkylR9R6, (C3-C14)cycloalkyl, aryl, phosphate, (C2-C6)heterocyclic having 1-3 heteroatoms selected from S, N and O, and (C2-C6)heteroaryl having 1-3 heteroatoms selected from S, N, and O; or optionally two R11 groups, together with any intervening atoms, form a fused (C3- C )cycloalkyl ring or a fused (C2-C6)heterocyclic ring having 1-3 heteroatoms selected from S, N and O; wherein said fused cycloalkyl ring or fused heterocyclic ring is optionally substituted with one to three R12 groups;
R12 is independently selected from the group consisting of (CrC6)alkyl, (CrC6)alkoxy, oxo, halo, hydroxyl, carboxyl, cyano, -OR6(R5)m, -OR6(R5)y, -R6(R5)m, and -NR6R6;
R14 is selected from the group consisting of (C-I-C-I ^heterocyclic and (Ci-Cii)heteroaryl, each independently having one to three heteroatoms selected from N and O;
R15 is independently selected from the group consisting of (C C6)alkyl, (C C6)alkoxy, -OR8, halo, oxo, dioxo, nitrile, -N02, and -C02R8;
each m is independently an integer from 1 to 3;
each n is independently an integer from 1 to 4; and
each y is independently an integer from 1 to 3.
2. The compound according to claim 1 , wherein Z is a bond or methylene.
3. The compound according to claim 2, wherein Z is a bond.
4. The compound according to claim 1 , wherein W is CH.
5. The compound according to claim 1 , wherein W is N.
6. The compound according to claim 1 , wherein A is selected from the group consisting of hydrogen, (C C6)alkyl, halo, hydroxyl, (C C6)alkoxy, -OR7, -OR6(R5)m, -OR6(R5)y, -R6(R5)m, (C3-Ci4)cycloalkyl, -NR6R6, -R6(C3-C14)cycloalkyl, (C2-C6)heterocyclic having 1-3 heteroatoms selected from S, N and O, and (C2-C6)heteroaryl having 1-3 heteroatoms selected from S, N, and O; wherein R10 is absent.
7. The compound according to claim 6, wherein A is selected from the group consisting of hydrogen, hydroxyl, bromo, fluoro, chloro, methyl, ethyl, propyl, butyl, pentyl, cyclopropyl, cyclopropylmethyl, dimethylamino, cyclopropyloxy, methoxy, ethoxy, propoxy, trifluoromethoxy, difluoromethoxy, pyrazolyl, furanyi, pyrrolyl, triazolyl, thiophenyl,
tetrahydrofuranyl, tetrahydropyranyl, pyridyl, and imidazolyl.
8. The compound according to claim 7, wherein A is selected from the group consisting of methoxy, ethoxy, hydroxyl, cyclopropyl, methyl, ethyl, butyl, bromo, chloro, furanyi, dimethylamino, and trifluoromethoxy.
9. The compound according to claim 6, wherein A is selected from the group consisting of halo, (C3-C 4)cycloalkyl, and (C2-C6)heteroaryl having 1-3 heteroatoms selected from S, N, and O.
10. The compound according to claim 8, wherein A is selected from the group consisting of bromo, furanyl, dimethylamino, butyl, trifluoromethoxy, and cyclopropyl.
11. The compound according to claim 10, wherein A is cyclopropyl.
12. The compound according to claim 1 , wherein R1 is selected from the group consisting of hydrogen, (CrC6)alkyl, (C3-C 4)cycloalkyl, -OSi, -OSi(R6)3, aryl, (C2-C6)heterocyclic having 1-3 heteroatoms selected from S, N and O, and (C2-C6)heteroaryl having 1-3 heteroatoms selected from S, N, and O; wherein said alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclic group is optionally substituted with one to three R11 groups.
13. The compound according to claim 12, wherein R1 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, pentyl, cyano, carboxyl, hydroxyl, acetate, thiazolyl, cyclopropyl, cyclobutyl, bicyclohexyl, bicyclopentyl, bicyclooctyl, cyclohexyl, cyclopentyl, cyclopentenyl, cyclohexenyl, cycloheptyl, phenyl, benzyl, pyridyl, pyridinyl, pyrrolidinyl, piperidinyl, thiophenyl, oxazolidinone, oxazolidine, oxazolidinedione, pyrazolyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, and thienyl; wherein R1 is optionally substituted with one to three R11 groups.
14. The compound according to claim 13, wherein R1 is selected from the group consisting of pyrrolidinyl, oxazolidinone, oxazolidine, oxazolidinedione, cyclopentyl, cyclobutyl, cyclohexyl, and bicyclohexyl.
15. The compound according to claim 14, wherein R1 is oxazolidinone.
16. The compound according to claim 14, wherein R1 is oxazolidine.
17. The compound according to claim 14, wherein R1 is oxazolidinedione.
18. The compound according to claim 14, wherein R1 is cyclobutyl.
19. The compound according to claim 14, wherein R is bicyclohexyl.
The compound according to claim 14, wherein R1 is cyclopentyl.
21. The compound according to claim 14, wherein R1 is cyclohexyl.
22. The compound according to claim 12, wherein R1 is substituted with two R1 groups.
23. The compound according to claim 12, wherein the R11 group is absent.
24. The compound according to claim 12, wherein R1 is substituted with one R11 group.
25. The compound according to claim 12, wherein R1 is substituted with one to two groups selected from oxo and hydroxyl.
26. The compound according to claim 1 , wherein R2 is selected from the group consisting of oxo, methyl, and ethyl, and n is integer from 1 to 2.
27. The compound according to claim 1 , wherein R2 is methyl and n is 1.
28. The compound according to claim 1 , wherein R2 is oxo and n is 1.
29. The compound according to claim 1 , wherein R2 is oxo and n is 2.
30. The compound according to claim 1 , wherein R2 is absent and n is zero.
31. The compound according to claim 1 , wherein R3 is selected from the group consisting of hydrogen, (C C6)alkyl, and (C3-C14)cycloalkyl; wherein said alkyl or cycloalkyi group is optionally substituted with one to three R12 groups.
32. The compound according to claim 31 , wherein R3 is selected from the group consisting of hydrogen, methyl, ethyl, and propyl.
33. The compound according to claim 31 , wherein R3 is methyl.
34. The compound according to claim 1 , wherein R4 is selected from the group consisting of hydrogen, hydroxyl, (C C6)alkyl, (Ci-C6)alkenyl, (C C6)alkoxy, amino, dimethyamino, halo, nitrile, (C3-C14)cycloalkyl, aryl, -aryl(R12)x, -aryl(R12)y, -OR6(R5)y, -OR6(R5)m -R6(R5)m, -alkyl(R5)yR6, -alkyl(R5)x(R6)y, and (C2-C6)heterocyclic having 1-3 heteroatoms selected from S, N and O.
35. The compound according to claim 34, wherein R4 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, fluorophenyl, difluorophenyl, phenyl, difluoromethoxy, piperidinylcarbonyl, cyclohexylmethyl, amino, phenylmethylamino, methyloxyethylamino, methylpropenyl, pyrrolyl, pyrrolidinyl, oxazolyl, pyridinyl, dimethylamino, methylcarboxylate, methylamino, isopropylene, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, chloro, fluoro, bromo, difluoroethyl, and trifluoromethyl.
36. The compound according to claim 35, wherein R4 is trifluoromethyl.
37. The compound according to claim 1 , wherein R11 is selected from the group consisting of hydroxyl, dioxo, oxo, nitrile, -OC(0)R6, -alkylR8, -R6(R5)m, halo, (C C6)alkyl, phosphate, and (CrC6)alkoxy; or optionally two R 1 groups, together with any intervening atoms, form a fused cyclopropyl ring; wherein said fused cyclopropyl ring is optionally substituted with one to two R 2 groups.
38. The compound according to claim 37, wherein R1 is selected from the group consisting of hydroxyl, dioxo, oxo, fluoro, difluoro, and phosphate.
39. The compound according to claim 37, wherein R11 is selected from the group consisting of hydroxyl and phosphate.
40. The compound according to claim 37, wherein R11 is phosphate.
41. The compound according to claim 37, wherein R11 is hydroxyl.
42. The compound according to claim 1 , wherein R12 is selected from the group consisting of halo, nitrile, and hydroxyl.
43. The compound according to claim 42, wherein R12 is absent.
44. The compound according to claim 1 , wherein m is three.
45. The compound according to claim 1 , wherein y is two.
46. The compound according to claim 1 , wherein n is one.
47. A compound selected from the group consisting of:
4-{[5-bromo-7-(trifluoromethyl)-1 H-benzimidazol-2-yl]carbonyl}-1-cyclopentyl-2-piperazinone, 4-{[6-bromo-1 -ethyl-4-(trifluoromethyl)-1 H-benzimidazol-2-yl]carbonyl}-1 -cyclopentyl-2- piperazinone,
4-{[6-bromo-1 -methyl-4-(trifluoromethyl)-1 H-benzimidazol-2-yl]carbonyl}-1 -cyclopentyl-2- piperazinone,
4-{[6-bromo-1 -propyl-4-(trifluoromethyl)-1 H-benzimidazol-2-yl]carbonyl}-1 -cyclopentyl-2- piperazinone,
4-{[6-bromo-1 -methyl-4-(trifluoromethyl)-1 H-benzimidazol-2-yl]carbonyl}-1 -cyclobutyl-2- piperazinone,
4-{[6-cyclopropyl-1-methyl-4-(trifluoromethyl)-1 H-benzimidazol-2-yl]carbonyl}-1-(4- hydroxycyclohexyl)-2-piperazinone,
4-{[6-cyclopropyl-1-methyl-4-(trifluoromethyl)-1 H-benzimidazol-2-yl]carbonyl}-1-(trans-4- hydroxycyclohexyl)-2-piperazinone,
4-(4-{[6-cyclopropyl-1 -methyl-4-(trifluoromethyl)-1 H-benzimidazol-2-yl]carbonyl}-2-oxo-1 - piperazinyl)cyclohexyl dihydrogen phosphate,
trans-4-(4-{[6-cyclopropyl-1-methyl-4-(trifluoromethyl)-1 H-benzimidazol-2-yl]carbonyl}-2-oxo-1- piperazinyl)cyclohexyl dihydrogen phosphate,
1- [bicyclo[3.1.0]hex-3-yl]-4-{[6-cyclopropyl-1-methyl-4-(trifluoromethyl)-1 H-benzimidazol-2- yl]carbonyl}-2-piperazinone,
1 -[(trans)-bicyclo[3.1.0]hex-3-yl]-4-{[6-cyclopropyl-1 -methyl-4-(trifluoromethyl)-1 H-benzimidazol-
2- yl]carbonyl}-2-piperazinone,
1-(cyclobutylmethyl)-4-{[6-cyclopropyl-1-methyl-4-(trifluoromethyl)-1 H-benzimidazol-2- yl]carbonyl}-2-piperazinone,
4-{[6-cyclopropyl-1-methyl-4-(trifluoromethyl)-1 H-benzimidazol-2-yl]carbonyl}-1-[3- hydroxycyclopentyl]-2-piperazinone,
4-{[6-cyclopropyl-1-methyl-4-(trifluoromethyl)-1 H-benzimidazol-2-yl]carbonyl}-1-[(1 R,3R)-3- hydroxycyclopentyl]-2-piperazinone,
3- (1-{[6-bromo-1-methyl-4-(trifluoromethyl)-1 H-benzimidazol-2-yl]carbonyl}-4-piperidinyl)-1 ,3- oxazoiidin-2-one,
3-(1-{[6-bromo-1-methyl-4-(trifluoromethyl)-1 H-benzimidazol-2-yl]carbonyl}-4-piperidinyl)-1 ,3- oxazolidine-2,4-dione,
3-(1-{[6-cyclopropyl-1-methyl-4-(trifluoromethyl)-1 H-benzimidazol-2-yl]carbonyl}-4-piperidinyl)- 1 ,3-oxazolidin-2-one, 3-(1 -{[6-cyclopropyl-1 -methyl-4-(trifluoro
1 ,3-oxazolidine-2,4-dione,
3- (1-{[6-(3-furanyl)-1-methyl-4-(trifluoromethyl)-1 H-benzimidazol-2-yl]carbonyl}-4-piperidinyl)- 1 ,3-oxazolidin-2-one,
4- [(4-bromo-6-cyclopropyl-1-methyl-1 H-benzimidazol-2-yl)carbonyl]-1-(trans-4-{[(1 ,1- dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2-piperazinone,
4-[(4-bromo-6-cyclopropyl-1 -methyl-1 H-benzimidazol-2-yl)carbonyl]-1 -(trans-4- hydroxycyclohexyl)-2-piperazinone,
4-[(7-bromo-5-cyclopropyl-1 -methyl-1 H-benzimidazol-2-yl)carbonyl]-1-(trans-4- hydroxycyclohexyl)-2-piperazinone,
4-[(4,6-dicyclopropyl-1-methyl-1 H-benzimidazol-2-yl)carbonyl]-1-(trans-4-hydroxycyclohexyl)-2- piperazinone,
6-cyclopropyl-2-{[4-(trans-4-hydroxycyclohexyl)-3-oxo-1 -piperazinyl]carbonyl}-1 -methyl-1 H- benzimidazole-4-carbonitrile,
4-[(6-cyclopropyl-1 -methyl-1 H-benzimidazol-2-yl)carbonyl]-1-(trans-4-hydroxycyclohexyl)-2- piperazinone,
4-[(6-cyclopropyl-4-ethyl-1 -methyl-1 H-benzimidazol-2-yl)carbonyl]-1-(trans-4- hydroxycyclohexyl)-2-piperazinone,
4-{[6-cyclopropyl-1-methyl-4-(1-methylethenyl)-1 H-benzimidazol-2-yl]carbonyl}-1-(trans-4- hydroxycyclohexyl)-2-piperazinone,
4-[(6-cyclopropyl-1 -methyl-4-phenyl-1 H-benzimidazol-2-yl)carbonyl]-1 -(trans-4- hydroxycyclohexyl)-2-piperazinone,
4-[(6-cyclopropyl-1 ,4-dimethyl-1 H-benzimidazol-2-yl)carbonyl]-1-(trans-4-hydroxycyclohexyl)-2- piperazinone,
4-{[6-cyclopropyl-1-methyl-4-(1-methylethyl)-1 H-benzimidazol-2-yl]carbonyl}-1-(trans-4- hydroxycyclohexyl)-2-piperazinone,
4-[(6-cyclopropyl-4-hydroxy-1 -methyl-1 H-benzimidazol-2-yl)carbonyl]-1 -(trans-4- hydroxycyclohexyl)-2-piperazinone,
4-(4-cyclobutyl-6-cyclopropyl-1 -methyl-1 H-benzo[d]imidazole-2-carbonyl)-1-((1 r,4r)-4- hydroxycyclohexyl)piperazin-2-one,
4-[(4-cyclopentyl-6-cyclopropyl-1 -methyl-1 H-benzimidazol-2-yl)carbonyl]-1-(trans-4- hydroxycyclohexyl)-2-piperazinone,
4-{[6-cyclopropyl-4-(3-fluorophenyl)-1 -methyl-1 H-benzimidazol-2-yl]carbonyl}-1-(trans-4- hydroxycyclohexyl)-2-piperazinone, 4-{[6-cyclopropyl-4-(4-fIuorophenyl)-1-methyl-1 H-benzimidazol-2-yl]carbonyl}-1-(trans-4- hydroxycyclohexyl)-2-piperazinone,
4-{[6-cycIopropyl-4-(3,5-difluorophenyl)-1-methyl-1 H-benzinnidazol-2-yl]carbonyl}-1-(trans-4- hydroxycyclohexyl)-2-piperazinone,
4-{[6-cycloprop l-1 -methyl-4-(methyloxy)-1 H-benzimidazol-2-yl]carbonyl}-1 -(trans-4- hydroxycyclohexyl)-2-piperazinone,
4-({6-cyclopropyl-4-[(difluoromethyl)oxy]-1-methyl-1 H-benzimidazol-2-yl}carbonyl)-1-(trans-4- hydroxycyclohexyl)-2-piperazinone,
4-{[6-cyclopropyl-4-(ethyloxy)-1-methyl-1 H-benzimidazol-2-yl]carbonyl}-1-(trans-4- hydroxycyclohexyl)-2-piperazinone,
4-({6-cyclopropy I- 1 ~methyl-4-[( 1 -methy lethyl)oxy]- 1 H-benzimidazol-2-yi}carbonyl)- 1 -(trans-4- hydroxycyclohexyl)-2-piperazinone,
4-[(4-cyclohexyl-6-cyclopropyl-1-methyl-1 H-benzimidazol-2-yl)carbonyl]-1-(trans-4- hydroxycyclohexyl)-2-piperazinone,
4-{[6-cyclopropyl-1-methyl-4-(1-pyrrolidinyl)-1 H-benzimidazol-2-yl]carbonyl}-1 -(trans-4- hydroxycyclohexyl)-2-piperazinone,
methyl 6-cyclopropyl-2-{[4-(trans-4-hydroxycyclohexyl)-3-oxo-1-piperazinyl]carbonyl}-1-methyl- 1 H-benzimidazole-4-carboxylate,
4-{[6-cyclopropyl-1 -methyl-4-(1 -piperidinylcarbonyl)-1 H-benzimidazol-2-yl]carbonyl}-1 -(trans-4- hydroxycyclohexyl)-2-piperazinone,
4-{[6-cyclopropyl-1-methyl-4-(2-methylpropyl)-1 H-benzimidazol-2-yl]carbonyl}-1-(trans-4- hydroxycyclohexyl)-2-piperazinone,
4-{[4-(cyclohexylmethyl)-6-cyclopropyl-1-methyl-1 H-benzimidazol-2-yl]carbonyl}-1-(trans-4- hydroxycyclohexyl)-2-piperazinone,
4-({6-cyclopropyl-1-methyl-4-[(phenylmethyl)amino]-1 H-benzimidazol-2-yl}carbonyl)-1-(trans-4- hydroxycyclohexyl)-2-piperazinone,
4-[(6-cyclopropyl-1-methyl-4-{[2-(methyloxy)ethyl]amino}-1 H-benzimidazol-2-yl)carbonyl]-1- (trans-4-hydroxycyclohexyl)-2-piperazinone,
4-{[6-cyclopropyl-1 -methyl-4-(1 H-pyrrol-2-yl)-1 H-benzimidazol-2-yl]carbonyl}-1 -(trans-4- hydroxycyclohexyl)-2-piperazinone,
4-{[6-cyclopropyl-1-methyl-4-(trifluoromethyl)-1 H-benzimidazol-2-yl]carbonyl}-1-(cis-4- hydroxycyclohexyl)-2-piperazinone,
4-{[6-cyclopropyl-1 -methyl-4-(trifluoromethyl)-1 H-benzimidazol-2-yl]carbonyl}-1 -(trans-4-{[(1 , 1 - dimethylethyl)(dimethyl)silyl]oxy}cyc!ohexyl)-2-piperazinone, 4-{[5-cyclopropyi-1-methyl-7-(trifluoromethyl)-1 H-benzimidazol-2-yl]carbonyl}-1-(trans-4-{[(1 ,1- dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-2-piperazinone,
4-{[5-cyclopropyl-1-methyl-7-(trifluoromethyl)-1 H-benzimidazol-2-yl]carbonyl}-1-(trans-4- hydroxycyclohexyl)-2-piperazinone,
4-{[4-bromo-6-(1 ,1-dimethylethyl)-1-methyl-1 H-benzimidazol-2-yl]carbonyl}-1-(tra
hydroxycyclohexyl)-2-piperazinone,
4-{[4-cyclopropyl-6-(1 ,1-dimethylethyl)-1-methyl-1 H-benzimidazol-2-yl]carbonyl}-1-(trans-4- hydroxycyclohexyl)-2-piperazinone,
4-{[6-bromo-4-(1 , 1 -dimethylethyl)-1 -methyl-1 H-benzimidazol-2-yl]carbonyl}-1 -(trans-4- hydroxycyclohexyl)-2-piperazinone,
4-{[6-cyclopropyl-4-(1 ,1-dimethylethyl)-1 -methyl-1 H-benzimidazol-2-yl]carbonyl}-1-(trans-4- hydroxycyclohexyl)-2-piperazinone,
4-[(4,6-dicyclopropyl-1 ,5-dimethyl-1 H-benzimidazol-2-yl)carbonyl]-1-(trans-4- hydroxycyclohexyl)-2-piperazinone,
4-({6-cyclopropyl-1-methyl-4-[(1 E)-1-methyl-1-propen-1-yl]-1 H-benzimidazol-2-yl}carbon (trans-4-hydroxycyclohexyl)-2-piperazinone,
4-({6-cyclopropyl-1 -methyl-4-[(1 Z)-1 -methyl-1 -propen-1 -yl]-1 H-benzimidazol-2-yl}carbonyl)-1 - (trans-4-hydroxycyclohexyl)-2-piperazinone,
4-[(5,7-dicyclopropyl-1 ,4-dimethyl-1 H-benzimidazol-2-yl)carbonyl]-1-(trans-4- hydroxycyclohexyl)-2-piperazinone,
4-[(4,6-dicyclopropyl-1 ,7-dimethyl-1 H-benzimidazol-2-yl)carbonyl]-1-(trans-4- hydroxycyclohexyl)-2-piperazinone,
4-[(4-amino-6-cyclopropyl-1 -methyl-1 H-benzimidazol-2-yl)carbonyl]-1-(trans-4- hydroxycyclohexyl)-2-piperazinone,
4-{[6-cyclopropyl-4-(dimethylamino)-1 -methyl-1 H-benzimidazol-2-yl]carbonyl}-1-(trans-4- hydroxycyclohexyl)-2-piperazinone,
1-cyclobutyl-4-{[6-cyclopropyl-1-methyl-4-(trifluoromethyl)-1 H-benzimidazol-2-yl]carbonyl}-5- ethyl-2-piperazinone,
(5R)-4-{[6-cyclopropyl-4-(1 ,1-dimethylethyl)-1 -methyl-1 H-benzimidazol-2-yl]carbonyl}-1-(trans-4- hydroxycyclohexyl)-5-methyl-2-piperazinone,
(5R)-4-{[6-(dimethylamino)-1-methyl-4-(trifluoromethyl)-1 H-benzimidazol-2-yl]carbonyl}-1-(trans- 4-hydroxycyclohexyl)-5-methyl-2-piperazinone,
(5R)-4-{[6-cyclopropyl-1-methyl-4-(trifluoromethyl)-1 H-benzimidazol-2-yl]carbonyl}-1-(trans-4- hydroxycyclohexyl)-5-methyl-2-piperazinone, 4-{[6-(dimethylamino)-1-methyl-4-(trifluoromethyl)-1 H-benzimidazol-2-yl]carbonyl}-1-(tra hydroxycyclohexyl)-2-piperazinone,
4-{[6-cyclopropyl-1-methyl-4-(1 ,3-oxazol-5-yl)-1 H-benzimidazol-2-yl]carbonyl}-1-(trans-4- hydroxycyclohexyl)-2-piperazinone,
1-cyclobutyl-4-{[6-(3-furanyl)-1-methyl-4-(trifluoromethyl)-1 H-benzimidazol-2-yl]carbonyl}-2- piperazinone,
1-cyclobutyl-4-{[6-cyclopropyl-1-methyl-4-(trifluoromethyl)-1 H-benzimidazol-2-yl]carbonyl}-2- piperazinone,
3-(1-{[6-(3-furanyl)-1-methyl-4-(trifluoromethyl)-1 H-benzimidazol-2-yl]carbonyl}-4-piperidinyl)- 1 ,3-oxazolidine-2,4-dione,
3-(1-{[6-cyclopropyl-4-(1 ,1-dimethyiethyl)-1-methyl-1 H-benzimidazol-2-yl]carbonyl}-4- piperidinyl)-1 ,3-oxazolidin-2-one,
3- (1-{[6-cyclopropyl-4-(1 ,1-dimethylethyl)-1-methyl-1 H-benzimidazol-2-yl]carbonyl}-4- piperidinyl)-1 ,3-oxazolidine-2,4-dione,
4- {[6-cyclopropyl-4-(2-fluorophenyl)-1-methyl-1 H-benzimidazol-2-yl]carbonyl}-1-(trans-4- hydroxycyclohexyl)-2-piperazinone,
4-{[6-cyclopropyl-4-(2,4-difluorophenyl)-1-methyl-1 H-benzimidazol-2-yl]carbonyl}-1-(trans-4- hydroxycyclohexyl)-2-piperazinone,
4-{[6-cyclopropyl-4-(2,5-difluorophenyl)-1-methyi-1 H-benzimidazol-2-yl]carbonyl}-1-(trans-4- hydroxycyclohexyl)-2-piperazinone,
4-{[6-cyclopropyl-1 -methyl-4-(2-pyridinyl)-1 H-benzimidazol-2-yl]carbonyl}-1 -(trans-4- hydroxycyclohexyl)-2-piperazinone,
4-{[6-cyclopropyl-1 -methyl-4-(3-pyridinyl)-1 H-benzimidazol-2-yl]carbonyl}-1 -(trans-4- hydroxycyciohexyl)-2-piperazinone,
4-{[6-cyclopropyl-1-methyl-4-(4-pyridinyl)-1 H-benzimidazol-2-yl]carbonyl}-1-(trans-4- hydroxycyclohexyl)-2-piperazinone,
4-({4-bromo-1-methyl-6-[(trifluoromethyl)oxy]-1 H-benzimidazol-2-yl}carbonyl)-1-(trans-4- hydroxycyclohexyl)-2-piperazinone,
4-({4-(3-fluorophenyl)-1-methyl-6-[(trifluoromethyl)oxy]-1 H-benzimidazol-2-yl}carbonyl)-1 -(trans- 4-hydroxycyclohexyl)-2-piperazinone,
4-({4-cyclopropyl-1-methyl-6-[(trifluoromethyl)oxy]-1 H-benzimidazol-2-yl}carbonyl)-1-(trans-4- hydroxycyclohexyl)-2-piperazinone,
4-{[6-cyclopropyl-1-methyl-4-(trifluoromethyl)-1 H-benzimidazol-2-yl]carbonyl}-1-[(1S,2S)-2- hydroxy-3-cyclopenten-1-yl]-2-piperazinone, 4-{[6-cyclopropyl-1 -methyl-4-(trifluoromethyl)-1 /-/-benzimidazol-2-yl]carbonyl}-1 - t(1 SR,3SR,5S ?)-2,2-difluorobicyclo[3.1.0]hex-3-yl]-2-piperazinone,
1- (3-cyclopenten-1-yl)-4-{[6-cyclopropyl-1-methyl-4-(trifluoromethyl)-1 H-benzimidazol-2- yl]carbonyl}-2-piperazinone,
4-{[6-cyclopropyl-1-methyl-4-(trifluoromethyl)-1 H-benzimidazol-2-yl]carbon
2- hydroxybicyclo[3.1.0]hex-3-yl]-2-piperazinone,
4-{[6-cyclopropyl-1-methyl-4-(trifluorom
2-hydroxybicyclo[3.1.0]hex-3-yl]-2-piperazinone, and
4-{[6-cyclopropyl-1 -methyl-4-(trifluoromethyl)-1 H-benzimidazol-2-yl]carbonyl}-1 -[2- hydroxybicyclo[3.1.0]hex-3~yl]~2-piperazinone, or a pharmaceutically acceptable salt thereof.
48. A compound having the structure:
Figure imgf000224_0001
H , or a pharmaceutically acceptable salt thereof.
49. A compound having the structure:
Figure imgf000225_0001
50. A compound having the structure:
Figure imgf000225_0002
, or a pharmaceutically acceptable salt thereof.
A compound having the structure:
Figure imgf000226_0001
, or a pharmaceutically acceptable salt thereof.
52. The use of a compound or salt as defined in claim 1 in the manufacture of a medicament for use in the treatment of a viral infection in a human.
53. A pharmaceutical composition comprising a pharmaceutically acceptable diluent and a therapeutically effective amount of a compound as defined in claim 1.
54. A method for treating a viral infection in a mammal mediated at least in part by a virus in the Flaviviridae family of viruses which method comprises administering to a mammal, that has been diagnosed with said viral infection or is at risk of developing said viral infection, a compound of claim 1.
55. The method of claim 54, wherein said virus is hepatitis C virus.
56. The method of claim 54, further comprising administration of a therapeutically effective amount of one or more agents active against hepatitis C virus.
57. The method of claim 56, wherein said agent active against hepatitis C virus is an inhibitor of HCV protease, HCV polymerase, HCV helicase, HCV entry, HCV assembly, HCV egress, HCV replicase, HCV NS5A protein, or inosine 5'-monophosphate dehydrogenase.
58. The method of claim 56, wherein said agent active against hepatitis C virus is interferon.
59. The method of claim 56, wherein said agent active against hepatitis C virus is ribavirin.
60. The method of claim 56, wherein said agent active against hepatitis C virus is interferon in combination with ribavirin.
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