WO2004054974A2 - Piperidine derivatives as ccr5 antagonists - Google Patents

Piperidine derivatives as ccr5 antagonists Download PDF

Info

Publication number
WO2004054974A2
WO2004054974A2 PCT/US2003/039644 US0339644W WO2004054974A2 WO 2004054974 A2 WO2004054974 A2 WO 2004054974A2 US 0339644 W US0339644 W US 0339644W WO 2004054974 A2 WO2004054974 A2 WO 2004054974A2
Authority
WO
WIPO (PCT)
Prior art keywords
methyl
optionally substituted
nmr
mhz
aryl
Prior art date
Application number
PCT/US2003/039644
Other languages
French (fr)
Other versions
WO2004054974A3 (en
Inventor
Wieslaw Mieczyslaw Kazmierski
Christopher Joseph Aquino
Neil Bifulco
Eric Eugene Boros
Brian Andrew Chauder
Pek Yoke Chong
Maosheng Duan
Jr. Felix Deanda
Cecilia Suarez Koble
Ed Williams Mclean
Jennifer Poole Peckham
Angilique C Perkins
James Benjamin Thompson
Dana Vanderwall
Original Assignee
Smithkline Beecham Corporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Smithkline Beecham Corporation filed Critical Smithkline Beecham Corporation
Priority to JP2004560838A priority Critical patent/JP2006511554A/en
Priority to US10/538,144 priority patent/US7645771B2/en
Priority to AU2003300902A priority patent/AU2003300902A1/en
Priority to EP03813419A priority patent/EP1569646A2/en
Priority to CA002509711A priority patent/CA2509711A1/en
Priority to BR0317230-9A priority patent/BR0317230A/en
Priority to MXPA05006354A priority patent/MXPA05006354A/en
Publication of WO2004054974A2 publication Critical patent/WO2004054974A2/en
Publication of WO2004054974A3 publication Critical patent/WO2004054974A3/en
Priority to NO20052739A priority patent/NO20052739L/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV

Definitions

  • the present invention relates to a novel class of piperidine derivatives useful as antagonists of the chemokine receptor CCR5, compositions containing such compounds and methods of treating HIV infection and associated conditions.
  • the invention also relates to methods of treatment or prophylaxis of other CCR5 mediated diseases and disorders.
  • HIV human immunodeficiency virus
  • AIDS acquired immunodeficiency syndrome
  • ARC AIDS-related complex
  • HIV requires a co-receptor for entry into target cells.
  • the chemokine receptors function together with CD4 as co-receptors for HIV.
  • CXCR4 and CCR5 have been identified as the main co-receptors for HIV-1.
  • CCR5 acts as a major co-receptor for fusion and entry of macrophage-tropic HIV into host cells. These chemokine receptors are thought to play an essential role in the establishment and dissemination of an HIV infection. Therefore, CCR5 antagonists are useful as therapeutic agents active against HIV.
  • CCR5 receptors have also been reported to mediate cell transfer in inflammatory and immunoregulatory diseases and disorders such as multiple sclerosis, rheumatoid arthritis, autoimmune diabetes, chronic implant rejection, asthma, rheumatoid arthritis, Crohns Disease, inflammatory bowel disease, chronic inflammatory disease, glomerular disease, nephrotoxic serum nephritis, kidney disease, Alzheimer's Disease, autoimmune encephalomyelitis, arterial thrombosis, allergic rhinitis, arteriosclerosis, Sjogren's syndrome (dermatomyositis), systemic lupus erythematosus, graft rejection, cancers with leukocyte infiltration of the skin or organs, human papilloma virus infection, prostate cancer, wound healing, amyotrophic lateral sclerosis, and immune mediated disorders.
  • CCR5 is an attractive target for the discovery of new therapeutics due to its important role in viral infections
  • the present invention features compounds that are CCR5 antagonists and therefore are useful in the inhibition of HIV replication, the prevention and/or treatment of infection by HIV, and in the treatment of AIDS and/or ARC. These compounds having the general formula I:
  • R 1 , R 2 , R 3 , X, Y, m, n and Ring A are as defined herein.
  • the compounds of this invention may also be either pharmaceutically acceptable salts or pharmaceutical composition ingredients.
  • the present invention also features pharmaceutical compositions, comprising the above-mentioned compounds that are suitable for the prevention or treatment of CCR5-related diseases and conditions.
  • the present invention also features methods of antagonizing CCR5 chemokine receptor activity in a biological sample comprising contacting the biological sample with an effective amount of compounds of formula I or pharmaceutically acceptable derivatives or compositions thereof.
  • the present invention also features methods of antagonizing CCR5 chemokine receptor activity in a patient comprising administering to the patient a therapeutically effective amount of compounds of formula I or pharmaceutically acceptable derivatives or compositions thereof.
  • the present invention further features methods of treating AIDS, methods of preventing infection by HIV, and methods of treating infection by HIV as monotherapy or in combination with other antivirals, anti-infectives, irnmunomodulators, antibiotics or vaccines.
  • the present invention further features methods of synthesizing compounds of formula I and preparing pharmaceutical compositions comprising these above-mentioned compounds.
  • the present invention features a compound of formula (I):
  • R 1 is alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl, wherein said alkyl is optionally substituted by one or more R 7 , said carbocyclyl or heterocyclyl is optionally substituted by one or more R 8 and said aryl or heteroaryl is optionally substituted by one or more R 6 ; or R 1 and X taken together form a saturated, partially saturated or aromatic 5-7 membered ring having 0-3 heteroatoms chosen from oxygen, sulfur, nitrogen and phosphorus that is fused to Ring A;
  • V is alkyl, -C(O)-, -S(O) 2 -, -C(O)O-, or -C(O)-N(R 0 )- (where V is attached to R + through the right hand side of the radical as shown hereinafter);
  • R + is alkyl, aralkyl, aryl, heteroaryl, heteroaralkyl, wherein said alkyl is optionally substituted by one or more R 7 and said aralkyl or aryl is optionally substituted by one or more R 6 ;
  • m is 0 or 1 ;
  • n is 0-5;
  • R 3 is H, halo, -N(R°) 2 , -N(R°)C(O)R°, -CN, -CF 3 , alkyl optionally substituted by one or more groups chosen from R 7 , and -S-aryl optionally substituted by -(CH 2 ) ⁇ - 6 -N(R°)SO
  • each R 7 is independently chosen from halogen, -CF3, -R°, -OR 0 , -SR°, aryl optionally substituted by R 6 , -NO 2 , -CN, -N(R°) 2 , -NR°C(O)R°, -NR°C(O)N(R°) 2 , -N(R°)C(S)N(R°) 2 , -NR°CO 2 R°, -NR°NR°C(O)R°, -NR 0 NR°C(O)N(R°)
  • each R* is independently H, alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl; provided that when R 1 is m-methylphenyl, X is a C 2 unsubstituted saturated alkylene chain, and R 2 substituted Ring A is 4-benzyl or 4-phenyl-4'- hydroxy substituted N-piperinyl, R 3 -(Y) m - is other than H, triphenylmethyl, benzoyl,
  • an optionally substituted group may have a substituent at each substitutable position of the group, and each substitution is independent of the other.
  • alkyl alone or in combination with any other term, refers to a C-i. 20 straight or branched acyclic hydrocarbon radical that is either completely saturated or contains one or more units of unsaturation.
  • an alkyl radical contains from one to twelve carbon atoms. More preferably, an alkyl radical contains from one to eight carbon atoms.
  • a C 2 - 20 linear or branched alkyl radical having at least one carbon-carbon double bond is also referred to as "alkenyl".
  • the double bond(s) of the unsaturated hydrocarbon chain may be in either the cis or trans configuration and may occur in any stable point along the chain.
  • a C- 2 - 2 o linear or branched alkyl having at least one carbon-carbon triple bond is also referred to as "alkynyl".
  • the tripe bond(s) in an alkynyl radical may occur in any stable point along the chain.
  • alkyl radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, n- hexyl, ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, pentenyl, hexenyl, hexadienyl, ethynyl, propynyl, butynyl, pentynyl and the like.
  • alkoxy refers to an alkyl ether radical (-O-alkyl).
  • alkoxy radicals include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like.
  • cycloalkyl refers to a monocyclic or polycyclic non-aromatic hydrocarbon ring radical having three to twenty carbon atoms, preferably from three to twelve carbon atoms, and more preferably from three to ten carbon atoms. If polycyclic, each ring in a carbocyclyl radical is non-aromatic unless otherwise indicated.
  • a carbocylyl radical is either completely saturated or contains one or more units of unsaturation but is not aromatic. The unsaturation, if present, may occur in any point in the ring that may result in any chemically stable configuration.
  • cycloalkyl also includes hydrocarbon rings that are fused to one or more aromatic rings, such as in tetrahydronaphthyl, where the radical or point of attachment is on the non-aromatic ring. Unless otherwise indicated, the term “cycloalkyl”, “carbocyclyl”,
  • Carbocyclic also includes each possible positional isomer of a non-aromatic hydrocarbon radical, such as in 1- decahydronaphthyl, 2- decahydronaphthyl, 1 -tetrahydronaphthyl and 2- tetrahydronaphthyl.
  • suitable cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, decahydronaphthyl, tetrahydronaphthyl and the like.
  • halogen refers fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).
  • aryl refers to an aromatic monocyclic or polycyclic hydrocarbon ring radical containing five to twenty carbon atoms, preferably from six to fourteen carbon atoms, and more preferably from six to ten carbon atoms. Also included within the scope of the term “aryl”, as it is used herein, is a group in which an aromatic hydrocarbon ring is fused to one or more non-aromatic carbocyclic or heteroatom-containing rings, such as in an indanyl, phenanthridinyl or tetrahydronaphthyl, where the radical or point of attachment is on the aromatic hydrocarbon ring.
  • aryl also includes each possible positional isomer of an aromatic hydrocarbon radical, such as in 1 -naphthyl, 2-naphthyl, 5-tetrahydronaphthyl, 6-tetrahydronaphthyl, 1 -phenanthridinyl, 2- phenanthridinyl, 3-phenanthridinyl, 4-phenanthridinyl, 7-phenanthridinyl, 8- phenanthridinyl, 9-phenanthridinyl and 10-phenanthridinyl.
  • aryl radicals include, but are not limited to, phenyl, naphthyl, indenyl, azulenyl, fluorenyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl, indanyl, phenanthridinyl and the like.
  • aralkyl refers to an alkyl group substituted by an aryl. Examples of aralkyl groups include, but are not limited to, benzyl and phenethyl.
  • heterocycle refers to a non-aromatic monocyclic or polycyclic ring radical containing three to twenty carbon atoms, preferably three to seven carbon atoms if monocyclic and eight to eleven carbon atoms if bicyclic, and in which one or more ring carbons, preferably one to four, are each replaced by a heteroatom such as N, O, and S. If polycyclic, each ring in a heterocyclyl radical is non-aromatic unless otherwise indicated.
  • a heterocyclic ring may be fully saturated or may contain one or more units of unsaturation but is not aromatic.
  • the unsaturation may occur in any point in the ring that may result in any chemically stable configuration.
  • the heterocyclic ring may be attached at a carbon or heteroatom that results in the creation of a stable structure.
  • Preferred heterocycles include 5-7 membered monocyclic heterocycles and 8-10 membered bicyclic heterocycles.
  • heterocycle is a group in which a non-aromatic heteroatom-containing ring is fused to one or more aromatic rings, such as in an indolinyl, chromanyl, phenanthridinyl or tetrahydro-quinolinyl, where the radical or point of attachment is on the non-aromatic heteroatom-containing ring.
  • heterocycle also includes each possible positional isomer of a heterocyclic radical, such as in 1-decahydroquinoline, 2-decahydroquinoline, 3-decahydroquinoline, 4- decahydroquinoline, 5-decahydroquinoline, 6-decahydroquinoline, 7- decahydroquinoline, 7-decahydroquinoline, 8-decahydroquinoline, 4a- decahydroquinoline, 8a-decahydroquinoline, 1 -indolinyl, 2-indolinyl, 3- indolinyl, 1-tetrahydroquinoline, 2-tetrahydro-quinoline, 3-tetrahydroquinoline and 4-tetrahydro-quinoline.
  • heterocyclylalkyl refers to an alkyl group substituted by a heterocyclyl.
  • heterocyclic groups include, but are not limited to, imidazolinyl, 2,3-dihydro-1 H-imidazolyl, imidazolidinyl, indazolinolyl, perhydropyridazyl, pyrrolinyl, pyrrolidinyl, 4H-pyrazolyl, piperidinyl, pyranyl, pyrazolinyl, piperazinyl, morpholinyl, thiamorpholinyl, thiazolidinyl, thiamorpholinyl, oxopiperidinyl, oxopyrrolidinyl, azepinyl, tetrahydrofuranyl, oxoazepinyl, tetrahydropyranyl, thiazolyl, dioxolyl, dioxinyl, oxathiolyl, benzodioxolyl, dithiolyl, dithiolanyl, tetra
  • heteroaryl refers to an aromatic monocyclic or polycyclic ring radical containing five to twenty carbon atoms, preferably five to ten carbon atoms, in which one or more ring carbons, preferably one to four, are each replaced by a heteroatom such as N, O, S and P.
  • Preferred heteroaryl groups include 5-6 membered monocyclic heteroaryls and 8-10 membered bicyclic heteroaryls.
  • heteroaryl is a group in which a heteroaromatic ring is fused to one or more aromatic or non-aromatic rings where the radical or point of attachment is on the heteroaromatic ring.
  • heteroaromatic rings include, but are not limited to, pyrido[3,4-d]pyrimidinyl, 7,8-dihydro- pyrido[3,4-d]pyrimidine and 5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine.
  • heteroaryl also includes each possible positional isomer of a heteroaryl radical, such as in 2-pyrido[3,4-d]pyrimidinyl and 4-pyrido[3,4-d]pyrimidinyl.
  • heteroarylkyl refers to an alkyl group substituted by a heteroaryl.
  • heteroaryl groups include, but are not limited to, imidazolyl, quinolyl, isoquinolyl, indolyl, indazolyl, pyridazyl, pyridyl, pyrrolyl, pyrazolyl, pyrazinyl, quinoxalyl, pyrimidinyl, pyridazinyl, furyl, thienyl, triazolyl, thiazolyl, carbazolyl, carbolinyl, tetrazolyl, benzofuranyl, oxazolyl, benzoxazolyl, isoxozolyl, isothiazolyl, thiadiazolyl, furazanyl, oxadiazolyl, benzimidazolyl, benzothienyl, quinolinyl, benzotriazolyl, benzothiazolyl, isoquinolinyl, isoindolyl, acridinyl and benzoisox
  • heteroatom means nitrogen, oxygen, sulfur, or phosphorus and includes any oxidized form of nitrogen, such as N(O) [N + -O " ], sulfur such as S(O) and S(O)2, phosphorus such as PO3 and PO 4 and the quaternized form of any basic nitrogen.
  • alkylene chain refers to a straight or branched hydrocarbon chain that may be fully saturated or have one or more units of unsaturation. The unsaturation may occur in any stable point along the chain.
  • the double bond(s) in the unsaturated alkylidene chain may be in either the cis or trans configuration.
  • a combination of substituents or variables is permissible only if such a combination results in a stable or chemically feasible compound.
  • a stable compound or chemically feasible compound is one in which the chemical structure is not substantially altered when kept at a temperature of 40 °C or less, in the absence of moisture or other chemically reactive conditions, for at least a week.
  • structures depicted herein are also meant to include all endo or exo, cis or trans isomers as well as all stereochemical forms of the structure, i.e., the R and S configurations for each asymmetric center. Therefore, racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereoisomers of the present compounds are expressly included within the scope of the invention. Although the specific compounds exemplified herein may be depicted in a particular stereochemical configuration, compounds having either the opposite stereochemistry at any given chiral center or mixtures thereof are also envisioned.
  • structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by a 13 C- or 14 C-enriched carbon are also within the scope of this invention.
  • certain compounds of this invention may exist in alternative tautomeric forms. All such tautomeric forms of the present compounds are within the scope of the invention. Unless otherwise indicated, the representation of either tautomer is meant to include the other.
  • Certain preferred compounds of the present invention are those represented by formula II:
  • Ring A is a heterocycle having one ring nitrogen and 0-1 additional ring oxygen or ring nitrogen.
  • Other preferred compounds of formula II are those wherein Ring A is piperidinyl, piperaziny, pyrrolidinyl, azabicyclo[3.2.1] octanyl, aza- bicyclo[3.2.1]octenyl or oxa-aza-bicyclo [4.3.1]decanyl.
  • Ring A is connected to the alkylene chain X through an endocyclic nitrogen.
  • R 2 is aryl, aralkyl, heteroaryl, heterocyclyl, -N(H)(-V m -R + ), or -N(alkyl)(-V m -R + ), wherein V is - C(O)-, -S(O) 2 -, -C(O)O- or -C(O)-N(H)-, m is 0 or 1 , R + is phenyl or benzyl, and said aryl, aralkyl, heteroaryl or heterocyclyl is optionally substituted.
  • R 2 of compounds of formula II is phenyl, naphthyl, benzyl, -NH-phenyl, -NH-benzyl, -NHC(O)-phenyl, -NHSO 2 -phenyl, -NHC(O)NH-phenyl, benzoimidazolyl, dihydrobenzo-imidazolyl, oxodihydrobenzoimidazolyl, 3H-indolyl, quinolinyl, dihydro-1H-isoindolyl, dioxodihydro-1 H-isoindolyl, tetrahydroquinoxalinyl, dioxotetrahydro- quinoxalinyl, 3H-imidazo[4,5-b]pyridinyl, dihydro-1 H-imidazo [4,5-b]pyridinyl, benzotriazolyl, oxadiazolyl or triazolyl, wherein each member
  • n is 1-3, and more preferably, n is 1- 2.
  • R 2 is attached to Ring A through a R 2 nitrogen.
  • Preferred R 3 of formula II includes optionally substituted alkyl, aryl, heteroaryl, heterocyclyl and carbocyclyl. More preferred R 3 of formula II includes optionally substituted fully saturated alkyl, 3-7 membered carbocyclyl, 5-7 membered aryl, 6-10 membered heteroaryl and 4-10 membered heterocyclyl.
  • R 3 of formula II includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclohexenyl, tetrahydrofuranyl, azetidinyl, piperidinyl, hexahydrofuro[2,3-b]furanyl, oxopyrrolidinyl, dihydro-2H-[1 ,3]thiazinyl, tetrahydro-pyrimidinyl, dihydrobenzo[1 ,4]dioxinyl, dihydro-2H-benzo[1 ,2,4]thiadiazinyl, dihydrobenzo[d]isothiazolyl, morpholinyl, dihydro-1 H-imidazolyl, dihydrobenzooxazolyl, chromenyl, dihydroquinolinyl, pyrrolyl, benzotriazolyl, benzothiazoly
  • R 3 includes halo, methylenedioxy, -OR 0 , R°, -C(O)OR°, -SO 2 R°, -SO 2 (OR°), -SO 2 N(R°) 2 , -SO 2 N(R°)OR°, and -SO 2 N(R°)C(O)R°.
  • R 3 More preferred substituents of R 3 includes Cl, Br, F, CF 3 , Me, tetrazolyl, methylenedioxy, -OMe, -C(O)OH, -SO 2 R°, -SO 2 (OH), -SO 2 NH 2 , -SO 2 NHMe, -SO 2 N(H)C(O)Me, and -SO 2 N(H)OMe.
  • -(Y) m -R 3 is selected from the following:
  • -(Y) m -R 3 is selected from the following:
  • m is 1
  • Y is -C(O)-
  • R 3 is aryl, heteroaryl, alkyl, or cycloalkyl, each optionally substituted.
  • m is 1
  • R 3 is optionally substituted aryl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, or optionally substituted heterocyclyl.
  • m is 1
  • Y is -(CH 2 )-
  • R 3 is optionally substituted aryl.
  • m is 1
  • Y is -C(O)O-
  • R 3 is optionally substituted alkyl or optionally substituted aryl.
  • m is 0 and R 3 is optionally substituted heteroaryl or optionally substituted heterocyclyl.
  • X is -(CH 2 )-, -(CH 2 -CH 2 )-, or -(CH 2 -CH 2 -CH 2 )-. Further X is optionally substituted by one or more halogen or oxo. Still further X is disubstituted with halogen. Still further X is disubstituted with fluoro. Specifically X may be -(CF 2 -CH 2 )-. Further X optionally has 1-3 heteroatoms selected from oxygen, phosphorus, sulfur, or nitrogen.
  • the A ring is selected from the following, where the asterisk (*) indicates the preferred, but not limiting, point(s) of substitution:
  • each R 2 with the asterisk (*) indicating a preferred, but not limiting, point of substitution from Ring A, independently is selected from
  • the ring A with two geminal R 2 s, is selected from:
  • a ring is tropane or piperidine, either optionally substituted with one or more R 2 .
  • A-R 2 is comprised of one of the following:
  • the A ring contains at least one additional nitrogen atom and said A ring optionally is N-substituted.
  • the A ring is N- substituted with -(CH 2 ) a -(V b -R+).
  • R 6 of formula II includes alkyl, halo, SO 2 R° and SO 2 N(R°) 2 . More preferred R 6 of formula II includes Me, F, Cl, SO 2 NH 2 , SO 2 Me, and methylenedioxy.
  • R 2 , R 3 , R 5 , R 6 , n and Ring A are as defined for formula I.
  • Preferred compounds of formula III are those wherein R 3 is optionally substituted aryl. More preferably, R 3 is phenyl optionally substituted by one or more alkyl (such as Me) or halo (such as F and Cl).
  • Other preferred compounds of the present invention are those represented by formulae IV-IX:
  • Preferred compounds of formula I have one or more, and more preferably all, of the features selected from the group consisting of: (a) R 1 is alkyl, aryl, heteroaryl or heterocyclyl, wherein said alkyl is optionally substituted by one or more R 7 , said aryl or heteroaryl is optionally substituted by one or more R 6 , and said heterocyclyl is optionally substituted by one or more R 8 ;
  • Ring A is an 8-10 membered bicyclic ring having 0-5 ring heteroatoms chosen from oxygen, sulfur and nitrogen;
  • R 2 is aryl, heteroaryl or heterocyclyl, wherein said aryl or heteroaryl is optionally substituted by one or more R 6 and said heterocyclyl is optionally substitued by one or more R 8 ;
  • More preferred compounds of the present invention have one or more, and more preferably all, of the features selected from the group consisting of:
  • R 1 is aryl optionally substituted by one or more R 6 ;
  • Ring A is an 8-9 membered bicyclic ring having one ring nitrogen and 0-4 additional ring heteroatoms chosen from oxygen, sulfur and nitrogen;
  • R 2 is heteroaryl optionally substituted by one or more R 6 , or heterocyclyl optionally substituted by one or more R 8 ;
  • R 3 is alkyl optionally substituted by one or more R 7 , aryl or heteroaryl wherein said aryl or heteroaryl is optionally substituted by one or more R 6 .
  • Other more preferred compounds of the present invention have one or more, and more preferably all, of the features selected from the group consisting of:
  • R 1 is phenyl optionally substituted by one or more groups chosen from alkyl, halo, -OR 0 , -CF 3 , R°, -SO 2 R°, methylenedioxy and - SO 2 N(R°)2; wherein each R° is independently R*;
  • Ring A is an 8-9 membered non-aromatic bicyclic ring having one ring nitrogen and 0-1 additional ring heteroatoms chosen from oxygen, sulfur and nitrogen;
  • Y is -CH(COOH)-, -CH(COOMe)-, -C(O)-,
  • R 3 is methyl, butyl, pentyl, cyclobutyl optionally substituted by one or more R 8 , phenyl, pyrazolyl, thiadiazolyl, benzotriazolyl, pyrrolyl, benzothiazolyl, benzofuranyl, furanyl, pyridyl, thienyl, isoxazolyl, triazolyl, thiazolyl, isothiazolyl, imidazolyl, indolyl, pyrazolo[3,4-b]pyridinyl, or quinoxalinyl, wherein each member of R 3 except methyl, butyl, pentyl and cyclobutyl is optionally substituted by one or more R 6 and said methyl, butyl and pentyl are optionally substituted by one or more R 7 .
  • R 1 is phenyl optionally substituted by one or more groups chosen from halo, -CF 3 , methyleneoxy, alkyl, alkoxy and sulfonamide;
  • X is a saturated C-2 alkylene chain
  • Ring A is azabicyclo[3.2.1]octanyl or piperidinyl
  • R 2 is benzoimidazolyl, imidazo[4,5-b]pyridinyl, benzotriazolyl, or oxadiazolyl, wherein each member of R 2 is optionally substituted by one or more groups chosen from alkyl, halo, R°, -SO 2 R°, -CF 3 , alkoxy, benzyl, -CH 2 -pyridyl and -NR°;
  • R 3 is methyl, butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptanyl, phenyl, naphthyl, thienyl, furanyl, benzofuranyl, thiazolyl, isothiazolyl, isoxazolyl, pyrazolyl, pyrrolyl, piperidinyl, pyrimidinyl, benzooxazole-2-thionyl, imidazolyl, oxiranyl, pyrazolo[3,4-b]pyridinyl, pyrazolo[1 ,5-a]pyrimidinyl, thioxodihydrotriazinonyl, dihydrotetrazolethionyl, benzotriazolyl, pyrrolidinonyl, pyrrolidine-2,5-dionyl
  • the compounds of this invention generally may be prepared from known or readily prepared starting materials, following methods known to those skilled in the art, such as those illustrated by general Scheme I below, wherein R corresponds to R 3 -(Y) m - in formula I, and by the examples described herein.
  • Compounds of the present invention are useful as CCR5 antagonists.
  • One aspect of the instant invention relates to methods of antagonizing CCR5 chemokine receptor activity in a biological sample comprising contacting the biological sample with compounds of formula I or pharmaceutically acceptable derivatives thereof.
  • Another aspect of the instant invention relates to methods of antagonizing CCR5 chemokine receptor activity in a patient comprising administering to the patient with a therapeutically effective amount of compounds of formula I or pharmaceutically acceptable derivatives thereof.
  • the antagonistic activity of the present compounds towards the chemokine receptor CCR5 may be assayed by methods known in the art, for example, by using the methods as described in example 801.
  • compositions may be formulated into compositions.
  • the composition is a pharmaceutical composition, which comprises a compound of formula I and pharmaceutically acceptable carrier, adjuvant or vehicle.
  • the composition comprises an amount of a CCR5 antagonist of the present invention effective to antagonize CCR5 chemokine receptor activity in a biological sample or in a patient.
  • compounds of this invention and pharmaceutical compositions thereof which comprise an amount of a CCR5 antagonist of the present invetion effective to antagonize CCR5 chemokine receptor activity to treat or prevent a CCR5-mediated disease or disorder and a pharmaceutically acceptable carrier, adjuvant or vehicle, may be formulated for administration to a patient, for example, for oral administration.
  • pharmaceutically effective amount refers to an amount of a compound of this invention that is effective in treating a CCR5-related disease, for example a virus infection, for example an HIV infection, in a patient either as monotherapy or in combination with other agents.
  • antagonist of CCR5 chemokine receptor refers to a compound that binds to the chemokine receptor CCR5 but fails to elicit a response thereby blocking agonist action.
  • antagonistizing CCR5 chemokine receptor refers to binding to the receptor but failing to elicit a response thereby blocking agonist action, i.e, inhibiting a function of CCR5.
  • an antagonist of CCR5 chemokine receptor may inhibit the binding of one or more ligands (e.g., MIP-1 ⁇ , RANTES, MIP-1 ⁇ , and gp120) to CCR5 and/or inhibit signal transduction mediated through CCR5 (e.g., GDP/GTP exchange by CCR5-associated G proteins, intracellular calcium flux).
  • ligands e.g., MIP-1 ⁇ , RANTES, MIP-1 ⁇ , and gp120
  • signal transduction mediated through CCR5 e.g., GDP/GTP exchange by CCR5-associated G proteins, intracellular calcium flux.
  • CCR5-mediated processes and cellular responses e.g., proliferation, migration, chemotactic responses, secretion or degranulation
  • CCR5 mediated disease or disorder or “CCR5 related disease or disorder” is used herein at all occurrences to mean any disease, disorder or other deleterious condition or state in which CCR5 is known to play a role.
  • treatment refers to the alleviation of symptoms of a particular disorder in a patient, or the improvement of an ascertainable measurement associated with a particular disorder, and may include the suppression of symptom recurrence in an asymptomatic patient such as a patient in whom a viral infection has become latent.
  • prophylaxis refers to preventing a disease or condition or preventing the occurrence of symptoms of such a disease or condition, in a patient.
  • patient refers to a mammal, including a human.
  • biological sample includes, without limitation, cell cultures or extracts thereof; preparations of an enzyme suitable for in vitro assay; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.
  • pharmaceutically acceptable carrier, adjuvant or vehicle refers to a carrier, adjuvant or vehicle that may be administered to a patient, together with a compound of this invention, and which does not destroy the pharmacological activity thereof and is nontoxic when administered in doses sufficient to deliver a therapeutic amount of the therapeutic agent.
  • pharmaceutically acceptable derivative means any pharmaceutically acceptable salt, ester, salt of an ester, or other derivative of a compound of this invention which, upon administration to a recipient, is capable of providing (directly or indirectly) a compound of this invention or an inhibitorily active metabolite or residue thereof.
  • Particularly favored derivatives are those that increase the bioavailability of the compounds of this invention when such compounds are administered to a patient (e.g., by allowing an orally administered compound to be more readily absorbed into the blood) or which enhance delivery of the parent compound to a biological compartment (e.g., the brain or lymphatic system) relative to the parent species.
  • Pharmaceutically acceptable salts of the compounds according to the invention include those derived from pharmaceutically acceptable inorganic and organic acids and bases.
  • suitable acids include hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycollic, lactic, salicyclic, succinic, toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic, ethanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic and benzenesulfonic acids.
  • Other acids, such as oxalic while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts.
  • Salts derived from appropriate bases include alkali metal (e.g. sodium), alkaline earth metal (e.g., magnesium), ammonium, NW 4 + (wherein W is C ⁇ . alkyl) and other amine salts.
  • Physiologically acceptable salts of a hydrogen atom or an amino group include salts of organic carboxylic acids such as acetic, lactic, tartaric, malic, isethionic, lactobionic and succinic acids; organic sulfonic acids such as methanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonic acids and inorganic acids such as hydrochloric, sulfuric, phosphoric and sulfamic acids.
  • Physio-logically acceptable salts of a compound with a hydroxy group include the anion of said compound in combination with a suitable cation such as Na + , NH + , and NW + (wherein W is a C ⁇ - 4 alkyl group).
  • Any reference to any of the above compounds also includes a reference to a pharmaceutically acceptable salt thereof.
  • Salts of the compounds of the present invention may be made by methods known to a person skilled in the art. For example, treatment of a compound of the present invention with an appropriate base or acid in an appropriate solvent will yield the corresponding salt.
  • Esters of the compounds of the present invention are independently selected from the following groups: (1) carboxylic acid esters obtained by esterification of the hydroxy groups, in which the non-carbonyl moiety of the carboxylic acid portion of the ester grouping is selected from straight or branched chain alkyl (for example, acetyl, n-propyl, t-butyl, or n-butyl), alkoxyalkyl (for example, methoxymethyl), aralkyl (for example, benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (for example, phenyl optionally substituted by, for example, halogen, C ⁇ _ alkyl, or C ⁇ - alkoxy or amino); (2) sulfonate esters, such as alkyl- or aralkylsulfonyl (for example, methanesulfonyl); (3) amino acid esters (for example, L-valyl or L-isoleucyl);
  • any alkyl moiety present advantageously contains from 1 to 18 carbon atoms, particularly from 1 to 6 carbon atoms, more particularly from 1 to 4 carbon atoms, Any cycloalkyl moiety present in such esters advantageously contains from 3 to 6 carbon atoms. Any aryl moiety present in such esters advantageously comprises a phenyl group.
  • the present invention features compounds according to the invention for use in medical therapy, for example for the treatment including prophylaxis of CCR5-related diseases and disorders, including but not limited to, viral infections such as an HIV infection and associated conditions.
  • the compounds of the present invention are CCR5 antagonists. Accordingly, these compounds are capable of targeting and inhibiting the entry of a virus, e.g, HIV, into its target cell.
  • the compounds according to the invention are especially useful for the treatment of AIDS and related clinical conditions such as AIDS related complex (ARC), progressive generalized lymphadenopathy (PGL), Kaposi's sarcoma, thromobocytopenic purpura, AIDS-related neurological conditions such as i
  • AIDS dementia complex multiple sclerosis or tropical paraperesis, anti-HIV antibody-positive and HIV-positive conditions, including such conditions in asymptomatic patients.
  • the present invention provides a method for the treatment including prevention of the symptoms or effects of a viral infection in an infected patient, for example, a mammal including a human, which comprises treating said patient with a pharmaceutically effective amount of a compound according to the invention.
  • the viral infection is a retroviral infection, in particular an HIV infection.
  • a further aspect of the invention includes a method for the treatment including prevention of the symptoms or effects of an HBV infection.
  • the compounds according to the invention may also be used in adjuvant therapy in the treatment of HIV infections or HIV-associated symptoms or effects, for example Kaposi's sarcoma.
  • the compounds of the present invention may also be used in the treatment (including prevention) of other CCR5-related diseases and conditions, including multiple sclerosis, rheumatoid arthritis, autoimmune diabetes, chronic implant rejection, asthma and topic disorders (for example, atopic dermatitis and allergies), rheumatoid arthritis, Crohns Disease, inflammatory bowel disease, chronic inflammatory disease, glomerular disease, nephrotoxic serum nephritis, kidney disease, Alzheimer's Disease, autoimmune encephalomyelitis, arterial thrombosis, allergic rhinitis, arteriosclerosis, Sjogren's syndrome (dermatomyositis), systemic lupus erythematosus, graft rejection, cancers with leukocyte infiltration of the skin or organs, human papilloma virus infection,
  • the present invention further provides a method for the treatment of a clinical condition in a patient, for example, a mammal including a human which clinical condition includes those which have been discussed hereinbefore, which comprises treating said patient with a pharmaceutically effective amount of a compound according to the invention.
  • the present invention also includes a method for the treatment including prophylaxis of any of the aforementioned diseases or conditions.
  • the present invention provides the use of a compound according to the invention in the manufacture of a medicament for the treatment including prophylaxis of any of the above mentioned CCR5- related diseases or conditions including viral infections (e.g., HIV infection) and associated conditions.
  • Reference herein to treatment extends to prophylaxis as well as the treatment of established conditions, disorders and infections, symptoms thereof, and associated clinical conditions.
  • Combination therapies according to the present invention comprise the administration of a compound of the present invention or a pharmaceutically acceptable derivative thereof and another pharmaceutically active agent.
  • the active ingredient(s) and pharmaceutically active agents may be administered simultaneously (i.e., concurrently) in either the same or different pharmaceutical compositions or sequentially in any order.
  • the amounts of the active ingredient(s) and pharmaceutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect.
  • therapeutic agents include, but are not limited to, agents that are effective for the treatment of viral infections or associated conditions.
  • the present invention further includes the use of a compound according to the invention in the manufacture of a medicament for simultaneous or sequential administration with at least another therapeutic agent, such as those defined hereinbefore.
  • Compounds of the present invention may be administered with an agent known to inhibit or reduce the metabolism of compounds, for example ritonavir.
  • the present invention features a method for the treatment including prophylaxis of a disease as hereinbefore described by administration of a compound of the present invention in combination with a metabolic inhibitor. Such combination may be administered simultaneously or sequentially.
  • a suitable dose for each of the above-mentioned conditions will be in the range of 0.01 to 250 mg per kilogram body weight of the recipient (e.g. a human) per day, preferably in the range of 0.1 to 100 mg per kilogram body weight per day and most preferably in the range 0.5 to 30 mg per kilogram body weight per day and particularly in the range 1.0 to 20 mg per kilogram body weight per day.
  • all weights of active ingredient are calculated as the parent compound of formula (I); for salts or esters thereof, the weights would be increased proportionally.
  • the desired dose may be presented as one, two, three, four, five, six or more sub- doses administered at appropriate intervals throughout the day. In some cases the desired dose may be given on alternative days. These sub-doses may be administered in unit dosage forms, for example, containing 10 to 1000 mg or 50 to 500 mg, preferably 20 to 500 mg, and most preferably 50 to 400 mg of active ingredient per unit dosage form.
  • compositions of the present invention comprise at least one active ingredient, as defined above, together with one or more acceptable carriers thereof and optionally other therapeutic agents.
  • Each carrier must be acceptable in the sense of being compatible with the other ingredients of the composition and not injurious to the patient.
  • phrases include those suitable for oral, rectal, nasal, topical (including transdermal, buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous, intradermal, and intravitreal) administration.
  • the compositions may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. Such methods represent a further feature of the present invention and include the step of bringing into association the active ingredients with the carrier, which constitutes one or more accessory ingredients.
  • the compositions are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers or finely divided solid carriers or both, and then if necessary shaping the product.
  • the present invention further includes a pharmaceutical composition as hereinbefore defined wherein a compound of the present invention or a pharmaceutically acceptable derivative thereof and another therapeutic agent are presented separately from one another as a kit of parts.
  • compositions suitable for transdermal administration may be presented as discrete patches adapted to remain in intimate contact with the epidermis of the recipient for a prolonged period of time.
  • patches suitably contain the active compound 1) in an optionally buffered, aqueous solution or 2) dissolved and/or dispersed in an adhesive or 3) dispersed in a polymer.
  • a suitable concentration of the active compound is about 1% to 25%, preferably about 3% to 15%.
  • the active compound may be delivered from the patch by electrotransport or iontophoresis as generally described in Pharmaceutical Research 3(6), 318 (1986).
  • compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, caplets, cachets or tablets each containing a predetermined amount of the active ingredients; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
  • the active ingredient may also be presented as a bolus, electuary or paste.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredients in a free-flowing form such as a powder or granules, optionally mixed with a binder (e.g. povidone, gelatin, hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (e.g. sodium starch glycollate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose) surface-active or dispersing agent.
  • Molded tablets may be made by molding a mixture of the powdered compound moistened with an inert liquid diluent in a suitable machine.
  • the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredients therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile. Tablets may optionally be provided with an enteric coating, to provide release in parts of the gut other than the stomach.
  • compositions suitable for topical administration in the mouth include lozenges comprising the active ingredients in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
  • compositions suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray Pharmaceutical compositions containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
  • compositions for rectal administration may be presented as a suppository with a suitable carrier comprising, for example, cocoa butter or a salicylate or other materials commonly used in the art.
  • a suitable carrier comprising, for example, cocoa butter or a salicylate or other materials commonly used in the art.
  • the suppositories may be conveniently formed by admixture of the active combination with the softened or melted carrier(s) followed by chilling and shaping in molds.
  • compositions suitable for parenteral administration include aqueous and nonaqueous isotonic sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the pharmaceutical composition isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents; and liposomes or other microparticulate systems which are designed to target the compound to blood components or one or more organs.
  • the pharmaceutical compositions may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injection, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
  • Unit dosage pharmaceutical compositions include those containing a daily dose or daily subdose of the active ingredients, as hereinbefore recited, or an appropriate fraction thereof.
  • compositions of this invention may include other agents conventional in the art having regard to the type of pharmaceutical composition in question, for example, those suitable for oral administration may include such further agents as sweeteners, thickeners and flavoring agents.
  • Analytical High Pressure Liguid Chromotography data was aquired using a Waters LC-UV system.
  • the system operated using a Waters Symmetry Shield RP18 3.9 x 150 mm, 5 ⁇ m column at 1.5 mL/minute.
  • the mobile phase consisted of Water (0.1 % DEA) and Acetonitrile (0.1 % DEA).
  • Preparative High Pressure Liquid Chromatography data was acquired using a Waters LC-UV system.
  • the system operated using a Waters
  • the mobile phase consisted of Water (0.1 % DEA) and Acetonitrile (0.1 % DEA).
  • the gradient used started with a 10% ACN (0.1 % DEA):90% H 2 O (0.1% DEA) and moved to 90% ACN (0.1% DEA):10% H 2 O (0.1% DEA) over 7 minutes.
  • Reserpine was used as the lock mass (m/z 609.2812) and to adjust mass scale.
  • exo-amine exo1-(8-azabicvclo[3.2.1]oct-3-yl)-2-methyl-1H- benzimidazole 8-Benzyl-8-azabicyclo[3.2.1]octan-3-one
  • the mixture turned cloudy.
  • the mixture was then cooled to ambient temperature and adjusted to pH ⁇ 12 using 50% NaOH in water.
  • the mixture was extracted with ethyl acetate (x3), dried over sodium sulfate and removed solvent to yield a brown oil.
  • the mixture was further purified by distillation, desired product collected -120 °C. 25 g crude product was recovered as a yellow oil to be carried on to next step.
  • Example 17 0 1 -((1 R.5S)-8-r2-(1 -benzoyl-4-phenylpiperidin-4-yl)ethyl1-8- azabicvclof3.2.1 loct-3-yl)-2-methyl-1 H-benzimidazole
  • 2-hydroxy-2-methylpropanoic acid (36 mg, 0.35 mmole) was dissolved in 0.92 ml of 1 ,2-dichloroethane. To this was added 1 ,1'-carbonyldiimidazole (37 mg, 0.23 mmole) and shaken for 30 min.
  • 2-Methyl-1- ⁇ 8-[2-(4-phenyl-4- piperidinyl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl ⁇ -1 H-benzimidazole (50 mg, 0.12 mmole) was added as a dry powder and shaking was resumed overnight. 1 ml of NaHCO 3 sat.
  • the approximately 100 milligrams of impure compound was dissolved in 300 microliters of DMSO and brought up to a final volume of 500 microliters using methanol.
  • This 500 microliter solution was injected by a Waters 2767 autosampler into an XTerra C18 5 micron particle HPLC column (19mmX150mm).
  • Initial solvent flow was 20ml/min with 30% methanol and 70% water at a pH of 11 using ammonium hydroxide as buffer. Void volume was 2 minutes, and a linear gradient to 100% methanol in 10 minutes with a five minute wash at 100% methanol eluted the compound in approximately 10 minutes.
  • the Boc-protected amine (1.02 mmoles) was dissolved in 5 mL DCM and treated with 5 mL TFA at ambient temperature for 1 h.
  • the reaction mixture was concentrated and treated with a biphasic mixture of EtOAc and saturated aqueous NaHCO 3 .
  • the mixture was stirred vigorously, and the solid filtered off and washed successively with water and EtOAc to give the TFA salt of the amine. Yields and representative data were included in the accompanying tables.
  • the product (73 mg, 101 ⁇ moles) was dissolved in 3 mL DCM and treated with 3 mL TFA at ambient temperature for 24h. The reaction mixture was concentrated, dissolved in DCM, washed with saturated aqueous NaHCO ⁇ , dried over MgSO 4 , filtered and concentrated. The crude product was purified by normal phase flash chromatography (SiO 2 , DCM/CH 3 OH) to give the desired product.
  • the accompanying tables list yields and representative data for compounds of the present invention.
  • Example 186 1 -((1 R.5SV8-(2- ⁇ -(2-fluorobenzovn-4-phenyl-4-piperidinyllethyl)-8- azabicvclo[3.2.noct-3-yl)-2-methyl-1 H-benzimidazole
  • Example 146 1 -((1 R,5S)-8- ⁇ 2- ⁇ -(2-chloro-6-fluorobenzoyl)-4-phenyl-4-piperidinvnethyl)-8- azabicvclor3.2. ⁇ oct-3-vD-2-methyl-1 H-benzimidazole
  • Example 105 1-((1 R,5SV8-(2- ⁇ -(2.2-dimethyl-4-pentenovn-4-phenyl-4-piperidinyllethyll-8- azabicvclor3.2.1 loct-3-v ⁇ -2-methyl-1 H-benzimidazole
  • Example 101 1 -((1 R.5S)-8-(2- ⁇ -(2.6-dichlorobenzovn-4-phenyl-4-piperidinv ⁇ ethyl)-8- azabicvclor3.2.11oct-3-ylY-2-methyl-1 H-benzimidazole
  • Example 334 1 -((1 R.5S)-8-(2- ⁇ -(2-ethylbutanovn-4-phenyl-4-piperidinv ⁇ ethyl)-8- azabicyclo[3.2.1loct-3-yl)-2-methyl-1 H-benzimidazole
  • Example 335 1-((1R,5SV8-f2-ri-(2-ethylbutanoyl)-4-phenyl-4-piperidinvnethyll-8- azabicvclor3.2.1 loct-3-v0-2-methyl-1 H-benzimidazole
  • Example 336 2-methyl-1 -((1 R.5S)-8-(2- ⁇ -(2-methylbenzoyl )-4-phenyl-4-piperidinv ⁇ ethyl)-8- azabicvclor3.2. ⁇ oct-3-yl)-1 H-benzimidazole
  • Example 339 4-methoxy-2-f(4-(2-r(1 R.5S)-3-(2-methyl-1 H-benzimidazol-1 -yll-8- azabicvclor3.2.1 loct-8-yllethyl)-4-phenyl-1 -piperidinv ⁇ carbonyllphenol
  • Example 28 1 -((1 R.5S)-8-(2- ⁇ -(2.2-dimethylbutanovn-4-phenyl-4-piperidinvnethyl)-8- azabicvclor3.2.11oct-3-yl 2-methyl-1 H-benzimidazole
  • Example 26 1 -f(4-(2-f(1 R.5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8-azabicvclor3.2.1 loct-8- v ⁇ ethyl
  • Example 342 1 -r(1 R,5S)-8-(2-(1 -r(3-chlorophenyl)sulfonyll-4-phenyl-4-piperidinyl)ethyl)-8- azabicvclor3.2.1 loct-3-v ⁇ -2-methyl-1 H-benzimidazole
  • Example 344 4-chlorophenyl 1.1 -dimethyl-2-(4-(2-r(1 R.5S)-3-(2-methyl-1 H-benzimidazol-1 - yl)-8-azabicvclor3.2.noct-8-yllethyl)-4-phenyl-1-piperidinyl)-2-oxoethyl ether
  • Example 345 1 -((1 R,5S)-8-(2-H -(3-cvclohexylpropanov0-4-phenyl-4-piperidinyllethyll-8- azabicvclor3.2. ⁇ oct-3-vD-2-methyl-1 H-benzimidazole
  • Example 350 2-methyl-1 -r(1 R.5S)-8-(2-(4-phenyl-1 -r2-(trifluoromethvnbenzoyl1-4- piperidinyl)ethvD-8-azabicvclor3.2.11oct-3-vn-1 H-benzimidazole
  • Example 351 1-((1 R.5S)-8-(2- ⁇ -(3-chloro-2-fluorobenzovn-4-phenyl-4-piperidinvnethyl)-8- azabicvclor3.2.1loct-3-v ⁇ -2-methyl-1 H-benzimidazole
  • Example 352 1 -IY1 R.5S)-8-(2-(1 -r(6-chloro-2-pyridinyl)carbonv ⁇ -4-phenyl-4- piperidinyl)ethyl)-8-azabicvclof3.2.1loct-3-yll-2-methyl-1 H-benzimidazole
  • Example 353 1 -((1 R.5S)-8-(2- ⁇ -(2-chloroisonicotinovD-4-phenyl-4-piperidinyllethyl)-8- azabicvclor3.2.noct-3-v ⁇ -2-methyl-1 H-benzimidazole
  • Example 354 1 -((1 R,5S)-8-(2- ⁇ -(4-chloro-2-fluorobenzoyl)-4-phenyl-4-piperidinvnethyll-8- azabicvclor3.2.11oct-3-yl)-2-methyl-1 H-benzimidazole
  • Example 355 1 -((1 R.5S 8-f2-M -(2.3-dimethylbenzoyl)-4-phenyl-4-piperidinvnethyl)-8- azabicvclor3.2.noct-3-yl)-2-methyl-1 H-benzimidazole
  • Example 356 1 -((1 R.5S)-8 2- ⁇ -(1 H-indol-5-ylcarbonyl)-4-phenyl-4-piperidinyllethyl)-8- azabicvclo[3.2.1 loct-3-yl)-2-methyl-1 H-benzimidazole
  • Example 357 1 -((1 R,5S)-8-(2-M -(1 H-indol-6-ylcarbonyl)-4-phenyl-4-piperidinvnethyl)-8- azabicvclor3.2. ⁇ oct-3-vD-2-methyl-1 H-benzimidazole
  • Example 361 2-methyl-1 -((1 R,5S)-8-(244-phenyl-1 -(3-phenyl-butanoylV4-piperidinv ⁇ ethyl)- 8-azabicvclor3.2.1loct-3-vh-1 H-benzimidazole
  • Example 362 3-(442-[(1 R.5S)-3-(2-methyl-1 H-benzimidazol-1 -vn-8-azabicvclor3.2.1loct-8- yrjethyl)-4-phenyl-1-piperidinyl)-3-oxopropyl phenyl ether
  • Example 363 1 -((1 R,5S)-8-(241 -(cvclohexylacetvh-4-phenyl-4-piperidinvnethyl)-8- azabicvclor3.2.1 loct-3-yl)-2-methyl-1 H-benzimidazole
  • Example 62 1 -((1 R.5SV84241 -(1 ,3-benzodioxol-5-ylcarbonvn-4-phenyl-4- piperidinvnethyl)-8-azabicvclor3.2.1loct-3-yl)-2-methyl-1 H-benzimidazole
  • Example 78 1 (1 R.5S V8-f2-(1 -butyryl-4-phenyl-4-piperidinvnethvn-8-azabicvclor3.2.1 loct- 3-yl)-2-methyl-1 H-benzimidazole
  • Example 83 1 -((1 R.5SV84241 1 H-indol-3-ylacetyl)-4-phenyl-4-piperidinyllethyl)-8- azabicvclor3.2.1 loct-3-v ⁇ -2-methyl-1 H-benzimidazole
  • Example 90 2-methyl-1 -((1 R.5S)-84241 1 -naphthovn-4-phenyl-4-piperidinyllethyll-8- azabicvclor3.2.1 loct-3-yl)-1 H-benzimidazole
  • Example 91 1 (1 R.5SV-84241 -(2,3-dichlorobenzovn-4-phenyl-4-piperidinyllethyl)-8- azabicvclor3.2.11oct-3-yl)-2-methyl-1 H-benzimidazole
  • Example 92 1 -methyl-2-(4424(1 R.5S)-342-methyl-1 H-benzimidazol-1 -yl)-8- azabicvclor3.2.11oct-8-v ⁇ ethyl ⁇ -4-phenyl-1 -piperidinvO-2-oxoethyl phenyl ether
  • Example 94 1 -((1 R.5S)-84241 2.3-dihvdro-1.4-benzodioxin-2-ylcarbonvn-4-phenyl-4- piperidinvnethyl)-8-azabicvclof3.2.noct-3-yl)-2-methyl-1 H-benzimidazole
  • Example 100 1 -((1 R.5S)-84241 -(2.4-dimethylbenzovn-4-phenyl-4-piperidinyllethyl)-8- azabicvclor3.2.1loct-3-yl)-2-methyl-1 H-benzimidazole
  • Example 104 1 -((1 R,5S)-84241 -(2.4-dimethylbenzoyl)-4-phenyl-4-piperidinyl1ethyl)-8- azabicvclo[3.2.1 loct-3-yl)-2-methyl-1 H-benzimidazole
  • Example 106 14(1 R.5S)-842-(14r2.2-dimethyl-3-(2-methyl-1- propenyl)cvclopropyl1carbonyl)-4-phenyl-4-piperidinv ⁇ ethvn-8- azabicvclor3.2. ⁇ oct-3-yl)-2-methyl-1 H-benzimidazole
  • Example 111 2-methyl-14(1 R.5S)-8-(244-phenyl-1 -f(1 -Phenylcvclopentvncarbonvn-4- piperidinyl)ethyl)-8-azabicyclor3.2.noct-3-vn-1 H-benzimidazole
  • Example 113 1 -((1 R,5S)-84241 -(2.4-dichlorobenzoylM-phenyl-4-piperidinv ⁇ ethvU-8- azabicvclof3.2.11oct-3-yl)-2-methyl-1 H-benzimidazole
  • Example 120 14(1 R.5S V842414(3.5-dimethoxyphenyl)acetyl1-4-phenyl-4-piperidinyllethv0- 8-azabicvclor3.2.11oct-3-yll-2-methyl-1 H-benzimidazole
  • Example 127 1 -((1 R.5SV84241 -(2,4-difluorobenzov0-4-phenyl-4-piperidinyllethyl)-8- azabicvclo[3.2.11oct-3-yl)-2-methyl-1 H-benzimidazole
  • Example 128 1 -((1 R.5S 84241 M .1 '-biphenvn-2-ylcarbonvn-4-phenyl-4-piperidinvnethyl)- 8-azabicvclor3.2.11oct-3-ylV2-methyl-1 H-benzimidazole
  • Example 138 methyl 24344424(1 R.5SV3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicvclor3.2.11oct-8-v ⁇ ethyll-4-phenyl-1 -piperidinyl)-3-oxopropyllphenyl ether
  • Example 139 1 ((1 R.5S 84241 -(cvclopentylacetyl)-4-phenyl-4-piperidinvnethyl)-8- azabicvclor3.2.1 loct-3-v0-2-methyl-1 H-benzimidazole
  • Example 142 1-r(1R.5S)-8-(241-r3-(1.3-benzodioxol-5-v ⁇ propanoyll-4-phenyl-4- piperidinyllethyl)-8-azabicvclo[3.2.11oct-3-vn-2-methyl-1 H-benzimidazole
  • Example 150 4.6-dimethyl-54(4424d R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicvclor3.2.noct-8-yl1ethyll-4-phenyl-1-piperidinyl)carbonyl1-2H-pyran-2- one
  • Example 156 1 (1 R.5S V84241 1 H-indol-3-ylcarbonyl)-4-phenyl-4-piperidinyllethyl)-8- azabicvclor3.2.1 loct-3-v ⁇ -2-methyl-1 H-benzimidazole
  • Example 158 3-r(442-r(1 R.5S)-3-(2-methyl-1 H-benzimidazol-1 -vn-8-azabicvclor3.2. Hoct-8- vnethyll-4-phenyl-1-piperidinyl)carbonvn-2H-chromen-2-one
  • Example 160 1 -((1 R.5SV84241 1 H-indol-4-ylcarbonvn-4-phenyl-4-piperidinv ⁇ ethyl)-8- azabicvclor3.2.1loct-3-yl)-2-methyl-1 H-benzimidazole
  • Example 162 1 -rd R,5S)-8-(241 -r(3-ethoxy-2-thienvncarbonvn-4-phenyl-4-piperidinyl)ethyl)- 8-azabicvclor3.2.11oct-3-v ⁇ -2-methyl-1 H-benzimidazole
  • Example 171 methyl 44344424(1 R,5S)-342-methyl-1 H-benzimidazol-1 -yl)-8- azabicvclor3.2.1loct-8-vnethyl)-4-phenyl-1 -pjperidinyl )-3-oxopropynphenyl ether
  • Example 173 1 -((1 R.5S)-842-n -(4-ethylbenzoyl)-4-phenyl-4- ⁇ iperidinyl1ethyl)-8- azabicyclor3.2.noct-3-yl)-2-methyl-1 H-benzimidazole
  • Example 175 1 -((1 R.5SV84241 -(4-chloro-2-methoxybenzov0-4-phenyl-4-piperidinyl1ethylV- 8-azabicvclor3.2.1loct-3-yl)-2-methyl-1 H-benzimidazole
  • Example 326B 1 H NMR (300 MHz, CD 3 OD) ⁇ ppm 1.97-2.45 (m, 12H), 2.62 (s, 3H),
  • Example 249 1 H NMR (300 MHz, CD 3 OD) ⁇ 7.63-8.00 (m, 3H), 7.49-7.59 (m, 1 H), 7.36-7.49 (m, 5H), 7.14-7.33 (m, 3H), 4.68-4.83 (m, 1H), 4.16-4.30 (m, 1 H), 3.36-3.51 (m, 2H, under methanol), 3.11-3.28 (m, 1 H), 2.56 (s, 3H), 2.34-2.51 (m, 3H), 2.23-2.34 (m, 1H), 1.85-2.01 (m, 10H), 1.59-1.77 (m, 2H), 1.18-1.38 (m, 4H).
  • Example 236 1 H NMR (300 MHz, CD 3 OD) ⁇ 7.64-7.98 (m, 3H), 7.48-7.59 (m, 1 H), 7.35-7.47 (m, 5H), 7.16-7.31 (m, 3H), 4.67-4.82 (m, 1 H), 4.13-4.30 (m, 1 H), 3.35-3.50 (m, 4H, under methanol), 3.11-3.27 (m, 1 H), 2.55 (s, 3H), 2.36-2.52 (m, 3H), 2.23-2.36 (m, 1H), 1.83-2.11 (m, 10H), 1.64-1.75 (m, 2H), 1.31 (s, 1 H), 0.98-1.15 (m, 7H).
  • Example 257 1 H NMR (300 MHz, CD 3 OD) ⁇ 7.33-7.59 (m, 6H), 7.13-7.31 (m, 3H), 4.66-4.85 (m, 1 H), 4.13-4.25 (m, 1 H), 3.94-4.13 (m, 1 H), 3.71-3.86 (m, 1 H), 3.35-3.41 (m, 1 H, under methanol), 3.09-3.27 (m, 1 H), 2.64-2.71 (m, 5H), 2.53-2.64 (m, 4H), 2.20-2.53 (m, 5H), 1.74-2.12 (m, 8H), 1.63-1.74 (m, 2H), 1.18-1.27 (m, 3H).
  • Example 258 1 H NMR (300 MHz, CD 3 OD) ⁇ 7.35-7.59 (m, 6H), 7.13-7.32 (m, 3H), 4.67-4.85 (m, 1 H), 3.98-4.32 (m, 1 H), 3.35-3.63 (m, 1 H, under methanol),
  • Example 262 1 H NMR (300 MHz, CD 3 OD) ⁇ 7.50-7.61 (m, 1H), 7.15-7.50 (m, 17H), 4.71-4.84 (m, 1 H), 4.48 (s, 2H), 4.06-4.24 (m, 1 H), 3.58-3.75 (m, 1 H), 3.35- 3.52 (m, 2H), 2.59-2.80 (m, 9H), 2.50 (s, 4H), 2.09-2.21 (m, 2H), 1.90-2.08 (m, 5H), 1.71-1.83 (m, 2H).
  • Example 235 1 H NMR (300 MHz, CD 3 OD) ⁇ 7.67-7.94 (m, 3H), 7.48-7.60 (m, 1 H), 7.34-7.48 (m, 5H), 7.13-7.33 (m, 3H), 4.66-4.83 (m, 1H), 4.16-4.29 (m, 1H), 3.33-3.49 (m, 4H, under methanol), 3.12-3.28 (m, 1 H), 2.57-2.61 (m, 1 H), 2.51-2.57 (m, 4H), 2.36-2.51 (m, 3H), 2.23-2.36 (m, 1H), 1.83-2.09 (m, 12H), 1.61-1.76 (m, 2H).
  • Example 288 1 H NMR (300 MHz, CD 3 OD) ⁇ 7.67-7.94 (m, 3H), 7.51-7.59 (m, 1 H), 7.38-7.51 (m, 2H), 7.16-7.30 (m, 4H), 6.97-7.08 (m, 1 H), 4.68-4.82 (m, 1 H), 4.13-4.29 (m, 1H), 3.35-3.54 (m, 3H, under methanol), 2.40-2.81 (m, 12H), 1.86-2.16 (m, 9H), 1.67-1.80 (m, 2H), 1.23-1.33 (m, 2H).
  • Example 364 1 H NMR (300 MHz, CD 3 OD) ⁇ 7.65-7.97 (m, 3H), 7.51-7.62 (m, 1 H), 7.38-7.51 (m, 2H), 7.13-7.32 (m, 4H), 6.94-7.12 (m, 1H), 4.68-4.82 (m, 1H), 4.08-4.30 (m, 1 H), 3.34-3.65 (m, 4H, under methanol), 2.84-3.06 (m, 2H), 2.67 (s, 3H), 2.44-2.61 (m, 4H), 2.32-2.44 (m, 1 H), 2.16-2.32 (m, 2H), 1.77- 2.16 (m, 9H), 1.27-1.39 (m, 2H), 1.00-1.17 (m, 3H).
  • Example 292 1 H NMR (300 MHz, CD 3 OD) ⁇ 7.64-7.98 (m, 3H), 7.50-7.58 (m, 1 H), 7.37-7.50 (m, 2H), 7.11-7.31 (m, 4H), 6.95-7.09 (m, 1 H), 4.65-4.81 (m, 1 H), 4.09-4.27 (m, 1 H), 3.36-3.56 (m, 4H, under methanol), 3.08-3.26 (m, 1 H), 2.57 (s, 3H), 2.31-2.51 (m, 4H), 2.16-2.31 (m, 1 H), 1.78-2.13 (m, 11 H), 1.64- 1.78 (m, 2H), 0.96-1.11 (m, 6H).
  • Example 308 1 H NMR (300 MHz, CD 3 OD) ⁇ 7.63-7.93 (m, 3H), 7.49-7.59 (m, 1 H), 7.38-7.48 (m, 1 H), 7.13-7.35 (m, 5H), 7.03-7.13 (m, 1 H), 4.67-4.83 (m, 1 H), 4.15-4.29 (m, 1 H), 3.34-3.41 (m, 5H, under methanol), 3.12-3.29 (m, 1 H), 2.52-2.61 (m, 6H), 2.40-2.52 (m, 3H), 2.34-2.40 (m, 4H), 2.19-2.34 (m, 1 H), 1.83-2.11 (m, 9H), 1.63-1.75 (m, 2H).
  • Example 309 1 H NMR (300 MHz, CD 3 OD) ⁇ 7.71-7.93 (m, 3H), 7.53-7.59 (m, 1 H), 7.40-7.49 (m, 2H), 7.17-7.29 (m, 4H), 6.97-7.08 (m, 1 H), 4.11-4.28 (m, 1 H), 3.48-3.61 (m, 1 H), 3.34-3.48 (m, 3H, under methanol), 3.12-3.30 (m, 1 H), 2.84-3.03 (m, 2H), 2.67 (s, 3H), 2.49-2.62 (m, 3H), 2.31-2.46 (m, 1 H), 2.16- 2.31 (m, 2H), 1.80-2.15 (m, 9H), 1.27-1.41 (m, 3H), 1.01-1.13 (m, 3H).
  • Example 293 1 H NMR (300 MHz, CD 3 OD) ⁇ 8.08 (s, 1 H), 7.61-7.76 (m, 2H), 7.50- 7.58 (m, 1 H), 7.36-7.49 (m, 2H), 7.13-7.31 (m, 4H), 6.94-7.07 (m, 1 H), 4.68- 4.82 (m, 1 H), 4.08-4.22 (m, 1H), 3.52-3.67 (m, 1 H), 3.35-3.51 (m, 4H, under methanol), 2.52-2.62 (m, 6H), 2.34-2.52 (m, 3H), 2.17-2.30 (m, 1 H), 1.81-2.14 (m, 11 H), 1.64-1.77 (m, 2H).
  • Example 275 1 H NMR (300 MHz, CD 3 OD) ⁇ 7.68-7.98 (m, 3H), 7.48-7.60 (m, 1 H), 7.35-7.48 (m, 5H), 7.24-7.35 (m, 1H), 7.14-7.24 (m, 2H), 4.66-4.82 (m, 1H), 4.16-4.30 (m, 1H), 3.34-3.43 (m, 6H, under methanol), 2.55 (s, 3H), 2.35-2.51 (m, 2H), 2.13-2.35 (m, 2H), 1.83-2.12 (m, 9H), 1.65-1.76 (m, 2H), 1.30 (s, 2 H), 0.41-0.61 (m, 3H).
  • Example 210 1 H NMR (300 MHz, CD 3 OD) ⁇ 7.91-8.00 (m, 1H), 7.87 (s, 1H), 7.64- 7.74 (m, 2H), 7.50-7.58 (m, 1 H), 7.36-7.49 (m, 5H), 7.22-7.32 (m, 1 H), 7.14- 7.22 (m, 2H), 4.69-4.82 (m, 1 H), 4.09-4.30 (m, 1 H), 3.47-3.66 (m, 1 H), 3.34- 3.39 (m, 3H, under methanol), 2.50-2.59 (m, 6H), 2.36-2.50 (m, 3H), 2.22- 2.35 (m, 1 H), 1.83-2.11 (m, 10H), 1.65-1.76 (m, 2H), 1.30 (s, 2 H).
  • Example 296 1 H NMR (300 MHz, CD 3 OD) ⁇ 7.89-8.00 (m, 1 H), 7.61-7.88 (m, 2H), 7.50-7.60 (m, 1 H), 7.34-7.50 (m, 2H), 7.12-7.34 (m, 4H), 6.94-7.07 (m, 1 H), 4.64-4.83 (m, 1 H), 4.10-4.27 (m, 1H), 3.34-3.54 (m, 3H, under methanol), 3.12-3.27 (m, 1 H), 2.56 (s, 3H), 2.30-2.51 (m, 3H), 2.16-2.30 (m, 1 H), 1.79- 2.12 (m, 11 H), 1.63-1.79 (m, 2H), 1.23-1.36 (m, 2H).
  • Example 297 1 H NMR (300 MHz, CD 3 OD) ⁇ 7.98-8.04 (m, 1 H), 7.87-7.96 (m, 1 H), 7.50-7.57 (m, 1 H), 7.38-7.48 (m, 3H), 7.15-7.28 (m, 4H), 6.96-7.05 (m, 1 H), 4.66-4.83 (m, 1 H), 4.13-4.24 (m, 1 H), 3.64-3.76 (m, 2H), 3.41-3.54 (m, 2H), 3.30-3.34 (m, 3H), 3.18-3.29 (m, 1 H), 2.543 (s, 3H), 2.30-2.51 (m, 3H), 2.15- 2.29 (m, 1 H), 1.84-2.09 (m, 9H), 1.66-1.76 (m, 2H), 1.27-1.32 (m, 1 H).
  • Example 278 1 H NMR (300 MHz, CD 3 OD) ⁇ 8.00-8.08 (m, 1 H), 7.85-7.98 (br.s, 1 H), 7.50-7.58 (m, 1 H), 7.36-7.46 (m, 1 H), 7.36-7.46 (m, 6H), 7.23-7.32 (m, 1 H), 7.14-7.22 (m, 2H), 4.67-4.83 (m, 1 H), 4.15-4.28 (m, 1 H), 3.18-3.58 (m, 7H), 2.51-2.57 (m, 3H), 2.34-2.50 (m, 3H), 1.81-2.09 (m, 10H), 1.62-1.75 (m, 2H), 1.26-1.33 (m, 1 H).
  • Example 279 1 H NMR (300 MHz, CD 3 OD) ⁇ 7.94-8.01 (m, 1H), 7.79-7.92 (m, 1H), 7.51-7.57 (m, 1 H), 7.37-7.47 (m, 6H), 7.23-7.31 (m, 1 H), 7.16-7.22 (m, 2H), 4.68-4.81 (m, 1 H), 4.16-4.29 (m, 1 H), 3.42-3.59 (m, 2H), 3.20-3.41 (m, 7H), 2.52-2.60 (m,4H), 2.25-2.49 (m, 3H), 1.85-2.09 (m, 8H), 1.66-1.75 (m, 1 H), 1.28-1.34 (s, 2H).
  • Example 281 1 H NMR (300 MHz, CD 3 OD) ⁇ 7.95-8.02 (m, 1H), 7.83-7.94 (br s, 1H), 7.50-7.57 (m, 1H), 7.37-7.48 (m, 6H), 7.23-7.30 (m, 1H), 7.15-7.23 (m, 2H), 4.67-4.83 (m, 1 H), 4.16-4.27 (m, 1 H), 3.30-3.33(m, 4H), 2.80-2.89 (m, 2H),
  • Example 282 1 H NMR (300 MHz, CD 3 OD) ⁇ 7.98-8.05 (m, . 1 H), 7.85-7.96 (m, 1 H),
  • Example 365 1 H NMR (300 MHz, CD 3 OD) ⁇ 7.81-8.10 (m, 2H), 7.47-7.60 (m, 1H), 7.35-7.47 (m, 5H), 7.14-7.31 (m, 3H), 4.69-4.84 (m, 1H), 4.14-4.31 (m, 1H), 3.35-3.49 (m, 2H, under methanol), 3.11-3.27 (m, 1 H), 2.50-2.64 (m, 6H), 2.36-2.50 (m, 3H), 2.22-2.36 (m, 1 H), 1.82-2.10 (m, 11 H), 1.62-1.75 (m, 2H), 1.11-1.20 (d, J 6.14 Hz, 2H).
  • Example 366 1 H NMR (300 MHz, CD 3 OD) ⁇ 7.64-7.95 (m, 3H), 7.49-7.59 (m, 1H), 7.34-7.48 (m, 2H), 7.10-7.30 (m, 4H), 6.95-7.06 (m, 1H), 4.72-4.83 (m, 1H), 4.11-4.25 (m, 1 H), 3.34-3.53 (m, 5H, under methanol), 3.07-3.29 (m, 1 H), 2.76-2.93 (m, 2H), 2.67 (s, 1 H), 2.42-2.60 (m, 4H), 2.29-2.42 (m, 1 H), 1.74- 2.29 (m, 12H), 1.26-1.56 (m, 3H), 0.80-0.96 (m, 3H).
  • Example 367 1 H NMR (300 MHz, CD 3 OD) ⁇ 7.65-7.92 (m, 2H), 7.47-7.65 (m, 2H), 7.37-7.47 (m, 1 H), 7.12-7.36 (m, 5H), 7.04-7.12 (m, 1 H), 4.69-4.83 (m, 1 H), 4.08-4.31 (m, 1 H), 3.34-3.47 (m, 3H, under methanol), 3.13-3.28 (m, 3H), 2.32-2.64 (m, 8H), 2.20-2.32 (m, 1H), 1.79-2.13 (m, 9H), 1.64-1.78 (m, 2H), 1.24-1.43 (m, 5H).
  • Te/ ⁇ -butyl 4-[3-(4-methoxybenzyl)-1 ,2,4-oxadiazol-5-yl]piperidine-1 - carboxylate was treated with 10 mL TFA/DCM (1 :1) for 30 min at ambient temperature. The reaction mixture was concentrated and the crude product was crystalized from EtOAc/Et 2 O, filtered and dried to give the TFA salt of 4- [3-(4-methoxybenzyl)-1 ,2,4-oxadiazol-5-yl]piperidine as a tan solid (1.23g, 3.17mmol, 32%, 3 steps).
  • the TFA or HCl salt of the amine (390 ⁇ moles) was combined with (1 - benzoyl-4-phenylpiperidin-4-yl)acetaldehyde (120 mg, 390 ⁇ moles, 1 eq.) in 4mL DCE and/or 4mL DMF and treated with NaBH(OAc) 3 (585 ⁇ moles, 1.5 eq.) with or without TEA (780 ⁇ moles, 2 eq.) at ambient temperature with agitation for 18h.
  • the reaction mixture was concentrated, dissolved in 5 mL DCM, and agitated 1 h with 5 mL of saturated aqueous NaHCO 3 .
  • the organic phase was separated and concentrated.
  • the HCl salt of the amine (1.66 mmoles) was combined with tert-butyl 4-(2-oxoethyl)-4-phenyl piperidine-1 -carboxylate (1.66 mmoles, 1 eq.) in 10 mL DCE and 10 mL DCM and treated with NaBH(OAc) 3 (2.49 mmoles, 1.5 eq.) with TEA (3.33 moles, 2 eq.) at ambient temperature with agitation for 18h.
  • the reaction mixture was washed with saturated aqueous NaHCO 3 , the organic phase separated, dried over MgSO 4 , filtered and concentrated.
  • the crude product was purified by normal phase flash chromatography (SiO 2 , CHCI 3 /CH 3 OH) to give the desired product. Yields and representative data are included in the accompanying tables.
  • Amine 1 prepared by the literature procedure described in WO 00/38680.
  • Enc o-terf-butyl 3-[(2-aminophenyl)amino]-8-azabicyclo[3.2.1]octane-8- carboxylate (WO 00/38680) (2.5 g, 7.80 mmol) was treated with 20 mL 1 ,1 ,1- triethoxypropane at reflux for 3h. The reaction mixture was concentrated to dryness, redissolved in CH 3 OH (10 mL), and treated with 6 N HCl at reflux for 1 h.
  • Enofo-te/t-butyl 3-[(2-aminophenyl)amino]-8-azabicyclo[3.2.1]octane-8- carboxylate (WO 00/38680) (1.8 g, 5.70 mmol) was treated with 20 mL [(3,3,3-triethoxypropyl)sulfonyl]benzene at 150 °C for 3h. The reaction mixture was concentrated to dryness, redissolved in CH 3 OH (10 mL), and treated with 6 N HCl at reflux for 1 h.

Abstract

The present invention relates to compounds of formula (I) or pharmaceutically acceptable derivatives thereof, useful in the treatment or prophylaxis of CCR5-related diseases and disorders, for example, in the inhibition of HIV replication, the prevention or treatment of an HIV infection, and in the treatment of the resulting acquired immune deficiency syndrome (AIDS).

Description

CCR5 ANTAGONISTS AS THERAPEUTIC AGENTS
FIELD OF THE INVENTION
The present invention relates to a novel class of piperidine derivatives useful as antagonists of the chemokine receptor CCR5, compositions containing such compounds and methods of treating HIV infection and associated conditions. The invention also relates to methods of treatment or prophylaxis of other CCR5 mediated diseases and disorders.
BACKGROUND OF THE INVENTION
The human immunodeficiency virus ("HIV") is the causative agent for acquired immunodeficiency syndrome ("AIDS"), a disease characterized by the destruction of the immune system, particularly of CD4 T-cells, with attendant susceptibility to opportunistic infections, and its precursor AIDS- related complex ("ARC"), a syndrome characterized by symptoms such as persistent generalized lymphadenopathy, fever and weight loss.
In addition to CD4, HIV requires a co-receptor for entry into target cells. The chemokine receptors function together with CD4 as co-receptors for HIV.
The chemokine receptors CXCR4 and CCR5 have been identified as the main co-receptors for HIV-1. CCR5 acts as a major co-receptor for fusion and entry of macrophage-tropic HIV into host cells. These chemokine receptors are thought to play an essential role in the establishment and dissemination of an HIV infection. Therefore, CCR5 antagonists are useful as therapeutic agents active against HIV.
CCR5 receptors have also been reported to mediate cell transfer in inflammatory and immunoregulatory diseases and disorders such as multiple sclerosis, rheumatoid arthritis, autoimmune diabetes, chronic implant rejection, asthma, rheumatoid arthritis, Crohns Disease, inflammatory bowel disease, chronic inflammatory disease, glomerular disease, nephrotoxic serum nephritis, kidney disease, Alzheimer's Disease, autoimmune encephalomyelitis, arterial thrombosis, allergic rhinitis, arteriosclerosis, Sjogren's syndrome (dermatomyositis), systemic lupus erythematosus, graft rejection, cancers with leukocyte infiltration of the skin or organs, human papilloma virus infection, prostate cancer, wound healing, amyotrophic lateral sclerosis, and immune mediated disorders. There is a continued need to find new therapeutic agents to treat human diseases. CCR5 is an attractive target for the discovery of new therapeutics due to its important role in viral infections, particularly HIV infections, and other inflammatory and immune diseases and disorders.
SUMMARY OF THE INVENTION
The present invention features compounds that are CCR5 antagonists and therefore are useful in the inhibition of HIV replication, the prevention and/or treatment of infection by HIV, and in the treatment of AIDS and/or ARC. These compounds having the general formula I:
Figure imgf000003_0001
wherein R1, R2, R3, X, Y, m, n and Ring A are as defined herein. The compounds of this invention may also be either pharmaceutically acceptable salts or pharmaceutical composition ingredients.
The present invention also features pharmaceutical compositions, comprising the above-mentioned compounds that are suitable for the prevention or treatment of CCR5-related diseases and conditions.
The present invention also features methods of antagonizing CCR5 chemokine receptor activity in a biological sample comprising contacting the biological sample with an effective amount of compounds of formula I or pharmaceutically acceptable derivatives or compositions thereof. The present invention also features methods of antagonizing CCR5 chemokine receptor activity in a patient comprising administering to the patient a therapeutically effective amount of compounds of formula I or pharmaceutically acceptable derivatives or compositions thereof. The present invention further features methods of treating AIDS, methods of preventing infection by HIV, and methods of treating infection by HIV as monotherapy or in combination with other antivirals, anti-infectives, irnmunomodulators, antibiotics or vaccines.
The present invention further features methods of synthesizing compounds of formula I and preparing pharmaceutical compositions comprising these above-mentioned compounds.
DETAILED DESCRIPTION OF THE INVENTION
The present invention features a compound of formula (I):
Figure imgf000004_0001
(I) or a pharmaceutically acceptable derivative thereof, wherein:
R1 is alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl, wherein said alkyl is optionally substituted by one or more R7, said carbocyclyl or heterocyclyl is optionally substituted by one or more R8 and said aryl or heteroaryl is optionally substituted by one or more R6; or R1 and X taken together form a saturated, partially saturated or aromatic 5-7 membered ring having 0-3 heteroatoms chosen from oxygen, sulfur, nitrogen and phosphorus that is fused to Ring A;
X is a C-ι-5 alkylene chain, wherein said Cι-5 alkylene chain is optionally substituted by one or more groups chosen from =O, =S and halo, and wherein said Ci-5 alkylene chain optionally contains 1-3 heteroatoms chosen from oxygen, sulfur, nitrogen and phosphorus; each R2 is independently chosen from -OR0, -C(O)R°, -C(O)N(R°)2, -N(R°)(-Vm-R+), -S(O)2-R°, -S(O)2-N(R°)2, -(CH2)a-N(R°)(-Vb-R+), -(CH2)a-(-Vb-R+), halo, alkyl, aryl, carbocyclyl, heteroaryl and heterocyclyl, wherein said alkyl is optionally substituted by one or more R7, said aryl or heteroaryl is optionally substituted by one or more R6, and said carbocyclyl or heterocyclyl is optionally substituted by one or more R8; or two adjacent R2s on Ring A are optionally taken together to form a fused, saturated, partially saturated or aromatic 4-7 membered ring having 0-3 heteroatoms chosen from oxygen, sulfur, nitrogen and phosphorus; or two geminal R2s are optionally taken together to form a spiro, saturated, partially saturated or aromatic 5-6 membered ring having 0-3 heteroatoms chosen from oxygen, sulfur and nitrogen, said fused or spiro ring being optionally substituted by one or more groups chosen from oxo, alkyl optionally substituted by one or more R7, and aryl optionally substituted by one or more R6; each a is independently 0-3; each b is independently 0 or 1 ;
V is alkyl, -C(O)-, -S(O)2-, -C(O)O-, or -C(O)-N(R0)- (where V is attached to R+ through the right hand side of the radical as shown hereinafter); R+ is alkyl, aralkyl, aryl, heteroaryl, heteroaralkyl, wherein said alkyl is optionally substituted by one or more R7 and said aralkyl or aryl is optionally substituted by one or more R6; m is 0 or 1 ; n is 0-5; R3 is H, halo, -N(R°)2, -N(R°)C(O)R°, -CN, -CF3, alkyl optionally substituted by one or more groups chosen from R7, and -S-aryl optionally substituted by -(CH2)ι-6-N(R°)SO2(R0), carbocyclyl, aryl, heteroaryl or heterocyclyl, wherein said carbocyclyl or heterocyclyl is optionally substituted by one or more R8, and said aryl or heteroaryl is optionally substituted by one or more R6;
Y is -(CR4R5)p-, -C(O)-, -C(O)C(O)-, -C(S)-, -O-(CH2)0-4-C(O)-, -N(R°)-C(O)-, -C(O)-N(R0)-, -N(R°)-C(S)-, -S(O)r, -O-C(=N-CN)-, -O-C(=N-R0)-, -S-C(=N-CN)-, -N(R°)-C(=N-CN)-, -C(=N-CN)-, -N(R°)-C[=N-C(O)-R0]-, -N(R°)-C[=N-S(O)t-R0]-, -N(R°)-C(=N-OR0)-, -N(R°)-C(=N-R0)-, -C(=N-R0)-, -(CH2)o-4-C(O)-O-, -C(=N-CN)-O-, -C(=N-R°)-O-, or -C(=N-CN)-S- (where Y is attached to R3 through the left hand side of the radical as shown hereinafter); each R4 is independently H or alkyl optionally substituted by R7; each R5 is independently chosen from H, -C(O)-OR°, aryl optionally substituted by R6, -C(O)-OR6, -C(O)-N(R°)2, -S(O)2-N(R°)2, -S(O)2-R°, and heteroaryl optionally substituted by R6; p is 1-5; t is 1 or 2; each R6 is independently chosen from halo, -CF3, -OCF3, -OR0, -SR°, -SCF3, -R°, methylenedioxy, ethylenedioxy, -NO2, -CN, -N(R°)2, -NR°C(O)R°, -NR0C(O)N(R°)2, -NR°C(S)N(R°)2, -NR°CO2R°, -NR°NR°C(O)R°, -NR0NR°C(O)N(R0)2, -NR0NR°CO2R0, -C(O)C(O)R°,
-C(O)CH2C(O)R°, -CO2R°, -O-C(O)R°, -C(O)R°, -C(O)N(R°)2, -OC(O)N(R°)2, -S(O)tR°, -S(O)t-OR°, -SO2N(R°)C(O)R°, -NR°SO2N(R0)2, -NR°SO2R°, -C(=S)N(R°)2, -C(=NH)-N(R°)2, -C(=N-OR°)-N(R°)2, -O-(CH2)o-6-SO2N(R0)2, -(CH2)ι.6NHC(O)R0, -SO2N(R°)2, -(CH2)ι-6-OR°, -(CH2)ι-6-SR°, -(CH2)ι-6-CN, -(CH2)ι-6-N(R0)2, -(CH2)ι-6CO2R0, -C(O)N(R0)N(R°)2, -C(O)N(R°)OH,
-C(O)N(R°)SO2R°, -S(O)tN(R°)OR, and -(CH2)ι-6-C(O)R0, wherein the two R°s on the same nitrogen optionally taken together forming a 5-8 membered saturated, partially saturated or aromatic ring having additional 0-4 ring heteroatoms chosen from oxygen, nitrogen, sulfur and phosphorus; each R7 is independently chosen from halogen, -CF3, -R°, -OR0, -SR°, aryl optionally substituted by R6, -NO2, -CN, -N(R°)2, -NR°C(O)R°, -NR°C(O)N(R°)2, -N(R°)C(S)N(R°)2, -NR°CO2R°, -NR°NR°C(O)R°, -NR0NR°C(O)N(R0)2, -NR°NR0CO2R0, -C(O)C(O)R°, -C(O)CH2C(O)R°, -CO2R°, -C(O)R°, -C(O)N(R°)-N(R0)2, -C(O)N(R°)2, -C(O)NR°SO2R0, -OC(O)N(R°)2, -S(O)tR°, -NR0SO2N(R°)2, -NR°SO2R°, -C(=S)N(R°)2,
-C(=NH)-N(R°)2, -(CH2)ι-6-C(O)R0, -SO2N(R°)2, -OCF3, -SCF3) -(CH2)ι-6-SR0, methylenedioxy, ethylenedioxy, -(CH2)ι-6-CN, -(CH2)ι-6-N(R°)2, -S(O)tN(R°)OR°, -(CH2)ι.6-C(O)R°, -C(=N-OR°)-N(R°)2, -O-(CH2)o-6-SO2N(R0)2, and -(CH2)-ι_6-NHC(O)R0, wherein the two R°s on the same nitrogen optionally taken together form a 5-8 membered saturated, partially saturated or aromatic ring having additional 0-4 ring heteroatoms chosen from oxygen, nitrogen, sulfur and phosphorous; each R8 is independently chosen from R7, =O, =S, =N(R°), and =N(CN); each R° is independently chosen from R*, -C(O)-aralkyl, -S(O)t-heteroaryl, carbocyclylalkyl, aralkyl, heteroaralkyl, and heterocyclylalkyl, wherein each member of R° except H is optionally substituted by one or more groups chosen from R*, -OR*, N(R*)2> =O, =S, halo, -CF3, -NO2, -CN, -C(O)R*, -CO2R*, -C(O)-aryl, -C(O)-heteroaryl, -O-aryl, aralkyl, -S(O)t-aryl, -NR*SO2R*, -NR*C(O)R*, -NR*C(O)N(R*)2) -N(R*)C(S)N(R*)2, -NR*CO2R*, -NR*NR*C(O)R*, -NR*NR*C(O)N(R*)2, -NR*NR*CO2R*, -C(O)C(O)R*, -C(O)CH2C(O)R*, -C(O)N(R*)N(R*)2,
-C(O)N(R*)2, -C(O)NR*SO2R*, -OC(O)N(R*)2, -S(O)tR*, -NR*SO2N(R*)2, and -SO N(R*)2 wherein the two R*s on the same nitrogen optionally taken together form a 5-8 membered saturated, partially saturated or aromatic ring having additional 0-4 ring heteroatoms chosen from oxygen, nitrogen, sulfur and phosphorus; and each R* is independently H, alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl; provided that when R1 is m-methylphenyl, X is a C2 unsubstituted saturated alkylene chain, and R2 substituted Ring A is 4-benzyl or 4-phenyl-4'- hydroxy substituted N-piperinyl, R3-(Y)m- is other than H, triphenylmethyl, benzoyl, 2,4-dimethoxybenzoyl, (3,5-dimethoxyphenyl)acetyl, or (3-chlorophenyl)acetyl.
As used herein, the following definitions shall apply unless otherwise indicated. The phrase "optionally substituted" is used interchangeably with the phrase "substituted or unsubstituted" or with the term "(un)substituted."
Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group, and each substitution is independent of the other.
The term "alkyl", alone or in combination with any other term, refers to a C-i.20 straight or branched acyclic hydrocarbon radical that is either completely saturated or contains one or more units of unsaturation.
Preferably, an alkyl radical contains from one to twelve carbon atoms. More preferably, an alkyl radical contains from one to eight carbon atoms. A C2-20 linear or branched alkyl radical having at least one carbon-carbon double bond is also referred to as "alkenyl". The double bond(s) of the unsaturated hydrocarbon chain may be in either the cis or trans configuration and may occur in any stable point along the chain. A C-2-2o linear or branched alkyl having at least one carbon-carbon triple bond is also referred to as "alkynyl". The tripe bond(s) in an alkynyl radical may occur in any stable point along the chain. The terms "alkoxy", "hydroxyalkyl", "alkoxyalkyl", and "alkoxycarbonyl", alone or in combination with any other term, include both straight and branched hydrocarbon chains.
Examples of alkyl radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, n- hexyl, ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, pentenyl, hexenyl, hexadienyl, ethynyl, propynyl, butynyl, pentynyl and the like.
The term "alkoxy" refers to an alkyl ether radical (-O-alkyl). Examples of alkoxy radicals include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like.
The term "cycloalkyl", "carbocyclyl", "carbocyclic", "carbocycle", or "carbocyclo", alone or in combination with any other term, refers to a monocyclic or polycyclic non-aromatic hydrocarbon ring radical having three to twenty carbon atoms, preferably from three to twelve carbon atoms, and more preferably from three to ten carbon atoms. If polycyclic, each ring in a carbocyclyl radical is non-aromatic unless otherwise indicated. A carbocylyl radical is either completely saturated or contains one or more units of unsaturation but is not aromatic. The unsaturation, if present, may occur in any point in the ring that may result in any chemically stable configuration. The term "cycloalkyl", "carbocyclyl", "carbocyclic", "carbocycle", or "carbocyclo" also includes hydrocarbon rings that are fused to one or more aromatic rings, such as in tetrahydronaphthyl, where the radical or point of attachment is on the non-aromatic ring. Unless otherwise indicated, the term "cycloalkyl", "carbocyclyl",
"carbocyclic", "carbocycle", or "carbocyclo" also includes each possible positional isomer of a non-aromatic hydrocarbon radical, such as in 1- decahydronaphthyl, 2- decahydronaphthyl, 1 -tetrahydronaphthyl and 2- tetrahydronaphthyl. Examples of suitable cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, decahydronaphthyl, tetrahydronaphthyl and the like.
The term "halogen" refers fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).
The term "aryl", alone or in combination with any other term, refers to an aromatic monocyclic or polycyclic hydrocarbon ring radical containing five to twenty carbon atoms, preferably from six to fourteen carbon atoms, and more preferably from six to ten carbon atoms. Also included within the scope of the term "aryl", as it is used herein, is a group in which an aromatic hydrocarbon ring is fused to one or more non-aromatic carbocyclic or heteroatom-containing rings, such as in an indanyl, phenanthridinyl or tetrahydronaphthyl, where the radical or point of attachment is on the aromatic hydrocarbon ring.
Unless otherwise indicated, the term "aryl" also includes each possible positional isomer of an aromatic hydrocarbon radical, such as in 1 -naphthyl, 2-naphthyl, 5-tetrahydronaphthyl, 6-tetrahydronaphthyl, 1 -phenanthridinyl, 2- phenanthridinyl, 3-phenanthridinyl, 4-phenanthridinyl, 7-phenanthridinyl, 8- phenanthridinyl, 9-phenanthridinyl and 10-phenanthridinyl. Examples of aryl radicals include, but are not limited to, phenyl, naphthyl, indenyl, azulenyl, fluorenyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl, indanyl, phenanthridinyl and the like. The term "aralkyl" refers to an alkyl group substituted by an aryl. Examples of aralkyl groups include, but are not limited to, benzyl and phenethyl. The term "heterocycle", "heterocyclic", or "heterocyclyl", alone or in combination with any other term, refers to a non-aromatic monocyclic or polycyclic ring radical containing three to twenty carbon atoms, preferably three to seven carbon atoms if monocyclic and eight to eleven carbon atoms if bicyclic, and in which one or more ring carbons, preferably one to four, are each replaced by a heteroatom such as N, O, and S. If polycyclic, each ring in a heterocyclyl radical is non-aromatic unless otherwise indicated. A heterocyclic ring may be fully saturated or may contain one or more units of unsaturation but is not aromatic. The unsaturation, if present, may occur in any point in the ring that may result in any chemically stable configuration. The heterocyclic ring may be attached at a carbon or heteroatom that results in the creation of a stable structure. Preferred heterocycles include 5-7 membered monocyclic heterocycles and 8-10 membered bicyclic heterocycles. Also included within the scope of the term "heterocycle", "heterocyclic", or "heterocyclyl" is a group in which a non-aromatic heteroatom-containing ring is fused to one or more aromatic rings, such as in an indolinyl, chromanyl, phenanthridinyl or tetrahydro-quinolinyl, where the radical or point of attachment is on the non-aromatic heteroatom-containing ring. Unless otherwise indicated, the term "heterocycle", "heterocyclic", or "heterocyclyl" also includes each possible positional isomer of a heterocyclic radical, such as in 1-decahydroquinoline, 2-decahydroquinoline, 3-decahydroquinoline, 4- decahydroquinoline, 5-decahydroquinoline, 6-decahydroquinoline, 7- decahydroquinoline, 7-decahydroquinoline, 8-decahydroquinoline, 4a- decahydroquinoline, 8a-decahydroquinoline, 1 -indolinyl, 2-indolinyl, 3- indolinyl, 1-tetrahydroquinoline, 2-tetrahydro-quinoline, 3-tetrahydroquinoline and 4-tetrahydro-quinoline. The term "heterocyclylalkyl" refers to an alkyl group substituted by a heterocyclyl.
Examples of heterocyclic groups include, but are not limited to, imidazolinyl, 2,3-dihydro-1 H-imidazolyl, imidazolidinyl, indazolinolyl, perhydropyridazyl, pyrrolinyl, pyrrolidinyl, 4H-pyrazolyl, piperidinyl, pyranyl, pyrazolinyl, piperazinyl, morpholinyl, thiamorpholinyl, thiazolidinyl, thiamorpholinyl, oxopiperidinyl, oxopyrrolidinyl, azepinyl, tetrahydrofuranyl, oxoazepinyl, tetrahydropyranyl, thiazolyl, dioxolyl, dioxinyl, oxathiolyl, benzodioxolyl, dithiolyl, dithiolanyl, tetrahydrothiophenyl, sulfolanyl, dioxanyl, dioxolanyl, tetahydrofurodihydrofuranyl, dihydropyranyl, tetrahydropyranodihydrofuranyl, tetradyrofurofuranyl, tetrahydropyranofuranyl, diazolonyl, phthalimidinyl, benzoxanyl, benzopyrrolidinyl, benzopiperidinyl, benzoxolanyl, benzothiolanyl and benzothianyl.
The term "heteroaryl", alone or in combination with any other term, refers to an aromatic monocyclic or polycyclic ring radical containing five to twenty carbon atoms, preferably five to ten carbon atoms, in which one or more ring carbons, preferably one to four, are each replaced by a heteroatom such as N, O, S and P. Preferred heteroaryl groups include 5-6 membered monocyclic heteroaryls and 8-10 membered bicyclic heteroaryls.
Also included within the scope of the term "heteroaryl" is a group in which a heteroaromatic ring is fused to one or more aromatic or non-aromatic rings where the radical or point of attachment is on the heteroaromatic ring. Examples include, but are not limited to, pyrido[3,4-d]pyrimidinyl, 7,8-dihydro- pyrido[3,4-d]pyrimidine and 5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine. Unless otherwise indicated, the term "heteroaryl" also includes each possible positional isomer of a heteroaryl radical, such as in 2-pyrido[3,4-d]pyrimidinyl and 4-pyrido[3,4-d]pyrimidinyl. The term "heteroaralkyl" refers to an alkyl group substituted by a heteroaryl.
Examples of heteroaryl groups include, but are not limited to, imidazolyl, quinolyl, isoquinolyl, indolyl, indazolyl, pyridazyl, pyridyl, pyrrolyl, pyrazolyl, pyrazinyl, quinoxalyl, pyrimidinyl, pyridazinyl, furyl, thienyl, triazolyl, thiazolyl, carbazolyl, carbolinyl, tetrazolyl, benzofuranyl, oxazolyl, benzoxazolyl, isoxozolyl, isothiazolyl, thiadiazolyl, furazanyl, oxadiazolyl, benzimidazolyl, benzothienyl, quinolinyl, benzotriazolyl, benzothiazolyl, isoquinolinyl, isoindolyl, acridinyl and benzoisoxazolyl. The term "heteroatom" means nitrogen, oxygen, sulfur, or phosphorus and includes any oxidized form of nitrogen, such as N(O) [N+-O"], sulfur such as S(O) and S(O)2, phosphorus such as PO3 and PO4 and the quaternized form of any basic nitrogen. Suitable substituents on a substitutable ring nitrogen include alkyl, -N(R')2, -C(0)R\ -CO2R\ -C(0)C(0)R\ -C(O)CH2C(O)R', -SO2R', -SO2N(R')2, -C(=S)N(R')2, -C(=NH)-N(R')2, and -NR'SO2R'; wherein R' is hydrogen, alkyl, phenyl (Ph), -OPh, -CH2Ph, wherein said alkyl or phenyl is optionally substituted by one or more groups independently chosen from alkyl, amino, alkylamino, dialkylamino, aminocarbonyl, halo, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, haloalkoxy, and haloalkyl. The term "alkylene chain" refers to a straight or branched hydrocarbon chain that may be fully saturated or have one or more units of unsaturation. The unsaturation may occur in any stable point along the chain. The double bond(s) in the unsaturated alkylidene chain may be in either the cis or trans configuration. A combination of substituents or variables is permissible only if such a combination results in a stable or chemically feasible compound. A stable compound or chemically feasible compound is one in which the chemical structure is not substantially altered when kept at a temperature of 40 °C or less, in the absence of moisture or other chemically reactive conditions, for at least a week.
Unless otherwise stated, structures depicted herein are also meant to include all endo or exo, cis or trans isomers as well as all stereochemical forms of the structure, i.e., the R and S configurations for each asymmetric center. Therefore, racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereoisomers of the present compounds are expressly included within the scope of the invention. Although the specific compounds exemplified herein may be depicted in a particular stereochemical configuration, compounds having either the opposite stereochemistry at any given chiral center or mixtures thereof are also envisioned.
Unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by a 13C- or 14C-enriched carbon are also within the scope of this invention. It will be apparent to one skilled in the art that certain compounds of this invention may exist in alternative tautomeric forms. All such tautomeric forms of the present compounds are within the scope of the invention. Unless otherwise indicated, the representation of either tautomer is meant to include the other. Certain preferred compounds of the present invention are those represented by formula II:
Figure imgf000013_0001
or a pharmaceutically acceptable derivative thereof, wherein R2, R3, R6, n, Y and Ring A are as defined for formula I. Preferred compounds of formula II are those wherein Ring A is a heterocycle having one ring nitrogen and 0-1 additional ring oxygen or ring nitrogen. Other preferred compounds of formula II are those wherein Ring A is piperidinyl, piperaziny, pyrrolidinyl, azabicyclo[3.2.1] octanyl, aza- bicyclo[3.2.1]octenyl or oxa-aza-bicyclo [4.3.1]decanyl. In some embodiments of the invention, Ring A is connected to the alkylene chain X through an endocyclic nitrogen.
Also preferred are compounds of formula II, wherein R2 is aryl, aralkyl, heteroaryl, heterocyclyl, -N(H)(-Vm-R+), or -N(alkyl)(-Vm-R+), wherein V is - C(O)-, -S(O)2-, -C(O)O- or -C(O)-N(H)-, m is 0 or 1 , R+ is phenyl or benzyl, and said aryl, aralkyl, heteroaryl or heterocyclyl is optionally substituted. More preferably, R2 of compounds of formula II is phenyl, naphthyl, benzyl, -NH-phenyl, -NH-benzyl, -NHC(O)-phenyl, -NHSO2-phenyl, -NHC(O)NH-phenyl, benzoimidazolyl, dihydrobenzo-imidazolyl, oxodihydrobenzoimidazolyl, 3H-indolyl, quinolinyl, dihydro-1H-isoindolyl, dioxodihydro-1 H-isoindolyl, tetrahydroquinoxalinyl, dioxotetrahydro- quinoxalinyl, 3H-imidazo[4,5-b]pyridinyl, dihydro-1 H-imidazo [4,5-b]pyridinyl, benzotriazolyl, oxadiazolyl or triazolyl, wherein each member of R2 is optionally substituted. Preferred substituents of R2 include alkyl, halo, -SO2R°, -CF3) alkoxy, -NR°, -N(R°)C(O)R°, -N(R°)C(O)OR°, -N(R0)C(S)N(R°)2, =O, -(CH2)ι-6-C(O)R°, optionally substituted alkyl, and optionally substituted aralkyl. More preferred substituents of R2 include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, F, Cl, -SO2CH3, -CF3, -OMe, -OEt, -NH2, -NHMe, -N(H)C(O)Me, -N(H)C(O)OMe, -N(H)C(O)OEt, -N(H)C(S)N(H)(Me), =O, -(CH2)2SO2Ph, =O, -CH2-C(O)-cyclopropyl, and methoxy substituted benzyl. Preferably, n is 1-3, and more preferably, n is 1- 2. In certain embodiments of the invention, R2 is attached to Ring A through a R2 nitrogen.
Preferred Y of formula II includes -C(O)-, -O-C(O)-, -N(R°)-C(O)-, -S(O)2-, ^O-C(=N-CN)-, -S-C(=N-CN)-, -N(R°)-C(=N-CN)-, -C(=N-CN)-, -N(R°)-C(S)-, -N(R°)-C(=N-OR0)-, -N(R°)-C[=N-S(O)t-R°], -O-C(=N-R0)-, -N(R°)-C[=N-C(O)-R°], -N(R°)-C(=N-R0)-, and -C(=N-R°)~. More preferably, each R° in Y is independently R* and m is 1.
Preferred R3 of formula II includes optionally substituted alkyl, aryl, heteroaryl, heterocyclyl and carbocyclyl. More preferred R3 of formula II includes optionally substituted fully saturated alkyl, 3-7 membered carbocyclyl, 5-7 membered aryl, 6-10 membered heteroaryl and 4-10 membered heterocyclyl. Even more preferred R3 of formula II includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclohexenyl, tetrahydrofuranyl, azetidinyl, piperidinyl, hexahydrofuro[2,3-b]furanyl, oxopyrrolidinyl, dihydro-2H-[1 ,3]thiazinyl, tetrahydro-pyrimidinyl, dihydrobenzo[1 ,4]dioxinyl, dihydro-2H-benzo[1 ,2,4]thiadiazinyl, dihydrobenzo[d]isothiazolyl, morpholinyl, dihydro-1 H-imidazolyl, dihydrobenzooxazolyl, chromenyl, dihydroquinolinyl, pyrrolyl, benzotriazolyl, benzothiazolyl, benzofuranyl, furanyl, pyridyl, thienyl, thiadiazolyl, isoxazolyl, 14
triazolyl, thiazolyl, benzoyl, isothiazolyl, imidazolyl, indolyl, pyrazolo[3,4- bjpyridinyl, quinoxalinyl, and phenyl. Preferred substituents of R3 includes halo, methylenedioxy, -OR0, R°, -C(O)OR°, -SO2R°, -SO2(OR°), -SO2N(R°)2, -SO2N(R°)OR°, and -SO2N(R°)C(O)R°. More preferred substituents of R3 includes Cl, Br, F, CF3, Me, tetrazolyl, methylenedioxy, -OMe, -C(O)OH, -SO2R°, -SO2(OH), -SO2NH2, -SO2NHMe, -SO2N(H)C(O)Me, and -SO2N(H)OMe.
In certain embodiments of the invention, -(Y)m-R3 is selected from the following:
Figure imgf000015_0001
More preferably, -(Y)m-R3 is selected from the following:
Figure imgf000016_0001
Figure imgf000017_0001
Figure imgf000018_0001
O. O
°γNH 2 O^NH.
HN HN HN'S^ N^N
*T *fr Y Y
Figure imgf000018_0002
Figure imgf000019_0001
In one embodiment m is 1 , Y is -C(O)-, and R3 is aryl, heteroaryl, alkyl, or cycloalkyl, each optionally substituted.
In one embodiment m is 1 , Y is -(C=N-CN)-O-, and R3 is optionally substituted aryl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, or optionally substituted heterocyclyl. In one embodiment m is 1 , Y is -(CH2)-, and R3 is optionally substituted aryl.
In one embodiment m is 1 , Y is -C(O)O-, and R3 is optionally substituted alkyl or optionally substituted aryl.
In one embodiment m is 0 and R3 is optionally substituted heteroaryl or optionally substituted heterocyclyl.
In one embodiment X is -(CH2)-, -(CH2-CH2)-, or -(CH2-CH2-CH2)-. Further X is optionally substituted by one or more halogen or oxo. Still further X is disubstituted with halogen. Still further X is disubstituted with fluoro. Specifically X may be -(CF2-CH2)-. Further X optionally has 1-3 heteroatoms selected from oxygen, phosphorus, sulfur, or nitrogen.
In one embodiment the A ring is selected from the following, where the asterisk (*) indicates the preferred, but not limiting, point(s) of substitution:
Figure imgf000021_0001
Figure imgf000021_0002
Figure imgf000021_0003
Suitably each R2, with the asterisk (*) indicating a preferred, but not limiting, point of substitution from Ring A, independently is selected from
Figure imgf000022_0001
Figure imgf000023_0001
Figure imgf000024_0001
In one embodiment the ring A, with two geminal R2s, is selected from:
Figure imgf000025_0001
Suitably the A ring is tropane or piperidine, either optionally substituted with one or more R2. Preferrably, A-R2 is comprised of one of the following:
Figure imgf000025_0002
25
Figure imgf000026_0001
Figure imgf000026_0002
Figure imgf000026_0003
Figure imgf000027_0001
Figure imgf000028_0001
Figure imgf000029_0001
In one embodiment the A ring contains at least one additional nitrogen atom and said A ring optionally is N-substituted. Suitably the A ring is N- substituted with -(CH2)a-(Vb-R+).
Preferred R6 of formula II includes alkyl, halo, SO2R° and SO2N(R°)2. More preferred R6 of formula II includes Me, F, Cl, SO2NH2, SO2Me, and methylenedioxy.
Other preferred compounds of the present invention are those represented by formula III:
Figure imgf000029_0002
or a pharmaceutically acceptable derivative thereof, wherein R2, R3, R5, R6, n and Ring A are as defined for formula I. Preferred compounds of formula III are those wherein R3 is optionally substituted aryl. More preferably, R3 is phenyl optionally substituted by one or more alkyl (such as Me) or halo (such as F and Cl). Other preferred compounds of the present invention are those represented by formulae IV-IX:
Figure imgf000030_0001
IV V VI
Figure imgf000030_0002
VII R3 in formulae IV-VII is as defined for formula I.
Preferred compounds of formula I have one or more, and more preferably all, of the features selected from the group consisting of: (a) R1 is alkyl, aryl, heteroaryl or heterocyclyl, wherein said alkyl is optionally substituted by one or more R7, said aryl or heteroaryl is optionally substituted by one or more R6, and said heterocyclyl is optionally substituted by one or more R8;
(b) X is a Cι_5 alkylene chain optionally substituted by one or more groups chosen from =O and halo;
(c) Ring A is an 8-10 membered bicyclic ring having 0-5 ring heteroatoms chosen from oxygen, sulfur and nitrogen;
(d) R2 is aryl, heteroaryl or heterocyclyl, wherein said aryl or heteroaryl is optionally substituted by one or more R6 and said heterocyclyl is optionally substitued by one or more R8;
(e) Y is -C(R°)[C(O)OR0]-, -C(O)-, -O-C(O)-, -N(R°)-C(O)-, -S(O)2-, -O-C(=N-CN)-, -S-C(=N-CN)-, -N(R°)-C(=N-CN)-, -C(=N-CN)-, -N(R°)-C(S)-, -N(R°)-C(=N-OR0)-, -N(R°)-C[=N-S(O)rR°], -O-C(=N-R0)-, -N(R°)-C[=N-C(O)-R°], -N(R°)-C(=N-R0)-, or -C(=N-R0)-; wherein each R° is independently R* and m is 1 ; and (f) R3 is alkyl, aryl, heteroaryl, heterocyclyl or carbocyclyl, wherein said alkyl is optionally substituted by one or more R7, said aryl or heteroaryl is optionally substituted by one or more R6, and said heterocyclyl or carbocyclyl is optionally substituted by one or more R8.
More preferred compounds of the present invention have one or more, and more preferably all, of the features selected from the group consisting of:
(a) R1 is aryl optionally substituted by one or more R6;
(b) X is a C2 alkylene chain optionally substituted by one or more groups chosen from =O and halo;
(c) Ring A is an 8-9 membered bicyclic ring having one ring nitrogen and 0-4 additional ring heteroatoms chosen from oxygen, sulfur and nitrogen;
(d) R2 is heteroaryl optionally substituted by one or more R6, or heterocyclyl optionally substituted by one or more R8;
(e) Y is -C(R°)[C(O)OR0]-, -CH(COOH)-, -C(O)-, -O-C(O)-, -N(R°)-C(O)-, -O-C(=N-CN)-, or -N(R°)-C(S)-; wherein each R° is independently R* and m is 1 ; and
(f) R3 is alkyl optionally substituted by one or more R7, aryl or heteroaryl wherein said aryl or heteroaryl is optionally substituted by one or more R6. Other more preferred compounds of the present invention have one or more, and more preferably all, of the features selected from the group consisting of:
(a) R1 is phenyl optionally substituted by one or more groups chosen from alkyl, halo, -OR0, -CF3, R°, -SO2R°, methylenedioxy and - SO2N(R°)2; wherein each R° is independently R*;
(b) X is a saturated C2 alkylene chain optionally substituted by one or more groups chosen from =O and halo; (c) Ring A is an 8-9 membered non-aromatic bicyclic ring having one ring nitrogen and 0-1 additional ring heteroatoms chosen from oxygen, sulfur and nitrogen;
(d) R2 is a 9-10 memebered bicyclic heteroaryl or heterocyclyl each having one to three ring nitrogens, wherein said heteroaryl is optionally substituted by one or more groups chosen from alkyl, halo, -SO2R°, -CF3, alkoxy, -NR°, -N(R°)C(O)R°, -N(R°)C(O)OR°, and -N(R°)C(S)N(R°)2 and said heterocyclyl is optionally substituted by one or more groups chosen from alkyl, halo, -SO2R°, -CF3) alkoxy, -NR°, -N(R°)C(O)R°, -N(R°)C(O)OR°, -N(R°)C(S)N(R°)2 and =O;
(e) Y is -CH(COOH)-, -CH(COOMe)-, -C(O)-,
-O-C(O)-, -N(R°)-C(O)-, -O-C(=N-CN)-, or -N(R°)-C(S)-; wherein each R° is independently H and m is 1 ; and
(f) R3 is methyl, butyl, pentyl, cyclobutyl optionally substituted by one or more R8, phenyl, pyrazolyl, thiadiazolyl, benzotriazolyl, pyrrolyl, benzothiazolyl, benzofuranyl, furanyl, pyridyl, thienyl, isoxazolyl, triazolyl, thiazolyl, isothiazolyl, imidazolyl, indolyl, pyrazolo[3,4-b]pyridinyl, or quinoxalinyl, wherein each member of R3 except methyl, butyl, pentyl and cyclobutyl is optionally substituted by one or more R6 and said methyl, butyl and pentyl are optionally substituted by one or more R7.
Even more preferred compounds of the present invention have one or more, and more preferably all, of the features selected from the group consisting of:
(a) R1 is phenyl optionally substituted by one or more groups chosen from halo, -CF3, methyleneoxy, alkyl, alkoxy and sulfonamide;
(b) X is a saturated C-2 alkylene chain;
(c) Ring A is azabicyclo[3.2.1]octanyl or piperidinyl;
(d) R2 is benzoimidazolyl, imidazo[4,5-b]pyridinyl, benzotriazolyl, or oxadiazolyl, wherein each member of R2 is optionally substituted by one or more groups chosen from alkyl, halo, R°, -SO2R°, -CF3, alkoxy, benzyl, -CH2-pyridyl and -NR°;
(e) Y is -C(O)-, -C(S)-, -C(O)C(O)-, -O-C(O)-, -CH(COOH)-, -CH(COOMe)-, -NH-C(O)-, -NH-C(S)-, -SO2-, -CH2-, or -O-C(=N-CN)- and m is 0 or 1; and
(f) R3 is methyl, butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptanyl, phenyl, naphthyl, thienyl, furanyl, benzofuranyl, thiazolyl, isothiazolyl, isoxazolyl, pyrazolyl, pyrrolyl, piperidinyl, pyrimidinyl, benzooxazole-2-thionyl, imidazolyl, oxiranyl, pyrazolo[3,4-b]pyridinyl, pyrazolo[1 ,5-a]pyrimidinyl, thioxodihydrotriazinonyl, dihydrotetrazolethionyl, benzotriazolyl, pyrrolidinonyl, pyrrolidine-2,5-dionyl, imidazolidin-2-onyl, indolyl, dihydrofuran-2-onyl, pyrimidine-2,4-dionyl, quinolinyl, pyran-2-onyl, benzothiazolyl, dihydrobenzo[1 ,4]dioxinyl, quinoxalinyl, chromen-4-onyl, tetrazolyl, pyridyl, thiadiazolyl or thiazinedionyl, wherein said R3 is optionally substituted by one or more groups chosen from -C(O)OR°, -C(O)N(R°)SO2R°, -N(R°)C(O)R°, -N(R°)C(O)OR°, NO2, CN, CF3, halo, methylenedioxy, -OR0, -N(R°)2, R°, tetrazolyl, -SO2R°, -SO2(OR°), -SO2N(R°)2, -SO2N(R°)OR°, -SO2N(CH2CH2OR0)2, -O-SO2N(R°)2, -NR°SO2R0, -N(R°)C(O)N(R°)2, -SO2N(R0)(CH2CF3), -SO2NH(cyclopropyl), and -SO2N(R°)-C(O)R°.
The compounds of this invention generally may be prepared from known or readily prepared starting materials, following methods known to those skilled in the art, such as those illustrated by general Scheme I below, wherein R corresponds to R3-(Y)m- in formula I, and by the examples described herein. Scheme
Figure imgf000034_0001
Other compounds of this invention may be prepared by one skilled in the art following the teachings of the specification coupled with knowledge in the art using reagents that are readily synthesized or commercially available.
Compounds of the present invention are useful as CCR5 antagonists. One aspect of the instant invention relates to methods of antagonizing CCR5 chemokine receptor activity in a biological sample comprising contacting the biological sample with compounds of formula I or pharmaceutically acceptable derivatives thereof. Another aspect of the instant invention relates to methods of antagonizing CCR5 chemokine receptor activity in a patient comprising administering to the patient with a therapeutically effective amount of compounds of formula I or pharmaceutically acceptable derivatives thereof. The antagonistic activity of the present compounds towards the chemokine receptor CCR5 may be assayed by methods known in the art, for example, by using the methods as described in example 801.
According to one embodiment of the invention, compounds of formulae l-VII or salts thereof may be formulated into compositions. In a preferred embodiment, the composition is a pharmaceutical composition, which comprises a compound of formula I and pharmaceutically acceptable carrier, adjuvant or vehicle. In one embodiment, the composition comprises an amount of a CCR5 antagonist of the present invention effective to antagonize CCR5 chemokine receptor activity in a biological sample or in a patient. In another embodiment, compounds of this invention and pharmaceutical compositions thereof, which comprise an amount of a CCR5 antagonist of the present invetion effective to antagonize CCR5 chemokine receptor activity to treat or prevent a CCR5-mediated disease or disorder and a pharmaceutically acceptable carrier, adjuvant or vehicle, may be formulated for administration to a patient, for example, for oral administration.
The term "pharmaceutically effective amount" or "therapeutically effective amount" refers to an amount of a compound of this invention that is effective in treating a CCR5-related disease, for example a virus infection, for example an HIV infection, in a patient either as monotherapy or in combination with other agents.
The term "antagonist of CCR5 chemokine receptor" refers to a compound that binds to the chemokine receptor CCR5 but fails to elicit a response thereby blocking agonist action. The term "antagonizing CCR5 chemokine receptor" refers to binding to the receptor but failing to elicit a response thereby blocking agonist action, i.e, inhibiting a function of CCR5. For example, an antagonist of CCR5 chemokine receptor may inhibit the binding of one or more ligands (e.g., MIP-1α, RANTES, MIP-1β, and gp120) to CCR5 and/or inhibit signal transduction mediated through CCR5 (e.g., GDP/GTP exchange by CCR5-associated G proteins, intracellular calcium flux). Accordingly, CCR5-mediated processes and cellular responses (e.g., proliferation, migration, chemotactic responses, secretion or degranulation) can be inhibited with an antagonist of CCR5. The term "CCR5 mediated disease or disorder" or "CCR5 related disease or disorder" is used herein at all occurrences to mean any disease, disorder or other deleterious condition or state in which CCR5 is known to play a role. The term "treatment" as used herein refers to the alleviation of symptoms of a particular disorder in a patient, or the improvement of an ascertainable measurement associated with a particular disorder, and may include the suppression of symptom recurrence in an asymptomatic patient such as a patient in whom a viral infection has become latent. The term "prophylaxis" refers to preventing a disease or condition or preventing the occurrence of symptoms of such a disease or condition, in a patient. As used herein, the term "patient" refers to a mammal, including a human.
As used herein, the term "subject" refers to a patient or a biological sample. The term "biological sample", as used herein, includes, without limitation, cell cultures or extracts thereof; preparations of an enzyme suitable for in vitro assay; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.
The term "pharmaceutically acceptable carrier, adjuvant or vehicle" refers to a carrier, adjuvant or vehicle that may be administered to a patient, together with a compound of this invention, and which does not destroy the pharmacological activity thereof and is nontoxic when administered in doses sufficient to deliver a therapeutic amount of the therapeutic agent. The term "pharmaceutically acceptable derivative" means any pharmaceutically acceptable salt, ester, salt of an ester, or other derivative of a compound of this invention which, upon administration to a recipient, is capable of providing (directly or indirectly) a compound of this invention or an inhibitorily active metabolite or residue thereof. Particularly favored derivatives are those that increase the bioavailability of the compounds of this invention when such compounds are administered to a patient (e.g., by allowing an orally administered compound to be more readily absorbed into the blood) or which enhance delivery of the parent compound to a biological compartment (e.g., the brain or lymphatic system) relative to the parent species.
Throughout this specification, the word "comprise" or variations such as "comprises" or "comprising" will be understood to imply the inclusion of a stated integer or groups of integers but not the exclusion of any other integer or group of integers.
Pharmaceutically acceptable salts of the compounds according to the invention include those derived from pharmaceutically acceptable inorganic and organic acids and bases. Examples of suitable acids include hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycollic, lactic, salicyclic, succinic, toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic, ethanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic and benzenesulfonic acids. Other acids, such as oxalic, while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts.
Salts derived from appropriate bases include alkali metal (e.g. sodium), alkaline earth metal (e.g., magnesium), ammonium, NW4 + (wherein W is Cι. alkyl) and other amine salts. Physiologically acceptable salts of a hydrogen atom or an amino group include salts of organic carboxylic acids such as acetic, lactic, tartaric, malic, isethionic, lactobionic and succinic acids; organic sulfonic acids such as methanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonic acids and inorganic acids such as hydrochloric, sulfuric, phosphoric and sulfamic acids. Physio-logically acceptable salts of a compound with a hydroxy group include the anion of said compound in combination with a suitable cation such as Na+, NH +, and NW + (wherein W is a Cι-4alkyl group).
Any reference to any of the above compounds also includes a reference to a pharmaceutically acceptable salt thereof.
Salts of the compounds of the present invention may be made by methods known to a person skilled in the art. For example, treatment of a compound of the present invention with an appropriate base or acid in an appropriate solvent will yield the corresponding salt.
Esters of the compounds of the present invention are independently selected from the following groups: (1) carboxylic acid esters obtained by esterification of the hydroxy groups, in which the non-carbonyl moiety of the carboxylic acid portion of the ester grouping is selected from straight or branched chain alkyl (for example, acetyl, n-propyl, t-butyl, or n-butyl), alkoxyalkyl (for example, methoxymethyl), aralkyl (for example, benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (for example, phenyl optionally substituted by, for example, halogen, Cι_ alkyl, or Cι- alkoxy or amino); (2) sulfonate esters, such as alkyl- or aralkylsulfonyl (for example, methanesulfonyl); (3) amino acid esters (for example, L-valyl or L-isoleucyl); (4) phosphonate esters and (5) mono-, di- or triphosphate esters. The phosphate esters may be further esterified by, for example, a C1-20 alcohol or reactive derivative thereof, or by a 2,3-di (C6-24)acyl glycerol.
In such esters, unless otherwise specified, any alkyl moiety present advantageously contains from 1 to 18 carbon atoms, particularly from 1 to 6 carbon atoms, more particularly from 1 to 4 carbon atoms, Any cycloalkyl moiety present in such esters advantageously contains from 3 to 6 carbon atoms. Any aryl moiety present in such esters advantageously comprises a phenyl group.
The present invention features compounds according to the invention for use in medical therapy, for example for the treatment including prophylaxis of CCR5-related diseases and disorders, including but not limited to, viral infections such as an HIV infection and associated conditions.
As discussed above, the compounds of the present invention are CCR5 antagonists. Accordingly, these compounds are capable of targeting and inhibiting the entry of a virus, e.g, HIV, into its target cell. The compounds according to the invention are especially useful for the treatment of AIDS and related clinical conditions such as AIDS related complex (ARC), progressive generalized lymphadenopathy (PGL), Kaposi's sarcoma, thromobocytopenic purpura, AIDS-related neurological conditions such as i
AIDS dementia complex, multiple sclerosis or tropical paraperesis, anti-HIV antibody-positive and HIV-positive conditions, including such conditions in asymptomatic patients.
According to another aspect, the present invention provides a method for the treatment including prevention of the symptoms or effects of a viral infection in an infected patient, for example, a mammal including a human, which comprises treating said patient with a pharmaceutically effective amount of a compound according to the invention. According to one aspect of the invention, the viral infection is a retroviral infection, in particular an HIV infection. A further aspect of the invention includes a method for the treatment including prevention of the symptoms or effects of an HBV infection.
The compounds according to the invention may also be used in adjuvant therapy in the treatment of HIV infections or HIV-associated symptoms or effects, for example Kaposi's sarcoma. The compounds of the present invention may also be used in the treatment (including prevention) of other CCR5-related diseases and conditions, including multiple sclerosis, rheumatoid arthritis, autoimmune diabetes, chronic implant rejection, asthma and topic disorders (for example, atopic dermatitis and allergies), rheumatoid arthritis, Crohns Disease, inflammatory bowel disease, chronic inflammatory disease, glomerular disease, nephrotoxic serum nephritis, kidney disease, Alzheimer's Disease, autoimmune encephalomyelitis, arterial thrombosis, allergic rhinitis, arteriosclerosis, Sjogren's syndrome (dermatomyositis), systemic lupus erythematosus, graft rejection, cancers with leukocyte infiltration of the skin or organs, human papilloma virus infection, prostate cancer, wound healing, amyotrophic lateral sclerosis, psoriasis, multiple sclerosis, chronic obstructive pulmonary disease (COPD), sarcoidosis, immune-mediated disorders, and bacterial infections, including bubonic and pneumonic plague, particularly infections of Yersinia pestis. The present invention further provides a method for the treatment of a clinical condition in a patient, for example, a mammal including a human which clinical condition includes those which have been discussed hereinbefore, which comprises treating said patient with a pharmaceutically effective amount of a compound according to the invention. The present invention also includes a method for the treatment including prophylaxis of any of the aforementioned diseases or conditions. In yet a further aspect, the present invention provides the use of a compound according to the invention in the manufacture of a medicament for the treatment including prophylaxis of any of the above mentioned CCR5- related diseases or conditions including viral infections (e.g., HIV infection) and associated conditions. Reference herein to treatment extends to prophylaxis as well as the treatment of established conditions, disorders and infections, symptoms thereof, and associated clinical conditions.
The above compounds according to the invention and their pharmaceutically acceptable derivatives may be employed in combination with other therapeutic agents for the treatment of the above infections or conditions. Combination therapies according to the present invention comprise the administration of a compound of the present invention or a pharmaceutically acceptable derivative thereof and another pharmaceutically active agent. The active ingredient(s) and pharmaceutically active agents may be administered simultaneously (i.e., concurrently) in either the same or different pharmaceutical compositions or sequentially in any order. The amounts of the active ingredient(s) and pharmaceutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect. Examples of such therapeutic agents include, but are not limited to, agents that are effective for the treatment of viral infections or associated conditions. Among these agents are (1 -alpha, 2-beta, 3-alpha)-9-[2,3- bis(hydroxymethyl)cyclobutyl]guanine [(-)BHCG, SQ-34514, lobucavir]; 9- [(2R,3R,4S)-3,4-bis(hydroxy methyl)2-oxetanosyl]adenine (oxetanocin-G); acyclic nucleosides, for example acyclovir, valaciclovir, famciclovir, ganciclovir, and penciclovir; acyclic nucleoside phosphonates, for example (S)-1-(3-hydroxy-2-phosphonyl-methoxypropyl) cytosine (HPMPC), [[[2-(6- amino-9H-purin-9-yl)ethoxy] methyljphosphinylidene] bis(oxymethylene)-2,2- dimethyl propanoic acid (bis-POM PMEA, adefovir dipivoxil), [[(1 R)-2-(6- amino-9H-purin-9-yl)-1-methylethoxy]methyl] phosphonic acid (tenofovir), and (R)-[[2-(6-Amino-9H-purin-9-yl)-1 -methylethoxyjmethyljphosphonic acid bis- (isopropoxycarbonyloxymethyl)ester (bis-POC-PMPA); ribonucleotide reductase inhibitors, for example 2-acetylpyridine 5-[(2- chloroanilino)thiocarbonyl) thiocarbonohydrazone and hydroxyurea; nucleoside reverse transcriptase inhibitors, for example 3'-azido-3'- deoxythymidine (AZT, zidovudine), 2',3'-dideoxycytidine (ddC, zalcitabine), 2',3'-dideoxyadenosine, 2',3'-dideoxyinosine (ddl, didanosine), 2',3'- didehydrothymidine (d4T, stavudine), (-)-beta-D-2,6-diaminopurine dioxolane (DAPD), 3'-azido-2',3'-dideoxythymidine-5'-H-phosphophonate (phosphonovir), 2'-deoxy-5-iodo-uridine (idoxuridine), (-)-cis-1 -(2- hydroxymethyl)-1 ,3-oxathiolane 5-yl)-cytosine (lamivudine), cis-1-(2- (hydroxymethyl)-1 ,3-oxathiolan-5-yl)-5-fluorocytosine (FTC), 3'-deoxy-3'- fluorothymidine, 5-chloro-2',3'-dideoxy-3'-fluorouridine, (-)-cis-4-[2-amino-6- (cyclo-propylamino)-9H-purin-9-yl]-2-cyclopentene-1 -methanol (abacavir), 9- [4-hydroxy-2-(hydroxymethyl)but-1-yl]-guanine (H2G), ABT-606 (2HM-H2G) and ribavirin; protease inhibitors, for example indinavir, ritonavir, nelfinavir, amprenavir, saquinavir, fosamprenavir, (R)-N-tert-butyl-3:[(2S,3S)-2-hydroxy- 3-N-[(R)-2-N-(isoquinolin-5-yloxyacetyl)amino-3-methylthio-propanoyl]amino- 4-phenylbutanoyl]-5,5-dimethyl-1 ,3-thiazolidine-4-carboxamide (KNI-272), 4R- (4alpha, 5alpha,6beta)]-1 ,3-bis[(3-aminophenyl)methyl]hexahydro-5,6- dihydroxy-4,7-bis(phenylmethyl)-2H-1 ,3-diazepin-2-one dimethanesulfonate (mozenavir), 3-[1-[3-[2-(5-trifluoromethylpyridinyl)- sulfonylamino]phenyl]propyl]-4- hydroxy-6alpha-phenethyl-6beta-propyl-5,6- dihydro-2-pyranone (tipranavir), N'-[2(S)-Hydroxy-3(S)-[N-(methoxycarbonyl)- l-tert-leucylamino]-4-phenylbutyl-N a,pha-(methoxycarbonyl)-N'-[4-(2- pyridyl)benzyl]-L- tert-leucylhydrazide (BMS-232632), 3-(2(S)-Hydroxy-3(S)- (3-hydroxy-2-methylbenzamido)-4-phenylbutanoyl)-5,5-dimethyl-N-(2- methylbenzyl)thiazolidine-4(R)-carboxamide (AG-1776), N-(2(R)-hydroxy- 1 (S)-indanyl)-2(R)-phenyl-methyl-4(S)-hydroxy-5-(1 -(1 -(4- benzo[b]furanylmethyl)-2(S)-N'-(tert-butyl carboxamido)piperazinyl)pentanamide (MK-944A); interferons such as α- interferon; renal excretion inhibitors such as probenecid; nucleoside transport inhibitors such as dipyridamole, pentoxifylline, N-acetylcysteine (NAC), Procysteine, -trichosanthin, phosphonoformic acid; as well as immunomodulators such as interleukin II or thymosin, granulocyte macrophage colony stimulating factors, erythropoetin, soluble CD4 and genetically engineered derivatives thereof; non-nucleoside reverse transcriptase inhibitors (NNRTIs), for example nevirapine (BI-RG-587), alpha- ((2-acetyl-5-methylphenyl)amino)-2,6-dichloro-benzeneacetamide (loviride), 1- [3-(isopropyl amino)-2-pyridyl]-4-[5-(methanesulfonamido)-1 H-indol-2- ylcarbonyljpiperazine monomethanesulfonate (delavirdine), (10R, 11S, 12S)- 12-Hydroxy-6, 6, 10, 11-tetramethyl-4-propyl-11 ,12-dihydro-2H, 6H, 10H- benzo(1 , 2-b:3, 4-b':5, 6-b")tripyran-2-one ((+) calanolide A), (4S)-6-Chloro-4- [1 E)-cyclopropyl ethenyl)-3,4- dihydro-4-(trifluoromethyl)-2(1 H)-quinazolinone (DPC-083), (S)-6-chloro-4-(cyclopropyl ethynyl)-1 ,4-dihydro-4- (trifluoromethyl)-2H-3,1-benzoxazin-2-one (efavirenz, DMP 266), 1 -(ethoxy methyl)-5-(1 -methylethyl)-6-(phenylmethyl)-2,4(1 H,3H)-pyrimidinedione (MKC- 442), and 5-(3,5-dichloro phenyl)thio-4-isopropyl-1-(4-pyridyl)methyl-1H- imidazol-2-ylmethyl carbamate (capravirine); glycoprotein 120 antagonists, for example PRO-2000, PRO-542 and 1 ,4-bis[3-[(2, 4- dichlorophenyl)carbonyl amino]-2-oxo-5,8-disodiumsulfanyl]naphthalyl-2, 5-dimethoxyphenyl-1 , 4- dihydrazone (FP-21399); cytokine antagonists, for example reticulose (Product-R), 1 ,1'-azobis-formamide (ADA), 1 ,11-(1 ,4-phenylenebis (methylene))bis-1 ,4,8,11-tetraazacyclotetradecane octahydrochloride (AMD- 3100); integrase inhibitors; and fusion inhibitors, for example T-20 and T- 1249.
The present invention further includes the use of a compound according to the invention in the manufacture of a medicament for simultaneous or sequential administration with at least another therapeutic agent, such as those defined hereinbefore. Compounds of the present invention may be administered with an agent known to inhibit or reduce the metabolism of compounds, for example ritonavir. Accordingly, the present invention features a method for the treatment including prophylaxis of a disease as hereinbefore described by administration of a compound of the present invention in combination with a metabolic inhibitor. Such combination may be administered simultaneously or sequentially.
In general a suitable dose for each of the above-mentioned conditions will be in the range of 0.01 to 250 mg per kilogram body weight of the recipient (e.g. a human) per day, preferably in the range of 0.1 to 100 mg per kilogram body weight per day and most preferably in the range 0.5 to 30 mg per kilogram body weight per day and particularly in the range 1.0 to 20 mg per kilogram body weight per day. Unless otherwise indicated, all weights of active ingredient are calculated as the parent compound of formula (I); for salts or esters thereof, the weights would be increased proportionally. The desired dose may be presented as one, two, three, four, five, six or more sub- doses administered at appropriate intervals throughout the day. In some cases the desired dose may be given on alternative days. These sub-doses may be administered in unit dosage forms, for example, containing 10 to 1000 mg or 50 to 500 mg, preferably 20 to 500 mg, and most preferably 50 to 400 mg of active ingredient per unit dosage form.
While it is possible for the active ingredient to be administered alone, it is preferable to present it as a pharmaceutical composition. The compositions of the present invention comprise at least one active ingredient, as defined above, together with one or more acceptable carriers thereof and optionally other therapeutic agents. Each carrier must be acceptable in the sense of being compatible with the other ingredients of the composition and not injurious to the patient.
Phamaceutical compositions include those suitable for oral, rectal, nasal, topical (including transdermal, buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous, intradermal, and intravitreal) administration. The compositions may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. Such methods represent a further feature of the present invention and include the step of bringing into association the active ingredients with the carrier, which constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers or finely divided solid carriers or both, and then if necessary shaping the product. The present invention further includes a pharmaceutical composition as hereinbefore defined wherein a compound of the present invention or a pharmaceutically acceptable derivative thereof and another therapeutic agent are presented separately from one another as a kit of parts.
Compositions suitable for transdermal administration may be presented as discrete patches adapted to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. Such patches suitably contain the active compound 1) in an optionally buffered, aqueous solution or 2) dissolved and/or dispersed in an adhesive or 3) dispersed in a polymer. A suitable concentration of the active compound is about 1% to 25%, preferably about 3% to 15%. As one particular possibility, the active compound may be delivered from the patch by electrotransport or iontophoresis as generally described in Pharmaceutical Research 3(6), 318 (1986).
Pharmaceutical compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, caplets, cachets or tablets each containing a predetermined amount of the active ingredients; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste.
A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredients in a free-flowing form such as a powder or granules, optionally mixed with a binder (e.g. povidone, gelatin, hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (e.g. sodium starch glycollate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose) surface-active or dispersing agent. Molded tablets may be made by molding a mixture of the powdered compound moistened with an inert liquid diluent in a suitable machine. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredients therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile. Tablets may optionally be provided with an enteric coating, to provide release in parts of the gut other than the stomach.
Pharmaceutical compositions suitable for topical administration in the mouth include lozenges comprising the active ingredients in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
Pharmaceutical compositions suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray Pharmaceutical compositions containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
Pharmaceutical compositions for rectal administration may be presented as a suppository with a suitable carrier comprising, for example, cocoa butter or a salicylate or other materials commonly used in the art. The suppositories may be conveniently formed by admixture of the active combination with the softened or melted carrier(s) followed by chilling and shaping in molds.
Pharmaceutical compositions suitable for parenteral administration include aqueous and nonaqueous isotonic sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the pharmaceutical composition isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents; and liposomes or other microparticulate systems which are designed to target the compound to blood components or one or more organs. The pharmaceutical compositions may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injection, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
Unit dosage pharmaceutical compositions include those containing a daily dose or daily subdose of the active ingredients, as hereinbefore recited, or an appropriate fraction thereof.
It should be understood that in addition to the ingredients particularly mentioned above the pharmaceutical compositions of this invention may include other agents conventional in the art having regard to the type of pharmaceutical composition in question, for example, those suitable for oral administration may include such further agents as sweeteners, thickeners and flavoring agents.
In order that the invention described herein may be more fully understood, the following examples are set forth. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting this invention in any manner.
EXAMPLES
General Procedures Plate purification chromatographic conditions: Prep. HPLC Conditions A
Approximately 100 milligrams of the impure compound was dissolved in 500 microliters of methanol. This 500 microliter solution was injected by a Waters 2767 autosampler into a Phenomenex Luna C18 5 micron particle HPLC column (21.20 mm X 150 mm). Initial solvent flow was 20ml/min with
30% methanol and 70% water at a pH of 2.5 using formic acid as buffer. Void volume was 2 minutes, and a linear gradient to 100% methanol in 10 minutes with a five minute wash at 100% methanol eluted the compound in approximately 10 minutes. A Micromass Platform LC mass spectrometer was used to monitor a split off the eluate for desired mass, and the purified fractions were collected using Micromass Fractionlynx software. About 35 mg of purified compound was isolated. Prep. HPLC Conditions B
Approximately 100 milligrams of the impure compound was dissolved in 300 microliters of DMSO and brought up to a final volume of 500 microliters using methanol. This 500 microliter solution was injected by a Waters 2767 autosampler into an XTerra C18 5 micron particle HPLC column (19mmX150mm). Initial solvent flow was 20 ml/min with 30% methanol and 70% water at a pH of 11 using ammonium hydroxide as buffer. Void volume was 2 minutes, and a linear gradient to 100% methanol in 10 minutes with a five minute wash at 100% methanol eluted the compound in approximately 10 minutes. A Micromass Platform LC mass spectrometer was used to monitor a split off the eluate for desired mass, and the purified fractions were collected using Micromass Fractionlynx software. About 35 mg of purified compound was isolated. Analytical and Preparative C18 HPLC chromatography Method W
Analytical High Pressure Liguid Chromotography data was aquired using a Waters LC-UV system. The system operated using a Waters Symmetry Shield RP18 3.9 x 150 mm, 5 μm column at 1.5 mL/minute. The mobile phase consisted of Water (0.1 % DEA) and Acetonitrile (0.1 % DEA).
The gradient used started with a 10% ACN (0.1 % DEA): 90% H2O (0.1% DEA) and moved to 90% ACN (0.1% DEA): 10% H2O (0.1 % DEA) over 7 minutes. There was a one minute wash of the column using 100% ACN (0.1 % DEA) for one minute, until eight minutes and then original conditions returned at 8.1 minutes to 8.5 minutes. Method Y
Preparative High Pressure Liquid Chromatography data was acquired using a Waters LC-UV system. The system operated using a Waters
Symmetry Shield RP18 3.9 x 150 mm, 5 μm column at 35 mL/minute. The mobile phase consisted of Water (0.1 % DEA) and Acetonitrile (0.1 % DEA).
The gradient used started with a 10% ACN (0.1 % DEA):90% H2O (0.1% DEA) and moved to 90% ACN (0.1% DEA):10% H2O (0.1% DEA) over 7 minutes.
There was a one minute wash of the column using 100% ACN (0.1% DEA) for one minute, until eight minutes and then original conditions returned at 8.1 minutes to 8.5 minutes.
Low resolution, open-access LC-MS data were acquired in either ESI pos/neg or APCI pos/neg mode with scanning from 100-1100 amu @ 0.5 sec/scan.
LC conditions: flowrate 0.8 mL/min. 85% H2O (0.1% formic acid) to 100% MeOH (0.075% formic acid) in 6 minutes. Phenomenex Max-RP column,
2.0x50 mm.
High Resolution Mass Spectra were acquired using Micromass LCT mass spectrometer (time-of-flight) with flow injection (FIA-MS) at 0.3 mL/min with 100% MeOH (0.1% formic acid), run time of 2 minutes, in ESI+ mode, scanning from 100-1100 amu @ 0.5 sec/scan.
Reserpine was used as the lock mass (m/z 609.2812) and to adjust mass scale.
Example 1 Compound IV of Scheme I was synthesized according to the procedure outlined in Scheme II below. Scheme II
Figure imgf000049_0001
1a 1b 1c V
Tert-Butyl 4-cvano-4-phenylpiperidine-1-carboxylate (1a)
To a suspension of 4-cyano-4-phenylpiperidine hydrochloride (50.4 g, 0.266 mol) in tetrahydrofuran (440 ml) was added triethylamine (95 ml), followed by addition of a solution of di-tert-butyl dicarbonate (47.95 g, 0.22mol) in tetrahydrofuran (150 ml) dropwise. The reaction mixture was stirred at room temperature for 2 hours. The solids were filtered and the filtrate was diluted with 200 ml of ethyl acetate, washed once with 200 ml of 1 N citric acid, once with 200 ml of saturated aqueous sodium bicarbonate and once with 200 ml of brine. After drying over sodium sulfate, the solution was concentrated to a colorless thick oil (64.40 g, 99%). 1H-NMR (300 MHz, CDCI3): δ 7.51-7.34 (m, 5H), 4.33-4.18 (m, 2H), 3.27-3.19 (m, 2H), 2.14-1.92 (m, 4H), and 1.51 (s, 9H). ES-LCMS m/z 308 (M+H).
Tert-Butyl 4-formyl-4-phenylpiperidine-1-carboxylate (1b)
To a solution of tert-butyl 4-cyano-4-phenylpiperidine-1-carboxylate (33.32 g. 0.116 mol) in toluene (600 ml), cooled to -78 °C was added a 1 M solution of diisobutylaluminum hydride in toluene (248 ml) over a period of 3 h. The reaction mixture was allowed to warm up to -35 °C over a period of 2 h and stirred at -35 °C for 1 hour. The reaction mixture was quenched by dropwise addition of 150 ml of methanol, followed by addition of 150 ml of saturated aqueous ammonium chloride and filteration through Celite. The organic layer was washed once with 200 ml of water, once with 200 ml of brine and after drying over sodium sulfate, the solution was concentrated to a light yellow oil (29.71 g, 88%). 1H-NMR (300 MHz, CDCI3): δ 9.43 (s, 1H), 7.55-7.18 (m, 5H), 3.92-3.82 (m, 2H), 3.31-3.18 (m, 2H), 2.40-1.92 (m, 4H), and 1.38 (s, 9H). ES-LCMS m/z 290 (M+H).
Tert-Butyl 4-f(E/Z)-2-methoxyethenyll-4-phenylpiperidine-1-carboxylate (1c)
To a slurry of (methoxymethyl)triphenyl-phosphonium chloride (7.39 g, 21.56 mmol) in tetrahydrofuran (90 ml) was added a 1 M solution of potassium tert-butoxide in tetrahydrofuran (22 ml) dropwise. The reaction mixture was stirred at room temperature for 30 minutes and a solution of tert-butyl 4- formyl-4-phenylpiperidine-1-carboxylate (6.24 g, 21.56 mmol) in tetrahydrofuran (18 ml) was added dropwise. The mixture was stirred at room temperature for 16 hours and then heated to reflux for 2 hours. The mixture was allowed to cool to room temperature, diluted with 100 ml of water and 100 ml of ethyl acetate. The aqueous layer was extracted twice with 100 ml portions of ethyl acetate and washed once with 100 ml of brine. After drying over sodium sulfate, the solution was concentrated to a brown oil, which was further purified by column chromatography on silica gel. Elution with a gradient of 10-40% ethyl acetate in hexanes afforded a 1 :1 mixture of E/Z isomers as a light yellow oil (4.64 g, 68%). 1H-NMR (300 MHz, CDCI3): δ 7.51-7.19 (m, 5H), 6.07 and 4.84 (d, J=13.0 Hz, 1 H), 5.95 and 4.23 (d, J=7.1 Hz, 1 H), 3.95-3.78 (m, 2H), 3.54 and 3.51 (s, 3H), 3.30-3.06 (m, 2H), 2.20- 2.09 (m, 2H), 1.98-1.76 (m, 2H), and 1.52 and 1.49 (s, 9H). ES-LCMS m/z 318 (M+H).
Tert-Butyl 4-(2-oxoethyl)-4-phenylpiperidine-1-carboxylate (Compound V)
To a solution of tert-butyl 4-[(E/Z)-2-methoxyethenyl]-4- phenylpiperidine-1 -carboxylate
(4.64 g, 14.61 mmol) in acetone (48 ml) was added dropwise a solution of p- toluenesulfonic acid monohydrate(1.95 g, 10.28 mmol) in water (24 ml). The reaction mixture was stirred at room temperature for 48 hours. Acetone was evaporated without using any heat, and the reaction mixture was made basic with solid sodium bicarbonate to pH 9, extracted with three 30 ml portions of dichloromethane and washed once with 30 ml of brine. After drying over sodium sulfate, the solution was concentrated to a colorless oil, which was further purified by column chromatography on silica gel. Elution with 25% ethyl acetate in hexanes afforded the product (2.23 g, 50%). 1H-NMR (300 MHz, CDCIs): δ 9.39 (s, 1 H), 7.43-7.25 (m, 5H), 3.69-3.61 (m, 2H), 3.31-3.22 (m, 2H), 2.65 (s, 2H), 2.28-2.23 (m, 2H), 1.92-1.83 (m, 2H), and 1.46 (s, 9H). ES-LCMS m/z 304 (M+H).
(1-Benzoyl-4-phenylpiperidine-4-yl) acetaldehvde (2)
(1-Benzoyl-4-phenylpiperidine-4-yl) acetaldehyde (2) was synthesized according to the procedure outlined below.
Figure imgf000051_0001
To a solution of tert-butyl 4-[(E/Z)-2-methoxyethenyl]-4- phenylpiperidine-1-carboxylate (8.75 g, 27.57 mmol) obtained by following the procedure outlined in example 1c above in tetrahydrofuran (27 ml) was added a 4M solution of hydrochloric acid in dioxane (9 ml). The reaction mixture was stirred at room temperature for 1 hour and concentrated to an oil. The mixture was dissolved in dichloromethane (40 ml) and cooled to 0 °C. A solution of benzoyl chloride (4.65 g, 33.08 mmol) in dichloromethane (5 ml)was added dropwise, followed by the addition of triethylamine 8.37 g, 82.71 mmol) in dichloromethane (5 ml). The mixture was stirred at room temperature for 1 hour, quenched by addition of 5 ml water, and washed once with 150 ml of saturated aqueous sodium bicarbonate and once with 150 ml of brine. After drying over sodium sulfate, the solution was concentrated to an oil, which was further purified by column chromatography on silica gel. Elution with a gradient of 25-50% ethyl acetate in hexanes afforded a light yellow oil (3.47 g, 41%). 1H-NMR (300 MHz, CDCI3): δ 9.37 (s, 1 H), 7.42-7.25 (m, 10H), 4.14- 4.09 (m, 1 H), 3.54-3.30 (m, 3H), 2.67 (s, 2H), 2.38-2.24 (m, 2H), and 1.97- 1.85 (m, 2H). ES-LCMS m/z 308 (M+H).
The synthesis of endo 1-(8-azabicvclor3.2.πoct-3-yl)-2-methyl-1 H- benzimidazole dihydrochloride (compound IV of Scheme I): a) endo tert-Butyl 3-Anilino-8-azabicyclo[3.2.1]octane-8-carboxylate
Figure imgf000052_0001
Sodium triacetoxyborohydride (125 g, 0.59 mol) was added portionwise during 45 min to a mechanically stirred mixture of terf-butyl 3-oxo-8- azabicyclo[3.2.1]octane-8-carboxylate (88.3 g, 0.39 mol), pulverized 4A molecular sieves (88g) and benzylamine (44.1 g, 0.41 mol) in dichloromethane (1 L) at rt under Nitrogen. The mixture was stirred at rt for 2 days. Saturated sodium carbonate solution (1 L) was added. The mixture was stirred for 1 h at room temperature, filtered and the aqueous was further extracted with dichloromethane (3 x 500 mL). The combined organic layers were dried and concentrated to a white solid (123 g, 99%). 1H NMR (400 MHz; CDCI3) δ 7.24-7.33 (m, 5H), 4.19 (m, 1 H), 4.10 (m, 1 H), 3.76 (s, 2H), 3.00 (t, 1H), 2.15 (m, 3H), 1.91 (m, 2H), 1.60 (m, 1 H), 1.57 (m, 1 H), 1.49 (m, 1 H), 1.48 (m, 1 H), 1.45 (s, 9H). AP-LCMS m/z 317 (M+1 ).
b) enofo tert-Butyl 3-Amino-8-azabicyclo[3.2.1]octane-8-carboxylate
A stirred mixture of ferf-butyl 3-anilino-8-azabicyclo[3.2.1]octane-8- carboxylate (123 g, 0.39 mol), ammonium formate (175 g, 2.78 mol) and 20% palladium hydroxide on carbon (12.3 g) in absolute ethanol (1.5 L) was heated to 50°C under nitrogen for 7 h. The mixture was filtered and the filtrate was concentrated. The residue in ethyl acetate was washed with water, dried and concentrated to give the product (65.4 g, 74%). 1H NMR (400 MHz; CDCI3) δ 4.19 (m, 1 H), 4.10 (m, 1 H), 3.30 (t, 1 H), 3.03-2.19 (m, 4H), 1.94 (m, 2H), 1.58 (m, 2H), 1.44 (s, 9H). AP-LCMS m/z 127 (M-99).
c) endo tert-Butyl 3-[(2-Nitrophenyl)amino]-8-azabicyclo[3.2.1]octane-8- carboxylate)
Figure imgf000053_0001
A mixture of terf-butyl 3-amino-8-azabicyclo[3.2.1]octane-8-carboxylate (65.4 g, 0.29 mol), Λ/,Λ/-diisopropylethylamine (56 mL, 0.32 mol) and 1-fluoro- 2-nitrobenzene (40.9 g, 0.29 mol) in 1-methyl-2-pyrrolidinone (200 mL) was heated at 70°C under nitrogen for 16 h. The reaction mixture was diluted with water (500 mL) and extracted with ethyl acetate (3 x 300 mL). The combined organic layers were dried and concentrated to an orange oil. urification was accomplished by chromatography on silica gel eluting with dichloromethane and ethyl acetate:hexane 1 :1 in succession to give an orange solid (98.2 g, 98%). 1H NMR (400 MHz; CDCI3) δ 8.74 (m, 1 H), 8.18 (m, 1 H), 7.43 (m, 1 H), 6.61 - 6.73 (m, 2H), 4.26 (m, 2H), 3.90 (t, 1 H), 2.26 - 2.32 (m, 2H), 2.03 (m, 4H), 1.83 (m, 2H), 1.44 (s, 9H).
d) endo tert-Butyl 3-[(2~Aminophenyl)amino]-8-azabicyclo[3.2.1]octane-8- carboxylate
Figure imgf000053_0002
A mixture of terf-butyl 3-[(2-nitrophenyl)amino]-8- azabicyclo[3.2.1]octane-8-carboxylate (98.2 g, 0.28 mol) and 10% palladium on carbon (10 g) in ethanohethyl acetate 1 :1 (1 L) was hydrogenated for 24 h at atmospheric pressure. Uptake of hydrogen was 17.4 L. The mixture was filtered through celite and concentrated to give the product (76.2 g, 86%). 1H NMR (400 MHz; CDCI3) δ 6.67-6.83 (m, 3H), 6.57 (m, 1 H), 4.25 (m, 1 H), 4.17 (m, 1 H), 3.70 (m, 2H), 3.32 (br s, 2H), 2.28 (m, 2H), 1.98-2.07 (m, 4H), 1.76 (m, 2H), 1.47 (s, 9H). AP-LCMS m/z 318 (M+1).
e) endo 1-(8-Azabicyclo[3.2.1]oct-3-yl)-2-methyl-1 H-benzimidazole Hydrochloride
Figure imgf000054_0001
A solution of tert-butyl 3-[(2-aminophenyl) amino]-8- azabicyclo[3.2.1]octane-8-carboxylate (76.2 g, 0.24 mol) in triethylorthoacetate (250 mL) was refluxed under nitrogen for 2.5 h. The mixture was concentrated, redissolved in ethyl acetate (500 mL), washed with water (2 x 200 mL), washed with brine, dried and concentrated to a dark oil. The oil was dissolved in ethanol (250 mL), treated with 6 N hydrochloric acid (200 mL) and refluxed for 2 h. The reaction mixture was cooled to room temperature, concentrated to 300 mL and the resulting pale pink precipitate was collected by filtering, washed with ethanol (50 mL) and dried (61.5 g, 92%). 1H NMR (400 MHz; DMSO-d6) δ 10.16 (d, J=10 Hz, 1 H), 9.47 (d, J=10 Hz, 1 H), 7.95 (d of d, J=3,6 Hz, 1 H), 7.79 (d of d, J=4,8 Hz, 1 H), 7.54 (m, 2H), 5.63 (m, 1 H), 4.13 (d, J=9 Hz, 2H), 2.88 (s, 3H), 2.71 (m, 2H), 2.17 (m, 6H). ES-LCMS m/z 242 (M+1).
The synthesis of exo-amine: exo1-(8-azabicvclo[3.2.1]oct-3-yl)-2-methyl-1H- benzimidazole 8-Benzyl-8-azabicyclo[3.2.1]octan-3-one
To cooled 192 ml of 0.025M HCl at 0°C was added 60 g (454 mmol) of 2,5-dimethoxytetrahydrofuran and the mixture was stirred at 0 °C for 17 hrs. Then sequentially 78g(543.6mmol) of benzyl amine, 66 g (452.0 mmol) of 3- oxopentanedioic acid, and 20.4 g (248.4 mmol) of sodium acetate in 360 ml of water was added all at 0°C. The mixture was allowed to warm to room temperature and was stirred at room temperature for 1 hr. The mixture was clear, golden yellow in color. The mixture was heated to 50 °C for 2 hrs. The mixture turned cloudy. The mixture was then cooled to ambient temperature and adjusted to pH~12 using 50% NaOH in water. The mixture was extracted with ethyl acetate (x3), dried over sodium sulfate and removed solvent to yield a brown oil. The mixture was further purified by distillation, desired product collected -120 °C. 25 g crude product was recovered as a yellow oil to be carried on to next step.
8-Benzyl-8-azabicyclo[3.2.1]octan-3-one oxime
* N-OH
4.85 g (22.56 mmol) of 8-benzyl-8-azabicyclo[3.2.1]octan-3-one was dissolved in 60 ml of ethanol. 3.13 g (45 mmol) hydroxylamine hydrochloride was then added followed by 1.8 g (45 mmol) of NaOH in 15 ml of water. The mixture was refluxed for 20 hrs and was cooled to ambient temperature. The solvent was removed in vaccuo. The residue was diluted with ethyl acetate and washed with water and the organic layer was dried over sodium sulfate. The solvent was removed to give 4.28 g of product as a light yellow solid. 8-Benzyl-8-azabicyclo[3.2.1]octan-3-amine ,
To 3.9 g (16.9mmol) 8-benzyl-8-azabicyclo[3.2.1]octan-3-one oxime was added 3.5 g of sodium in 200 ml of pentanol by portion over 1 hr. The mixture was refluxed for 3 hrs and cooled to ambient temperature. The reaction mixture was quenched with water and extracted with 6 N HCl. The aqueous layer was basified using NaOH pellets and extracted with EtOAc. The organic layer was dried over magnesium sulfate and the solvent was removed to afford 2.9 g (80%) of crude product as a brown oil.
8-Benzyl-N-(2-nitrophenyl)-8-azabicyclo[3.2.1]octan-3-amine
0~ r <?: vj "*>
5.62g(27.82mmol) 8-benzyl-8-azabicyclo[3.2.1]octan-3-amine(u17094- 94) and 9.7ml(55.46mmoml) of Hunig's base were dissolved in 200ml NMP. 4.32g(30.60mmol) 1-fluoro-2-nitrobenzene was then added and the mixture was stirred at RT for 3 hrs. The reaction mixture was diluted with EtOAc and washed with water and dried over sodium sulfate. The solvent was removed partially under reduced pressure and was left in refrigerator overnight. The solid was filtered off to afford 2.92 g of product as a yellow powder. The solvent was removed from filtration to give additional 5.7 g of product as an orange-yellow residue.
N-(8-Benzyl-8-azabicyclo[3.2.1]oct-3-yl)benzene-1 ,2-diamine
Figure imgf000056_0001
2.92 g (9.04 mmol) 8-benzyl-N-(2-nitrophenyl)-8- azabicyclo[3.2.1]octan-3-amine was dissolved in 150 ml EtOAc and 25 ml Methanol. 1g Pd/C was then added and the mixture was stirred at 1 atm H2 for 3.5 hrs. Yellow color disappeared and the reaction mixture was filtered through celite. The solvent was removed to afford 2.2 g of desired solid.
1-(8-Benzyl-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole
Figure imgf000057_0001
7.7 g (25.08 mmol) N-(8-benzyl-8-azabicyclo [3.2.1]oct-3-yl)benzene-
1 ,2-diamine was refluxed in 200 ml of 1 ,1 ,1 -triethoxyethane for 18 hrs. The mixture was cooled to ambient temperature and the solvent was then removed. The residue was dissolved in toluene and 1.8 g (9.47 mmol) of p- toluenesulfonic acid was added and the reaction mixture was heated to reflux while stirring for 18 hrs. The mixture was cooled to ambient temperature and filtered off solid and removed toluene under reduced pressure. The crude product was purified by flash column chromatography with 5% methanol and 0.5% ammonium hydroxide in dichloromethane on silica gel. 2.2g of the product was recovered as a yellow residue.
1-(8-Azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole
Figure imgf000057_0002
2.2 g (6.65 mmol) 1-(8-benzyl-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H- benzimidazole was dissolved in 150 ml ethanol and 2.09 g (33.23 mmol) ammonium formate and 0.4 g palladium hydroxide (20% on carbon) were added. The mixture was refluxed for 2.5 hrs. The mixture was cooled to ambient temperature and filtered through celite. The solvent was removed under reduced pressure and the crude product was purified by column chromatography CH2CI:CH3OH:NH4OH(95:5:0.5) to afford 1.06 g of the desired product as a solid.
Example 2
Endo 2-methyl-1 -{8-[2-(4-phenylpiperidin-4-yl)ethyl]-8- azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole dihydrochloride (compound II in Scheme I) was prepared by following the procedure depicted in Scheme III below. Scheme III
Figure imgf000058_0001
tert-butyl 4-(2-K1 R. 5S)-3-(2-methyl-1 H-benzimidazol-1-yl)-8-endo- azabicyclor3.2.1loct-8-yl)ethyl)-4-phenylpiperidine-1 -carboxylate (III)
To a solution of 483 mg (2.0 mmol) of endo 1-(8-Azabicyclo[3.2.1]oct- 3-yl)-2-methyl-1 H-benzimidazole dihydrochloride (IV) and of 606 mg (2.0 mmol) tert-butyl 4-(2-oxoethyl)-4-phenylpiperidine-1 -carboxylate (V) in 25 mL dichloroethylene was added 847 mg (4.0 mmol) of sodium triacetoxyborohydride at room temperature and stirred for 30 minutes. The reaction was quenched with 10% aqueous sodium bicarbonate, solvents were removed and the residue partitioned between ethyl acetate and water, resulting in 925 mg of tert-butyl 4-{2-[(1 R, 5S)-3-(2-methyl-1H-benzimidazol-1- yl)-8-eoc/o-azabicyclo[3.2.1]oct-8-yl)ethyl}-4-phenylpiperidine-1 -carboxylate III (87.6% yield). 1H NMR (400 MHz, CDCI3): δ 7.21 (1 H, d, J=8.3 Hz), 6.63-6.97 (8H, m), 4.15 (1 H, m), 3.20 (2H, m), 2.78m (4H, m), 2.12 (3H, s), 1.92 (2H, m), 1.70 (2H, m), 1.45 (6H, m), 1.33 (4H, m), 1.18 (2H, m), and 1.02 (9H, s). 13C NMR (400 MHz, CDCI3): δ 155.2, 152.0, 144.9, 143.6, 133.8, 128.7, 126.8, 126.3, 121.6, 119.7, 111.0, 79.6, 57.4, 48.1 , 46.3, 42.0, 41.0 (broad), 40.2 (broad), 39.4 (quat), 36.6, 35.8 (broad), 30.0, 28.7, and 14.9. MS ES+ (m/z) M+1 = 529.61.
endo 2-methyl-1-(8-r2-(4-phenylpiperidin-4-yl)ethvn-8-azabicvclor3.2.noct-3- yl)-1 H-benzimidazole dihydrochloride (Compound II)
0.67g (1.27 mmol) of tert-butyl 4-{2-[(1 R, 5S)-3-(2-methyl-1H- benzimidazol-1-yl)-8-enc o-azabicyclo[3.2.1]oct-8-yl)ethyl}-4-phenylpiperidine- 1 -carboxylate III was dissolved in 5 mL dichloromethane and added 14 mL of 4N hydrochloric acid in dioxane. The mixture was stirred at room temperature for 30 minutes, resulting in a gummy precipitate. Solvents were decanted and the gum dried in vacuo, resulting in 0.63 g (quantitative) of endo 2-methyl-1- {8-[2-(4-phenylpiperidin-4-yl)ethyl]-8-azabicyclo[3.2.1 ]oct-3-yl}-1 H- benzimidazole dihydrochloride II, which was subsequently used without additional work-up. MS ES+ (m/z) M+1 = 429.30.
Neutralization of Dihydrochloride II to Free base Ha: endo 2-Methyl-1-(8-r2-(4- phenylpiperidin-4-yl)ethvπ-8-azabicyclor3.2.11oct-3-yll-1 H-benzimidazole (Compound Ha)
2-methyl-1-{8-[2-(4-phenylpiperidin-4-yl)ethyl]-8-azabicyclo[3.2.1]oct-3- yl}-1 H-benzimidazole dihydrochloride was partitioned between saturated sodium bicarbonate solution (300 mL) and dichloromethane (600 mL). The organic layer was dried over anhydrous sodium sulfate. After evaporation of solvents, 2-methyl-1 -{8-[2-(4-phenylpiperidin-4-yl)ethyl]-8- azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole Ha was obtained as foam, which was used for the next step without further purification. Example 3 1-(8-(2-ri-(2.2-Dimethylpropanoyl)-4-phenylpiperidin-4-vnethyl -8- azabicvclor3.2.1loct-3-yl)-2-methyl-1 H-benzimidazole (3)
Figure imgf000060_0001
To a solution of endo 2-methyl-1 -{8-[2-(4-phenylpiperidin-4-yl)ethyl]-8- azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole dihydrochloride II (0.18 g, 0.42 mmol) in dichloromethane (5 ml) was added triethylamine (0.117 ml), followed by addition of trimethylacetyl chloride (0.056 g, 0.462 mmol). The mixture was stirred at room temperature for 1 h and 0.5 ml water and 1 ml saturated aqueous sodium bicarbonate were added. The mixture was extracted three times with 5 ml of ethyl acetate and washed once with 5 ml brine. After drying over sodium sulfate, the solution was concentrated to a tan oil, which was further purified by column chromatography on silica gel. Elution with a gradient of 2.5-5% methanol in dichloromethane afforded a colorless oil (0.142 g, 66%). 1H-NMR (300 MHz, DMSO-d6) δ 7.49 (d, J=7.2 Hz, 1 H), 7.40- 7.35 (m, 5H), 7.23-7.20 (m, 1 H), 7.14-7.08 (m, 2H), 4.54-4.50 (m, 1 H), 3.80- 3.76 (m, 2H), 3.34-3.23 (m, 4H), 2.49 (s, 3H), 2.38-2.32 (m, 2H), 2.09-2.05 (m, 2H), 1.87-1.74 (m, 10H), 1.59-1.57 (m, 2H), 1.18 (s, 6H), 1.11 (s, 3H). ES- LCMS m/z 513 (M+H). HRMS m/z (M+H)+ calcd 513.3593, (M+H)+ obsvd 513.3586. Example 4 4-r(4-(2-r3-(2-Methyl-1 H-benzimidazol-1-yl)-8-azabicvclor3.2.noct-8-yllethyl|- 4-phenylpiperidin-1 -vDcarbonyllbenzene-sulfonamide (4)
Figure imgf000061_0001
4-[(4-{2-[3-(2-Methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1 ]oct-8- yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]benzenesulfonamide (25.8 mg, 83%) was obtained as amorphous solid from 2-methyl-1-{8-[2-(4-phenylpiperidin-4- yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1 -/-benzimidazole dihydrochloride II (25.3 mg, 0.05 mmol) and p-carboxybenzenesulfonamide (10 mg, 0.05 mmol) by the similar procedure outlined for example 5. 1H NMR (300 MHz, DMSO-d6) δ 7.86 ( d, J=8.2 Hz, 2 H), 7.57 (d, J=8.4 Hz, 2 H), 7.49-7.47 (m, 2 H), 7.39-7.34 (m, 4 H), 7.24-7.20 (m, 1 H), 7.14-7.06 (m, 2 H), 4.52-4.47 (m, 1 H), 3.89 (br, 1 H), 3.22-3.15 (m, 6 H), 2.44 (s, 3 H), 2.42-2.30 (m, 2 H), 2.14-2.08 (br, 2 H), 1.87-1.72 (m, 10 H), 1.58 (d, J=7.6 Hz, 2 H). HRMS m/z (M+H)+ calcd 612.3008; obsd 612.2993.
Example 5 2-chloro-5-IT4-(2-r3-(2-methyl-1 H-benzimidazol-1 -yl)-8-azabicvclor3.2.1 loct-8- vnethylV4-phenylpiperidin-1 -vDcarbonyll benzenesulfonamide example 5 via carbodiimide coupling
Figure imgf000061_0002
To a stirred solution of 2-methyl-1-{8-[2-(4-phenylpiperidin-4-yl)ethyl]-8- azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole dihydrochloride II (102 mg, 0.2 mmol) in dichloromethane (15 mL) was added 3-chloro-4-sulfamoylbenzoic acid (48 mg, 0.2 mmol) and triethylamine (60 μL, 0.4 mmol). The resulting mixture was then cooled down on an ice-water bath before the addition of 1- [3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (38 mg, 0.2 mmol) and 4-dimethylaminopyridine (4.8 mg, 0.0 4mmol). After being stirred overnight at ambient temperature, the reaction mixture was diluted with dichloromethane (40 mL) and washed with saturated sodium bicarbonate solution. The organic phase was dried over anhydrous sodium sulfate. After evaporation of the solvent, the crude product was purified by flash chromatography on silical gel, eluting with a gradient of 0-10% methanol in ethyl acetate to afford 2-chloro-5-[(4-{2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl] benzenesulfonamide as amorphous solid (69 mg, 53%). 1H NMR (300 MHz, DMSO-de) δ 7.87-7.71 (m, 3 H), 7.57 (s, 1 H), 7.50-7.47 (m, 2 H), 7.38-7.33 (m, 4 H), 7.24 (s, 1 H), 7.14-7.06 (m, 2 H), 4.49 (m, 1 H), 3.98 (m, 1 H), 3.42- 3.23 (m, 5 H), 3.06-3.00 (m, 1 H), 2.43 (s, 3 H), 2.39-2.22 (m, 2 H), 2.17-2.08 (m, 2 H), 1.92-1.76 (m, 10 H), 1.58-1.56 (br, 2 H). HRMS m/z (M+H)+ calcd 646.2619; obsd 646.2610.
example 5 via HATU coupling
To a stirred solution of 2-methyl-1-{8-[2-(4-phenylpiperidin-4-yl)ethyl]-8- azabicyclo[3.2.1 ]oct-3-yl}-1 H-benzimidazole dihydrochloride (200 mg, 0.4 mmol) in DMF (8 mL) was added 3-chloro-4-sulfamoylbenzoic acid (94 mg, 0.4 mmol), triethylamine (166 μL, 1.2 mmol) and HATU (152 mg, 0.4 mmol). The resulting mixture was stirred at ambient temperature for 3 hours before being diluted with methylene chloride (50 mL). The reaction was then washed with saturated sodium bicarbonate solution. The organic phase was dried over anhydrous sodium sulfate. After evaporation of the solvent, the crude product was purified by flash chromatography on silical gel, eluting with a gradient of 0-10% methanol in ethyl acetate to afford 2-chloro-5-[(4-{2-[3-(2- methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4- phenylpiperidin-1-yl)carbonyl] benzenesulfonamide as amorphous solid (120 mg, 47%). 1H NMR (300 MHz, DMSO-d6) δ 7.87-7.71 (m, 3 H), 7.57 (s, 1 H), 7.50-7.47 (m, 2 H), 7.38-7.33 (m, 4 H), 7.24 (s, 1 H), 7.14-7.06 (m, 2 H), 4.49 (m, 1 H), 3.98 (m, 1 H), 3.42-3.23 (m, 5 H), 3.06-3.00 (m, 1 H), 2.43 (s, 3 H), 2.39-2.22 (m, 2 H), 2.17-2.08 (m, 2 H), 1.92-1.76 (m, 10 H), 1.58-1.56 (br, 2 H). HRMS m/z (M+H)+ calcd: 646.2619; obsd: 646.2610.
Example 6
Figure imgf000063_0001
Phenyl N-cvano-4-f2-r3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicvclor3.2.1]oct-8-yllethyl)-4-phenylpiperidine-1-carboximidoate (6)
Figure imgf000063_0002
To a stirred solution of 2-methyl-1-{8-[2-(4-phenylpiperidin-4-yl)ethyl]-8- azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole dihydrochloride II (253 mg, 0.5 mmol) in dichloromethane (20 mL) was added triethyl-amine (140 μL, 1 mmol) and diphenylcyanocarbonimide (143 mg, 0.6 mmol). The resulting mixture was stirred at ambient temperature for 4 hours before it was quenched with saturated sodium bicarbonate solution. The layers were separated and the aqueous layer was extracted with dichloromethane (2 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate. After evaporation of the solvent, the residue was purified by flash chromatography on silical gel, eluting with a gradient of 0-10% methanol in ethyl acetate to afford phenyl Λ/-cyano-4-{2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidine-1-carboximidoate as amorphous solid (270 mg, 94%). 1H NMR (300 MHz, CDCI3) δ 7.69-7.66 (m,
1 H), 7.41-7.36 (m, 4 H), 7.30-7.21 (m, 5 H), 7.19-7.12 (m, 2 H), 7.06-7.03 (m,
2 H), 4.65-4.58 (m, 1 H), 4.07 (br, 1 H), 3.37 (br, 2 H), 3.23 (br, 2 H), 2.56 (s, 3 H), 2.40-2.32 (m, 4 H), 1.93-1.82 (m, 11 H), 1.62 (d, J =7.9, 2 H). HRMS m/z (M+H)+ calcd 573.3344; obsd 573.3348.
Example 7 Methyl N-cvano-4-(2-r3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicvclo[3.2.1loct-8-vnethyl)-4-phenylpiperidine-1 -carboximidoate (7)
Figure imgf000064_0001
To a stirred solution of phenyl Λ/-cyano-4-{2-[3-(2-methyl-1H- benzimidazol-1-yl)-8-azabicyclo[3.2.1] oct-8-yl]ethyl}-4-phenylpiperidine-1- carboximidoate 6 (35 mg, 0.06 mmol) in THF (1 mL) was added sodium methoxide in methanol (100 μL, -0.8 M, freshly made from methanol and sodium). The resulting mixture was stirred at ambient temperature for 30 minutes before evaporation of the solvent. The crude product was then purified by flash chromatography on silical gel, eluting with a gradient of 0- 15% methanol in ethyl acetate to afford methyl N-cyano-4-{2-[3-(2-methyl-1 H- benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidine-1- carboximidoate as amorphous solid (21.8 mg, 72 %). 1H NMR (300 MHz, • CDCI3) δ 7.69-7.66 (m, 1 H), 7.42-7.37 (m, 2H), 7.32-7.24 (m, 4H), 7.21-7.13 (m, 2H), 4.64 (br, 1 H), 4.19-4.07 (br, 2H), 3.92 (s, 3H), 3.40-3.27 (m, 4H), 2.59 (s, 3H), 2.35-2.30 (m, 4H), 1.97-1.83 (m, 10H), 1.66-1.63 (m, 2H). HRMS m/z (M+H)+ calcd 511.3185; obsd 511.3211. Example 8
Figure imgf000065_0001
2-r(4-(2-r3-(2-methyl-1 H-benzimidazol-1 -yl)-8-azabicvclo-r3.2.11oct-8-yllethyl)- 4-phenylpiperidin-1-yl)carbonyl1benzoic acid (8)
Figure imgf000065_0002
To a stirred solution of 2-methyl-1-{8-[2-(4-phenylpiperidin-4-yl)ethyl]-8- azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole dihydrochloride II (25.3 mg, 0.05 mmol) in 1 ,2-dichloroethane (3 mL) was added triethyl amine (14 μL, 0.1 mmol) and phthalic anhydride (7.4 mg, 0.05 mmol). The resulting mixture was stirred at ambient temperature for 4 hours. After evaporation of the solvents, the residue was purified by flash chromatography on silical gel, eluting with a gradient of 10-30% methanol in ethyl acetate to afford 2-[(4-{2-[3-(2-methyl- 1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1] oct-8-yl]ethyl}-4-phenylpiperidin-1- yl)carbonyl]benzoic acid as amorphous solid (29 mg, quant.). 1H NMR (300 MHz, DMSO-de) δ 7.94 (d, J=6.6 Hz, 1 H), 7.53-7.50 (m, 1 H), 7.48-7.36 (m, 7H), 7.25-7.21 (m, 1 H), 7.17-7.09 (m, 3H), 4.61-4.54 (m, 1 H), 3.26 (br, 4H), 3.95 (br, 1 H), 3.09 (br, 1 H), 2.46 (s, 3H), 2.42-2.32 (m, 3H), 2.24-2.06 (m,
1 H), 2.00-1.86 (m, 5H), 1.86-1.76 (m, 5H), 1.61 (d, J=7.7Hz, 2H). HRMS m/z (M+H)+ calcd 577.3179; obsd 577.3176.
Example 9 methyl 2-r(4 2-r3-(2-methyl-1 H-benzimidazol-1 -yl)-8-azabicvclor3.2.1loct-8- vnethyl)-4-phenylpiperidin-1 -vDcarbonyllbenzoate (9)
Figure imgf000066_0001
To a stirred solution of 2-[(4-{2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]benzoic acid 8 (40 mg, 0.07mmol) in methanol (2 mL) was added
(trimethylsilyl)diazomethane (0.35 mL, 2.0 M in hexanes). The resulting mixture was further stirred for 30 minutes. After evaporation of solvents, the residue was purified by flash chromatography on silical gel, eluting with a gradient of 0-10% methanol in ethyl acetate to afford methyl 2-[(4-{2-[3-(2- methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1 ]oct-8-yl]ethyl}-4- phenylpiperidin-1-yl)carbonyl]benzoate 9 as an oil (40 mg, quant.). 1H NMR (400 MHz, CDCI3) δ 8.01 (d, J=7.6Hz, 1 H), 7.64 (d, J=7.7Hz, 1 H), 7.54 (s, 1 H), 7.45-7.41 (m, 1 H), 7.37-7.34 (m, 2), 7.29-7.21 (m, 5H), 7.18-7.10 (m, 2H), 4.63-4.53 (m, 1 H), 4.21-4.18 (m, 1 H), 3.86 (br, 3H), 3.44 (br, 1H), 3.24 (br, 3H), 3.08 (br, 1 H), 2.53 (s, 3H), 2.36-2.34 (m, 3H), 1.91-1.71 (m, 11 H), 1.59 (d, J=7.0Hz, 2H). HRMS m/z (M+H)+ calcd 591.3335; obsd 591.3353. Example 10 methyl 3-r(4-{2-r3-(2-methyl-1 H-benzimidazol-1 -yl)-8-azabicvclof3.2.1loct-8- vnethyli-4-phenylpiperidin-1 -vDcarbonyllbenzoate (10)
Figure imgf000067_0001
To a stirred solution of 2-methyl-1 -{8-[2-(4-phenylpiperidin-4-yl)ethyl]-8- azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole lla (300 mg, 0.7 mmol) in dichloromethane (10 mL) was added isophthalic acid monomethyl ester (138.9 mg, 0.77 mmol) and triethyl amine (107 μL, 0.77 mmol). The resulting mixture was then cooled down on an ice-water bath before the addition of 1- [3-(dimethylamino)propyl]-3-ethyl carbodiimide hydrochloride (146.7 mg, 0.77 mmol) and 4-dimethylaminopyridine (8.5mg. 0.07mmole). After being stirred for 4 hours at ambient temperature, the reaction mixture was quenched with saturated sodium bicarbonate solution and extracted with dichloromethane (3 X 40 mL). The combined organic phase was dried over anhydrous sodium sulfate. After evaporation of the solvent, the crude product was purified by flash chromatography on silica gel, eluting with a gradient of 0-10% methanol in ethyl acetate to afford methyl 2-[(4-{2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1 ]oct-8-yl]ethyl}-4-phenylpiperidin-1 -yl)carbonyl]benzoate 10 as amorphous solid (297 mg, 72%). 1H NMR (300 MHz, CDCI3) δ 8.13-8.08 (m, 2H), 7.70 (d, J=8.3Hz, 1 H), 7.63 (d, J=7.5Hz, 1 H), 7.53 (t, J=7.7 Hz, 1 H),
7.45-7.40 (m, 2H), 7.35-7.30 (m, 4H), 7.20-7.15 (m, 2H), 4.68 (br, 1 H), 4.2 (br, 1 H), 3.96 (s, 3H), 3.57 (br, 1 H), 3.43-4.31 (m, 4H), 2.60 (s, 3H), 2.42 (br, 3H), 2.19 (br, 1 H), 1.99-1.92 (m, 10H), 1 ,69 (br, 2H). HRMS m/z (M+H)+ calcd 591.33335; obsd 591.3325. Example 11 3-r(4-(2-r3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicvclo-r3.2.1loct-8-yllethyl)- 4-phenylpiperidin-1-yl)carbonyl1benzoic acid (11)
Figure imgf000068_0001
To a precooled (0 °C) stirred solution of methyl 3-[(4-{2-[3-(2-methyl-
I H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1- yl)carbonyl]benzoate 10 (20 mg, 0.034mmol) in a 2 mL-mixed solvent of THF- H2O (3:1) was added lithium hydroxide monohydrate (4.3 mg, 0.1 mmol). The resulting mixture was stirred for 2 hours at 0 °C before being buffered with saturated sodium bicarbonate solution. The reaction mixture was then extracted with dichloromethane (3 x 20 mL). The combined extracts were washed with brine and dried over anhydrous sodium sulfate. After evaporation of the solvent, the crude product was purified by flash chromatography on silical gel, eluting with a gradient of 10-30% methanol in ethyl acetate to afford 3-[(4-{2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1 ]oct-8-yl]ethyl}-4-phenylpiperidin-1 -yl)carbonyl]benzoic acid
II as white powder solid (18 mg, 95%). 1H NMR (300 MHz, DMSO-d6) δ 7.98 (s, 1 H), 7.91 (s, 1 H), 7.51 (d, J=6.9Hz, 1 H), 7.40-7.36 (m, 7H), 7.26-7.24 (m, 2H), 7.14-7.08 (m, 2H), 4.55-4.49 (m, 1 H), 3.92 (br, 1 H), 3.34 (br, 1 H), 4.24 (br, 2H), 2.45 (s, 3H), 2.39-2.32 (m, 3H), 2.14 (br, 3H), 1.86-1.73 (m, 10H), 1.59 (d, J=7.3 Hz, 2H). HRMS m/z (M+H)+ calcd 577.3179; obsd 577.3192. Example 12 ethyl 2-ethyl-2-r(4-f2-lϊ1 R.5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicvclor3.2.1loct-8-yllethyl)-4-phenylpiperdin-1-yl)carbonvnbutonate (12)
Figure imgf000069_0001
2-(ethoxycarbonyl)-2-ethylbutanoic acid
Figure imgf000069_0002
A solution of diethyl-malonic acid diethyl ester (3.0g, 13.89mmol) and potassium hydroxide (0.778g, 13.89mmol) in ethanol (50ml) was stirred at room temperature for 18 hrs. The solvent was evaporated off and the residue was dissolved in water (20 ml) and extracted with dichloromethane (20ml). This organic layer was discarded. The aqueous layer was then acidified with concentrated HCl and extracted with dichloromethane (3 x 20 ml). The combined organic layers were dried over magnesium sulfate and concentrated to give a colorless oil 12a (1.9 g, 72%). 1H NMR (300MHz, Methanol-d4) δ 4.17 (m, 2H), 1.89 (m, 4H), 1.25 (m, 3H), 0.83 (m, 6H). ES- LCMS m/z 188 (M+H)
A solution of 2-(ethoxycarbonyl)-2-ethylbutanoic acid 12a (0.043g, 0.25mmol), 1-1'-Carbonyldiimdazole (0.048g, 0.25mmol) and 1- Hydroxybenzotriazole hydrate (0.034g, 0.25mmol) in dichloromethane (8ml) was stirred for 10 min at RT. Then 2-methyl-1-{8-[2-(4-phenylpiperidin-4- yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole Ha (0.090g, 0.21mmol) and triethylamine (0.64g, 0.088ml, 0.63mm'ol) were added and stirred for 18 hrs at room temperature. The reaction was diluted with dichloromethane (10ml) and extracted 1M citric acid (3 x 10ml). The aqueous layer was neutralized with 1M sodium carbonate and extracted with dichloromethane (3 x 10ml). Organic layer was dried using magnesium sulfate and solvent evaporated to white oil. The desired product was further purified column chromatography on silica gel using an elution gradient of dichloromethane: methanol (100:0 to 90:10) to afford the product as a colorless oil (0.115g, 91%). 1H NMR (300MHz, CDCI3) δ 7.88 (d, 1 H), 7.67 (t, 1 H), 7.40-7.15 (m, 7H), 5.20-4.50 (m, 3H), 4.15 (m,3 H), 3.41 (m, 3H), 3.12 (m, 2H), 2.55 (s, 3H), 2.45 (m, 1 H), 2.20-1.60 (m, 16H), 1.44 (s, 1 H), 1.21 (m, 3H) 0.87 (m, 6H). HRMS C37H5oN4O3 m/z (M+H)Caι. 599.3961 ; (M+H)0bs.599.3981.
Example 13
2-ethyl-2-IT4-(2-lϊ1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicvclor3.2.noct-8-vnethyl)-4-phenylpiperdin-1-yl)carbonyllbutonic acid
Figure imgf000070_0001
A solution of ethyl 2-ethyl-2-[(4-{2-[(1 R,5S)-3-(2-methyl-1 H- benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperdin-1- yl)carbonyl]butonate 12 (0.100 g, 0.17 mmol), 5 N NaOH (10 ml) and ethanol (4 ml) was stirred at 90 °C for 3 hrs. The reaction was evaporated to dryness and residue was suspend in water (10 ml) and neutralized with 1 N HCl. The aqueous layer was extracted with ethyl acetate (3 x 10 ml). The organic layer was dried using magnesium sulfate and concentrated down to form a white oil 13 (0.060 g, 62%). 1H NMR (300 MHz, CDCI3) δ 7.80 (d, 1 H), 7.38-7.23 (m, 8H), 4.73 (m, 1H), 4.12 (m, 1 H), 3.20 (m, 3H), 2.66 (s, 3H), 2.24 (m, 2H), 2.05-1.70 (m, 9H), 1.60 (m, 2H), 1.35-1.05 (m, 15H). HRMS C35H46N4O3 m/z (M+H)cai. 571.3648; (M+H)0bs. 571.3650. Example 14 Ethyl 1 -K4-I2-K1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicvclor3.2.11oct-8-yllethyl}-4-phenylpiperidin-1 - vDcarbonyllcyclobutanecaboxylate
Figure imgf000071_0001
1 -(ethoxycarbonyl) cyclobutanecarboxylic acid
Figure imgf000071_0002
A solution of diethyl ester (1.6 g, 8.20 mmol) and potassium hydroxide (0.459 g, 8.20 mmol) in ethanol (50 ml) was stirred at room temperature for 18 hrs. The solvent was evaporated off and the residue was dissolved in water (20 ml) and extracted with dichloromethane (20 ml). This organic layer was discarded. The aqueous layer was then acidified with concentrated HCl and extracted with dichloromethane (3 x 20 ml). The combined organic layers were dried over magnesium sulfate and concentrated to give a colorless oil (0.900 g, 63%). 1H NMR (300MHz, CDCI3) δ 4.25 (m, 2H), 2.60 (m, 4H), 2.00 (m, 2H), 1.30 (m, 3H). ES-LCMS m/z 172 (M+H).
A solution of 1-(ethoxycarbonyl)cyclobutane carboxylic acid (0.043 g, 0.25 mmol), 1-1'-carbonyl-diimdazole (0.048 g, 0.25 mmol) and 1- Hydroxybenzo-triazole hydrate (0.034 g, 0.25 mmol) in dichloro-methane (8 ml) was stirred for 10 min at RT. Then 2-methyl-1-{8-[2-(4-phenylpiperidin-4- yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole Ha (0.090 g, 0.21 mmol) and triethylamine (0.64 g, 0.088 ml, 0.63 mmol) were added and stirred for 18 hrs at room temperature. The reaction was diluted with dichloromethane (10 ml) and extracted 1 M citric acid (3 x 10 ml). The aqueous layer was neutralized with 1 M sodium carbonate and extracted with dichloromethane (3 x 10 ml). The organic layer was dried using magnesium sulfate and the solvent evaporated to white oil. The desired product was further purified column chromatography on silica gel using an elution gradient of dichloromethane: methanol (100:0 to 90:10) to afford the product as a colorless oil 14 (0.085g, 70%). 1H NMR (300 MHz, CDCI3) δ 7.89 (m, 1 H), 7.67 (m, 1 H), 7.26 (m, 7H), 4.86 (m, 1H), 4.25-3.90 (m, 3H), 3.89 (s, 2H), 3.21 (m, 2H), 2.96 (m, 1 H), 2.70-2.35 (m, 9H), 2.55-1.55 (m, 16H), 1.22 (m, 3H). HRMS C36H46N4O3 m/z 583.3648 (M+H)Caι.. 583.3623 (M+H)0bs..
Example 15
1 -r(4-(2-IT1 R.5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8-azabicvclo[3.2.1 loct-8- yllethyl)-4-phenylpiperidin-1-yl)carbonvncvclobutanecaboxylic acid
Figure imgf000072_0001
A solution of ethyl 1-[(4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)- 8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]cyclobutane- caboxylate from example 14 (0.050 g, 0.086 mmol), 5 N NaOH (10 ml) and ethanol (4 ml) was stirred at 90°C for 3 hrs. The reaction was evaporated to dryness and residue was suspend in water (10 ml) and neutralized with 1 N HCl. The aqueous layer was extracted with ethyl acetate (3 x 10 ml). The organic layer was dried using magnesium sulfate and concentrated down to form a white oil (0.032 g, 67%). 1H NMR (300 MHz, CDCI3) δ 7.68 (d, 1 H), 7.27 (m, 8H), 4.63 (m, 1 H), 3.84 (m, 1H), 3.41 (m, 1 H), 3.25-2.95 (m, 4H), 2.87 (m, 1 H), 2.58 (s, 3H), 2.45-2.20 (m, 4H), 2.05 (m, 2H), 1.89 (m, 8H), 1.63 (m, 5H), 1.61 (s, 2H). HRMS C34H42N4O3 m/z 555.3335 (M+H)Caι.. 555.3320
Figure imgf000072_0002
Example 16 Endo-1-(8-{2-[4-(3-chlorophenyl)-1-(2,2-dimethylpropanoyl)piperidin-4- yl]ethyl}-8-azabicyclo [3.2.1]oct-3-yl)-2-methyl-1 H-benzimidazole (16) was synthesized according to the method outlined below.
Figure imgf000073_0001
tert-butyl 4-(1 -cvano-2-ethoxy-2-oxoethylidene)piperidine-1 -carboxylate (16a)
Figure imgf000073_0002
A mixture of ferf-butyl 4-oxo-1-piperidinecarboxylate (25.25 g, 127 mmol), ethyl cyanoacetate (13.8 ml, 130 mmol), ammonium acetate (2.73 g, 35.4 mmol), glacial acetic acid (6.3 ml) and benzene (250 ml) was heated for 4 hours at reflux under Dean Stark conditions. The reaction mixture was cooled to room temperature and washed successively with water, sodium bicarbonate solution and brine. Drying, filtration and evaporation of the organic phase provided fetf-butyl 4-(1-cyano-2-ethoxy-2- oxoethylidene)piperidine-1 -carboxylate as an oil that crystallized on standing (37 g, 99%). 1H NMR (400 MHz, CDCI3): δ 4.28 (q, 2H, J = 7 Hz), 3.60 (br t, 2H, J = 6 Hz), 3.54 (br t, 2H, J = 6 Hz), 3.12 (t, 2H, J = 6 Hz), 2.76 (t, 2H, J = 6 Hz), 1.47 (s, 9H), and 1.35 (t, 3H, J = 7 Hz). ES-LCMS m/z 293 (M-1).
tert-butyl 4-(3-chlorophenyl)-4-(1 -cvano-2-ethoxy-2-oxoethyl)piperidine-1 • carboxylate (16b)
Figure imgf000074_0001
A solution of 1-chloro-3-iodobenzene (14.1 g, 59.28 mmol) in diethyl ether (12 ml) was added dropwise to a mixture of magnesium turnings (1.59 g, 65.4 mmol) in diethyl ether (50 ml) at room temperature. When the Grignard reaction was complete, the resulting organomagnesium reagent was added dropwise to a stirred mixture of compound 16a (5.0 g, 17 mmol) and cuprous iodide (800 mg, 4.2 mmol) in tetrahydrofuran (30 mL) cooled to 0°C. The reaction mixture was stirred 1 hour at 0°C and then quenched with saturated ammonium chloride solution. Ethyl acetate (500 ml) was added and the mixture was washed successively with saturated ammonium chloride, water and brine. The organic layer was dried and concentrated and the resulting crude material was purified by column chromatography on silica gel eluting with 4:1 hexane:ethyl acetate. This afforded tert-butyl 4-(3- chlorophenyl)-4-(1 -cyano-2-ethoxy-2-oxoethyl)piperidine-1 -carboxylate (16b) as an oil (5.2 g, 75%). 1H NMR (400 MHz, CDCI3): δ 7.37-7.26 (m, 4H), 3.99 (br.q, 2H, J=6Hz), 3.91 (br m, 2H), 3.58 (s, 1 H), 2.88 (br.m, 2H), 2.52 (ddd, 2H, J=6, 4, 3Hz), 2.04 (m, 2H), 1.43 (s, 9H), and 1.06 (t, 3H, J = 6 Hz). ES- LCMS m/z 429 (M+Na+). H-(tert-butoxycarbonyl)-4-(3-chlorophenyl)piperidin-4-yl cvano)acetic acid (16c)
Figure imgf000075_0001
A solution of 16b (5.2 g, 12.8 mmol) was dissolved in ethanol (30 ml) and 4 M aqueous sodium hydroxide (30 ml, 120 mmol) was added. The resulting solution was stirred at room temperature for 6.5 hours and then stored at 0°C overnight. Concentrated hydrochloric acid (10 ml) was added dropwise at 0°C and the mixture was then adjusted to pH~4 with 1 M hydrochloric acid. The solution was extracted with ethyl acetate (500 ml) and the aqueous phase was acidified to pH~3 and re-extracted with ethyl acetate. Both ethyl acetate layers were combined and washed with water and brine and then dried and concentrated to afford [1 -(tert-butoxycarbonyl)-4-(3- chlorophenyl) piperidin-4-yl](cyano)acetic acid (16c) as a rigid foam (3.75 g, 77%). This material was used without further purification.
tert-butyl 4-(3-chlorophenyl)-4-(cvanomethyl) piperidine-1 -carboxylate (16d)
Figure imgf000075_0002
16d (3.75 g, 9.90 mmol) was dissolved in acetonitrile (30 ml) and cupric oxide (355 mg, 0.025 mmol) was added. This mixture was heated at reflux with stirring for 30 minutes and then cooled to room temperature and filtered through celite. Evaporation of the filtrate gave tert-butyl 4-(3- chlorophenyl)-4-(cyanomethyl)piperidine-1 -carboxylate 16d as an oil that crystallized on standing (3.0 g, 91 %). 1H NMR (400 MHz, CDCI3): δ 7.37-7.27 (m, 4H), 3.74 (br.m, 2H), 3.08 (br.t, 2H, J=11Hz), 2.55 (s, 2H), 2.27 (br.dd, 2H, J = 11 , 3Hz), 1.86 (ddd, 2H, J=14, 11 , 4Hz), and 1.44 (s, 9H). tert-butyl 4-(3-chlorophenyl)-4-(2-oxoethyl)piperidine-1 -carboxylate (16e)
Figure imgf000076_0001
A solution of 16d (1.96 g, 5.85 mmol) in dichloromethane (25 mL) was cooled to -30°C and a 1M solution of diisobutyl aluminum hydride in dichloromethane (15.5 ml, 17.5 mmol) was added dropwise. During this addition the internal temperature was maintained at or below -35°C. When the addition was complete, the reaction mixture was stirred 30 min and then quenched at -35°C with methanol (0.7 ml) followed by saturated citric acid solution (50 ml). The mixture was allowed to warm to room temperature and then extracted with dichloromethane. Combined dichloromethane layers were dried, filtered and evaporated to provide tert-butyl 4-(3-chlorophenyl)-4-(2- oxoethyl)piperidine-1 -carboxylate (16e) as an oil (1.3 g, 66%). 1H NMR (400 MHz, CDCI3): δ 9.40 (t, 1H, J = 3 Hz), 7.34-7.22 (m, 4H), 3.61 (m, 2H), 3.26 (ddd, 2H, J=13, 9, 3Hz), 2.66 (d, 2H, J=3Hz), 2.19 (m, 2H), 1.86 (ddd, 2H, J=13, 9, 3Hz), and 1.44 (s, 9H). 13C NMR (100MHz, CDCI3): δ 201.4 (CH), 154.97 (C), 145.8 (C), 135.2 (C), 130.4 (CH), 127.3 (CH), 127.0 (CH), 124.9 (CH), 79.9 (C), 54.6 (2CH2), 53.3 (C), 39.2 (CH2), 35.5 (2CH2), and 28.6 (3CH3).
tert-butyl endo-4-(3-chlorophenyl)-4 2-r3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicvclor3.2.11oct-8-yllethyl}piperidine-1 -carboxylate (16f )
Figure imgf000076_0002
Sodium triacetoxyborohydride (286 mg, 1.35 mmol) was added in one portion to a stirred mixture of 3-encfo-1-(8-azabicyclo[3.2.1]oct-3-yl)-2-methyl- 1 H-benzimidazole dihydrochloride (compound IV, 250 mg, 0.90 mmol), 16e (304 mg, 0.90 mmol), triethylamine (0.25 ml, 1.79 mmol) and powdered molecular sieves (250 mg) in dichloromethane (3 ml). After stirring 1 hour at room temperature, the reaction was quenched with saturated sodium bicarbonate solution and the dichloromethane layer was removed. The aqueous layer was extracted with dichloromethane and the combined organic layers were dried, filtered and concentrated to afford tert-butyl endoA-{3- chlorophenyl)-4-{2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1 ]oct- 8-yl]ethyl}piperidine-1 -carboxylate as a rigid foam (500 mg, 99%). 1H NMR (400 MHz, DMSO-de): δ 7.47 (dd, 1 H, J = 7, 2 Hz), 7.40 (br s, 1 H), 7.39-7.35 (m, 3H), 7.27 (d, 1 H, J = 7 Hz), 7.11 (dd, 1 H, J = 7, 6 Hz), 7.08 (dd, 1 H, J = 7, 6 Hz), 4.50 (m, 1 H, J = 8 Hz), 3.48 (m, 2H); 3.24 (m, 2H), 3.11 (m, 2H), 2.48 (s, 3H), 2.35 (br dd, 2H, J = 15, 9 Hz), 1.98 (m , 2H), 1.90-1.70 (m, 10H), 1.59 (d, 2H, J = 8 Hz), and 1.36 (s, 9H). ES-LCMS m/z 585 (M+Na+).
endo-1 -(8-(2-r4-(3-chlorophenyl) piperidin-4-yllethyl)-8-azabicvclor3.2.11oct-3- yl)-2-methyl-1 H-benzimidazole dihydrochloride (16q)
Figure imgf000077_0001
To a stirring solution of the product from example 16f (500 mg, 0.888 mmol) in dichloromethane (6 ml) was added a 4 M solution of hydrogen chloride in 1 ,4-dioxane (7 ml, 28 mmol). After stirring 15 minutes at room temperature, the supernatant was decanted. The remaining precipitate was triturated with ethyl acetate and dried under high vacuum to afford enofo-1-(8- {2-[4-(3-chlorophenyl)piperidin-4-yl]ethyl}-8-azabicyclo [3.2.1]oct-3-yl)-2- methyl-1 H-benzimidazole dihydrochloride (16g) as a pink solid (548 mg, 100%). This material was used without further purification. ES-LCMS m/z 463 (M+H). endo-1-(8-l2-r4-(3-chlorophenyl)-1-(2.2-dimethylpropanoyl)piperidin-4- vnethyl)-8-azabicvclor3.2.1loct-3-yl)-2-methyl-1 H-benzimidazole (16)
Figure imgf000078_0001
To a solution of 16g (165 mg, 0.308 mmol) and triethylamine (0.086 ml, 5 0.616 mmol) in dichloromethane (3 ml) was added pivaloyl chloride (0.040 ml, 0.325 mmol). After stirring 1 hour at room temperature the reaction mixture was quenched with saturated sodium bicarbonate solution. The organic layer was separated, dried and concentrated. Purification of the resulting material by chromatography on silica gel eluting with 24:1 dichloromethane:methanol o gave enc/o-1 -(8-{2-[4-(3-chlorophenyl)-1 -(2,2-dimethylpropanoyl)piperidin-4- yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole (16) as a rigid white foam (100 mg, 59%). 1H NMR (400 MHz, DMSO-d6): δ 7.48 (d, 1 H, J = 7 Hz), 7.42 (s, 1 H), 7.41-7.34 (m, 3H), 7.28 (d, 1 H, J = 7 Hz), 7.11 (br.t, 1 H, J = 7 Hz), 7.08 (br.t, 1 H, J = 7), 4.50 (m, 1 H, J = 8 Hz), 3.73 (m, 2H), 5 3.29 (s, 3H), 3.25 (m, 4H), 2.35 (br.dd, 2H, J~22, 9 Hz), 2.02 (m 2H), 1.84- 1.73 (m, 10H), 1.59 (d, 2H, J = 8 Hz), and 1.16 (s, 9H). ES-LCMS m/z 547 (M+H). HRMS C33H43CIN4O m/z 547.3186 (M+H)Caι. 547.3204 (M+H)0bs..
Example 17 0 1 -((1 R.5S)-8-r2-(1 -benzoyl-4-phenylpiperidin-4-yl)ethyl1-8- azabicvclof3.2.1 loct-3-yl)-2-methyl-1 H-benzimidazole
Figure imgf000078_0002
To a stirred solution oi endo 2-methyl-1-{8-[2-(4-phenylpiperidin-4- yl)ethyl]-8-azabicyclo[3.2.1] oct-3-yl}-1 H-benzimidazole dihydrochloride II (0.53 g, 1.06 mmol) in dichloromethane (10 mL) and triethylamine (0.32 g, 3.18 mmol) was added benzoyl chloride (0.156g, 1.11 mmol) at O °C. The ice bath was then removed and the mixture allowed to stir for 30 min. The solvents were then removed in vacuo and the resulting solid was partitioned between ethyl acetate and water (3x). The organic layer was dried with magnesium sulfate and the solvent removed in vacuo, yielding crude 17, which was them purified using the supercritical fluid chromatography, resulting in 525 mg of pure 1-{(1 R,5S)-8-[2-(1-benzoyl-4-phenylpiperidin-4-yl)ethyl]-8- azabicyclo[3.2.1]oct-3-yl}-2-methyl-1 H-benzimidazole 17 (yield 93%). 1H NMR (400 MHz, CDCI3) δ 7.20 (1 H, m), 6.94 (7H, m), 6.82 (4H, m), 6.70 (2H, m), 4.15 (1 H, m), 3.75 (1 H, m), 3.11 (1 H, m), 2.98 (4H, m), 2,93 (1H, m), 2.78 (3H, m), 2.05 (3H, s), 2.04 (2H, m), 1.88 (3H, m), 1.70 (1 H, m), 1.59-1.24 (4H, m), 1.14 (2H, m). HRMS m/z (M+H)+ Caic 533.3280; (M+H)+obs 533.3300.
Example 18
1 -((1 R,5S)-8-(2-M -(cvclopentylcarbonyl)-4-phenylpiperidin-4-yl1ethyl)-8- azabicvclo[3.2.11oct-3-yl)-2-methyl-1 H-benzimidazole
Figure imgf000079_0001
To a stirred solution of endo 2-methyl-1 -{8-[2-(4-phenylpiperidin-4- yl)ethyl]-8-azabicyclo[3.2.1] oct-3-yl}-1 H-benzimidazole dihydrochloride II (0.38 g, 0.75 mmol) in dichloromethane (7 mL) and triethylamine (0.227g, 2.25 mmol) was added cyclopentantane carbonyl chloride (0.104g, 0.79 mmol) at 0 °C. The ice bath was then removed and the mixture allowed to stir for 20 min. The solvents were then removed in vacuo and the solid partitioned between dichloroethane and water (3x), and the organic layer evaporated in vacuo resulting in 0.270 g of crude product. Following SFC purification, 156 mg of the desired product 1-((1 R,5S)-8-{2-[1- (cyclopentylcarbonyl)-4-phenylpiperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3- yl)-2-methyl-1 H-benzimidazole (18). 1H NMR (400 MHz, CD3OD) δ 7.40 (1H, m), 7.25 (5H, m), 7.10 (3H, m), 4.52 (1 H, m), 3.84 (1 H, m), 3.63 (1 H, m), 3.20- 2.94 (4H, m), 2.86 (1 H, m), 2.39 (3H, s), 2.10 (4H, m), 1.92-1.36 (20H, m). HRMS m/z (M+H)+ Caic 525.3606; (M+H)+ 0bs 525.3593.
Example 19 i
1 -((1 R,5S)-8-f2-π -(2-furoyl)-4-phenylpiperidin-4-vnethyl)-8- azabicvclof3.2.11oct-3-yl)-2-methyl-1 H-benzimidazole
Figure imgf000080_0001
To a stirred solution of endo 2-methyl-1-{8-[2-(4-phenylpiperidin-4- yl)ethyl]-8-azabicyclo[3.2.1] oct-3-yl}-1 H-benzimidazole dihydrochloride II (0.35 g, 0.69 mmol) in dichloromethane (7 mL) and triethylamine (0.209 g, 2.07 mmol) was added 2-furoyl chloride (0.094g, 0.72 mmol) at 0 °C. The ice bath was then removed and the mixture allowed to stir for 30 min. The solvents were then removed in vacuo and the solid was added ethyl acetate and water. The insoluble precipitate was then filtered off and subsequently characterized as the desired product 19. Additional 0.18 g of the desired product 19 was obtained by extracting the organic layer with water (3x), drying with magnesium sulfate and evaporating solvents in vacuo. Following the SFC purification, on a portion of crude 19, 60 mg of the desired product 1- ((1 R,5S)-8-{2-[1 -(2-furoyl)-4-phenylpiperidin-4-yl]ethyl}-8-azabicyclo[3.2.1 ]oct- 3-yl)-2-methyl-1 H-benzimidazole 19 was obtained (calculated yield 86%). 1H NMR (400 MHz, CD3OD) δ 7.57 (1 H, dist. d, J=1.1 Hz), 7.47 (1 H, d, J=7.1 Hz), 7.43-7.29 (5H, m), 7.26-7.09 (3H, m), 6.89 (1H, d, J=3.6Hz), 6.48 (1H, dd, J=1.8, 3.6Hz), 4.08 (2H, m), 3.84 (2H, m), 2.60 (5H, m), 2.42 (3H, s), 2.30 (2H, m), 2.20 (2H, m), 2.05 (7H, m), 1.83 (2H, m). HRMS m/z (M+H)+ Caic 523.3062; (M+H)+0 s 523.3073.
Example 20 2-methyl-1 -(4 2-r3-(2-methyl-1 H-benzimidazol-1 -yl)-8-azabicvclor3.2.11oct-8- yl]ethyl)-4-phenyl-1 -piperidinyl)-1 -oxo-2-propanol
Figure imgf000081_0001
2-hydroxy-2-methylpropanoic acid (36 mg, 0.35 mmole) was dissolved in 0.92 ml of 1 ,2-dichloroethane. To this was added 1 ,1'-carbonyldiimidazole (37 mg, 0.23 mmole) and shaken for 30 min. 2-Methyl-1-{8-[2-(4-phenyl-4- piperidinyl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole (50 mg, 0.12 mmole)was added as a dry powder and shaking was resumed overnight. 1 ml of NaHCO3 sat. was added to the reaction mixture and shaken, followed by filtration through a hydrophobic frit and concentrated to an oil. The oil was separated on silica using gradient flash chromatography (0-8% MeOH in CHCI3) to afford 2-methyl-1-(4-{2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenyl-1-piperidinyl)-1-oxo-2-propanol 20 23.7 mg (38%) as a white glassy solid. 1H NMR (300 MHz, CDCI3) δ 7.7-7.6 (m, 1 H), 7.1-7.4 (m, 8H), 4.7 (s, 1H), 4.0 (s, 2H), 3.2-3.4 (m, 4H), 2.6 (s, 3H), 2.2-2.5 (m, 5H), 2.1-1.7 (m, 11 H), 1.7-1.5 (m, 2H).
Selected coupling methods used in the synthesis of compoounds of formula I from II or Ha (Scheme I) Method A (HATU)
Figure imgf000082_0001
To 117 μmoles of each acid was added 117 μmoles (1 eq.) of amine- scaffold dissolved in 1 mL DMF and 351 μmoles (3 eq.) of DIPEA in 1 mL DMF at ambient temperature. After shaking 5 min to affect dissolution of materials, 117 μmoles (1 eq.) of HATU in 1 mL DMF was added and the reaction mixture and shaken at ambient temperature for 16 h. 351 μmoles of solid supported MP-Carbonate (Argonaut Technologies, Inc.) was added to the reaction mixture and shaken an additional 20h. The resin-bound carbonate was filtered off and the reaction mixture concentrated to dryness. The approximately 100 milligrams of impure compound was dissolved in 300 microliters of DMSO and brought up to a final volume of 500 microliters using methanol. This 500 microliter solution was injected by a Waters 2767 autosampler into an XTerra C18 5 micron particle HPLC column (19mmX150mm). Initial solvent flow was 20ml/min with 30% methanol and 70% water at a pH of 11 using ammonium hydroxide as buffer. Void volume was 2 minutes, and a linear gradient to 100% methanol in 10 minutes with a five minute wash at 100% methanol eluted the compound in approximately 10 minutes. A Micromass Platform LC mass spectrometer was used to monitor and split off the eluate for desired mass, and the purified fractions were collected using Micromass Fractionlynx software. Isolated compounds were characterized by LC-MS and 1H NMR. Yields and representative data were included in the accompanying tables. Method B (anhydride)
Figure imgf000083_0001
To 117 μmoles of the anhydride in 1 mL DCM was added 117 μmoles (1 eq.) of amine-scaffold dissolved in 1 mL DCM and stirred at ambient temperature for 1 h. In some cases, product crystalized from the reaction mixture and was isolated by filtration. Otherwise, the reaction mixture was concentrated and purified either by normal phase flash chromatography (SiO2) CHCI3/CH3OH) or by reverse phase mass-directed HPLC as described in the Preparative HPLC Conditions A. Yields and representative data were included in the accompanying tables.
Method C - example of TFA-mediated Boc-deprotection -Example 21
Figure imgf000083_0002
Boc-derivative (248 μmoles) was dissolved in 3 mL DCM and treated with 3 mL TFA for 40 min at ambient temperature. The reaction mixture was concentrated and pumped dry to give the TFA salt (example 21 , mass 224 mg, Exact Mass = 543.3573) as a clear oil. Yield and representative data were included in the accompanying tables. Method D - sulfonamide via sulfonyl chloride or amide via acyl chloride Example 22 and Example 23
Figure imgf000084_0001
Product from example 21 (91 μmoles) was dissolved in 2 mL DCM and cooled to 0°C was treated with TEA (273 μmoles, 3 eq.) followed by either acetyl chloride or methanesulfonyl chloride (91 μmoles, 1 eq.). The reaction mixture was stirred 5 min at 0°C and then allowed to warm to ambient temperature and stirred an additional 30 min. The reaction mixture was diluted with 10 mL DCM, washed successively with saturated NaHCO3 and brine, dried over MgSO , filtered, and concentrated to give the acetyl derivative (example 22) or methylsulfonyl (example 23), respectively. Products were purified by reverse phase mass-directed HPLC as described in Preparative HPLC Conditions A. Yields and representative data were included in the accompanying tables.
Method E - example of TFA-mediated Boc-deprotection
Figure imgf000084_0002
The Boc-protected amine (1.02 mmoles) was dissolved in 5 mL DCM and treated with 5 mL TFA at ambient temperature for 1 h. The reaction mixture was concentrated and treated with a biphasic mixture of EtOAc and saturated aqueous NaHCO3. The mixture was stirred vigorously, and the solid filtered off and washed successively with water and EtOAc to give the TFA salt of the amine. Yields and representative data were included in the accompanying tables.
Method F - HATU mediated formation of amides - Example 24
Figure imgf000085_0001
3-[(4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]benzoic acid (259 mg, 449 μmoles) was combined with 2,4-dimethoxybenzylamine (449 μmoles, 1 eq.) in 3 mL DMF with DIPEA (449 μmoles, 1 eq.) and treated with HATU (449 μmoles, 1 eq.) at ambient temperature for 16 h. The reaction mixture was concentrated, dissolved in EtOAc, washed successively with saturated NaHCO3 and brine, dried over MgSO4, filtered, and concentrated. Products were purified by reverse phase HPLC as described in Preparative HPLC Conditions A to give the desired product. Yields and representative data were included in the accompanying tables.
Figure imgf000085_0002
The product (73 mg, 101 μmoles) was dissolved in 3 mL DCM and treated with 3 mL TFA at ambient temperature for 24h. The reaction mixture was concentrated, dissolved in DCM, washed with saturated aqueous NaHCOβ, dried over MgSO4, filtered and concentrated. The crude product was purified by normal phase flash chromatography (SiO2, DCM/CH3OH) to give the desired product. The accompanying tables list yields and representative data for compounds of the present invention.
Figure imgf000086_0001
Figure imgf000086_0002
Figure imgf000087_0001
Figure imgf000088_0001
Figure imgf000089_0001
Figure imgf000090_0001
Figure imgf000091_0001
Figure imgf000092_0001
Figure imgf000093_0001
Figure imgf000094_0001
Figure imgf000095_0001
Figure imgf000096_0001
Figure imgf000097_0001
Figure imgf000098_0001
98
Figure imgf000099_0001
O 20040
99
Figure imgf000100_0001
Figure imgf000101_0001
Figure imgf000102_0001
Figure imgf000103_0001
Figure imgf000104_0001
Figure imgf000105_0001
Figure imgf000106_0001
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000109_0001
Figure imgf000110_0001
Figure imgf000111_0001
Figure imgf000112_0001
Figure imgf000113_0001
Figure imgf000114_0001
Figure imgf000115_0001
Figure imgf000116_0001
Figure imgf000117_0001
Figure imgf000118_0001
Proton NMR data for selected compounds from the above table:
Example 186 1 -((1 R.5SV8-(2-π -(2-fluorobenzovn-4-phenyl-4-piperidinyllethyl)-8- azabicvclo[3.2.noct-3-yl)-2-methyl-1 H-benzimidazole
Figure imgf000119_0001
1H NMR (400 MHz, Methanol-d4, ppm) δ 1.3 (m, 1 H), 1.7 (m, 2H), 1.9 (m, 6H), 2.0 (m, 2H), 2.2 (m, 1 H), 2.4 (m, 3H), 2.5 (s, 3H), 3.2 (m, 1H), 3.3 (m, 4H), 3.5 (m, 1 H), 4.2 (m, 1 H), 4.7 (m, 1 H), 7.2 (m, 2H), 7.2 (m, 2H), 7.4 (m, 6H), 7.5 (m, 3 H).
Example 147 2-r.4-(2-r(1 R.5S)-3-(2-methyl-1 H-benzimidazol-1 -ylV8-azabicvclol3.2. Hoct-8- yllethyl)-4-phenyl-1-piperidinyl)carbonvπquinoline
Figure imgf000119_0002
1H NMR (400 MHz, Methanol-d4, ppm) δ 1.9 (s, 1 H), 2.3 (m, 2H), 2.6 (m, 9H), 2.9 (m, 1 H), 3.1 (m, 3H), 3.2 (m, 2H), 3.9 (m, 5H), 4.2 (m, J=3.6Hz, 1H), 4.8 (m, 1H), 5.4 (m, 1H), 7.8 (m, 2H), 7.9 (m, 1H), 8.0 (m, 1 H), 8.0 (m, J=8.2Hz, 1 H), 8.1 (s, 5H), 8.1 (m, 3H), 8.1 (m, J=4.3, 2.5Hz, 1 H), 8.2 (m, 1 H). Example 146 1 -((1 R,5S)-8-{2-π -(2-chloro-6-fluorobenzoyl)-4-phenyl-4-piperidinvnethyl)-8- azabicvclor3.2.πoct-3-vD-2-methyl-1 H-benzimidazole
Figure imgf000120_0001
1H NMR (400 MHz, Methanol-d4, ppm) δ 1.2 (m, 1 H), 1.6 (m, 2H), 1.8 (m, 8H), 1.9 (m, 2H), 2.3 (m, 4H), 2.4 (m, 3H), 3.1 (m, 1 H), 3.3 (m, 3H), 4.1 (m, 1H), 4.6 (m, 1 H), 7.1 (m, 2H), 7.2 (m, 2H), 7.3 (m, 6H), 7.4 (m, 1H), 7.4 (m, 1 H).
Example 166 2,2-dimethyl-3-(4-(2-r(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -vH-8- azabicvclor3.2.noct-8-yl]ethyl}-4-phenyl-1-piperidinyl)-3-oxo-1 -phenyl-1 - propanol
Figure imgf000120_0002
1H NMR (400 MHz, Methanol-d4, ppm) δ 1.8 (m, 3H), 1.9 (s, 3H), 2.3 (m, 3H), 2.5 (m, 5H), 2.7 (m, 4H), 3.0 (m, 2H), 3.1 (m, 3H), 3.2 (m, 3H), 4.0 (m, 5H), 4.7 (m, 2H), 5.4 (m, 1 H), 7.8 (m, 2H), 7.9 (m, 2H), 7.9 (m, 1 H), 8.0 (m, 1 H), 8.1 (m, 6H), 8.2 (m, 2H). Example 105 1-((1 R,5SV8-(2-π-(2.2-dimethyl-4-pentenovn-4-phenyl-4-piperidinyllethyll-8- azabicvclor3.2.1 loct-3-vπ-2-methyl-1 H-benzimidazole
Figure imgf000121_0001
1H NMR (400 MHz, Methanol-d4, ppm) δ 0.6 (m, 1 H), 0.9 (m, 1 H), 1.5 (m, 1 H), 1.7 (m, 3H), 1.9 (m, 9H), 2.3 (m, 2H), 2.4 (m, 4H), 2.5 (d, J=6.1 Hz, 3H),
3.1 (m, 1 H), 3.3 (m, 5H), 4.0 (m, 3H), 4.8 (m, 1 H), 5.0 (m, 2H), 5.7 (m, 1 H),
7.2 (m, 2H), 7.2 (m, 1 H), 7.4 (m, 5H), 7.5 (m, 1 H).
Example 101 1 -((1 R.5S)-8-(2-π -(2.6-dichlorobenzovn-4-phenyl-4-piperidinvπethyl)-8- azabicvclor3.2.11oct-3-ylY-2-methyl-1 H-benzimidazole
Figure imgf000121_0002
1H NMR (400 MHz, Methanol-d4, ppm) δ 1.2 (m, 1 H), 1.6 (m, 2H), 1.8 (m, 6H), 1.9 (m, 2H), 2.2 (m, 1 H), 2.3 (m, 3H), 2.4 (m, 3H), 3.1 (m, 1 H), 3.3 (m, 5H), 4.1 (m, 1 H), 4.7 (m, 1 H), 7.1 (m, 2H), 7.2 (m, 1 H), 7.3 (m, 5H), 7.4 (m, 2H), 7.4 (m, 1 H), 7.4 (m, 1 H). Example 84 1-r(1 R.5SV8-(2-(1- 2-chloro-3-Pyridinvncarbonvn-4-phenyl-4- piperidinyl)ethvπ-8-azabicvclor3.2.11oct-3-yll-2-methyl-1 H-benzimidazole
Figure imgf000122_0001
1H NMR (400 MHz, Methanol-d4, ppm) δ 1.6 (d, J=7.5Hz, 2H), 1.9 (m, 9H), 2.2 (d, J=15.7Hz, 1H), 2.4 (m, 3H), 2.5 (m, 3H), 3.1 (m, 1 H), 3.3 (m, 5H), 4.1 (dd, J=9.3, 4.3Hz, 1 H), 4.7 (m, 1 H), 7.1 (m, 2H), 7.2 (m, 1 H), 7.3 (m, 5H), 7.4 (m, 2H), 7.8 (m, 1 H), 8.4 (m, 1 H).
Example 334 1 -((1 R.5S)-8-(2-π -(2-ethylbutanovn-4-phenyl-4-piperidinvπethyl)-8- azabicyclo[3.2.1loct-3-yl)-2-methyl-1 H-benzimidazole
Figure imgf000122_0002
1H NMR (400 MHz, Methanol-d4, ppm) δ 1.4 (t, J=7.5Hz, 3H), 1.6 (t, J=7.5Hz, 3H), 1.9 (m, 1 H), 2.2 (m, 6H), 2.5 (m, 9H), 2.9 (m, 2H), 3.1 (m, 2H), 3.2 (d, J=6.4Hz, 3H), 3.4 (m, 1 H), 3.9 (m, 1 H), 4.0 (none, 2H), 4.0 (m, 1 H), 4.5 (m, 1 H), 4.7 (m, 1 H), 5.4 (m, 1 H), 7.8 (m, 2H), 7.9 (m, 1 H), 8.1 (m, 5H), 8.2 (m, 1 H). Example 335 1-((1R,5SV8-f2-ri-(2-ethylbutanoyl)-4-phenyl-4-piperidinvnethyll-8- azabicvclor3.2.1 loct-3-v0-2-methyl-1 H-benzimidazole
Figure imgf000123_0001
1H NMR (400 MHz, Methanol-d4, ppm) δ 1.2 (s, 1 H), 1.6 (m, 2H), 1.8 (m, 9H), 2.2 (m, 1H), 2.3 (m, 3H), 2.4 (m, 3H), 3.1 (m, 1 H), 3.3 (m, 4H), 4.1 (m, 1H), 4.7 (m, 1H), 7.1 (m, 2H), 7.2 (m, 2H), 7.3 (m, 1H), 7.3 (m, 5H), 7.4 (dd, J=8.6, 6.1Hz, 1H), 7.4 (m, 1H).
Example 336 2-methyl-1 -((1 R.5S)-8-(2-π -(2-methylbenzoyl )-4-phenyl-4-piperidinvπethyl)-8- azabicvclor3.2.πoct-3-yl)-1 H-benzimidazole
Figure imgf000123_0002
1H NMR (400 MHz, Methanol-d4, ppm) δ 1.2 (m, 1 H), 1.6 (m, 2H), 1.7 (m, 1H), 1.9 (m, 8H), 2.1 (m, 2H), 2.3 (m, 4H), 2.4 (m, 3H), 3.1 (m, 1H), 3.3 (m, 5H), 4.1 (m, 1H), 4.6 (m, 1H), 7.1 (m, 7H), 7.3 (m, 5H), 7.4 (m, 1H). Example 337 3-r(4-(2-f(1 R.5S)-3-(2-methyl-1 H-benzimidazol-1 -vn-8-azabicvclor3.2.11oct-8- vnethyll-4-phenyl-1-piperidinvπcarbonvn-2-pyridinol
Figure imgf000124_0001
1H NMR (400 MHz, DMSO-d6) δ ppm 1.5 (m, 2H), 1.8 (m, 9H), 2.0 (m, 2H), 2.3 (m, 3H), 2.4 (s, 3H), 3.2 (d, J=6.4Hz, 4H), 3.7 (s, 2H), 4.5 (m, 1 H), 6.4 (m, 2H), 7.0 (d, J=8.6Hz, 1 H), 7.1 (m, 2H), 7.2 (m, 1H). 7.3 (m, 5H), 7.4 (m, 1 H), 9.8 (s, 1 H).
Example 338 5-methoxy-2-r(4 2-r(1 R.5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicvclor3.2.11oct-8-yllethyl)-4-phenyl-1-piperidinyl)carbonvnphenol
Figure imgf000124_0002
1H NMR (400 MHz, DMSO-d6) δ ppm 1.5 (m, 2H), 1.8 (m, 8H), 2.1 (m, 2H), 2.3 (m, 2H), 2.4 (m, 3H), 2.4 (m, 1 H), 3.2 (d, J=7.1 Hz, 3H), 3.3 (s, 3H), 3.6 (m, 2H), 3.7 (s, 2H), 4.5 (m, 1 H), 6.4 (m, 2H), 7.0 (d, J=8.2Hz, 1H), 7.1 (m, 2H), 7.2 (m, 1 H), 7.3 (m, 5H), 7.4 (m, 1 H), 9.8 (s, 1H). Example 339 4-methoxy-2-f(4-(2-r(1 R.5S)-3-(2-methyl-1 H-benzimidazol-1 -yll-8- azabicvclor3.2.1 loct-8-yllethyl)-4-phenyl-1 -piperidinvπcarbonyllphenol
Figure imgf000125_0001
1H NMR (400 MHz, DMSO-d6) δ ppm 1.5 (m, 2H), 1.8 (m, 9H), 2.0 (m, 2H), 2.3 (m, 2H), 2.4 (m, 3H), 2.5 (m, 1 H), 3.2 (m, 6H), 3.6 (s, 2H), 3.8 (m, 1 H), 4.4 (m, 1 H), 6.6 (d, J=2.9Hz, 1H), 6.7 (d, J=8.6Hz, 1 H), 6.8 (m, 1H), 7.1 (m, 2H), 7.2 (m, 1 H), 7.3 (m, 5H), 7.4 (dd, J=8.2, 6.4Hz, 1 H), 9.2 (s, 1 H).
Example 340 6-r(4 2-r(1 R.5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8-azabicvclor3.2. noct-8- yllethyl)-4-phenyl-1-piperidinyl)carbonyl1-2-pyridinol
Figure imgf000125_0002
1H NMR (400 MHz, DMSO-d6) δ ppm 1.5 (m, 2H), 1.8 (m, 8H), 2.1 (m, 2H),
2.3 (m, 2H), 2.4 (m, 3H), 2.5 (m, 1 H), 3.3 (m, 7H), 3.8 (s, 1 H), 4.5 (m, 1 H), 6.3 (d, J=6.4Hz, 1 H), 6.4 (d, J=9.3Hz, 1 H), 7.1 (m, 2H), 7.2 (m, 1 H), 7.3 (m, 5H),
7.4 (m, 2H). Example 341 1 -r(4-(2-r(1 R.5S)-3-(2-methyl-1 H-benzimidazol-1 -yl V8-azabicvclor3.2.1 ct-8- vnethyl)-4-phenyl-1-piperidinyl)carbonvncvclopentanol
Figure imgf000126_0001
1H NMR (400 MHz, DMSO-d6) δ ppm 1.7 (m, 15H), 2.0 (m, 3H), 2.3 (m, 2H), 2.4 (m, 4H), 2.5 (m, 1 H), 2.7 (m, 1 H), 3.2 (m, 7H), 3.8 (d, J=109.2Hz, 1 H), 4.5 (m, 1H), 7.1 (m, 2H), 7.1 (m, 1H), 7.3 (m, 5H), 7.4 (m, J=7.1 Hz, 1 H).
Example 51 5-r(4-f2-r(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -vn-8-azabicvclor3.2. Hoct-8- vnethyl)-4-phenyl-1-piperidinyl)carbonvn-2-furansulfonamide
Figure imgf000126_0002
1H NMR (400 MHz, DMSO-d6) δ ppm 1.2 (s, 1 H), 1.5 (m, 2H), 1.8 (m, 8H), 2.1 (m, 1H), 2.3 (m, 2H), 2.4 (s, 3H), 2.5 (m, 3H), 3.2 (m, 2H), 3.2 (m, 1H), 3.4 (m, 2H), 3.8 (m, 2H), 4.5 (m, 1 H), 7.1 (m, 2H), 7.2 (t, J=7.0Hz, 1 H), 7.3 (m, 5H), 7.4 (m, 1 H). Example 50 3-r(4-(2-r(1 R.5SV3-(2-methyl-1 H-benzimidazol-1 -vn-8-azabicvclor3.2.noct-8- vπethyl)-4-phenyl-1 -piperidinyl)carbonvπ-1 -benzofuran-6-ol
Figure imgf000127_0001
1H NMR (400 MHz, DMSO-d6) δ ppm 1.5 (m, 2H), 1.7 (m, 9H), 2.1 (d, J=5.7Hz, 2H), 2.3 (m, 2H), 2.4 (s, 3H), 2.5 (m, 2H), 2.5 (m, 1 H), 3.2 (m, 2H), 3.3 (m, 1 H), 3.7 (m, 2H), 4.5 (m, 1 H), 6.8 (dd, J=8.6, 2.1 Hz, 1 H), 6.9 (d, J=1.8Hz, 1 H), 7.1 (m, 2H), 7.2 (t, J=7.0Hz, 1 H), 7.3 (m, 6H), 7.4 (m, 1 H), 8.0 (s, 1 H).
Example 44 4-r(4 2-IT1 R.5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8-azabicvclor3.2.1 loct-8- vnethyl}-4-phenyl-1-piperidinvπcarbonyll-1.3-benzoxazole-2(3H)-thione
Figure imgf000127_0002
1H NMR (400 MHz, DMSO-d6) δ ppm 1.7 (s, 3H), 1.9 (m, 7H), 2.0 (m, 3H), 2.2 (m, 1 H), 2.4 (m, 5H), 2.5 (m, 2H), 3.1 (m, 2H), 3.4 (m, 2H), 3.9 (m, 1 H), 4.6 (m, 1 H), 7.1 (m, 4H), 7.2 (m, 1 H), 7.3 (m, 6H), 7.4 (m, 1 H). Example 43 N-r2,2-dimethyl-3-(4-f2-r(1 R.5S)-3-(2-methyl-1H-benzimidazol-1-vn-8- azabicvclor3.2.11oct-8-vnethyl)-4-phenyl-1 -pjperidinyl)-3- oxopropanoyllmethane sulfonamide
Figure imgf000128_0001
3-Ethoxy-2,2-dimethyl-3-oxopropanoic acid (100 mg, 0.624 mmole) was added to a stirring suspension of 2.5 equivalents of PS-DCC from Argonaut and 3 equivalents of dimethylaminopyridine in DCM. To this was added methanesulfonamide (41.6 mg, 0.437 mmole). The solution was filtered of and concentrated to give 69.3 mg of ethyl 2,2-dimethyl-3-[(methy- lsulfonyl)amino]-3-oxopropanoate (67% yield crude). MS ES- 236 (M-H). 1H NMR (300 MHz, Chloroform-d) δ ppm 1.4 (t, J=6.7Hz, 3H), 1.6 (s, 6H), 3.3 (m, 3H), 4.3 (m, 2H). Ethyl 2,2-dimethyl-3-[(methylsulfonyl)amino]-3-oxopropanoate was hydrolyzed without purification in 2 ml of 1 ,4-dioxane and 2 ml of 1 M LiOH at 45 °C. The solvent was removed under vacuum and the residue 2,2-dimethyl-/V- (methylsulfonyl)-3-oxo-alanine was used in the next step without further purification. MS ES- 209 (M-H) 1H NMR (400 MHz, methanol-d4) δ ppm 1.4 (s, 6H) and 3.2 (s, 3H). Example 43 N-r2.2-dimethyl-3-(4-f2-r(1R.5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicvclor3.2.noct-8-yllethyl)-4-phenyl-1-piperidinvπ-3-oxopropanovn methanesulfonamide was made using the HATU coupling method A. MS ES+ 620 (M+H). 1H NMR (300 MHz, methanol-d4) δ ppm 1.4 (m, 4H), 1.9 (s, 2H),
2.2 (m, 2H), 2.3 (s, 4H), 2.4 (m, 2H), 2.8 (m, 2H), 2.8 (s, 3H), 2.9 (m, 2H), 3.2 (d, J=7.5Hz, 2H), 3.3 (m, 2H), 3.5 (s, 1H), 4.1 (d, J=8.5Hz, 2H), 4.9 (s, 6H),
5.3 (s, 1H), 7.3 (m, 1H), 7.5 (d, J=4.2Hz, 4H), 7.6 (m, 2H), 7.8 (m, 2H).
Example 42
N-(4-IΪ4-(2-Γ(1 R.5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8-azabicvclor3.2.1 loct- 8-vnethyl)-4-phenyl-1-piperidinvπcarbonvn-2-pyridinyl)acetamide
Figure imgf000129_0001
1H NMR (400 MHz, methanol-d4) δ ppm 1.6 (m, 2H), 1.8 (m, 9H), 2.2 (m, 2H), 2.3 (m, 3H), 2.4 (m, 3H), 3.2 (m, 8H), 3.4 (m, 1 H), 4.0 (m, 1 H), 4.7 (m, 1 H), 7.0 (dd, J=5.0, 1.4Hz, 1H), 7.1 (m, 2H), 7.2 (m, 1 H), 7.3 (m, 5H), 7.4 (m, 1H), 8.0 (s, 1 H), 8.3 (d, J=5.0Hz, 1H).
> Example 39
4-[(4-f2-r(1 R.5SV3-(2-methyl-1 H-benzimidazol-1 -yl)-8-azabicvclor3.2.11oct-8- vnethyl)-4-phenyl-1-piperidinvπcarbonyl1-1 ,2.5-thiadiazol-3-ol
Figure imgf000130_0001
1H NMR (300 MHz, DMSO-d6) δ ppm 1.6 (d, J=7.5Hz, 2H), 1.8 (m, 7H), 2.1 (s, 2H), 2.3 (s, 2H), 2.5 (s, 3H), 2.5 (m, 2H), 3.1 (m, 1 H), 3.4 (m, 6H), 3.8 (s, 1 H), 4.5 (s, 1 H), 7.1 (m, 2H), 7.2 (m, 1 H), 7.4 (m, 5H), 7.5 (m, 1 H).
Example 37 1.1-dimethyl-2-(4-(2-r(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicvclor3.2.1loct-8-vnethyl}-4-phenyl-1-piperidinyl)-2-oxoethylformamide
Figure imgf000130_0002
1H NMR (400 MHz, methanol-d4) δ ppm 1.5 (m, 6H), 1.7 (m, 2H), 1.9 (m, 8H), 2.2 (s, 2H), 2.4 (m, 2H), 2.5 (s, 3H), 3.3 (m, 4H), 3.3 (m, 2H), 3.6 (m, 1 H), 4.0 (s, 2H, 4.7 (m, 1 H), 7.2 (m, 2H), 7.2 (m, 1 H), 7.4 (m, 5H), 7.5 (m, 1 H), 8.0 (s, 1 H). Example 36 N-(4-r(4-(2- 1 R,5S)-3-(2-methyl-1 H-benzimidazol-1-yl)-8-azabicvclor3.2.noct- 8-vnethvU-4-phenyl-1-piperi-dinvπcarbonvnphenyl)methanesulfonamide formate salt
Figure imgf000131_0001
1H NMR (400 MHz, methanol-d4) δ ppm 1.8 (m, 11 H), 2.2 (m, 3H), 2.3 (m, 1 H), 2.4 (m, 5H), 2.9 (m, 3H), 3.2 (m, 3H), 3.4 (m, 2H), 3.6 (m, 1 H), 4.0 (m, J=4.3Hz, 1H), 4.7 (m, 1H), 7.1 (m, 2H), 7.2 (m, 1 H), 7.2 (m, 2H), 7.3 (m, 6H), 7.4 (m, 1H).
Example 35 N.N.2.5-tetramethyl-4-r(4-(2-r(1 R.5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicvclof3.2.11oct-8-vnethyl}-4-phenyl-1-piperidinyl)carbόnvn-3- furansulfonamide formate salt
Figure imgf000131_0002
1H NMR (400 MHz, chloroform-d) δ ppm 1.6 (m, 2H), 1.8 (m, 8H), 2.1 (m, 5H),
2.3 (m, 4H), 2.4 (m, 6H), 2.6 (m, 3H), 2.7 (m, 3H), 3.1 (m, 2H), 3.3 (m, 2H),
3.4 (m, 1H), 4.0 (m, 1H), 4.7 (m, 1H), 7.1 (m, 2H), 7.1 (m, 1H), 7.3 (m, 5H), 7.4 (m, 1H). Example 33 2-methyl-1 -K1 R.5S)-8-(2-f 1 -l2-methyl-2-(1 H-1.2.4-triazol-1 -yl)propanoyll-4- phenyl-4-piperidinyl}ethyl)-8-azabicvclor3.2.11oct-3-vn-1 H-benzimidazole
Figure imgf000132_0001
1H NMR (300 MHz, chloroform-d) δ ppm 1.5 (m, 5H), 1.7 (d, J=15.1Hz, 3H), 1.9 (m, 10H), 2.0 (s, 2H), 2.4 (m, 3H), 2.6 (s, 3H), 3.0 (m, 5H), 4.6 (m, 1H), 7.2 (m, 5H), 7.3 (m, 3H), 7.6 (m, 1 H), 8.0 (s, 1H), 8.1 (s, 1H).
Example 31 1-f(1R.5SV8-r2-(1-isobutyryl-4-phenyl-4-piperidinvnethyll-8- azabicvclor3.2.Hoct-3-yl)-2-methyl-1 H-benzimidazole
Figure imgf000132_0002
1H NMR (300 MHz, chloroform-d) δ ppm 1.1 (d, J=6.7Hz, 3H), 1.1 (d, J=6.7Hz, 3H), 1.2 (m, 2H), 1.6 (m, J=7.3, 7.3Hz, 2H), 1.8 (m, 8H), 2.2 (m, 2H) 2.4 (m, 2H), 2.5 (m, 3H), 2.8 (m, 1H), 3.2 (m, 4H), 3.7 (m, 1H), 4.0 (m, 1H), 4.7 (m, 1H), 7.2 (m, 3H), 7.3 (m, 5H), 7.7 (m, 1 H). Example 30 benzyl 1 ,1-dimethyl-2-(4 2-r(1 R.5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicvclor3.2.1loct-8-vπethyl)-4-phenyl-1-piperidinvπ-2-oxoethylcarbamate
Figure imgf000133_0001
1H NMR (400 MHz, chloroform-d) δ ppm 1.0 (m, J=7.1 , 7.1 Hz, 1 H), 1.5 (m, 8H), 1.8 (d, J=6.1 Hz, 4H), 1.9 (m, 7H), 2.1 (m, 3H), 2.3 (m, 2H), 2.5 (s, 3H), 3.3 (m, 4H), 4.6 (m, 1 H), 5.0 (s, 2H), 7.1 (m, 3H), 7.3 (m, 8H), 7.4 (t, J=7.7Hz, 2H), 7.6 (m, 1 H).
Example 29 1-r(4-(2-r(1 R.5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8-azabicvclor3.2.1loct-8- yllethyll-4-phenyl-1-piperidinyl)carbonvncvclopropanol
Figure imgf000133_0002
1H NMR (400 MHz, chloroform-d) δ ppm 0.9 (m, J=20.3Hz, 2H), 1.0 (m, 2H), 1.3 (m, 4H), 1.6 (m, 3H), 1.8 (m, 6H), 2.2 (m, 2H), 2.4 (m, 2H), 2.6 (s, 3H), 3.2 (d, J=3.2Hz, 4H), 4.1 (m, 2H), 4.6 (m, 1 H), 7.1 (m, 2H), 7.3 (m, 4H), 7.4 (t, J=7.7Hz, 2H), 7.6 (d, J=7.1 Hz, 1 H). Example 28 1 -((1 R.5S)-8-(2-π -(2.2-dimethylbutanovn-4-phenyl-4-piperidinvnethyl)-8- azabicvclor3.2.11oct-3-yl 2-methyl-1 H-benzimidazole
Figure imgf000134_0001
1H NMR (400 MHz, chloroform-d) δ ppm 0.9 (t, J=7.5Hz, 3H), 1.2 (s, 6H), 1.6 (m, 4H), 1.8 (m, 8H), 2.2 (dd, J=12.5, 3.2Hz, 2H), 2.3 (m, 2H), 2.5 (m, 1 H), 2.6 (s, 3H), 3.0 (m, 1H), 3.2 (m, 4H), 3.9 (m, 2H), 4.6 (m, 1H), 7.1 (m, 2H), 7.2 (m, 1 H), 7.3 (m, 3H), 7.4 (m, 2H), 7.6 (m, 1 H).
Example 27 2.2-dimethyl-3-(4-(2-lϊ1 R.5S)-3-(2-methyl-1 H-benzimidazol-1 -vO-8- azabicvclof3.2.1loct-8-vnethyl)-4-phenyl-1-piperidinyl)-3-oxo-1-propanol
Figure imgf000134_0002
1H NMR (400 MHz, chloroform-d) δ ppm 1.0 (d, J=6.8Hz, 2H), 1.2 (s, 6H), 1.6 (m, 2H), 1.8 (m, 4H), 1.9 (m, 4H). 2.2 (dd, J=12.0, 2.7Hz, 2H), 2.3 (m, 2H), 2.6 (s, 3H), 3.2 (m, J=11.1 , 11.1 Hz, 4H), 3.5 (s, 2H), 3.8 (m, 1 H), 3.9 (d, J=13.2Hz, 2H), 4.6 (m, 1 H), 7.1 (m, 2H), 7.3 (m, 4H), 7.4 (m, 2H), 7.6 (m, 1H). Example 26 1 -f(4-(2-f(1 R.5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8-azabicvclor3.2.1 loct-8- vπethyl|-4-phenyl-1-piperidinv0carbonyllcvclopropanecarbonitrile
Figure imgf000135_0001
To a solution of 1-cyanocyclopropane-carboxylic acid (38.9 mg, 0.351 mmole) in 1 ml of DCE was added carbonyldiamidazole (38.0 mg, 0.234 mmole) and the mixture was stirred until gas evolution stopped. 2-Methyl-1- {(1 R,5S)-8-[2-(4-phenyl-4-piperidinyl)ethyl]-8-azabicyclo[3.2.1 ]oct-3-yl}-1 H- benzimidazole (50.0 mg, 0.117 mmole) was added and the resulting mixture was stirred overnight. The solvent was evaporated and the reaction mixture was flashed on silica using a gradient of 1-8% MeOH in CHCI3 to afford 1-[(4- {2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8- yl]ethyl}-4-phenyl-1 -piperidinyl)carbonyl]cyclopropanecarbonitrile. MS ES+ 522 (M+H). 1H NMR (300 MHz, chloroform-d) δ ppm 1.6 (m, J=43.1Hz, 6H), 1.9 (d, J=25.3Hz, 10H), 2.4 (m, J=10.0Hz, 4H), 2.6 (s, 3H), 3.3 (m, 3H), 3.5 (m, 1H). 4.1 (m, 2H), 4.7 (m, 1H), 7.3 (m, 8H), 7.7 (m, 1H).
Example 25 1-r(1 R.5S)-8-(2-f1-[(3-chloro-2-thienvncarbonvn-4-phenyl-4-piperidinyllethyl)- 8-azabicvclof3.2.1 loct-3-yll-2-methyl-1 H-benzimidazole
Figure imgf000136_0001
1H NMR (300 MHz, methanol-d4) δ ppm 0.9 (m, 1 H), 1.1 (m, 3H), 1.6 (d, J=12.2Hz, 2H), 1.9 (m, 8H), 2.3 (m, 4H), 2.4 (s, 3H), 3.2 (m, 2H), 3.6 (m, 1 H), 4.0 (m, J=7.1 Hz, 1 H), 4.7 (m, 1 H), 6.9 (d, J=5.2Hz, 1 H), 7.1 (m, 2H), 7.2 (d, J=6.2Hz, 1 H), 7.3 (m, 5H), 7.4 (m, J=1.5Hz, 1 H), 7.6 (d, J=5.2Hz, 1H).
Example 342 1 -r(1 R,5S)-8-(2-(1 -r(3-chlorophenyl)sulfonyll-4-phenyl-4-piperidinyl)ethyl)-8- azabicvclor3.2.1 loct-3-vπ-2-methyl-1 H-benzimidazole
Figure imgf000136_0002
1H NMR (300 MHz, chloroform-d) δ ppm 1.6 (m, 2H), 1.7 (m, 4H), 1.9 (m, 8H), 2.4 (m, 4H), 2.6 (s, 3H), 2.8 (m, 2H), 3.4 (m, 2H), 4.6 (m, 1 H), 7.2 (m, 5H), 7.3 (m, 3H), 7.4 (t, J=7.9Hz, 1H), 7.5 (m, 1H), 7.6 (d, J=7.8Hz, 1H), 7.7 (m, 1 H), 7.7 (m, J=1.8, 1.8Hz, 1 H). Example 343 2-methyl-1-r(1 R.5S)-8-(2-(1-r(3-methylphenyl)sulfonyll-4-phenyl-4- piperidinyltethvD-8-azabicvclor3.2.1loct-3-yll-1 H-benzimidazole
Figure imgf000137_0001
1H NMR (300 MHz, chloroform-d) δ ppm 1.6 (m, 2H), 1.7 (dd, J=9.3, 5.6Hz, 2H), 1.9 (m, 8H), 2.3 (m, 4H), 2.4 (s, 3H), 2.5 (d, J=13.9Hz, 3H), 2.8 (m, 2H), 3.2 (m, 2H), 3.4 (m, 2H), 4.5 (m, 1 H), 7.1 (m, 5H), 7.3 (m, 5H), 7.5 (m, 2H), 7.6 (m, 1 H).
Example 344 4-chlorophenyl 1.1 -dimethyl-2-(4-(2-r(1 R.5S)-3-(2-methyl-1 H-benzimidazol-1 - yl)-8-azabicvclor3.2.noct-8-yllethyl)-4-phenyl-1-piperidinyl)-2-oxoethyl ether
Figure imgf000137_0002
1H NMR (300 MHz, chloroform-d) δ ppm 1.3 (m, 1 H), 1.6 (m, 11 H), 1.9 (m, 7H), 2.2 (m, J=10.7Hz, 1 H), 2.4 (m, J=23.3Hz, 2H), 2.6 (s, 3H), 3.1 (m, 1 H), 3.2 (m, 2H), 3.4 (m, 1 H), 4.2 (m, 2H), 4.6 (m, 1H), 6.8 (m, 2H), 7.2 (m, 8H), 7.3 (m, 2H)f 7.7 (m, 1 H). Example 34 2-r(4-(2-r(1 R.5S)-3-(2-methyl-1 H-benzimidazol-1 -vn-8-azabicvclor3.2.noct-8- yl1ethyl}-4-phenyl-1 -piperi-dinvOcarbonv-lphenyl dimethylsulfamate formate salt
Figure imgf000138_0001
1H NMR (400 MHz, chloroform-d) δ ppm 1.9 (m, 10H), 2.3 (m, 9H), 2.7 (s, 3H), 2.9 (s, 3H), 3.1 (m, 2H), 3.4 (m, 3H), 4.1 (m, J=13.6Hz, 1 H), 4.7 (m, 1 H), 7.1 (m, 2H), 7.2 (m, 4H), 7.3 (m, 4H), 7.4 (m, 2H), 7.4 (m, 1 H).
Example 37 5-methyl-3-r(4-(2-r(1 R.5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicvclof3.2.11oct-8-yl1ethylH~phenyl-1 -piperidinvDcarbonylM-isothiazolol
Figure imgf000138_0002
1H NMR (300 MHz, DMSO-d6) δ ppm 2.7 (m, 3H), 3.1 (m, 4H), 3.3 (m, 10H), 3.6 (m, 2H), 3.8 (s, 6H), 4.0 (m, 3H), 4.2 (m, 1H), 4.7 (m, 1H), 8.6 (m, j=4.6, 4.6Hz, 2H), 8.7 (d, J=6.6Hz, 1 H), 8.8 (d, J=14.8Hz, 5H), 8.9 (m, 1 H). Example 38 N-(5-r(4-(2-r(1 R.5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8-azabicvclor3.2. Hoct- 8-yllethyl)-4-phenyl-1-piperidinvπcarbonvn-1.3-thiazol-2-yl)acetamide
Figure imgf000139_0001
1H NMR (400 MHz, methanol-d4) δ ppm 1.6 (s, 1 H), 2.0 (m, 12H), 2.5 (m, 5H), 3.1 (s, 2H), 3.2 (m, 2H), 3.5 (m, 4H), 3.7 (m, 2H), 4.0 (m, 2H), 7.1 (m, 4H), 7.3 (m, 5H), 7.5 (m, 1 H).
Example 43 2-(isopropylamino)-5-r(4-f2-r(1 R.5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicvclor3.2.noct-8-vnethyl)-4-phenyl-1-piperidinvncarbonvn-4-pyrimidinol
Figure imgf000139_0002
1H NMR (400 MHz, DMSO-d6) δ ppm 1.1 (dd, J=20.0, 6.4Hz, 5H), 1.6 (d, J=7.8Hz, 2H), 1.8 (m, 8H), 2.1 (m, 2H), 2.4 (m, 2H), 2.5 (d, J=7.5Hz, 3H), 2.5 (m, 1 H), 3.3 (m, 8H), 3.8 (m, J=21.0Hz, 1 H), 4.0 (m, 1 H), 4.5 (m, 1 H), 6.7 (s, 1 H), 7.1 (m, 2H), 7.2 (m, 1 H), 7.4 (m, 5H), 7.5 (m, 1H), 7.8 (s, 1 H). Example 45 3,3.5-trimethyl-5-f(4-(2-r(1 R.5S)-3-(2-methyl-1 H-benzimidazol-1 -vH-8- azabicvclor3.2.1 loct-8-vπethyll-4-phenyl-1 -piper-dinvOcarbonvH-2- pyrrol id inone
Figure imgf000140_0001
1H NMR (400 MHz, DMSO-d6) δ ppm 0.9 (m, 3H), 1.1 (s, 3H), 1.4 (m, 2H), 1.6 (m, 2H), 1.8 (m, 8H), 2.0 (m, 3H), 2.3 (m, 3H), 2.5 (m, 1 H), 3.3 (m, 4H), 3.3 (d, J=11.1 Hz, 5H), 3.7 (m, J=1.4Hz, 2H), 4.5 (m, 1 H), 7.1 (m, 2H), 7.2 (m, 1 H), 7.4 (m, 5H), 7.5 (m, 1 H), 7.8 (s, 1 H).
Example 46 N-(2-r(4-(2-r(1 R,5SV3-(2-methyl-1 H-benzimidazol-1-vn-8-azabicvclor3.2.noct- 8-vnethyl>-4-phenyl-1-piperidinyl)carbonyll-3-pyridinyl>acetamide
Figure imgf000140_0002
1H NMR (400 MHz, DMSO-d6) δ ppm 1.6 (m, 2H), 1.8 (m, 8H), 2.0 (s, 3H), 2.2 (m, 2H), 2.4 (m, 2H), 2.4 (s, 3H), 2.5 (m, 2H), 3.1 (m, 1 H), 3.3 (m, 3H), 3.4 (dd, J=7.0, 3.0Hz, 1H), 3.9 (m, 1 H), 4.5 (m, 1 H), 7.1 (m, 2H), 7.2 (m, 1 H), 7.4 (m, 5H), 7.4 (dd, J=8.2, 4.6Hz, 1 H), 7.5 (m, 1 H), 8.0 (m, 1 H), 8.3 (m, 1 H), 9.7 (s, 1 H). Example 52 N-r2-(4-(2-r(1 R.5S)-3-(2-methyl-1 H-benzimidazol-1 -vn-8-azabicvclor3.2.noct- 8-vnethyl}-4-phenyl-1-piperidinvπ-2-oxo-1-phenylethvnacetamide
Figure imgf000141_0001
1H NMR (400 MHz, DMSO-d6) δ ppm 1.6 (m, 3H), 1.8 (m, 9H), 2.0 (m, 2H), 2.4 (m, 2H), 2.5 (m, 3H), 3.2 (m, 4H), 3.4 (d, J=11.4Hz, 3H), 3.6 (m, 2H), 3.8 (m, 1 H), 4.5 (m, 1 H), 5.9 (dd, J=24.6, 7.8Hz, 1H), 7.1 (m, 2H), 7.3 (m, 10H), 7.5 (d, J=7.1 Hz, 1 H), 8.5 (dd, J=7.8, 5.4Hz, 1 H).
Example 59 6-chloro-5-f(4-(2-r(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.11oct-8-yllethyl)-4-phenyl-1 -piperidinyl)carbonvπ-3- pyridinesulfonamide
Figure imgf000141_0002
1H NMR (400 MHz, methanol-d4) δ ppm 1.6 (m, 2H), 1.8 (m, 8H), 2.0 (d, J=6.6Hz, 2H), 2.2 (d, J=7.7Hz, 2H), 2.4 (m, 4H), 2.5 (s, 3H), 3.1 (m, 2H), 3.3 (m, 3H), 4.1 (m, 1 H), 4.7 (s, 1 H), 7.1 (m, 2H), 7.2 (m, 1 H), 7.3 (m, 5H), 7.4 (m, 1 H), 8.2 (m, J=61.5, 2.4Hz, 1 H), 8.8 (dd, J=2.4, 1.5Hz, 1 H). , Example 345 1 -((1 R,5S)-8-(2-H -(3-cvclohexylpropanov0-4-phenyl-4-piperidinyllethyll-8- azabicvclor3.2.πoct-3-vD-2-methyl-1 H-benzimidazole
Figure imgf000142_0001
1H NMR (400 MHz, methanol-d4) δ ppm 0.8 (m, 2H), 1.2 (m, 4H), 1.4 (q, J=7.4Hz, 2H), 1.8 (m, 16H), 2.2 (m, 2H), 2.3 (m, 4H), 2.5 (s, 3H), 3.1 (m, 1 H), 3.2 (m, 4H), 3.7 (dd, J=9.5, 4.8Hz, 1 H), 3.9 (m, 1 H), 4.7 (m, 1 H), 7.1 (m, 3H), 7.3 (m, 5H), 7.4 (m, 1H).
Example 346 N-r2-(4-(2-r(1 R.5S)-3-(2-methyl-1 H-benzimidazol-1-vn-8-azabicvclor3.2.noct- 8-yl1ethyl)-4-phenyl-1-piperidinyl)-2-oxoethyllbenzamide
Figure imgf000142_0002
1H NMR (400 MHz, methanol-d4) δ ppm 1.7 (m, 2H), 1.9 (m, 10H), 2.4 (m, 4H), 2.5 (m, J=3.6Hz, 3H), 3.2 (m, 1H), 3.3 (m, 4H), 3.8 (m, 1H), 4.0 (m, 1 H), 4.3 (m, 2H), 4.7 (m, 1 H), 7.2 (m, 3H), 7.4 (m, 7H), 7.5 (m, 2H), 7.9 (m, 1 H). Example 347 2-methyl-1-((1 R,5S)-8-f2-r4-phenyl-1-(3-pyridinyl carbonvn-4- piperidinvnethyll-8-azabicvclof3.2.noct-3-vπ-1 H-benzimidazole
Figure imgf000143_0001
1H NMR (400 MHz, methano W) δ ppm 1.6 (m, 2H), 1.9 (m, 10H), 2.2 (m, 1 H), 2.3 (m, 4H), 2.4 (s, 3H), 3.2 (m, 3H), 3.5 (m, 1 H), 4.1 (m, J=13.2Hz, 1 H), 4.7 (m, 1 H), 7.1 (m, 3H), 7.3 (m, 5H), 7.4 (m, 2H), 7.8 (m, 1 H), 8.5 (d, J=1.4Hz, 1 H), 8.6 (dd, .7=5.0, 1.8Hz, 1 H).
Example 348 3-(4-(2-r(1 R.5S)-3-(2-methyl-1 H-benzimidazol-1 -vn-8-azabicvclor3.2.noct-8- yllethylH-phenyl-1 -piperidinyl)-3-oxo-2-phenyl-1 -propanol
Figure imgf000143_0002
1H NMR (400 MHz, methanol-d4) δ ppm 1.6 (m, 2H), 1.8 (m, 10H), 2.1 (m, 1 H), 2.4 (m, 2H), 2.5 (s, 3H), 2.5 (s, 2H), 3.1 (m, 3H), 3.3 (m, 2H), 3.7 (m, 2H), 4.1 (m, 2H), 4.7 (m, 1 H), 7.3 (m, 13H), 7.5 (m, 1 H). Example 349 4-r2-(4-(2-r(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicvclor3.2.noct- 8-yllethyl)-4-phenyl-1-piperidinvπ-2-oxoethvnphenol
Figure imgf000144_0001
1H NMR (400 MHz, methanol-d4) δ ppm 1.4 (m, 1H), 1.6 (m, 1H), 2.0 (m, 8H), 2.3 (m, 2H), 2.4 (s, 3H), 2.5 (m, 2H), 3.0 (m, 1 H), 3.1 (m, 1H), 3.4 (s, 1H), 3.6 (m, 5H), 3.9 (m, 1H), 4.9 (m, 1H), 6.6 (m, 2H), 7.0 (m, 2H), 7.2 (m, 3H), 7.3 (m, 5H), 7.4 (m, 1H), 7.5 (m, 1H).
Example 350 2-methyl-1 -r(1 R.5S)-8-(2-(4-phenyl-1 -r2-(trifluoromethvnbenzoyl1-4- piperidinyl)ethvD-8-azabicvclor3.2.11oct-3-vn-1 H-benzimidazole
Figure imgf000144_0002
1H NMR (400 MHz, methanol-d4) δ ppm 1.8 (m, 10H), 2.1 (m, 3H), 2.4 (m, 6H), 3.0 (m, 2H), 3.2 (m, 1H), 3.4 (m, 2H), 4.1 (m, 1 H), 4.7 (m, 1H), 7.1 (m, 3H), 7.3 (m, 1H), 7.3 (m, 5H), 7.4 (m, 1H), 7.6 (m, 3H). Example 351 1-((1 R.5S)-8-(2-π-(3-chloro-2-fluorobenzovn-4-phenyl-4-piperidinvnethyl)-8- azabicvclor3.2.1loct-3-vπ-2-methyl-1 H-benzimidazole
Figure imgf000145_0001
1H NMR (400 MHz, methanol-d4) δ ppm 1.7 (m, 2H), 1.9 (m, 10H), 2.3 (m, 1 H), 2.4 (m, 3H), 2.5 (s, 3H), 3.2 (m, 2H), 3.4 (m, 1 H), 3.4 (m, 2H), 4.2 (m, 1 H), 4.7 (m, 1 H), 7.2 (m, 2H), 7.3 (m, 2H), 7.4 (m, 6H), 7.5 (m, 1 H), 7.6 (m, 1H).
Example 352 1 -IY1 R.5S)-8-(2-(1 -r(6-chloro-2-pyridinyl)carbonvπ-4-phenyl-4- piperidinyl)ethyl)-8-azabicvclof3.2.1loct-3-yll-2-methyl-1 H-benzimidazole
Figure imgf000145_0002
1H NMR (400 MHz, mθthanoktø) δ ppm 1.6 (m, 2H), 1.9 (m, 10H), 2.2 (m, 1H), 2.4 (m, 3H), 2.4 (s, 3H), 3.2 (m, 1H), 3.3 (m, 3H), 3.5 (m, 1H), 4.1 (m, 1 H), 4.7 (m, 1 H), 7.1 (m, 3H), 7.3 (m, 5H), 7.4 (m, 3H), 7.8 (t, J=7.7Hz, 1 H). Example 353 1 -((1 R.5S)-8-(2-π -(2-chloroisonicotinovD-4-phenyl-4-piperidinyllethyl)-8- azabicvclor3.2.noct-3-vπ-2-methyl-1 H-benzimidazole
Figure imgf000146_0001
1H NMR (400 MHz, methanol-d4) δ ppm 1.7 (m, 2H), 1.9 (m, 10H), 2.3 (m, 1H), 2.4 (m, 3H), 2.5 (s, 3H), 2.6 (m, 1H), 3.3 (m, 3H), 3.5 (m, 1H), 4.2 (m, 1H), 4.7 (m, 1H), 7.2 (m, 3H), 7.4 (m, 6H), 7.5 (m, 2H), 8.5 (d, J=5.0Hz, 1H).
Example 354 1 -((1 R,5S)-8-(2-π -(4-chloro-2-fluorobenzoyl)-4-phenyl-4-piperidinvnethyll-8- azabicvclor3.2.11oct-3-yl)-2-methyl-1 H-benzimidazole
Figure imgf000146_0002
1H NMR (400 MHz, methanol-d4) δ ppm 1.6 (m, 2H), 1.8 (m, 10H), 2.2 (m, 1 H), 2.3 (m, 3H), 2.4 (s, 3H), 2.5 (m, 1H), 3.1 (m, 1H), 3.3 (m, 2H), 3.4 (m, 1H), 4.1 (m, 1H), 4.6 (m, 1H), 7.1 (m, 2H), 7.2 (m, 1H), 7.3 (m, 8H), 7.4 (m, 1H). Example 355 1 -((1 R.5S 8-f2-M -(2.3-dimethylbenzoyl)-4-phenyl-4-piperidinvnethyl)-8- azabicvclor3.2.noct-3-yl)-2-methyl-1 H-benzimidazole
Figure imgf000147_0001
1H NMR (400 MHz, methanol-d4) δ ppm 1.8 (m, 10H), 2.0 (s, 3H), 2.1 (m, 1 H), 2.2 (m, 3H), 2.3 (m, 4H), 2.4 (m, 3H), 2.5 (m, 1 H), 3.0 (m, 1 H), 3.3 (m, 4H), 4.1 (m, 1 H), 4.6 (m, 1 H). 6.8 (d, J=7.1 Hz, 1 H), 7.1 (m, 5H), 7.3 (m, 5H), 7.4 (m, 1H).
Example 356 1 -((1 R.5S)-8 2-π -(1 H-indol-5-ylcarbonyl)-4-phenyl-4-piperidinyllethyl)-8- azabicvclo[3.2.1 loct-3-yl)-2-methyl-1 H-benzimidazole
Figure imgf000147_0002
1H NMR (400 MHz, methanol-d4) δ ppm 1.6 (m, 2H), 1.9 (m, 10H), 2.2 (m, 3H), 2.4 (m, 4H), 3.3 (m, 2H), 3.7 (m, 1H), 4.1 (m, 1H), 4.5 (m, 2H), 4.7 (m, 1H), 6.4 (d, J=2.5Hz, 1 H), 7.1 (m, 2H), 7.2 (m, 1H), 7.2 (d, J=3.2Hz, 1H), 7.3 (m, 8H), 7.4 (m, 1H), 7.6 (s, 1H). 147
Example 357 1 -((1 R,5S)-8-(2-M -(1 H-indol-6-ylcarbonyl)-4-phenyl-4-piperidinvnethyl)-8- azabicvclor3.2.πoct-3-vD-2-methyl-1 H-benzimidazole
Figure imgf000148_0001
1H NMR (400 MHz, methanol-d4) δ ppm 1.2 (m, 2H), 1.6 (m, 2H), 1.8 (m, 8H), 2.2 (m, 5H), 2.4 (m, 3H), 2.5 (m, 1 H), 3.3 (m, 2H), 3.6 (m, 1H), 4.0 (m, 1H), 4.6 (m, 1H), 6.4 (d, J=2.1Hz, 1H), 7.0 (dd, J=7.8, 1.4Hz, 1H), 7.1 (m, 2H), 7.2 (m, 1H), 7.3 (d, J=3.2Hz, 1 H), 7.3 (m, 6H), 7.4 (s, 1 H), 7.4 (m, 1 H), 7.5 (m, 1H).
Example 358 2-chloro-6-IT4-(2-lϊ1 R.5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicvclor3.2.noct-8-yl1ethyl)-4-phenyl-1-piperidinyl)carbonyllphenol
Figure imgf000148_0002
1H NMR (400 MHz, methanokW) δ ppm 1.3 (m, 2H), 1.7 (m, 2H), 2.0 (m, 10H), 2.4 (m, 5H), 2.5 (m, 3H), 3.6 (m, 2H), 4.1 (m, 1H), 4.7 (m, 1H), 6.9 (t, J=7.7Hz, 1H), 7.1 (d, J=7.5Hz, 1H), 7.2 (m, 3H), 7.4 (m, 6H), 7.5 (m, 1H). Example 359 2-methyl-1 (1 R.5S)-8-(2-f 143-(2-methylphenvn propanovn-4-phenyl-4- piperidinyllethv0-8-azabicvclor3.2.11oct-3-yll-1 H-benzimidazole
Figure imgf000149_0001
1H NMR (400 MHz, methanol-d4) δ ppm 1.2 (m, 1 H), 1.4 (m, 1 H), 1.6 (m, 4H), 1.9 (m, 6H), 2.1 (m, 1 H), 2.3 (m, 3H), 2.3 (m, 2H), 2.5 (m, 3H), 2.6 (m, 4H), 2.8 (m, 2 H), 3.0 (m, 2H), 3.2 (d, J=5.7 Hz, 1 H), 3.5 (m, 1H), 3.9 (m, 1 H), 4.6 (m, 1 H), 7.0 (m, 2H), 7.0 (m, 2H), 7.1 (m, 2H), 7.1 (m, 1 H), 7.3 (m, 5H), 7.4 (m, 1 H).
Example 360 2-methyl-14(1 R,5S)-8-(2~f 14(4-methylcvclohexyl) carbonvn-4-phenyl-4- piperidinyl)ethyl)-8-azabicvclor3.2.noct-3-yl1-1 H-benzimidazole
Figure imgf000149_0002
1H NMR (400 MHz, methanokW) δ ppm 0.8 (m, 2H), 0.9 (m, 4H), 1.5 (m, 18H), 2.3 (m, 4H), 2.5 (m, 3H), 2.5 (m, 1 H), 3.1 (m, 1 H), 3.2 (m, 3H), 3.7 (m, 1 H), 3.9 (m, 1 H), 4.7 (m, 1 H), 7.1 (m, 2H), 7.2 (m, 1 H), 7.3 (m, 5H), 7.4 (m, 1H). Example 361 2-methyl-1 -((1 R,5S)-8-(244-phenyl-1 -(3-phenyl-butanoylV4-piperidinvπethyl)- 8-azabicvclor3.2.1loct-3-vh-1 H-benzimidazole
Figure imgf000150_0001
1H NMR (400 MHz, methanol-d4) δ ppm 1.2 (m, 4H), 1.4 (m, 1 H), 1.6 (m, 3H), 1.9 (m, 8H), 2.3 (m, 2H), 2.5 (m, 1 H), 2.7 (m, 2H), 3.0 (m, 2H), 3.0 (m, 1 H), 3.2 (m, 4H), 3.5 (m, 1 H), 3.7 (m, 1 H), 3.9 (m, 1 H), 4.7 (m, 1H), 7.1 (m, 5H), 7.3 (m, 8H), 7.4 (m, 1 H).
Example 362 3-(442-[(1 R.5S)-3-(2-methyl-1 H-benzimidazol-1 -vn-8-azabicvclor3.2.1loct-8- yrjethyl)-4-phenyl-1-piperidinyl)-3-oxopropyl phenyl ether
Figure imgf000150_0002
1H NMR (400 MHz, methanol-d4) δ ppm 1.3 (m, 4H), 1.8 (m, 10H), 2.4 (m, 4H), 2.5 (s, 3H), 2.6 (m, 1H), 2.9 (m, 2H), 3.2 (m, 1 H), 3.4 (m, 2H), 3.8 (m, 1 H), 4.0 (m, 1 H), 4.8 (m, 1 H), 6.9 (m, 3H), 7.2 (m, 5H), 7.4 (m, 5H), 7.5 (m, 1 H). Example 363 1 -((1 R,5S)-8-(241 -(cvclohexylacetvh-4-phenyl-4-piperidinvnethyl)-8- azabicvclor3.2.1 loct-3-yl)-2-methyl-1 H-benzimidazole
Figure imgf000151_0001
1H NMR (400 MHz, methanol-d4) δ ppm 1.0 (m, 2H), 1.2 (m, 3H), 1.7 (m, 9H), 1.9 (m, 11H), 2.3 (m, 4H), 2.4 (m, 2H), 2.5 (s, 3H), 3.2 (m, 1H), 3.3 (m, 1 H), 3.8 (m, 1 H), 4.0 (m, 1 H), 4.8 (m, 1 H), 7.2 (m, 2H), 7.2 (m, 1H), 7.4 (m, 5H), 7.5 (m, 1H).
Example 62 1 -((1 R.5SV84241 -(1 ,3-benzodioxol-5-ylcarbonvn-4-phenyl-4- piperidinvnethyl)-8-azabicvclor3.2.1loct-3-yl)-2-methyl-1 H-benzimidazole
Figure imgf000151_0002
1H NMR (400 MHz, methanol-d4) δ ppm 1.3 (m, 2H), 1.7 (m, 2H), 1.9 (m, 11 H), 2.3 (m, 5H), 2.5 (d, J=6.4Hz, 3H), 2.6 (m, 1 H), 3.3 (m, 1 H), 3.7 (m, 1H), 4.1 (m, 1H), 4.7 (m, 1H), 6.9 (m, 2H), 7.2 (m, 2H), 7.2 (m, 1H), 7.4 (m, 6H), 7.5 (m, 1 H). Example 63 14(1 R,5S)-8-(2 14fluoro(phenvnacetyll-4-phenyl-4-piperidinyl)ethvn-8- azabicvclor3.2.11oct-3-yll-2-methyl-1 H-benzimidazole
Figure imgf000152_0001
1H NMR (400 MHz, methanol-d4) δ ppm 1.9 (m, 14H), 2.3 (m, 3H), 2.5
(m, 3H), 3.0 (m, 3H), 3.6 (m, 1 H), 4.0 (m, 11-1), 4.7 (m, 1H), 6.3 (dd, J=48.3, 20.9Hz, 1 H), 7.3 (m, 14H).
Example 64 3-r(442-r(1R.5SV3-(2-methyl-1 H-benzimidazol-1 -vn-8-azabicvclor3.2.1loct-8- vnethyl)-4-phenyl-1-piperidinyl)carbonvn-2-pyridinylamine
Figure imgf000152_0002
1H NMR (400 MHz, methanol-d4) δ ppm 1.7 (m, 2H), 1.9 (m, 10H), 2.3 (m, 4H), 2.5 (s, 3H), 3.3 (m, 2H), 3.8 (m, 4H), 4.7 (m, 1H), 6.7 (dd, J=7.3, 5.2Hz, 1 H), 7.2 (m, 3H), 7.4 (m, 5H), 7.5 (m, 1 H), 8.0 (dd, J=5.2, 2.0Hz, 1 H).
Example 66 24(4424(1 R.5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8-azabicvclor3.2.11oct-8- yllethyl -phenyl-l-piperidinvhcarbonyll^H-chromen^-one
Figure imgf000153_0001
1H NMR (400 MHz, methanol-d4) δ ppm 1.3 (m, 3H), 1.7 (m, 2H), 2.0 (m, 8H), 2.4 (m, 4H), 2.5 (m, 3H), 2.9 (m, 1H), 3.1 (m, 1H), 3.3 (m, 2H), 3.6 (m, 1H), 4.1 (m, 1H), 4.8 (m, 1H), 7.2 (m, 2H), 7.3 (m, 1H), 7.4 (m, 5H), 7.5 (m, 2H), 7.6 (d, J=7.8Hz, 1H), 7.8 (m, 1H), 8.2 (dd, J=8.0, 1.6Hz, 1H).
Example 67 2-methyl-14(1 R,5S)-8-(244-phenyl-1 -r3-(trifluoromethyl)benzoyll-4- piperidinyl)ethyl)-8-azabicvclor3.2.1loct-3-yll-1 H-benzimidazole
Figure imgf000153_0002
1H NMR (400 MHz, methanol-d4) δ ppm 1.3 (m, 1 H), 1.7 (m, 2H), 1.9 (m, 10H), 2.3 (m, 1H), 2.4 (m, 4H), 2.5 (s, 3H), 3.3 (m, 2H), 3.5 (m, 1H), 4.2 (m, 1H), 4.7 (m, 1H), 7.2 (m, 2H), 7.2 (m, 1H), 7.4 (m, 5H), 7.5 (m, 1H), 7.7 (m,2H), 7.7 (s, 1H), 7.8 (m, 1H). Example 71 2-methyl-14(1 R.5S)-8-(2 143-(4-methylphenyl) propanoyl1-4-phenyl-4- piperidinyl)ethyl)-8-azabicvclor3.2.11oct-3-yll-1 H-benzimidazole
Figure imgf000154_0001
1H NMR (400 MHz, methanol-d4) δ ppm 1.5 (m, 1 H), 1.7 (m, 4H), 1.8
(m, 2H), 1.9 (m, 10H), 2.2 (m, 1 H), 2.2 (s, 3H), 2.4 (m, 2H), 2.5 (m, 3H), 2.8 (m, 2H), 3.2 (m, 2H), 3.6 (m, 1 H), 3.9 (m, 1 H), 4.7 (m, 1 H), 7.1 (m, 3H), 7.2 (m, 3H), 7.4 (m, 6H), 7.5 (m, 1 H).
Example 72
1 -((1 R,5S)-84241 -(3.4-dichlorobenzoyl -phenyl-4-piperidinvnethyl)-8- azabicvclor3.2.1 loct-3-vπ-2-methyl-1 H-benzimidazole
Figure imgf000154_0002
1H NMR (400 MHz, methanol-d4) δ ppm 1.7 (m, 2H), 1.9 (m, 11 H), 2.3 (m, 1 H), 2.4 (m, 4H), 2.5 (m, 3H), 3.3 (m, 2H), 3.6 (m, 1 H), 4.1 (m, 1 H), 4.7 (m, 1 H), 7.2 (m, 2H), 7.2 (m, 1 H), 7.3 (dd, J=8.2, 1.8Hz, 1 H), 7.4 (m, 5H), 7.5 (m, 1 H), 7.6 (m, 2H). Example 73 1 -((1 R.5SV84241 -(3-chlorobenzovn-4-phenyl-4-piperidinvπethyl)-8- azabicvclor3.2.11oct-3-vh-2-methyl-1 H-benzimidazole
Figure imgf000155_0001
1H NMR (400 MHz, methanol-d4) δ ppm 1.7 (m, 2H), 1.9 (m, 10H), 2.2
(m, 1 H), 2.4 (m, 3H), 2.5 (s, 3H), 3.3 (m, 4H), 3.6 (m, 1 H), 4.1 (m, J=11.1 , 4.3Hz, 1 H), 4.7 (m, 1 H), 7.2 (m, 2H), 7.2 (m, 1 H), 7.3 (m, 1 H), 7.4 (m, 5H), 7.4 (m, 2H), 7.5 (m, 1 H).
Example 74
1 -((1 R.5SV84241 -(mesitylcarbonyl)-4-phenyl-4-piperidinvnethyll-8- azabicvclof3.2.1loct-3-yl)-2-methyl-1 H-benzimidazole
Figure imgf000155_0002
1H NMR (400 MHz, methanol-d4) δ ppm 1.7 (m, 2H), 1.8 (m, 1 H), 1.9 (m, 10H), 2.1 (s, 3H), 2.2 (m, 1 H), 2.3 (m, 6H), 2.4 (m, 3H), 2.5 (m, 3H), 3.1 (m, 1 H), 3.3 (m, 3H), 4.2 (m, 1 H), 4.7 (m, 1 H), 6.9 (s, 1 H), 7.2 (m, 2H), 7.2 (m, 1 H), 7.4 (m, 5H), 7.5 (m, 1 H).
Example 78 1 (1 R.5S V8-f2-(1 -butyryl-4-phenyl-4-piperidinvnethvn-8-azabicvclor3.2.1 loct- 3-yl)-2-methyl-1 H-benzimidazole
Figure imgf000156_0001
1H NMR (400 MHz, methanol-d4) δ ppm 1.0 (t, J=7.4Hz, 3H), 1.6 (m, 4H), 1.9 (m, 10H), 2.4 (m, 7H), 2.5 (s, 3H), 3.2 (m, 1 H), 3.3 (m, 2H), 3.7 (m, 1 H), 4.0 (d, J=3.7 Hz, 1 H), 4.7 (m, 1 H), 7.2 (m, 2H), 7.2 (m, 1 H), 7.4 (m, 5H), 7.5 (m, 1 H).
Example 79 1-((1 R.5S)-842-π-(3-fluorobenzovn-4-phenyl-4-piperidinyllethyl)-8- azabicvclor3:2.1 loct-3-yl)-2-methyl-1 H-benzimidazole
Figure imgf000156_0002
1H NMR (400 MHz, methanol-d4) δ ppm 1.7 (m, 2H), 2.0 (m, 10H), 2.2 (m, 1 H), 2.4 (m, 3H), 2.5 (m, 3H), 3.3 (m, 4H), 3.5 (m, J=5.6, 1.6Hz, 1 H), 4.1 (m, J=4.0Hz, 1 H), 4.7 (m, 1 H), 7.2 (m, 6H), 7.4 (m, 5H), 7.5 (m, 1 H), 7.5 (m, 1 H). Example 81 N4(1S,2R)-2-hvdroxy-14(4424(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -vH-8- azabicvclor3.2.11oct-8-yl1ethyll-4-phenyl-1- piperidinvDcarbonyllpropyllacetamide
Figure imgf000157_0001
1H NMR (400 MHz, methanol-d4) δ ppm 1.2 (m, 3H), 1.7 (m, 2H), 1.9 (m, 13H), 2.4 (m, 5H), 2.5 (s, 3H), 3.3 (m, 5H), 4.0 (m, 3H), 4.8 (m, 2H), 7.2 (m, 2H), 7.2 (m, 1 H), 7.4 (m, 5H), 7.5 (m, 1 H).
Example 82 2-methyl-1 -((1 R.5S)-84244-phenyl-1 -(4.4.4-trifluorobutanoyl)-4- piperidinyllethyl}-8-azabicvclo[3.2.1loct-3-yl)-1 H-benzimidazole
Figure imgf000157_0002
1H NMR (400 MHz, methanol-d4) δ ppm 1.7 (m, 2H), 1.9 (m, 10H), 2.3 (m, 2H), 2.5 (m, 4H), 2.5 (s, 3H), 2.7 (m, 2H), 3.2 (m, 1 H), 3.3 (m, 3H), 3.7 (m, 1 H), 4.0 (m, 1 H), 4.7 (m, 1 H), 7.2 (m, 2H), 7.2 (m, 1 H), 7.4 (m, 5H), 7.5 (m, 1 H). Example 83 1 -((1 R.5SV84241 1 H-indol-3-ylacetyl)-4-phenyl-4-piperidinyllethyl)-8- azabicvclor3.2.1 loct-3-vπ-2-methyl-1 H-benzimidazole
Figure imgf000158_0001
1H NMR (400 MHz, methanol-d4) δ ppm 1.4 (m, 1 H), 1.7 (m, 6H), 1.9
(m, 6H), 2.0 (m, 1H), 2.2 (m, 1H), 2.4 (m, 2H), 2.5 (s, 3H), 3.1 (m, 1H), 3.2 (m, 3H), 3.8 (m, 2H), 3.9 (m, 1H), 4.1 (m, 1H), 4.7 (m, 1H), 7.0 (t, J=7.0Hz, 1H), 7.1 (m, 2H), 7.2 (m, 3H), 7.4 (m, 6H), 7.5 (m, 1H), 7.6 (d, J=7.8Hz, 1H).
Example 85
2-methyl-1 (1R.5S)-842-ri-(3-nitrobenzovn-4-phenyl-4-piperidinyllethyl>-8- azabicvclor3.2.11oct-3-yl)-1 H-benzimidazole
Figure imgf000158_0002
1H NMR (400 MHz, methanol-d4) δ ppm 1.7 (m, 2H), 2.0 (m, 12H), 2.3 (m, 1H), 2.4 (m, 3H), 2.5 (s, 3H), 3.3 (m, 2H), 3.6 (m, 1H), 4.2 (m, J=13.6Hz, 1H), 4.7 (m, 1H), 7.2 (m, 3H), 7.4 (m, 5H), 7.5 (m, 1H), 7.7 (t, J=7.8Hz, 1H), 7.8 (d, J=7.8Hz, 1H), 8.3 (s, 1H), 8.3 (d, J=8.2 Hz, 1H). Example 86 5,5-dimethyl-44(4424(1 R,5SV3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicvclor3.2.11oct-8-vnethyll-4-phenyl-1-piperidinyl)carbonyl1dihvdro-2(3H)- furanone
Figure imgf000159_0001
1H NMR (400 MHz, methanol-d4) δ ppm 1.2 (m, 2H), 1.5 (m, 3H), 1.9 (m, 14H), 2.4 (m, 4H), 2.5 (s, 3H), 2.8 (m, 2H), 3.1 (m, 1 H), 3.4 (m, 2H), 3.8 (m, 2H), 4.1 (m, 1 H), 4.8 (m, 1 H), 7.2 (m, 3H), 7.4 (m, 5H), 7.5 (m, 1 H).
Example 88 2-methyl-1 -((1 R.5S)-84241 -(2-nitrobenzoyl)-4-phenyl-4-piperidinyllethyl)-8- azabicvclor3.2.1loct-3-yl)-1 H-benzimidazole
Figure imgf000159_0002
1H NMR (400 MHz, methanol-d4) δ ppm 1.3 (m, 1 H), 1.7 (m, 2H), 2.0 (m, 10H), 2.2 (m, 1 H), 2.4 (m, 3H), 2.5 (m, J=1.4 Hz, 3H), 3.2 (m, 2H), 3.4 (m, 2H), 4.2 (m, 1 H), 4.7 (m, 1 H), 7.2 (m, 2H), 7.3 (m, 1 H), 7.4 (m, 6H), 7.5 (m, 1 H), 7.7 (m, 1 H), 7.8 (m, 1 H), 8.2 (m, 1 H). Example 90 2-methyl-1 -((1 R.5S)-84241 1 -naphthovn-4-phenyl-4-piperidinyllethyll-8- azabicvclor3.2.1 loct-3-yl)-1 H-benzimidazole
Figure imgf000160_0001
1H NMR (400 MHz, methanol-d4) δ ppm 0.6 (m, 2H), 1.8 (m, 12H), 2.4
(m, 4H), 2.5 (m, 3H), 3.3 (m, 2H), 3.5 (m, 1 H), 4.3 (m, 1 H), 4.7 (m, 1H), 7.2 (m, 2H), 7.2 (m, 1 H), 7.4 (m, 6H), 7.5 (m, 5H), 7.9 (m, 2H).
Example 91 1 (1 R.5SV-84241 -(2,3-dichlorobenzovn-4-phenyl-4-piperidinyllethyl)-8- azabicvclor3.2.11oct-3-yl)-2-methyl-1 H-benzimidazole
Figure imgf000160_0002
1H NMR (400 MHz, methanol-d4) δ ppm 1.8 (m, 2H), 1.9 (m, 8H), 2.1 (m, 2H), 2.3 (m, 1 H), 2.5 (m, 3H), 2.5 (m, 3H), 3.2 (m, 1 H), 3.4 (m, 4H), 4.2 (m, 1 H), 4.8 (m, 1 H), 7.2 (m, 2H), 7.3 (m, 1 H), 7.4 (m, 7H), 7.5 (m, 1 H), 7.6 (m, 1 H). ,
Example 92 1 -methyl-2-(4424(1 R.5S)-342-methyl-1 H-benzimidazol-1 -yl)-8- azabicvclor3.2.11oct-8-vπethyl}-4-phenyl-1 -piperidinvO-2-oxoethyl phenyl ether
Figure imgf000161_0001
1H NMR (400 MHz, methanol-d4) δ ppm 1.5 (dd, J=19.8, 6.6Hz, 3H),
1.9 (m, 13H), 2.3 (m, 2H), 2.4 (m, 2H), 2.5 (m, 3H), 3.1 (m, 1H), 3.3 (m, 2H), 3.9 (m, 2H), 4.7 (m, 1H), 5.1 (m, 1H), 6.9 (m, 3H), 7.2 (m, 5H), 7.4 (m, 5H), 7.5 (m, 1H).
Example 93
3-r(442-r(1 R.5SV3-(2-methyl-1 H-benzimidazol-1 -yl)-8-azabicvclor3.2.noct-8- yl1ethyl)-4-phenyl-1-piperidinyl)carbonyl1-4H-chromen-4-one
Figure imgf000161_0002
1H NMR (400 MHz, methanol-d4) δ ppm 1.7 (m, 2H), 1.9 (m, 8H), 2.1 (m, 2H), 2.4 (m, 4H), 2.5 (m, J=1.4Hz, 3H), 3.3 (m, 4H), 3.5 (m, 1 H), 4.2 (s, 1 H), 4.8 (m, 1H), 7.0 (m, 1 H), 7.2 (m, 2H), 7.3 (m, 1 H), 7.4 (m, 5H), 7.5 (m, 2H), 7.7 (d, J=7.8Hz, 1 H), 7.8 (m, 1 H), 8.2 (dd, J=8.2, 1.4Hz, 1 H). Example 94 1 -((1 R.5S)-84241 2.3-dihvdro-1.4-benzodioxin-2-ylcarbonvn-4-phenyl-4- piperidinvnethyl)-8-azabicvclof3.2.noct-3-yl)-2-methyl-1 H-benzimidazole
Figure imgf000162_0001
1H NMR (400 MHz, methanol-d4) δ ppm 1.7 (m, 2H) 2.0 (m, 10H) 2.3 (m, 4H) 2.6 (m, 3H) 3.1 (m, 1 H) 3.4 (m, 3H) 4.0 (m, 2H) 4.2 (m, 1 H) 4.4 (m, 1 H) 4.8 (m, 1 H) 5.1 (m, 1 H) 6.8 (m, 3H) 6.9 (m, 1 H) 7.2 (m, 2H) 7.3 (t, J=7.0Hz, 1H) 7.4 (m, 5H) 7.5 (m, 1 H).
Example 96 2-methyl-1 -((1 R,5S)-84241 -(4-methylbenzovn-4-phenyl-4-piperidinvπethyl)-8- azabicvclor3.2.11oct-3-yl)-1 H-benzimidazole
Figure imgf000162_0002
1H NMR (400 MHz, methanol-d4) δ ppm 1.7 (m, 2H), 1.9 (m, 10H), 2.2 (m, 2H), 2.4 (m, 7H), 2.5 (s, 3H), 3.3 (m, 2H), 3.6 (m, 1 H), 4.1 (m, 1 H), 4.7 (m, 1 H), 7.2 (m, 2H), 7.3 (m, 5H), 7.4 (m, 5H), 7.5 (m, 1H).
Example 97 1 -((1 R.5SV84241 -(4-ethoxybenzoyl)-4-phenyl-4-piperidinyllethyl)-8- azabicvclor3.2.1loct-3-vπ-2-methyl-1 H-benzimidazole
Figure imgf000163_0001
1H NMR (400 MHz, methanol-d4) δ ppm 1.3 (m, 1 H), 1.4 (t, J=7.1 Hz,
3H), 1.7 (m, 2H), 1.9 (m, 10H), 2.3 (m, 4H), 2.5 (m, 3H), 3.3 (m, 3H), 3.7 (m, 1H), 4.1 (m, 3H), 4.7 (m, 1H), 7.0 (m, 2H), 7.2 (m, 2H), 7.2 (m, 1H), 7.4 (m, 2H), 7.4 (m, 5H), 7.5 (m, 1 H).
Example 99
1 -((1 R.5SV84241 -(2-ethoxybenzovn-4-phenyl-4-piperidinyllethyll-8- azabicvclor3.2.11oct-3-yl)-2-methyl-1 H-benzimidazole
Figure imgf000163_0002
1H NMR (400 MHz, methanol-d4) δ ppm 1.2 (t, J=7.1 Hz, 2H), 1.5 (t, J=7.0Hz, 2H), 1.9 (m, 12H), 2.3 (m, 5H), 2.5 (m, 3H), 3.2 (m, 1 H), 3.4 (m, 3H), 4.0 (q, J=7.1 Hz, 1 H), 4.1 (m, 2H), 4.7 (m, 1 H), 7.0 (m, 3H), 7.2 (m, 3H), 7.4 (m, 5H), 7.5 (d, J=7.1 Hz, 1 H). Example 100 1 -((1 R.5S)-84241 -(2.4-dimethylbenzovn-4-phenyl-4-piperidinyllethyl)-8- azabicvclor3.2.1loct-3-yl)-2-methyl-1 H-benzimidazole
Figure imgf000164_0001
1H NMR (400 MHz, methanol-d4) δ ppm 1.9 (m, 13H), 2.2 (m, 3H), 2.3
(m, 7H), 2.5 (s, 3H), 3.1 (m, 1 H), 3.4 (m, 3H), 4.1 (m, J=11.1 , 4.6Hz, 1 H), 4.7 (m, 1 H), 7.1 (m, 3H), 7.2 (m, 2H), 7.2 (m, 1 H), 7.4 (m, 5H), 7.5 (m, 1H).
Example 104 1 -((1 R,5S)-84241 -(2.4-dimethylbenzoyl)-4-phenyl-4-piperidinyl1ethyl)-8- azabicvclo[3.2.1 loct-3-yl)-2-methyl-1 H-benzimidazole
Figure imgf000164_0002
1H NMR (400 MHz, methanol-d4) δ ppm 1.3 (m, 1 H), 1.7 (m, 5H), 1.9 (m, 7H), 2.2 (m, 1 H), 2.4 (m, 4H), 2.5 (s, 3H), 3.1 (m, 1 H), 3.2 (m, 3H), 3.8 (m, 2H), 4.1 (t, J=5.5Hz, 1H), 4.7 (d, J=8.6Hz, 1H), 6.7 (dd, J=8.6, 2.1 Hz, 1 H), 7.0 (d, J=2.5 Hz, 1 H), 7.1 (s, 1 H), 7.2 (m, 4H), 7.3 (m, 5H), 7.4 (dd, J=5.9, 2.7Hz, 1 H), 7.5 (m, 1 H). Example 106 14(1 R.5S)-842-(14r2.2-dimethyl-3-(2-methyl-1- propenyl)cvclopropyl1carbonyl)-4-phenyl-4-piperidinvπethvn-8- azabicvclor3.2.πoct-3-yl)-2-methyl-1 H-benzimidazole
Figure imgf000165_0001
1H NMR (400 MHz, methanol-d4) δ ppm 1.2 (m, 3H), 1.3 (m, 2H), 1.8 (m, 20H), 2.2 (m, 3H), 2.4 (m, 3H), 2.5 (s, 3H), 3.4 (m, 1H), 3.8 (m, 2H), 4.1 (m, 1 H), 4.8 (m, 1H), 4.9 (m, 1H), 5.1 (dd, J=35.7, 8.9Hz, 1H), 7.2 (m, 2H), 7.2 (m, 1 H), 7.4 (m, 5H), 7.5 (m, 1 H).
Example 107 2-methyl-1 (1 R,5S)-842-(4-phenyl-14r4-ftrifluoro-methyl)-3- pyridinvncarbonyl)-4-piperidinyl)ethvn-8-azabicvclor3.2.1]oct-3-yl}-1 H- benzimidazole
Figure imgf000165_0002
1H NMR (400 MHz, methanol-d4) δ ppm 1.3 (m, 1 H), 1.9 (m, 12H), 2.3 (m, 1 H), 2.4 (m, 4H), 2.5 (m, 3H), 3.2 (m, 1 H), 3.4 (m, 2H), 4.2 (m, 1H), 4.7 (m, 1 H), 7.2 (m, 2H), 7.3 (m, 1 H), 7.4 (m, 5H), 7.5 (m, 1 H), 7.8 (dd, J=13.7, 5.2Hz, 1 H), 8.7 (m, J=72.4Hz, 1 H), 8.9 (t, J=5.7Hz, 1 H). Example 108 1-r(4424(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1-vn-8-azabicvclor3.2.1loct-8- yllethyll-4-phenyl-1-piperidinyl)carbonvncyclopropanecarboxamide
Figure imgf000166_0001
1H NMR (400 MHz, methanol-d4) δ ppm 1.3 (m, 7H), 1.7 (m, 2H), 2.0
(m, 10H), 2.4 (m, 4H), 2.5 (s, 2H), 3.3 (m, 4H), 3.8 (m, 1 H), 4.1 (m, J=11.4, 6.1 Hz, 1 H), 4.7 (m, 1 H), 7.2 (m, 2H), 7.2 (m, 1 H), 7.4 (m, 5H), 7.5 (m, 1 H).
Example 109 2-methyl-14(1 R.5S)-8-(2414(2-methylcvclopropyl) carbonyll-4-phenyl-4- piperidinyl>ethyl)-8-azabicvclor3.2.11oct-3-vn-1 H-benzimidazole
Figure imgf000166_0002
1H NMR (400 MHz, methanol-d4) δ ppm 1.1 (m, 5H), 1.9 (m, 14H), 2.3 (m, 4H), 2.6 (m, 3H), 3.2 (m, 1 H), 3.3 (m, 2H), 3.5 (m, 1 H), 4.0 (m, 2H), 4.7 (m, 1 H), 7.2 (m, 2H), 7.2 (m, 1 H), 7.4 (m, 5H), 7.5 (m, 1 H).
Example 111 2-methyl-14(1 R.5S)-8-(244-phenyl-1 -f(1 -Phenylcvclopentvncarbonvn-4- piperidinyl)ethyl)-8-azabicyclor3.2.noct-3-vn-1 H-benzimidazole
Figure imgf000167_0001
1H NMR (400 MHz, methanol-d4) δ ppm 1.2 (m, 1 H), 1.7 (m, 10H), 2.0 (m, 7H), 2.3 (m, 6H), 2.5 (m, 3H), 2.9 (m, 1 H), 3.2 (m, 3H), 3.4 (m, 1H), 4.0 (m, 1 H), 4.7 (m, 1 H), 7.2 (m, 7H), 7.3 (m, 5H), 7.4 (m, 1 H), 7.5 (m, 1 H).
Example 113 1 -((1 R,5S)-84241 -(2.4-dichlorobenzoylM-phenyl-4-piperidinvπethvU-8- azabicvclof3.2.11oct-3-yl)-2-methyl-1 H-benzimidazole
Figure imgf000167_0002
1H NMR (400 MHz, methanol-d4) δ ppm 1.7 (m, 2H), 1.9 (m, 11 H), 2.3 (m, 1 H), 2.4 (m, 4H), 2.5 (m, J=2.5Hz, 3H), 3.2 (m, 1 H), 3.3 (m, 2H), 4.2 (m, 1 H), 4.7 (m, J=10.9, 9.1 Hz, 1 H), 7.2 (m, 2H), 7.2 (m, 1 H), 7.4 (m, 6H), 7.5 (m, 3H).
Example 117 2-methyl-1-((1 R.5SV842-r4-phenyl-1-(4-vinylbenzovn-4-piperidinvnethyl)-8- azabicvclor3.2.11oct-3-yl)-1 H-benzimidazole
Figure imgf000168_0001
1H NMR (400 MHz, methanol-d4) δ ppm 1.7 (m, 2H), 1.9 (m, 10H), 2.2 (m, 1 H), 2.4 (m, 4H), 2.5 (m, 3H), 3.3 (m, 4H), 3.6 (m, 1 H), 4.1 (m, J=11.1 , 4.3 Hz, 1 H), 4.7 (m, 1 H), 5.3 (d, J=11.1 Hz, 1 H), 5.9 (d, J=17.5Hz, 1 H), 6.8 (dd, J=17.7, 10.9Hz, 1 H), 7.2 (m, 2H), 7.2 (m, 1 H), 7.4 (d, 7H), 7.5 (m, 2H).
Example 120 14(1 R.5S V842414(3.5-dimethoxyphenyl)acetyl1-4-phenyl-4-piperidinyllethv0- 8-azabicvclor3.2.11oct-3-yll-2-methyl-1 H-benzimidazole
Figure imgf000168_0002
1H NMR (400 MHz, methanol-d4) δ ppm 1.7 (m, 5H), 1.9 (m, 8H), 2.2 (m, 2H), 2.4 (m, 3H), 2.5 (m, 3H), 3.2 (m, 4H), 3.7 (m, 8H), 4.0 (m, 1 H), 4.7 (t, 1 H), 6.4 (t, J=2.1 Hz, 1 H), 6.4 (d, J=2.1 Hz, 1 H), 7.2 (m, 2H), 7.2 (m, 1 H), 7.4 (m, 5H), 7.5 (m, 1 H). Example 123 methyl 441 (4424(1 R.5SY-3-(2-methyl-1 H-benzimi-dazol-1-yl)-8- azabicvclol"3.2.11oct-8-yriethyl)-4-phenyl-1- piperidinvDcarbonyllcvclopropyDphenyl ether
Figure imgf000169_0001
1H NMR (400 MHz, methanol-d4) δ ppm 1.3 (m, 6H), 1.7 (m, 2H), 2.0 (m, 8H), 2.2 (m, 1 H), 2.4 (m, 3H), 2.5 (s, 3H), 3.2 (m, 5H), 3.7 (s, 3H), 3.8 (m, 1 H), 4.0 (m, 1 H), 4.7 (m, 1 H), 6.9 (m, 2H), 7.1 (m, 2H), 7.2 (m, 3H), 7.3 (m, 4H), 7.5 (m, 1 H).
Example 127 1 -((1 R.5SV84241 -(2,4-difluorobenzov0-4-phenyl-4-piperidinyllethyl)-8- azabicvclo[3.2.11oct-3-yl)-2-methyl-1 H-benzimidazole
Figure imgf000169_0002
1H NMR (400 MHz, methanol-d4) δ ppm 1.7 (m, 2H), 1.9 (m, 8H), 2.3 (m, 1 H), 2.4 (m, 3H), 2.5 (m, 3H), 3.2 (m, 1 H), 3.3 (m, 5H), 3.5 (m, 1 H), 4.2 (m, 1 H), 4.7 (m, 1 H), 7.1 (m, J=9.6, 9.6Hz, 2H), 7.2 (m, 2H), 7.2 (m, 1 H), 7.4 (m, 6H), 7.5 (m, 1 H). Example 128 1 -((1 R.5S 84241 M .1 '-biphenvn-2-ylcarbonvn-4-phenyl-4-piperidinvnethyl)- 8-azabicvclor3.2.11oct-3-ylV2-methyl-1 H-benzimidazole
Figure imgf000170_0001
1H NMR (400 MHz, methanol-d4) δ ppm 1.5 (m, 3H), 1.9 (m, 8H), 2.2 (m, 1 H), 2.4 (m, 2H), 2.5 (m, 3H), 2.8 (m, 1 H), 3.0 (m, 1H), 3.2 (m, 3H), 3.4 (m, 1 H), 3.8 (m, 1 H), 4.2 (m, 1 H), 4.7 (m, 1 H), 7.4 (m, 18H).
Example 130 2-methyl-14(1 R,5S)-84244-phenyl-14(1 -phenylcvclopropyl)carbonyl1-4- piperidinyl)ethvD-8-azabicvclor3.2.πoct-3-vH-1 H-benzimidazole
Figure imgf000170_0002
1H NMR (400 MHz, methanol-d4) δ ppm 1.3 (m, 5H), 1.6 (m, 2H), 1.7 (m, 3H), 1.9 (m, 8H), 2.2 (m, 1 H), 2.4 (m, 2H), 2.5 (m, 3H), 3.2 (m, 3H), 3.8 (m, 1 H), 4.0 (m, J=12.1 , 5.7Hz, 1 H), 4.7 (m, 1 H), 7.2 (m, 6H), 7.3 (m, 6H), 7.4 (m, 1 H), 7.5 (m, 1 H). Example 131 1 (1 R.5S 842414441 H-imidazol-1 -vnbenzoylM-DhenvM-piperidinvDethyl V 8-azabicvclor3.2.noct-3-yl1-2-methyl-1 H-benzimidazole
Figure imgf000171_0001
1H NMR (400 MHz, methanol-d4) δ ppm 1.7 (m, 2H), 2.0 (m, 10H), 2.3 (m, 1H), 2.4 (m, 4H), 2.5 (m, 3H), 3.4 (m, 3H), 3.6 (m, 1H), 4.2 (m, 1H), 4.7 (m, 1H), 7.2 (m, 3H), 7.2 (m, 1H), 7.4 (m, 6H), 7.5 (m, 1H), 7.6 (m, 2H), 7.6 (d, J=1.4Hz, 1H),7.7(m,2H).
Example 133 1-((1R.5SV84241-(4-isopropylbenzov0-4-phenyl-4-piperidinyl1ethyl)-8- azabicvclof3.2.noct-3-yl)-2-methyl-1 H-benzimidazole
Figure imgf000171_0002
1H NMR (400 MHz, methanokW) δ ppm 1.3 (m, 6H), 1.7 (m, 2H), 1.9 (m, 10H), 2.2 (m, 1H), 2.4 (m, 3H), 2.5 (s, 3H), 2.9 (m, 1H), 3.3 (m, 4H), 3.6 (m, 1H), 4.1 (m, 1H), 4.7 (m, 1H), 7.2 (m, 2H), 7.2 (m, 1H), 7.3 (m, 3H), 7.4 (m,6H), 7.5(m, 1H). Example 134 methyl 34(4424(1 R.5S)-3-(2-methyl-1 H-benzimidazol-1 -ylV8- azabicvclor3.2.noct-8-vnethyl}-4-phenyl-1-piperidinv carbonyl1-2-pyridinyl ether
Figure imgf000172_0001
1H NMR (400 MHz, methanol-d4) δ ppm 1.7 (m, J=7.5Hz, 2H), 1.9 (m, 10H), 2.2 (m, 1 H), 2.4 (m, 3H), 2.5 (m, 3H), 3.2 (m, 1 H), 3.3 (m, 4H), 3.9 (d, J=54.6Hz, 3H), 4.2 (m, 1 H), 4.7 (m, 1 H), 7.1 (m, 1 H), 7.2 (m, 2H), 7.2 (d, J=4.6Hz, 1 H), 7.4 (m, 5H), 7.5 (m, 1 H), 7.6 (dd, J=53.7, 7.3Hz, 1 H), 8.2 (dd, J=5.2, 2.0Hz, 1 H).
Example 136 2-r(442-r(1 R.5SV3-(2-methyl-1 H-benzimidazol-1 -vn-8-azabicvclor3.2.1 ct-8- yl]ethyl}-4-phenyl-1-piperidinyl)carbonyl1phenyl propyl ether
Figure imgf000172_0002
1H NMR (400 MHz, methanol-d4) δ ppm 1.0 (m, 3H), 1.6 (m, 1 H), 1.7 (m, 2H), 1.9 (m, 11 H), 2.2 (m, 1 H), 2.4 (m, 4H), 2.5 (d, J=7.1 Hz, 3H), 3.2 (m, 2H), 3.4 (m, 2H), 3.9 (t, J=6.4Hz, 1H), 4.1 (m, 2H), 4.7 (m, 1H), 7.1 (m, 4H), 7.2 (m, 2H), 7.2 (m, 1 H), 7.4 (m, 5H), 7.5 (m, 1 H). Example 138 methyl 24344424(1 R.5SV3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicvclor3.2.11oct-8-vπethyll-4-phenyl-1 -piperidinyl)-3-oxopropyllphenyl ether
Figure imgf000173_0001
1H NMR (400 MHz, methanol-d4) δ ppm 1.5 (m, 1 H), 1.7 (m, 3H), 1.8 (m, 2H), 1.9 (m, 6H), 2.1 (m, 1 H), 2.2 (m, 1 H), 2.4 (m, 2H), 2.5 (m, J=5.7Hz, 3H), 2.6 (m, 4H), 2.9 (m, 2H), 3.1 (m, 2H), 3.3 (m, 1H), 3.6 (m, 1H), 3.8 (s, 3H), 4.0 (m, 1 H), 4.7 (m, 1 H), 6.8 (t, J=7.0Hz, 1 H), 6.9 (d, J=8.2Hz, 1 H), 7.1 (dd, J=7.5, 1.8Hz, 1 H), 7.2 (m, 2H), 7.2 (m, 1 H), 7.4 (m, 5H), 7.5 (m, 1 H).
Example 139 1 -((1 R.5S 84241 -(cvclopentylacetyl)-4-phenyl-4-piperidinvnethyl)-8- azabicvclor3.2.1 loct-3-v0-2-methyl-1 H-benzimidazole
Figure imgf000173_0002
1H NMR (400 MHz, methanol-d4) δ ppm 1.2 (m, 1 H), 1.6 (m, 4H), 1.9 (m, 12H), 2.2 (m, 3H), 2.4 (m, 4H), 2.6 (m, 3H), 2.8 (t, J=5.7Hz, 1 H), 2.9 (d, J=2.1 Hz, 1 H), 3.2 (m, 1 H), 3.3 (m, 3H), 3.5 (m, 1 H), 3.8 (m, 1 H), 4.0 (m, 1 H), 4.7 (m, 1 H), 7.2 (m, 2H), 7.2 (m, 1 H), 7.4 (m, 5H), 7.5 (m, 1 H). Example 141 2-r(442-f(1R.5SV3-(2-methyl-1H-benzimidazol-1-ylV8-azabicvclor3.2.11oct-8- yllethyll-4-phenyl-1-piperidinyl)carbonvn-4(1HVαuinolinone
Figure imgf000174_0001
1H NMR (400 MHz, methanol-d4) δ ppm 1.7 (m, 2H), 2.0 (m, 10H), 2.4 (m, 4H), 2.5 (m, 3H), 3.3 (m, 4H), 3.6 (m, 1H), 4.2 (m, 1H), 4.7 (m, 1H), 6.3 (s, 1H), 7.2 (m, 2H), 7.3 (m, 1H), 7.4 (m, 7H), 7.5 (m, 1H), 7.6 (d, J=8.2Hz, 1H), 7.7 (m, 1H), 8.3 (d, J=7.1Hz, 1H).
Example 142 1-r(1R.5S)-8-(241-r3-(1.3-benzodioxol-5-vπpropanoyll-4-phenyl-4- piperidinyllethyl)-8-azabicvclo[3.2.11oct-3-vn-2-methyl-1 H-benzimidazole
Figure imgf000174_0002
1H NMR (400 MHz, methanol-d4) δ ppm 1.5 (m, 1H), 1.7 (m, 3H), 1.8 (m, 2H), 2.0 (m, 7H), 2.2 (m, 1H), 2.4 (m, 2H), 2.5 (s, 3H), 2.6 (m, 3H), 2.8 (m, 2H), 3.2 (m, 2H), 3.3 (m, J=3.9Hz, 1H), 3.6 (m, 1H), 3.9 (m, 1H), 4.7 (m, 1H), 5.8 (d, J=1.4Hz, 1 H), 5.9 (s, 1H), 6.7 (m, 3H), 7.2 (m, 2H), 7.2 (m, 1H), 7.4 (m, 5H), 7.5 (m, 1H). Example 144 2-methyl-14(1 R,5S)-8-(2414(4-methyl-1.2.3-thiadiazol-5-vncarbonyl1-4- phenyl-4-piperidinyl) ethvπ-8-azabicvclor3.2.11oct-3-vn-1 H-benzimidazole
Figure imgf000175_0001
1H NMR (400 MHz, methanol-d4) δ ppm 1.4 (m, 2H), 1.7 (m, 2H), 1.9 (m, 10H), 2.4 (m, 5H), 2.6 (m, 3H), 2.8 (m, 1 H), 3.0 (m, 1 H), 3.3 (m, 1 H), 3.4 (m, 1 H), 3.6 (m, 1 H), 4.2 (m, 1H), 4.8 (m, 1 H), 7.2 (m, 2H), 7.2 (m, 1H), 7.4 (m, 5H), 7.5 (m, 1 H).
Example 145 2-methyl-14(1 R,5S)-842-(4-phenyl-1 -propionyl-4-piperidinvnethvπ-8- azabicvclo[3.2.11oct-3-yl|-1 H-benzimidazole
Figure imgf000175_0002
1H NMR (400 MHz, methanol-d4) δ ppm 1.1 (t, J=7.5Hz, 3H), 1.7 (m, 2H), 1.9 (m, 10H), 2.3 (s, 2H), 2.4 (m, 4H), 2.5 (d, J=6.6Hz, 3H), 3.2 (m, 2H),
3.3 (m, 2H), 3.6 (m, 1H), 4.0 (m, 1 H), 4.7 (m, 1 H), 7.2 (m, 2H), 7.2 (m, 1 H),
7.4 (m, 5H), 7.5 (m, 1 H). Example 149 2-r(442-r(1R.5SV3-(2-methyl-1H-benzimidazol-1-vn-8-azabicvclor3.2.1loct-8- yl1ethyll-4-phenyl-1-piperidinvπcarbonvn-3-pyridinol
Figure imgf000176_0001
1H NMR (400 MHz, methanol-d4) δ ppm 1.7 (m, 2H), 2.0 (m, 10H), 2.4 (m, 5H), 2.5 (m, 3H), 3.2 (m, 1H), 3.3 (m, 3H), 3.5 (m, 1H), 4.2 (m, J=4.6Hz, 1H), 4.7 (m, 1H), 7.2 (m, 2H), 7.2 (m, 1H), 7.3 (m, 2H), 7.4 (m, 5H), 7.5 (m, 1H), 8.1 (dd, J=3.9, 2.1Hz, 1H).
Example 150 4.6-dimethyl-54(4424d R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicvclor3.2.noct-8-yl1ethyll-4-phenyl-1-piperidinyl)carbonyl1-2H-pyran-2- one
Figure imgf000176_0002
1H NMR (400 MHz, methanol-d4) δ ppm 1.6 (m, 2H), 1.9 (m, 13H), 2.1 (m, 1H), 2.2 (m, J=6.4Hz, 1H), 2.3 (m, 3H), 2.4 (m, 4H), 2.5 (m, J=1.4Hz, 3H), 2.8 (m, 1H), 3.0 (m, 1H), 3.6 (m, 1H), 4.2 (m, 1H), 4.7 (m, 1H), 6.1 (d, J=21.8Hz, 1H), 7.2 (m, 2H), 7.2 (m, 1H), 7.4 (m, 5H), 7.5 (m, 1H). Example 151 N41-[(442-F(1 R.5SV3-(2-methyl-1 H-benzimidazol-1-vπ-8-azabicvclor3.2.1loct- 8-yl1ethyl)-4-phenyl-1-piperidinvπcarbonyl1propyllurea
Figure imgf000177_0001
1H NMR (400 MHz, methanol-d4) δ ppm 0.9 (m, 3H), 1.6 (m, 4H), 1.9
(m, 11H), 2.4 (m, 6), 2.5 (m, J=1.8Hz, 3H), 2.8 (m, 1H), 3.0 (m, 2H), 3.4 (m, 1 H), 3.8 (m, 1 H), 4.1 (m, 1 H), 4.7 (m, 1 H), 4.8 (m, 1 H), 7.2 (m, 2H), 7.2 (m, 1 H), 7.4 (m, 5H), 7.5 (m, 1 H).
Example 154
1 -rd R,5S)-8-(241 -r(3.5-difluorophenvnacetvn-4-phenyl-4-piperidinyl)ethvn-8- azabicvclor3.2.1Joct-3-vn-2-methyl-1 H-benzimidazole
Figure imgf000177_0002
1H NMR (400 MHz, methanol-d4) δ ppm 1.8 (m, 12H), 2.3 (m, 2H), 2.4 (m, 4H), 2.5 (s, 3H), 3.2 (m, 1 H), 3.3 (m, 2H), 3.8 (m, 2H), 4.0 (m, 1 H), 4.7 (m, 1 H), 6.8 (m, 2H), 7.2 (m, 2H), 7.2 (m, 1 H), 7.4 (m, 6H), 7.5 (m, 1 H).
Example 156 1 (1 R.5S V84241 1 H-indol-3-ylcarbonyl)-4-phenyl-4-piperidinyllethyl)-8- azabicvclor3.2.1 loct-3-vπ-2-methyl-1 H-benzimidazole
Figure imgf000178_0001
1H NMR (400 MHz, methanol-d4) δ ppm 1.7 (m, 2H), 1.9 (m, 10H), 2.4 (m, 7H), 2.5 (s, 3H), 2.8 (m, 1H), 3.1 (m, 1H), 3.5 (m, J=10.3, 10.3Hz, 1H), 4.1 (dd, J=11.6, 6.2Hz, 1H), 4.7 (m, 1H), 7.2 (m, 4H), 7.2 (m, 1H), 7.4 (m, 7H), 7.5 (m, 1 H), 7.6 (m, 1 H).
Example 157 1 -((1 R,5S)-84241 -(24luoro-5-methylbenzovn-4-phenyl-4-piperidinyllethyl)-8- azabicvclor3.2.11oct-3-vP-2-methyl-1 H-benzimidazole
Figure imgf000178_0002
1H NMR (400 MHz, methanol-d4) δ ppm 1.7 (m, 2H), 1.9 (m, 10H), 2.4 (m, 10H), 2.9 (m, 1H), 3.2 (m, 2H), 3.4 (m, 1H), 3.5 (m, 1H), 4.2 (m, 1H), 4.7 (m, 1H), 7.1 (m, 1H), 7.2 (m, 2H), 7.3 (m, 1H), 7.4 (m, 7H), 7.5 (m, 1H).
Example 158 3-r(442-r(1 R.5S)-3-(2-methyl-1 H-benzimidazol-1 -vn-8-azabicvclor3.2. Hoct-8- vnethyll-4-phenyl-1-piperidinyl)carbonvn-2H-chromen-2-one
Figure imgf000179_0001
1H NMR (400 MHz, methanol-d4) δ ppm 1.7 (m, 2H), 1.9 (m, 10H), 2.4 (m, 5H), 2.5 (m, 3H), 2.9 (m, 1 H), 3.2 (m, 2H), 3.6 (m, 1 H), 4.1 (m, 1H), 4.7 (m, 1 H), 7.0 (m, 1 H), 7.2 (m, 4H), 7.4 (m, 6H), 7.5 (m, J=6.8Hz, 1 H), 7.7 (m, 1 H), 8.1 (s, 1 H).
Example 159 2-methyl-1 -((1 R,5S)-84241 -(3-methylbutanoyl)-4-phenyl-4-piperidinvnethyll-8- azabicvclor3.2.1]oct-3-yl)-1 H-benzimidazole
Figure imgf000179_0002
1H NMR (400 MHz, methanol-d4) δ ppm 1.0 (m, 6H), 1.7 (m, 2H), 1.9 (m, 12H), 2.3 (m, 4H), 2.4 (m, 2H), 2.5 (m, J=6.4Hz, 3H), 3.2 (m, 1 H), 3.3 (m, 2H), 3.8 (m, 1 H), 4.0 (m, 1 H), 4.7 (m, 1 H), 7.2 (m, 2H), 7.2 (m, 1 H), 7.4 (m, 5H), 7.5 (m, 1 H). Example 160 1 -((1 R.5SV84241 1 H-indol-4-ylcarbonvn-4-phenyl-4-piperidinvπethyl)-8- azabicvclor3.2.1loct-3-yl)-2-methyl-1 H-benzimidazole
Figure imgf000180_0001
1H NMR (400 MHz, methanol-d4) δ ppm 1.6 (m, 2H), 1.9 (m, 13H), 2.2 (m, 1 H), 2.4 (m, 5H), 3.3 (m, 2H), 3.5 (m, 2H), 4.2 (m, 1H), 4.7 (m, 1H), 6.4 (d, J=2.9Hz, 1H), 7.0 (d, J=7.1Hz, 1H), 7.2 (m, 2H), 7.2 (m, 1H), 7.3 (m, J=3.4, 3.4Hz, 1 H), 7.4 (m, 6H), 7.5 (d, J=8.2Hz, 1H), 7.5 (m, 1H).
Example 162 1 -rd R,5S)-8-(241 -r(3-ethoxy-2-thienvncarbonvn-4-phenyl-4-piperidinyl)ethyl)- 8-azabicvclor3.2.11oct-3-vπ-2-methyl-1 H-benzimidazole
Figure imgf000180_0002
1H NMR (400 MHz, methanol-d4) δ ppm 1.4 (t, J=7.1 Hz, 3H), 1.7 (m, 2H), 2.0 (m, 11H), 2.4 (m, 4H), 2.5 (m, 3H), 3.3 (m, 4H), 3.9 (m, 2H), 4.2 (m, 2H), 4.7 (m, 1 H), 6.9 (d, J=5.7Hz, 1H), 7.2 (m, 2H), 7.2 (m, 1 H), 7.4 (m, 5H), 7.5 (m, 1H). Example 163 2-methyl-1-r(1R.5S)-8-(241-r(1-methylcvclopropyn carbonyll-4-phenyl-4- piperidinyl)ethylV8-azabicvclor3.2.noct-3-vn-1 H-benzimidazole
Figure imgf000181_0001
1H NMR (400 MHz, methanol-d4) δ ppm 0.6 (d, J=1.4Hz, 2H), 0.9 (m, 2H), 1.3 (d, J=20.0Hz, 3H), 1.7 (m, 2H), 1.9 (m, 10H), 2.3 (m, 4H), 2.5 (s, 3H), 2.8 (m, 1 H), 3.0 (m, 1 H), 3.3 (m, 2H), 4.0 (m, 2H), 4.7 (m, 1 H), 7.2 (m, 2H), 7.2 (m, 1 H), 7.4 (m, 5H), 7.5 (m, 1 H).
Example 164 methyl 34344424(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicvclor3.2.1loct-8-vnethyl}-4-phenyl-1-piperidinyl)-3-oxopropynphenyl ether
Figure imgf000181_0002
1H NMR (400 MHz, methanol-d4) δ ppm 1.4 (m, 1 H), 1.7 (m, 2H), 1.8 (m, 1H), 2.0 (m, 11H), 2.2 (m, 1H), 2.4 (m, 2H), 2.5 (m, 3H), 2.7 (m, 2H), 2.9 (m, 2H), 3.1 (m, 2H), 3.6 (m, 1 H), 3.7 (s, 3H), 4.0 (m, 1 H), 4.7 (m, 1 H), 6.7 (dd, J=7.8, 2.1 Hz, 1 H), 6.8 (m, 2H), 7.2 (m, 2H), 7.2 (m, 1 H), 7.4 (m, 6H), 7.5 (m, 1 H). Example 167 methyl 3-1344424(1 R.5S)-3-(2-methyl-1 H-benzimidazol-1 -vO-8- azabicvclor3.2.11oct-8-yllethyl)-4-phenyl-1 -pjperidinyl V3-oxopropyllphenyl ether
Figure imgf000182_0001
1H NMR (400 MHz, methanol-d4) δ ppm 1.7 (m, 2H), 1.9 (m, 10H), 2.3 (m, 1H), 2.4 (m, 3H), 2.5 (s, 3H), 3.2 (m, 1H), 3.3 (m, 3H), 3.5 (m, 1H), 4.2 (m, J=8.9, 4.6Hz, 1H), 4.7 (m, 1H), 7.2 (m, 2H), 7.2 (m, 4H), 7.4 (m, 5H), 7.5 (m, 1H).
Example 168 5-r(442-r(1R.5S)-3-(2-methyl-1 H-benzimidazol-1 -vn-8-azabicvclor3.2.1loct-8- yllethyl)-4-phenyl-1-piperidinyl)carbonyll-2-pyridinylamine
Figure imgf000182_0002
1H NMR (400 MHz, methanol-d4) δ ppm 1.7 (m, 2H), 2.0 (m, 10H), 2.3 (m, 5H), 2.5 (m, 3H), 2.9 (m, 2H), 3.3 (m, 3H), 3.9 (m, 2H), 4.7 (m, 1H), 6.6 (d, J=8.6Hz, 1H), 7.2 (m, 2H), 7.2 (m, 1H), 7.4 (m, 5H), 7.5 (m, 2H), 8.0 (d, J=2.1Hz, 1H). Example 169 1 -rd R.5SV842414(2,6-dimethoxy-3-pyridinvn carbonvπ-4-phenyl-4- piperidinyl)ethvD-8-azabicvclor3.2.11oct-3-vπ-2-methyl-1 H-benzimidazole
Figure imgf000183_0001
1H NMR (400 MHz, methano -4) δ ppm 1.7 (m, 2H), 1.9 (m, 10H), 2.2 (m, 1H), 2.4 (m, 4H), 2.5 (m, 3H), 3.2 (m, 1H), 3.3 (m, 2H), 3.4 (m, 1H), 4.0 (m, 6H), 4.1 (m, 1 H), 4.7 (m, 1 H), 6.4 (d, J=7.8Hz, 1 H), 7.2 (m, 2H), 7.2 (t, J=6.4Hz, 1 H), 7.4 (m, 5H), 7.5 (m, 2H).
Example 171 methyl 44344424(1 R,5S)-342-methyl-1 H-benzimidazol-1 -yl)-8- azabicvclor3.2.1loct-8-vnethyl)-4-phenyl-1 -pjperidinyl )-3-oxopropynphenyl ether
Figure imgf000183_0002
1H NMR (400 MHz, methanol-d4) δ ppm 1.4 (m, 1H), 1.7 (m, 3H), 1.9 (m, 8H), 2.1 (m, 1H), 2.4 (m, 3H), 2.5 (s, 3H), 2.8 (m, 3H), 3.1 (m, 2H), 3.3 (m, 2H), 3.6 (m, 2H), 3.7 (d, J=12.8Hz, 3H), 3.9 (m, 1H), 4.7 (m, 1H), 6.8 (m, 2H), 7.1 (m, 2H), 7.2 (m, 2H), 7.4 (m, 6H), 7.5 (m, 1H). Example 172 2-methyl-1 -((1 R.5SV84241 -(4-nitrobenzoyl)-4-phenyl-4-piperidinvπethyl)-8- azabicvclor3.2.11oct-3-ylV1 H-benzimidazole
Figure imgf000184_0001
1H NMR (400 MHz, methanol-d4) δ ppm 1.7 (d, J=7.8Hz, 2H), 2.0 (d, J=12.5Hz, 8H), 2.5 (d, J=7.1 Hz, 3H), 2.7 (s, 3H), 2.8 (m, J=13.6Hz, 2H), 3.1 (s, 1 H), 3.3 (m, 3H), 3.5 (s, 2H), 4.2 (m, 1 H), 4.8 (d, J=31.8Hz, 1H), 7.2 (m, 3H), 7.4 (m, 8H), 7.7 (m, 1 H), 8.3 (d, J=8.9Hz, 1H).
Example 173 1 -((1 R.5S)-842-n -(4-ethylbenzoyl)-4-phenyl-4-ρiperidinyl1ethyl)-8- azabicyclor3.2.noct-3-yl)-2-methyl-1 H-benzimidazole
Figure imgf000184_0002
1H NMR (400 MHz, methanol-d4) δ ppm 1.3 (m, 3H), 1.7 (m, 2H), 1.9 (m, 8H), 2.2 (m, 1 H), 2.4 (m, 4H), 2.5 (s, 3H), 2.7 (m, 4H), 3.3 (m, 3H), 3.6 (m, 1 H), 4.1 (m, 1H), 4.7 (m, 1 H), 7.2 (m, 2H), 7.2 (m, 1 H), 7.3 (m, 3H), 7.4 (m, 6H), 7.5 (m, 1H). Example 175 1 -((1 R.5SV84241 -(4-chloro-2-methoxybenzov0-4-phenyl-4-piperidinyl1ethylV- 8-azabicvclor3.2.1loct-3-yl)-2-methyl-1 H-benzimidazole
Figure imgf000185_0001
1H NMR (400 MHz, methanol-d4) δ ppm 1.7 (m, 2H), 1.9 (m, 10H), 2.2 (m, 1 H), 2.4 (m, 3H), 2.5 (m, 3H), 3.1 (m, 2H), 3.3 (m, 3H), 3.8 (m, J=57.4Hz, 3H), 4.1 (m, 1H), 4.7 (m, 1H), 7.0 (m, 1H), 7.1 (m, 2H), 7.2 (m, 2H), 7.3 (m, 1 H), 7.4 (m, 5H), 7.5 (m, 1 H).
Example 178 2-methyl-1 -((1 R.5S V84241 -(2-methyl-3-phenylpropanovn-4-phenyl-4- piperidinvπethyl)-8-azabicvclor3.2.11oct-3-vD-1 H-benzimidazole
Figure imgf000185_0002
1H NMR (400 MHz, methanol-d4) δ ppm 1.1 (m, J=16.8, 6.8Hz, 3H),
1.4 (m, 1 H), 1.6 (m, 4H), 1.9 (m, 8H), 2.1 (m, J=69.7, 13.7Hz, 2H), 2.4 (m, 3H), 2.8 (m, 3H), 3.1 (m, 1 H), 3.2 (m, 2H), 3.4 (m, 1 H), 3.7 (m, 2H), 4.1 (m, J=13.6Hz, 1 H), 4.7 (m, 1 H), 7.0 (m, 1 H), 7.1 (m, 1 H), 7.2 (m, 5H), 7.4 (m, 6H),
7.5 (m, 1 H). Example 179 2-methyl-1-r(1 R.5S)-8-(244-phenyl-1-r(3EV4-phenyl-3-butenoyll-4- piperidinyl)ethylV8-azabicvclor3.2.noct-3-yl1-1 H-benzimidazole
Figure imgf000186_0001
1H NMR (400 MHz, methanol-d4) δ ppm 1.7 (m, 2H), 1.9 (m, 11 H), 2.4
(m, 5H), 2.5 (s, 3H), 3.2 (m, 1 H), 3.4 (m, 3H), 3.8 (m, 1 H), 4.0 (m, 1H), 4.7 (m, 1 H), 6.3 (m, 1 H), 6.5 (d, J=16.1 Hz, 1 H), 7.2 (m, 2H), 7.3 (m, 3H), 7.4 (m, 8H), 7.5 (m, 1 H).
Example 181
14(1 R.5S)-842-(1 f1 -(4-chlorophenyl)cvclopropyπ carbonyll-4-phenyl-4- piperidinvπethvH-8-azabicvclo r3.2.11oct-3-yll-2-methyl-1 H-benzimidazole
Figure imgf000186_0002
1H NMR (400 MHz, methanol-d4) δ ppm 1.4 (m, 4H), 1.7 (m, 4H), 1.9 (m, 8H), 2.1 (s, 1 H), 2.3 (m, 1 H), 2.4 (m, 3H), 2.5 (s, 3H), 3.2 (m, 3H), 3.8 (m, 1 H), 4.0 (m, 1 H), 4.7 (m, 1 H), 7.2 (m, 4H), 7.4 (m, 8H), 7.5 (m, 1 H). Example 183 2-methyl-1 (1 R.5S)-84244-phenyl-1 -r4-(trifluoromethvnbenzoyll-4- piperidinyl)ethvπ-8-azabicvclor3.2.noct-3-vn-1 H-benzimidazole
Figure imgf000187_0001
1H NMR (400 MHz, methanol-d4) δ ppm 1.7 (m, 2H), 1.9 (m, 10H), 2.2
(m, 1 H), 2.4 (m, 4H), 2.5 (m, 3H), 3.3 (m, 4H), 4.2 (m, J=8.9, 4.6Hz, 1H), 4.7 (m, 1 H), 7.2 (m, 2H), 7.2 (m, 1 H), 7.4 (m, 5H), 7.5 (m, 1 H), 7.6 (d, J=7.8Hz, 2H), 7.8 (d, J=7.8Hz, 2H).
Example 326A
44(4424(1 R.5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8-azabicvclor3.2.1 loct-8- vnethyl|-4-phenyl-1-piperidinyl)carbonyl1-2-imidazolidinone
Figure imgf000187_0002
1H NMR (400 MHz, methanol-d4) δ ppm 1.7 (m, 2H), 1.9 (m, 12H), 2.3 (m, 3H), 2.4 (m, 2H), 2.5 (s, 3H), 3.2 (m, 4H), 3.5 (m, 1 H), 3.6 (m, 1 H), 3.8 (m, 1 H), 4.0 (m, 1 H), 4.7 (m, 1 H), 7.2 (m, 2H), 7.2 (m, 1 H), 7.4 (m, 5H), 7.5 (m, 1 H).
Example 326B 1H NMR (300 MHz, CD3OD) δ ppm 1.97-2.45 (m, 12H), 2.62 (s, 3H),
2.70-2.93 (m, 5H), 3.12 (m, 1 H), 3.42 (m, 1H), 4.02-4.20 (m, 3H), 5.35 (m, 1 H), 7.23 (m, 1 H), 7.33-7.44 (m, 5H), 7.62 (m, 2H), 8.73 (m, 3H). Example 249 1H NMR (300 MHz, CD3OD) δ 7.63-8.00 (m, 3H), 7.49-7.59 (m, 1 H), 7.36-7.49 (m, 5H), 7.14-7.33 (m, 3H), 4.68-4.83 (m, 1H), 4.16-4.30 (m, 1 H), 3.36-3.51 (m, 2H, under methanol), 3.11-3.28 (m, 1 H), 2.56 (s, 3H), 2.34-2.51 (m, 3H), 2.23-2.34 (m, 1H), 1.85-2.01 (m, 10H), 1.59-1.77 (m, 2H), 1.18-1.38 (m, 4H).
Example 236 1H NMR (300 MHz, CD3OD) δ 7.64-7.98 (m, 3H), 7.48-7.59 (m, 1 H), 7.35-7.47 (m, 5H), 7.16-7.31 (m, 3H), 4.67-4.82 (m, 1 H), 4.13-4.30 (m, 1 H), 3.35-3.50 (m, 4H, under methanol), 3.11-3.27 (m, 1 H), 2.55 (s, 3H), 2.36-2.52 (m, 3H), 2.23-2.36 (m, 1H), 1.83-2.11 (m, 10H), 1.64-1.75 (m, 2H), 1.31 (s, 1 H), 0.98-1.15 (m, 7H).
Example 21
1H NMR (300 MHz, CD3OD) δ 7.71-7.86 (m, 2H), 7.55-7.68 (m, 2H), 7.40-7.55 (m, 4H), 7.27-7.40 (m, 1 H), 5.22-5.46 (m, 1 H), 4.31-4.46 (d, J=12.25 Hz, 1 H), 4.03-4.28 (m, 2H), 3.99 (s, 2H), 3.77-3.97 (m, 2H), 3.42-3.61 (m, 1 H), 3.35 (s, 3H), 2.87-3.02 (m, 2H), 2.83 (s, 3H), 2.66-2.79 (m, 2H), 2.33- 2.52 (m, 3H), 2.10-2.33 (m, 7H), 1.72-2.08 (m, 2H), 1.40 (s, 1 H), 1.19-1.36 (m, 5H).
Example 252 1H NMR (300 MHz, CD3OD) δ 7.49-7.59 (m, 1 H), 7.33-7.49 (m, 5H), 7.12-7.31 (m, 3H), 4.67-4.84 (m, 1 H), 3.97-4.12 (m, 1 H), 3.76-3.89 (m, 1 H), 3.34-3.40 (m, 1 H, under methanol), 3.12-3.26 (m, 1 H), 2.65 (s, 3H), 2.51-2.61 (m, 5H), 2.36-2.51 (m, 2H), 2.22-2.36 (m, 2H), 1.74-2.12 (m, 10H), 1.61-1.74 (m, 2H), 1.21-1.32 (d, J=1.69 Hz, 6H).
Example 253
1H NMR (300 MHz, CD3OD) δ 7.48-7.61 (m, 1 H), 7.14-7.48 (m, 13H), 5.03-5.15 (m, 1 H), 4.66-4.82 (m, 1 H), 3.91-4.09 (m, 1 H), 3.57-3.77 (m, 1 H), 3.00-3.29 (m, 2H), 2.71-2.95 (m, 2H), 2.62-2.71 (m, 6H), 2.57 (s, 3H), 2.32- 2.51 (m, 2H), 2.08-2.30 (m, 1H), 1.60-2.08 (m, 10H).
Example 254 1H NMR (300 MHz, CD3OD) δ 7.50-7.59 (m, 1 H), 7.34-7.50 (m, 5H),
7.14-7.31 (m, 3H), 4.67-4.83 (m, 1 H), 4.33-4.52 (bs, 1 H), 3.92-4.15 (bs, 1 H), 3.48-3.70 (bs, 1 H), 3.08-3.27 (bs, 1 H), 2.62-2.70 (m, 6H), 2.51-2.62 (m, 3H), 2.35 (s, 3H), 1.78-2.08 (m, 8H), 1.55-1.73 (m, 4H).
Example 255
1H NMR (300 MHz, CD3OD) δ 7.32-7.60 (m, 6H), 7.11-7.32 (m, 3H), 4.69-4.84 (m, 1 H), 3.34-3.41 (m, 2H, under methanol), 2.66 (s, 1 H), 2.56 (s, 3H), 2.36-2.52 (m, 2H), 2.21-2.35 (m, 2H), 1.49-2.21 (m, 18H).
Example 256
1H NMR (300 MHz, CD3OD) δ 7.33-7.59 (m, 6H), 7.12-7.31 (m, 3H), 4.71-4.85 (m, 1 H), 3.84-4.15 (m, 1 H), 3.34-3.50 (m, 2H, under methanol), 2.63-2.75 (m, 7H), 2.56 (s, 3H), 2.35-2.52 (m, 2H), 2.20-2.35 (m, 2H), 1.49- 2.10 (m, 17H), 1.28 (s, 2H).
Example 257 1H NMR (300 MHz, CD3OD) δ 7.33-7.59 (m, 6H), 7.13-7.31 (m, 3H), 4.66-4.85 (m, 1 H), 4.13-4.25 (m, 1 H), 3.94-4.13 (m, 1 H), 3.71-3.86 (m, 1 H), 3.35-3.41 (m, 1 H, under methanol), 3.09-3.27 (m, 1 H), 2.64-2.71 (m, 5H), 2.53-2.64 (m, 4H), 2.20-2.53 (m, 5H), 1.74-2.12 (m, 8H), 1.63-1.74 (m, 2H), 1.18-1.27 (m, 3H).
Example 258 1H NMR (300 MHz, CD3OD) δ 7.35-7.59 (m, 6H), 7.13-7.32 (m, 3H), 4.67-4.85 (m, 1 H), 3.98-4.32 (m, 1 H), 3.35-3.63 (m, 1 H, under methanol),
2.66 (s, 6H), 2.56 (s, 3H), 2.36-2.52 (m, 2H), 2.24-2.36 (m, 2H), 1.77-2.09 (m, 10H), 1.60-1.77 (m, 4H), 1.30 (s, 1 H), 0.77-0.96 (t, J=7.26 Hz, 6H). Example 260 1H NMR (300 MHz, CD3OD) δ 7.50-7.61 (m, 1 H), 7.13-7.50 (m, 13H), 4.62-4.81 (m. 1 H), 3.89-4.13 (m, 1H), 3.69-3.89 (m, 1H), 3.12-3.31 (m, 2H), 2.62-2.71 (m, 7H), 2.56 (s, 3H), 2.28-2.47 (m, 2H), 2.06-2.27 (m, 1 H), 1.73- 2.03 (m, 5H), 1.51-1.73 (m, 7H).
Example 262 1H NMR (300 MHz, CD3OD) δ 7.50-7.61 (m, 1H), 7.15-7.50 (m, 17H), 4.71-4.84 (m, 1 H), 4.48 (s, 2H), 4.06-4.24 (m, 1 H), 3.58-3.75 (m, 1 H), 3.35- 3.52 (m, 2H), 2.59-2.80 (m, 9H), 2.50 (s, 4H), 2.09-2.21 (m, 2H), 1.90-2.08 (m, 5H), 1.71-1.83 (m, 2H).
Example 263 1H NMR (300 MHz, CD3OD) δ 7.51-7.60 (m, 1 H), 7.10-7.51 (m, 13H),
4.61-4.79 (m, 1H), 3.38-4.14 (m, 1H), 3.68-3.88 (m, 1H), 3.14-3.29 (m, 2H), 2.58-2.72 (m, 8H), 2.53 (s, 3H), 2.28-2.48 (m, 2H), 2.06-2.28 (m, 1 H), 1.75- 2.03 (m, 5H), 1.55-1.73 (m, 6H).
Example 264
1H NMR (300 MHz, CD3OD) δ 7.73-7.96 (dd, 1 H, J=43.02, 7.44), 7.49- 7.68 (m, 2H), 7.34-7.48 (m, 5H), 7.12-7.34 (m, 3H), 4.67-4.83 (m, 1 H), 4.12- 4.31 (m, 1H), 3.34-3.44 (m, 3H, under methanol), 3.12-3.28 (m, 1 H), 2.56 (s, 3H), 2.35-2.52 (m, 3H), 2.23-2.35 (m, 1H), 1.83-2.12 (m, 11H), 1.62-1.78 (m, 2H), 1.10-1.21 (d, J=6.23 Hz, 2H).
Example 265 1H NMR (300 MHz, CD3OD) δ 7.985-8.04 (m, 2H), 7.62-7.77 (m, 2H), 7.49-7.61 (m, 1H), 7.33-7.48 (m, 5H), 7.12-7.33 (m, 3H), 4.66-4.84 (m, 1H), 4.09-4.27 (m, 1 H), 3.64-3.80 (t, J=5.8 Hz, 4H), 3.46-3.64 (m, 1 H), 2.61-2.73 (m, 7H), 2.51-2.60 (m, 3H), 2.35-2.50 (m, 3H), 2.19-2.35 (m, 1 H), 1.79-2.15 (m, 9H), 1.57-1.79 (m, 3H), 1.19-1.41 (m, 3H). Example 235 1H NMR (300 MHz, CD3OD) δ 7.67-7.94 (m, 3H), 7.48-7.60 (m, 1 H), 7.34-7.48 (m, 5H), 7.13-7.33 (m, 3H), 4.66-4.83 (m, 1H), 4.16-4.29 (m, 1H), 3.33-3.49 (m, 4H, under methanol), 3.12-3.28 (m, 1 H), 2.57-2.61 (m, 1 H), 2.51-2.57 (m, 4H), 2.36-2.51 (m, 3H), 2.23-2.36 (m, 1H), 1.83-2.09 (m, 12H), 1.61-1.76 (m, 2H).
Example 237 1H NMR (300 MHz, CD3OD) δ 7.66-7.94 (m, 3H), 7.48-7.58 (m, 1 H),
7.35-7.48 (m, 5H), 7.13-7.33 (m, 3H), 4.68-4.83 (m, 1H), 4.15-4.29 (m, 1H), 3.34-3.46 (m, 6H, under methanol), 3.16-3.28 (m, 4H), 3.02-3.14 (m, 2H), 2.55 (s, 3H), 2.35-2.50 (m, 3H), 2.24-2.35 (m, 1 H), 1.83-2.13 (m, 11 H), 1.63- 1.77 (m, 2H).
Example 288 1H NMR (300 MHz, CD3OD) δ 7.67-7.94 (m, 3H), 7.51-7.59 (m, 1 H), 7.38-7.51 (m, 2H), 7.16-7.30 (m, 4H), 6.97-7.08 (m, 1 H), 4.68-4.82 (m, 1 H), 4.13-4.29 (m, 1H), 3.35-3.54 (m, 3H, under methanol), 2.40-2.81 (m, 12H), 1.86-2.16 (m, 9H), 1.67-1.80 (m, 2H), 1.23-1.33 (m, 2H).
Example 364 1H NMR (300 MHz, CD3OD) δ 7.65-7.97 (m, 3H), 7.51-7.62 (m, 1 H), 7.38-7.51 (m, 2H), 7.13-7.32 (m, 4H), 6.94-7.12 (m, 1H), 4.68-4.82 (m, 1H), 4.08-4.30 (m, 1 H), 3.34-3.65 (m, 4H, under methanol), 2.84-3.06 (m, 2H), 2.67 (s, 3H), 2.44-2.61 (m, 4H), 2.32-2.44 (m, 1 H), 2.16-2.32 (m, 2H), 1.77- 2.16 (m, 9H), 1.27-1.39 (m, 2H), 1.00-1.17 (m, 3H).
Example 291 1H NMR (300 MHz, CD3OD) δ 7.68-7.96 (m, 3H), 7.50-7.59 (m, 1 H),
7.38-7.50 (m, 2H), 7.14-7.33 (m, 4H), 6.95-7.11 (m, 1 H), 4.68-4.83 (m, 1 H), 4.08-4.32 (m, 1 H), 3.34-3.61 (m, 5H, under methanol), 2.61-2.71 (m, 4H), 2.57 (s, 3H), 2.08-2.31 (m, 2H), 1.84-2.08 (m, 7H), 1.69-1.84 (m, 1 H), 1.30 (s, 4H), 0.39-0.67 (m, 4H).
Example 292 1H NMR (300 MHz, CD3OD) δ 7.64-7.98 (m, 3H), 7.50-7.58 (m, 1 H), 7.37-7.50 (m, 2H), 7.11-7.31 (m, 4H), 6.95-7.09 (m, 1 H), 4.65-4.81 (m, 1 H), 4.09-4.27 (m, 1 H), 3.36-3.56 (m, 4H, under methanol), 3.08-3.26 (m, 1 H), 2.57 (s, 3H), 2.31-2.51 (m, 4H), 2.16-2.31 (m, 1 H), 1.78-2.13 (m, 11 H), 1.64- 1.78 (m, 2H), 0.96-1.11 (m, 6H).
Example 308 1H NMR (300 MHz, CD3OD) δ 7.63-7.93 (m, 3H), 7.49-7.59 (m, 1 H), 7.38-7.48 (m, 1 H), 7.13-7.35 (m, 5H), 7.03-7.13 (m, 1 H), 4.67-4.83 (m, 1 H), 4.15-4.29 (m, 1 H), 3.34-3.41 (m, 5H, under methanol), 3.12-3.29 (m, 1 H), 2.52-2.61 (m, 6H), 2.40-2.52 (m, 3H), 2.34-2.40 (m, 4H), 2.19-2.34 (m, 1 H), 1.83-2.11 (m, 9H), 1.63-1.75 (m, 2H).
Example 309 1H NMR (300 MHz, CD3OD) δ 7.71-7.93 (m, 3H), 7.53-7.59 (m, 1 H), 7.40-7.49 (m, 2H), 7.17-7.29 (m, 4H), 6.97-7.08 (m, 1 H), 4.11-4.28 (m, 1 H), 3.48-3.61 (m, 1 H), 3.34-3.48 (m, 3H, under methanol), 3.12-3.30 (m, 1 H), 2.84-3.03 (m, 2H), 2.67 (s, 3H), 2.49-2.62 (m, 3H), 2.31-2.46 (m, 1 H), 2.16- 2.31 (m, 2H), 1.80-2.15 (m, 9H), 1.27-1.41 (m, 3H), 1.01-1.13 (m, 3H).
Example 310
1H NMR (300 MHz, CD3OD) δ 7.67-7.93 (m, 3H), 7.51-7.57 (m, 1 H), 7.40-7.45 (m, 1 H), 7.17-7.33 (m, 5H), 7.05-7.12 (m, 1 H), 4.69-4.84 (m, 1 H), 4.11-4.31 (m, 1 H), 3.35-3.48 (m, 2H, under methanol), 3.13-3.28 (m, 1 H), 2.79-2.94 (m, 2H), 2.67 (s, 3H), 2.57 (s, 2H), 2.41-2.53 (m, 2H), 2.33-2.41 (m, 3H), 2.20-2.33 (m, 1H), 1.82-2.11 (m, 9H), 1.63-1.77 (m, 2H), 1.39-1.57 (m, 2H), 0.80-0.96 (m, 3H). Example 311 1H NMR (300 MHz, CD3OD) δ 7.68-7.97 (m, 3H), 7.50-7.59 (m, 1 H), 7.38-7.48 (m, 1 H), 7.15-7.36 (m, 6H), 7.04-7.15 (m, 1 H), 4.69-4.83 (m, 1 H), 4.14-4.34 (m, 1 H), 3.34-3.48 (m, 2H, under methanol), 3.13-3.26 (m, 1 H), 2.67 (s, 2H), 2.57 (s, 3H), 2.42-2.51 (m, 2H), 2.33-2.42 (m, 3H), 2.13-2.33 (m, 2H), 1.81-2.13 (m, 9H), 1.66-1.79 (d, J= 7.76 Hz, 2H), 1.31 (s, 3H), 0.44-0.65 (m, 4H).
Example 312 1H NMR (300 MHz, CD3OD) δ 7.66-7.94 (m, 3H), 7.51-7.56 (m, 1 H),
7.39-7.45 (m, 1 H), 7.16-7.33 (m, 5H), 7.05-7.13 (m, 1 H), 4.72-4.83 (m, 1 H), 4.13-4.31 (m, 1 H), 3.35-3.49 (m, 3H, under methanol), 3.10-3.27 (m, 1 H), 2.68 (s, 2H), 2.55 (s, 3H), 2.34-2.51 (m, 6H), 2.20-2.34 (m, 1 H), 1.85-2.12 (m, 10H), 1.65-1.77 (m, 2H), 1.31 (s, 1 H), 0.97-1.12 (m, 6H).
Example 293 1H NMR (300 MHz, CD3OD) δ 8.08 (s, 1 H), 7.61-7.76 (m, 2H), 7.50- 7.58 (m, 1 H), 7.36-7.49 (m, 2H), 7.13-7.31 (m, 4H), 6.94-7.07 (m, 1 H), 4.68- 4.82 (m, 1 H), 4.08-4.22 (m, 1H), 3.52-3.67 (m, 1 H), 3.35-3.51 (m, 4H, under methanol), 2.52-2.62 (m, 6H), 2.34-2.52 (m, 3H), 2.17-2.30 (m, 1 H), 1.81-2.14 (m, 11 H), 1.64-1.77 (m, 2H).
Example 273 1H NMR (300 MHz, CD3OD) δ 7.66-7.94 (m, 3H), 7.49-7.57 (m, 1H), 7.35-7.49 (m, 5H), 7.23-7.33 (m, 1 H), 7.14-7.23 (m, 2H), 4.67-4.83 (m, 1 H), 4.16-4.30 (m, 1 H), 3.34-3.43 (m, 4H, under methanol), 3.11-3.26 (m, 1 H), 2.86-3.03 (m, 2H), 2.55 (s, 3H), 2.36-2.52 (m, 3H), 2.22-2.36 (m, 1 H), 1.86- 2.11 (m, 11 H), 1.64-1.76 (m, 2H), 1.01-1.14 (dd, J=16.03, 7.5 Hz, 3H,).
Example 274
1H NMR (300 MHz, CD3OD) δ 7.65-7.94 (m, 3H), 7.48-7.60 (m, 1 H), 7.35-7.48 (m, 5H), 7.23-7.30 (m, 1 H), 7.15-7.23 (m, 2H), 4.66-4.82 (m, 1 H), 4.16-4.27 (m, 1 H), 3.34-3.46 (m, 4H, under methanol), 3.10-3.27 (m, 1 H), 2.77-2.92 (m, 2H), 2.55 (s, 3H), 2.35-2.51 (m, 3H), 2.21-2.35 (m, 1 H), 1.84- 2.09 (m, 11H), 1.61-1.75 (m, 2H), 1.37-1.56 (m, 2H), 0.81-0.94 (dd, J=16.10, 7.48 Hz, 3H).
Example 275 1H NMR (300 MHz, CD3OD) δ 7.68-7.98 (m, 3H), 7.48-7.60 (m, 1 H), 7.35-7.48 (m, 5H), 7.24-7.35 (m, 1H), 7.14-7.24 (m, 2H), 4.66-4.82 (m, 1H), 4.16-4.30 (m, 1H), 3.34-3.43 (m, 6H, under methanol), 2.55 (s, 3H), 2.35-2.51 (m, 2H), 2.13-2.35 (m, 2H), 1.83-2.12 (m, 9H), 1.65-1.76 (m, 2H), 1.30 (s, 2 H), 0.41-0.61 (m, 3H).
Example 210 1H NMR (300 MHz, CD3OD) δ 7.91-8.00 (m, 1H), 7.87 (s, 1H), 7.64- 7.74 (m, 2H), 7.50-7.58 (m, 1 H), 7.36-7.49 (m, 5H), 7.22-7.32 (m, 1 H), 7.14- 7.22 (m, 2H), 4.69-4.82 (m, 1 H), 4.09-4.30 (m, 1 H), 3.47-3.66 (m, 1 H), 3.34- 3.39 (m, 3H, under methanol), 2.50-2.59 (m, 6H), 2.36-2.50 (m, 3H), 2.22- 2.35 (m, 1 H), 1.83-2.11 (m, 10H), 1.65-1.76 (m, 2H), 1.30 (s, 2 H).
Example 294
1H NMR (300 MHz, CD3OD) δ 7.74-7.96 (dd, J=38.00, 7.77 Hz, 1 H), 7.49-7.68 (m, 2H), 7.35-7.49 (m, 2H), 7.12-7.32 (m, 4H), 6.94-7.09 (m, 1 H), 4.66-4.83 (m, 1 H), 4.12-4.25 (m, 1 H), 3.34-3.54 (m, 3H, under methanol), 3.13-3.28 (m, 1 H), 2.56 (s, 3H), 2.30-2.52 (m, 3H), 2.16-2.30 (m, 1 H), 1.79- 2.09 (m, 9H), 1.64-1.78 (m, 2H), 1.26-1.39 (m, 1H), 1.09-1.19 (d, .7=6.13 Hz, 3H).
Example 295 1H NMR (300 MHz, CD3OD) δ 7.99-8.10 (m, 1 H), 7.86-7.99 (m, 1 H), 7.50-7.59 (m, 1H), 7.36-7.50 (m, 3H), 7.13-7.30 (m, 4H), 6.95-7.07 (m, 1H), 4.67-4.83 (m, 1H), 4.13-4.25 (m, 1H), 3.42-3.59 (m, 1H), 3.34-3.41 (m, 2H, under methanol), 2.56 (s, 3H), 2.30-2.50 (m, 3H), 2.18-2.30 (m, 1 H), 1.80- 2.12 (m, 10H), 1.65-1.80 (m, 2H), 1.22-1.42 (m, 1 H), 1.09-1.19 (d, J=6.23 Hz, 3H).
Example 296 1H NMR (300 MHz, CD3OD) δ 7.89-8.00 (m, 1 H), 7.61-7.88 (m, 2H), 7.50-7.60 (m, 1 H), 7.34-7.50 (m, 2H), 7.12-7.34 (m, 4H), 6.94-7.07 (m, 1 H), 4.64-4.83 (m, 1 H), 4.10-4.27 (m, 1H), 3.34-3.54 (m, 3H, under methanol), 3.12-3.27 (m, 1 H), 2.56 (s, 3H), 2.30-2.51 (m, 3H), 2.16-2.30 (m, 1 H), 1.79- 2.12 (m, 11 H), 1.63-1.79 (m, 2H), 1.23-1.36 (m, 2H).
Example 297 1H NMR (300 MHz, CD3OD) δ 7.98-8.04 (m, 1 H), 7.87-7.96 (m, 1 H), 7.50-7.57 (m, 1 H), 7.38-7.48 (m, 3H), 7.15-7.28 (m, 4H), 6.96-7.05 (m, 1 H), 4.66-4.83 (m, 1 H), 4.13-4.24 (m, 1 H), 3.64-3.76 (m, 2H), 3.41-3.54 (m, 2H), 3.30-3.34 (m, 3H), 3.18-3.29 (m, 1 H), 2.543 (s, 3H), 2.30-2.51 (m, 3H), 2.15- 2.29 (m, 1 H), 1.84-2.09 (m, 9H), 1.66-1.76 (m, 2H), 1.27-1.32 (m, 1 H).
Example 298
1H NMR (300 MHz, CD3OD) δ 7.67-7.95 (m, 3H), 7.50-7.58 (m, 1 H), 7.39-7.46 (m, 2H), 7.15-7.27 (m, 4H), 6.96-7.06 (m, 1 H), 4.65-4.83 (m, 1 H),
4.11-4.26 (m, 1H), 3.63-3.80 (m, 2H), 3.37-3.54 (m, 2H), 3.29-3.34 (m, 3H),
3.11-3.27 (m, 1 H), 2.54 (s, 3H), 2.31-2.51 (m, 3H), 2.17-2.29 (m, 1 H), 1.86-
2.09 (m, 9H), 1.64-1.77 (m, 2H), 1.27-1.33 (m, 1H).
Example 315
1H NMR (300 MHz, CD3OD) δ 7.64-7.97 (m, 3H), 7.50-7.56 (m, 1 H), 7.38-7.45 (m, 1 H), 7.14-7.33 (m, 5H), 7.04-7.12 (m, 1H), 4.67-4.83 (m, 1H), 4.16-4.27 (m, 1 H), 3.37-3.46 (m, 1 H), 3.30-3.34 (m, 5H), 3.11-3.27 (m, 1 H), 2.54 (s, 3H), 2.41-2.51 (m, 2H), 2.33-2.40 (m, 3H), 2.22-2.32 (m, 1H), 1.81- 2.10 (m, 10H), 1.64-1.74 (m, 2H), 1.27-1.35 (m, 1 H). Example 278 1H NMR (300 MHz, CD3OD) δ 8.00-8.08 (m, 1 H), 7.85-7.98 (br.s, 1 H), 7.50-7.58 (m, 1 H), 7.36-7.46 (m, 1 H), 7.36-7.46 (m, 6H), 7.23-7.32 (m, 1 H), 7.14-7.22 (m, 2H), 4.67-4.83 (m, 1 H), 4.15-4.28 (m, 1 H), 3.18-3.58 (m, 7H), 2.51-2.57 (m, 3H), 2.34-2.50 (m, 3H), 1.81-2.09 (m, 10H), 1.62-1.75 (m, 2H), 1.26-1.33 (m, 1 H).
Example 279 1H NMR (300 MHz, CD3OD) δ 7.94-8.01 (m, 1H), 7.79-7.92 (m, 1H), 7.51-7.57 (m, 1 H), 7.37-7.47 (m, 6H), 7.23-7.31 (m, 1 H), 7.16-7.22 (m, 2H), 4.68-4.81 (m, 1 H), 4.16-4.29 (m, 1 H), 3.42-3.59 (m, 2H), 3.20-3.41 (m, 7H), 2.52-2.60 (m,4H), 2.25-2.49 (m, 3H), 1.85-2.09 (m, 8H), 1.66-1.75 (m, 1 H), 1.28-1.34 (s, 2H).
Example 280
1H NMR (300 MHz, CD3OD) δ 7.95-8.02 (m, 1H), 7.82-7.93 (m, 1H), 7.51-7.56 (m, 1H) 7.37-7.47 (m, 6H), 7.23-7.30 (m, 1H), 7.15-7.23 (m, 2H), 4.66-4.83 (m, 1 H), 4.15-4.29 (m, 1 H), 3.17-3.58 (m, 8H), 2.86-2.99 (q, 2H), 2.52-2.56 (s, 3H), 2.35-2.50 (m, 3H), 1.81-2.10 (m, 8H), 1.63-1.74 (q, 2H), 1.27-1.34 (s, 1 H), 1.01-1.13 (t, 3H).
Example 281 1H NMR (300 MHz, CD3OD) δ 7.95-8.02 (m, 1H), 7.83-7.94 (br s, 1H), 7.50-7.57 (m, 1H), 7.37-7.48 (m, 6H), 7.23-7.30 (m, 1H), 7.15-7.23 (m, 2H), 4.67-4.83 (m, 1 H), 4.16-4.27 (m, 1 H), 3.30-3.33(m, 4H), 2.80-2.89 (m, 2H),
2.54 (s, 3H), 2.35-2.51 (m, 3H), 2.24-2.34 (m, 1 H), 1.84-2.11 (m, 8H), 1.65- 1.76 (m, 2H), 1.40-1.55 (m, 2H), 1.30 (s, 2H), 0.88 (t, J=7.4Hz, 3H).
Example 282 1H NMR (300 MHz, CD3OD) δ 7.98-8.05 (m,.1 H), 7.85-7.96 (m, 1 H),
7.50-7.57 (m, 1H), 7.37-7.50 (m, 6H), 7.22-7.32 (m, 1H), 7.15-7.22 (m, 2H), 4.67-4.83 (m, 1H), 4.16-4.29 (m, 1H), 3.37-3.59 (m, 2H), 3.29-3.34 (m, 4H), 2.54 (s, 3H), 2.36-2.51 (m, 3H), 2.17-2.35 (m, 2H), 1.82-2.10 (m, 8H), 1.64- 1.75 (m, 2H), 1.31 (s, 2H), 0.44-0.62 (m, 4H).
Example 283 1H NMR (300 MHz, CD3OD) δ 7.96-8.03 (m, 1 H), 7.84-7.95 (m, 1 H), 7.50-7.57 (m, 1H), 7.37-7.47 (m, 6H), 7.22-7.30 (m, 1H), 7.15-7.22 (m, 2H), 4.68-4.83 (m, 1H), 4.16-4.28 (m, 1H), 3.18-3.53 (m, 7H), 2.54 (s, 3H), 2.35- 2.51 (m, 3H), 2.24-2.35 (m, 1H), 1.84-2.09 (m, 8H), 1.65-1.75 (m, 2H), 1.28- 1.32 (m, 2H), 1.01-1.09 (d, J=6.4Hz, 6H).
Example 303 1H NMR (300 MHz, CD3OD) δ 7.95-8.02 (m, 1 H), 7.84-7.94 (m, 1 H), 7.50-7.57 (m, 1H), 7.37-7.48 (m, 3H), 7.25-7.28 (m, 1H), 7.14-7.25 (m, 4H), 6.96-7.05 (m, 1H), 4.66-4.82 (m, 1H), 4.12-4.24 (m, 1H), 3.18-3.56 (m, 6H), 2.88-2.98 (q, J=7.3Hz, 2H), 2.4 (s, 3H), 2.31-2.51 (m, 3H), 2.18-2.29 (m, 1 H), 1.83-2.09 (m, 8H), 1.65-1.76 (m, 2H), 1.28-1.32 (m, 1H), 1.08 (t, J=7.3Hz, 3H).
Example 304 1H NMR (300 MHz, CD3OD) δ 7.95-8.02 (m, 1H), 7.83-7.93 (m, 1 H),
7.51-7.57 (m, 1H), 7.38-7.48 (m, 3H), 7.26-7.29 (m, 1H), 7.16-7.26 (m, 3H), 6.97-7.07 (m, 1 H), 4.68-4.83 (m, 1 H), 4.10-4.24 (m, 1 H), 3.37-3.54 (m, 1 H), 3.30-3.54 (m, 4H), 2.80-2.88 (t, J=7.0Hz, 2H), 2.54 (s, 3H), 2.31-2.50 (m, 3H), 2.17-2.30 (m, 1H), 1.83-2.11 (m, 8H), 1.68-1.77 (m, 2H), 1.41-1.55 (m, 2H), 1.30 (m, 3H), 0.88 (t, J=7.0Hz, 3H).
Example 305
1H NMR (300 MHz, CD3OD) δ 7.98-8.05 (m, 1H), 7.86-7.97 (m, 1H),
7.51-7.57 (m, 1 H), 7.39-7.50 (m, 3H), 7.25-7.29 (m, 1 H), 7.16-7.25 (m, 3H), 6.96-7.06 (m, 1H), 4.68-4.82 (m, 1H), 4.13-4.25 (m, 1H), 3.42-3.59 (m, 2H),
3.30-3.34 (m, 4H), 3.19-3.29 (m, 1H), 2.54 (s, 3H), 2.32-2.51 (m, 3H), 2.16- 2.28 (m, 2H), 1.83-2.10 (m, 8H), 1.66-1.77 (m, 2H), 1.30 (s, 1 H), 0.45-0.62 (m, 4H).
Example 306 1H NMR (300 MHz, CD3OD) δ 7.96-8.04 (m, 1 H), 7.86-7.94 (m, 1 H),
7.50-7.56 (m, 1 H), 7.38-7.48 (m, 3H), 7.16-7.28 (m, 4H), 6.97-7.05 (m, 1 H), 4.67-4.82 (m, 1H), 4.13-4.24 (m, 1H), 3.37-3.55 (m, 4H), 3.30-3.34 (m, 4H), 3.18-3.29 (m, 1 H), 2.55 (s, 3H), 2.32-2.49 (m, 3H), 2.19-2.28 (m, 1 H), 1.85- 2.10 (m, 8H), 1.67-1.76 (m, 2H), 1.28-1.32 (m, 1 H), 1.02-1.10 (d, J=6.6Hz, 6H).
Example 284
1H NMR (300 MHz, CD3OD) δ 7.97-8.04 (m, 1H), 7.85-7.97 (m, 1 H),
7.50-7.57 (m, 1H), 7.37-7.48 (m, 6H), 7.23-7.30 (m, 1H), 7.14-7.23 (m, 2H), 4.67-4.82 (m, 1 H), 4.16-4.27 (m, 1 H), 3.63-3.77 (m, 2H), 3.37-3.52 (m, 2H),
3.30-3.34 (m, 3H), 3.18-3.29 (m, 1 H), 2.55 (s, 3H), 2.36-2.50 (m, 3H), 2.23-
2.34 (m, 1 H), 1.83-2.09 (m, 9H), 1.64-1.73 (m, 2H), 1.30 (s, 1 H).
Example 285 1H NMR (300 MHz, CD3OD) δ 7.75-7.94 (m, 3H), 7.50-7.57 (m, 1H),
7.36-7.46 (m, 5H), 7.23-7.30 (m, 1H), 7.14-7.23 (m, 2H), 4.66-4.82 (m, 1H), 4.17-4.28 (m, 1 H), 3.62-3.82 (m, 2H), 3.36-3.47 (m, 2H), 3.30-3.34 (m, 4H), 3.11-3.26 (m, 1 H), 2.54 (s, 3H), 2.37-2.51 (m, 3H), 2.23-2.34 (m, 1 H), 1.85- 2.10 (m, 8H), 1.64-1.74 (m, 2H), 1.30 (s, 1 H).
Example 365 1H NMR (300 MHz, CD3OD) δ 7.81-8.10 (m, 2H), 7.47-7.60 (m, 1H), 7.35-7.47 (m, 5H), 7.14-7.31 (m, 3H), 4.69-4.84 (m, 1H), 4.14-4.31 (m, 1H), 3.35-3.49 (m, 2H, under methanol), 3.11-3.27 (m, 1 H), 2.50-2.64 (m, 6H), 2.36-2.50 (m, 3H), 2.22-2.36 (m, 1 H), 1.82-2.10 (m, 11 H), 1.62-1.75 (m, 2H), 1.11-1.20 (d, J=6.14 Hz, 2H). Example 366 1H NMR (300 MHz, CD3OD) δ 7.64-7.95 (m, 3H), 7.49-7.59 (m, 1H), 7.34-7.48 (m, 2H), 7.10-7.30 (m, 4H), 6.95-7.06 (m, 1H), 4.72-4.83 (m, 1H), 4.11-4.25 (m, 1 H), 3.34-3.53 (m, 5H, under methanol), 3.07-3.29 (m, 1 H), 2.76-2.93 (m, 2H), 2.67 (s, 1 H), 2.42-2.60 (m, 4H), 2.29-2.42 (m, 1 H), 1.74- 2.29 (m, 12H), 1.26-1.56 (m, 3H), 0.80-0.96 (m, 3H).
Example 367 1H NMR (300 MHz, CD3OD) δ 7.65-7.92 (m, 2H), 7.47-7.65 (m, 2H), 7.37-7.47 (m, 1 H), 7.12-7.36 (m, 5H), 7.04-7.12 (m, 1 H), 4.69-4.83 (m, 1 H), 4.08-4.31 (m, 1 H), 3.34-3.47 (m, 3H, under methanol), 3.13-3.28 (m, 3H), 2.32-2.64 (m, 8H), 2.20-2.32 (m, 1H), 1.79-2.13 (m, 9H), 1.64-1.78 (m, 2H), 1.24-1.43 (m, 5H).
Synthesis of Acids
Acid 1 ; 2-methyl-2-(1H-tetraazol-5-yl)propanoic acid
Figure imgf000199_0001
Ethyl 2-methyl-2-(1H-tetraazol-5-yl)propanoate
Figure imgf000199_0002
The title compound was prepared from ethyl 2-cyano-2- methylpropanoate (3.67 g, 26 mmoles) via the literature procedure [J. Org. Chem., 58(15), 4139 (1993)] to give 3.83 g (80%) of pure product as an amber solid. 13C NMR (300 MHz, CDCI3) δ 174.04, 159.73, 62.74, 42.30, 25.74, 14.12. 2-methyl-2-(1 H-tetraazol-5-yl)propanoic acid
Figure imgf000200_0001
Ethyl 2-methyl-2-(1H-tetraazol-5-yl) propanoate (1.50 g, 8.14 mmoles) was dissolved in 8 mL EtOH and treated with 6.7 mL 6N NaOH at ambient temperature for 18h. The reaction mixture was concentrated to dryness and the resultant solid was extracted with EtOH. Inorganics were filtered off and the filtrate were concentrated to give the title compound (1.24 g, 7.94 mmoles, 98%) as a tan solid. 13C NMR (300 MHz, D2O) δ 176.88, 159.60, 41.69, 24.07.
Acid 2: N-(tert-butoxycarbonyl)-3-hydroxy-L-valine
XX
HO f OH /^ o 3-Hydroxy-L-valine (500 mg, 3.75 mmoles) in 10 mL DMF with TEA (1 eq.) was treated with di(terf-butyl)dicarbonate (3.75 mmoles, 1 eq.) for 18h at ambient temperature. The reaction mixture was diluted with water, pH adjusted to 10 with 6 N NaOH, washed with EtOAc, and the aqueous phase was isolated. The aqueous phase was combined with fresh DCM, pH adjusted to 4 with 1 N HCl. The organic phase was isolated, dried over MgSO4, filtered and concentrated to give the title compound (68%) as a clear oil. 1H NMR (300 MHz, CD3OD) δ 4.09 (s, 1H), 1.46 (s, 9H), 1.30 (s, 3H), 1.26 (s, 3H).
Synthesis of Sulfonamide Benzoid Acids via Chlorosulfonylation/amination Procedure Method G - primary sulfonamide, lower sulfonamides
4-chloro-3-(chlorosulfonyl)benzoic acid
Figure imgf000200_0002
At 5-10 °C, to stirred chlorosulfonic acid (200 mL) was added 4- chlorobenzoic acid (78 g, 0.5 mol). The reaction mixture was then brought up to 150~160 °C for 5 hours. After being cooled down to room temperature, the reaction mixture was slowly poured onto a large amount of ice and extracted with ether. The combined organic extracts were washed with ice water and dried over anhydrous magnesium sulfate. Evaporation of solvents afforded 4- chloro-3-(chlorosulfonyl)benzoic acid as a solid (76 g), which was directly used in the next steps.
4-Fluoro-3-(chlorosulfonyl)benzoic acid, 2,6-difluoro-3- (chlorosulfonyl)benzoic acid, 2,6-dichloro-3-(chlorosulfonyl)benzoic acid, 3,4- difluoro-5-(chloro-sulfonyl)benzoic acid, 2,6-methyl-3-(chlorosulfonyl) benzoic acid, 4-bromo-3-(chlorosulfonyl)benzoic acid, 2,6-difluoro-3- (chlorosulfonyl)benzoic acid, 4-methoxy-3-(chlorosulfonyl)benzoic acid, 5- chloro-3-(chloro-sulfonyl)-2-hydroxybenzoic acid, 2-chloro-5-(chloro- sulfonyl)benzoic acid, and 3-(chlorosulfonyl)-44luorobenzoic acid were prepared with the same procedure as above except for varying temperatures and heating time based on substrates. In some cases, the pure product was obtained as a precipitate from the ice quench in which case the product was filtered off and no extraction was necessary.
Synthesis of 3-(aminosulfonyl)-4-fluorobenzoic acid
Figure imgf000201_0001
To -50 mL of liquid ammonia at -78 °C was added 7.0 grams of freshly prepared 4-fluoro-3-(chloro-sulfonyl)benzoic acid. The excess ammonia was then naturally evaporated to dryness overnight at room temperature. The crude solid was dissolved in water (50 mL) and acidified to pH~6 with HCl (cone). After removal of the precipitate by filtration, the filtrate was further acidified to pH ~1. The desired product was precipitated and collected by filtration (5.0 g). ES LC-MS m/z (M-1 )- 218. Acids 16, 22, 31, 37, 43, and 49 were prepared by this same method. Yields and representative data are included in the accompanying tables.
Method H - secondary and tertiary sulfonamides
Figure imgf000202_0001
To the sulfonyl halide (8.00 mmoles) in 6 mL THF was added a 2N solution of the amine (24.0 mmoles, 3 eq.) in THF and the mixture was stirred overnight at ambient temperature. The reaction mixture was concentrated to dryness and partitioned between DCM and H2O. The pH was adjusted to 10 with 6N NaOH and the aqueous phase was isolated. The aqueous phase was acidified to pH 2 with 6N HCl and the reaction mixture was stirred vigorously to give a white precipitate. The precipitate was filtered off, washed with water and air dried to give the desired product. In cases where precipitation did not occur, the aqueous phase was extracted with EtOAc, organic phases were combined, dried over MgSO , filtered, and concentrated to give the desired products. Yields and representative data are included in the accompanying tables.
Table of Carboxylic Acids
Figure imgf000202_0002
Figure imgf000203_0001
Figure imgf000204_0001
Figure imgf000205_0001
Figure imgf000206_0001
Figure imgf000207_0001
Example 368 1-benzoyl-4-(2-(4-r3-(4-methoxybenzylV1.2.4-oxadiazol-5-yllpiDeridin-1- vDethylH-phenylpiperidine
Figure imgf000208_0001
tert-butyl 4-[3-(4-methoxybenzyl)-1,2,4-oxadiazol-5-yl]piperidine-1 -carboxylate
Figure imgf000208_0002
1-(fe/f-Butoxycarbonyl)piperidine-4-carboxylic acid (2.29 g, 10.0 mmoles) in 10 mL DMF was treated with 1 ,1'-carbonyldiimidazole (1.62 g, 10 mmoles, 1 eq.) at ambient temperature for 30 min until CO2 evolution ceased. (1Z)--V-hydroxy-2-(4-methoxyphenyl)ethanimidamide [J. Med. Chem., 36(11), 1529 (1993)] (10.0 mmoles, 1 eq.) was dissolved in 5 mL DMF and added to the reaction mixture. The reaction mixture was heated at 70 °C for 6h then at 120°C for an additional 6h. The reaction mixture was diluted with EtOAc and washed successively with water, 1 N citric acid, saturated aqueous NaHCO3, and brine. The organic phase was isolated, dried over MgSO4, filtered and concentrated to give the title compound as an amber oil. 1H NMR (300 MHz, CDCI3) δ 7.26 (d, 2H, J=8.5Hz), 6.88 (d, 2H, J=8.5Hz), 4.10 (m, 2H), 4.00 (s, 2H), 3.80 (s, 3H), 3.08 (m, 1 H), 2.97-2.90 (m, 2H), 2.04 (m, 2H), 1.87-1.73 (m, 2H), 1.47 (s, 9H). ES-LCMS m/z 395.99 (M+Na).
4-[3-(4-methoxybenzyl)-1,2,4-oxadiazol-5-yl]piperidine
Figure imgf000208_0003
Te/ϊ-butyl 4-[3-(4-methoxybenzyl)-1 ,2,4-oxadiazol-5-yl]piperidine-1 - carboxylate was treated with 10 mL TFA/DCM (1 :1) for 30 min at ambient temperature. The reaction mixture was concentrated and the crude product was crystalized from EtOAc/Et2O, filtered and dried to give the TFA salt of 4- [3-(4-methoxybenzyl)-1 ,2,4-oxadiazol-5-yl]piperidine as a tan solid (1.23g, 3.17mmol, 32%, 3 steps). 1H NMR (300 MHz, DMSO-d6) δ 7.22 (d, 2H, J=8.5Hz), 6.88 (d, 2H, J=8.5Hz), 4.00 (s, 2H), 3.72 (s, 3H), 3.43-3.29 (m, 2H), 3.02 (m, 2H), 2.17 (m, 2H), 1.92-1.80 (m, 2H). ES-LCMS m/z 274.30 (M+H).
1 -benzoyl-4-(2-{4-[3-(4-methoxybenzyl)-1 , 2, 4-oxadiazol-5-yl]piperidin- 1 - yl}ethyl)-4-phenylpiperidine
Figure imgf000209_0001
The TFA salt of 4-[3-(4-methoxybenzyl)-1 ,2,4-oxadiazol-5-yl]piperidine (29 mg, 0.076 mmol) was combined with (1-benzoyl-4-phenylpiperidin-4- yl)acetaldehyde (21 mg, 0.069 mmol) in 2 mL DCM and treated with NaBH(OAc)3 (43 mg, 0.203 mmol) at ambient temperature with agitation for 18h. 1 mL of saturated aqueous NaHCO3 was added and agitated 1 h. The organic phase was separated and concentrated. The crude product was purified by HPLC to give 1-benzoyl-4-(2-{4-[3-(4-methoxybenzyl)-1 ,2,4- oxadiazol-5-yl]piperidin-1-yl}ethyl)-4-phenylpiperidine (16.1 mg, 0.026 mmol, 38%) as the formate salt. 1H NMR (300 MHz, CD3OD) δ 7.49-7.37 (m, 9H), 7.28 (m, 1H), 7.20 (d, 2H, J=8.8Hz), 6.86 (d, 2H, J=8.8Hz), 4.19 (m, 1H), 3.96 (s, 2H), 3.76 (s, 3H), 3.59 (m, 1 H), 3.37-3.20 (m, 3H), 3.12-2.95 (m, 3H), 2.45- 1.73 (m, 13H). ES-LCMS m/z 565.29 (M+H). HRMS C35H4oN4O3 m/z 565.3179 (M+H)cai. 565.3183 (M+H)0 s, Example 369 3-1T5-I1 -I2-(1 -benzoyl-4-phenylpiperidin-4-vπethvn piperidin-4-yl)-1.2.4- oxad iazol-3-yl)meth yll pyrid ine
Figure imgf000210_0001
(1Z)-N'-hydroxy-2-pyridin-3-ylethanimidamide
Figure imgf000210_0002
Hydroxylamine hydrochloride (0.87 g, 0.0125 mmol) was added to 0.5M NaOCHβ (25 mL, 0.0125 mmol) and stirred at ambient temperature for 30 min. The reaction mixture was filtered and the filtrate was combined with pyridin-3-ylacetonitrile (1.18 g, 0.010 mmol). The resultant mixture was heated at reflux for 2h, stirred at ambient temperature overnight and concentrated to give crude (1Z)--V-hydroxy-2-pyridin-3-ylethanimidamide which was used immediately without purification. ES-LCMS m/z 152.18 (M+H).
tert-butyl 4-[3-(pyridin-3-ylmethyl)-1 ,2, 4-oxadiazol-5-yl]piperidine-1 - carboxylate
Figure imgf000210_0003
1-(7etf-butoxycarbonyl)piperidine-4-carboxylic acid (2.29 g, 0.010 mmol) was treated with 1 ,1'-carbonyldiimidazole (1.62 g, 0.010 mmol) in DMF (5 mL) at ambient temperature for 30 min. Following this activation period, the crude (1Z)--V-hydroxy-2-pyridin-3-ylethanimidamide (0.010 mmol) was added and the reaction mixture heated at 70 °C for 6h followed by 120°C for an additional 6h. The reaction mixture was cooled and partitioned between EtOAc and water. The organic phase was separated, washed successively with saturated NaHCO3 and brine, dried over MgSO , filtered and concentrated to give erf-butyl 4-[3-(pyridin-3-ylmethyl)-1 ,2,4-oxadiazol-5- yl]piperidine-1 -carboxylate. 1H NMR (300 MHz, CDCI3) δ 8.61 (s, 1 H), 8.53 (m, 1 H), 7.67 (d, 1H, J=7.7Hz), 7.28 (m, 1H), 4.20-4.05 (m, 2H), 4.08 (s, 2H), 3.08 (m, 1 H), 2.94 (m, 2H), 2.04 (m, 2H), 1.87-1.73 (m, 2H), 1.47 (s, 9H). ES- LCMS m/z 367.36 (M+Na).
3-[(5-piperidin-4-yl-1 ,2,4-oxadiazol-3-yl)methyl] pyridine
Figure imgf000211_0001
terf-Butyl 4-[3-(pyridin-3-ylmethyl)-1 ,2,4-oxadiazol-5-yl]piperidine-1 - carboxylate was treated with 10 mL TFA/DCM (1 :1 ) for 30 min at ambient temperature. The reaction mixture was concentrated to give the di-TFA salt of
3-[(5-piperidin-4-yl-1 ,2,4-oxadiazol-3-yl)methyl]pyridine as an amber oil (4.0 g, 8.47 mmol, 85%, 3 steps). 1H NMR (300 MHz, DMSO-d6) δ 8.78 (s, 1 H), 8.70
(d, 1 H, J=5.0Hz), 8.51 (br.s, 1H), 8.18 (d, 1 H, J=7.9Hz), 7.75 (m, 1 H), 4.30 (s,
2H), 3.44-3.30 (m, 3H), 3.09-3.00 (m, 2H), 2.20-2.16 (m, 2H), 1.93-1.80 (m,
2H).
Example 370
3-IT5-{1 -|2-(1 -benzoyl-4-phenylpiperidin-4-yl)ethvπ piperidin-4-yll-1 ,2.4- oxadiazol-3-yl)methvnpyridine
Figure imgf000211_0002
The TFA salt of 3-[(5-piperidin-4-yl-1 ,2,4-oxadiazol-3-yl)methyl]pyridine (27 mg, 0.076 mmol) was combined with (1-benzoyl-4-phenylpiperidin-4- yl)acetaldehyde (21 mg, 0.069 mmol) in 2 mL DCM and treated with NaBH(OAc)3 (43 mg, 0.203 mmol) at ambient temperature with agitation for 18h. 1mL of saturated aqueous NaHCO3 was added and agitated 1h. The organic phase was separated and concentrated. The crude product was purified by HPLC (METHOD) to give 3-[(5-{1-[2-(1-benzoyl-4-phenylpiperidin- 4-yl)ethyl]piperidin-4-yl}-1 ,2,4-oxadiazol-3-yl)methyl]pyridine (14.2 mg, 0.024 mmol, 34%) as the formate salt. , 1H NMR (300 MHz, CD3OD) δ 8.52-8.44 (m, 2H), 7.80 (d, 1 H, J=7.9Hz), 7.48-7.38 (m, 10H), 7.26 (m, 1 H), 4.19 (m, 1 H), 4.13 (s, 2H), 3.59 (m, 1 H), 3.36-3.29 (m, 3H), 3.12-3.02 (m, 3H), 2.47-1.45 (m, 13H). ES-LCMS m/z 536.25 (M+H). HRMS C33H37N5O2 m/z 536.3026 (M+H)Cai. 536.3018 (M+H)0 s,
Reductive Amination Method I
Figure imgf000212_0001
The TFA or HCl salt of the amine (390 μmoles) was combined with (1 - benzoyl-4-phenylpiperidin-4-yl)acetaldehyde (120 mg, 390 μmoles, 1 eq.) in 4mL DCE and/or 4mL DMF and treated with NaBH(OAc)3 (585 μmoles, 1.5 eq.) with or without TEA (780 μmoles, 2 eq.) at ambient temperature with agitation for 18h. The reaction mixture was concentrated, dissolved in 5 mL DCM, and agitated 1 h with 5 mL of saturated aqueous NaHCO3. The organic phase was separated and concentrated. The crude product was purified either by normal phase flash chromatography (SiO2, CHCI3/CH3OH) or by reverse phase mass-directed HPLC as described in Preparative HPLC Conditions A. Yields and representative data are included in the accompanying tables.
Figure imgf000212_0002
The HCl salt of the amine (1.66 mmoles) was combined with tert-butyl 4-(2-oxoethyl)-4-phenyl piperidine-1 -carboxylate (1.66 mmoles, 1 eq.) in 10 mL DCE and 10 mL DCM and treated with NaBH(OAc)3 (2.49 mmoles, 1.5 eq.) with TEA (3.33 moles, 2 eq.) at ambient temperature with agitation for 18h. The reaction mixture was washed with saturated aqueous NaHCO3, the organic phase separated, dried over MgSO4, filtered and concentrated. The crude product was purified by normal phase flash chromatography (SiO2, CHCI3/CH3OH) to give the desired product. Yields and representative data are included in the accompanying tables.
Figure imgf000213_0001
Figure imgf000213_0002
Figure imgf000214_0001
Figure imgf000215_0002
Additional analytical data of selected compounds from table above:
Example 371 Endo-λ -(8-[2-(1 -benzoyl-4-phenylpiperidin-4-vπethyll-8-azabicyclo[3.2.11oct-3- yll-1 H-benzimidazole
1H NMR (300 MHz, CD3OD) δ 8.46 (s, 1 H), 7.70 (m, 1 H), 7.51-7.28 (m, 13H), 4.80 (m, 1 H), 4.23 (m, 1 H), 3.71 (m, 2H), 3.62 (m, 1 H), 3.35-3.22 (m, 2H), 2.74-1.67 (m, 16H). HRMS C34H38N4O m/z 519.3124 (M+H)Caι.;
Figure imgf000215_0001
Example 372 Endo- -(8-r2-(1-benzoyl-4-phenylpiperidin-4-vπethvn-8-azabicvclor3.2.noct-3- ylV-2-ethyl-1 H-benzimidazole
1H NMR (300 MHz, CD3OD) δ ppm 1.35 (t, J=7.8 Hz, 3H), 1.76-2.53 (m, 16H), 2.89 (q, J=7.7Hz, 2H), 3.31-3.46 (m, 4H), 3.62 (m, 1 H), 4.19 (m, 1 H), 4.80 (m, 1 H), 7.17-7.29 (m, 3H), 7.39-7.49 (m, 10H), 7.57 (m, 1H). Example 380 Eπc/o-1-(8-r2-(1-benzoyl-4-phenylpiperidin-4-vπethvn-8-azabicvclor3.2.1loct-3- yl|-2-methoxy-1 H-benzimidazole
1H NMR (300 MHz, CD3OD) δ 7.49-7.39 (m, 10H), 7.32 (m, 1 H), 7.24 (m, 1 H), 7.16 (m, 2H), 4.81 (pent, 1 H), 4.25 (m, 1 H), 4.17 (s, 3H), 3.75 (m, 2H), 3.63 (m, 1 H), 3.35-3.27 (m, 2H), 2.65-1.79 (m, 16H). ES-LCMS m/z 549.38 (M+H). HRMS C35H40N4O2 m/z 549.3230 (M+H)Cai.. 549.3217
Figure imgf000216_0001
Example 381
Et7 o-1-(8-r2-(1-benzoyl-4-phenylpiperidin-4-yl)ethvn-8-azabicvclor3.2.1loct-3- yl)-2-ethoxy-1 H-benzimidazole
1H NMR (300 MHz, CD3OD) δ 7.51-7.39 (m, 10H), 7.32 (m, 1 H), 7.24
(m, 1 H), 7.16 (m, 2H), 4.85 (pent, 1 H), 4.57 (q, 2H, J = 7.0Hz), 4.23 (m, 1 H), 3.73 (m, 2H), 3.63 (m, 1 H), 3.35-3.27 (m, 2H), 2.65-1.79 (m, 16H). ES-LCMS m/z 563.40 (M+H). HRMS C36H42N4O2 m/z 563.3386 (M+H)cai.- 563.3368
(M+H)obs,
Example 382 Enc/o-1-{8-r2-(1-benzoyl-4-phenylpiperidin-4-yl)ethvn-8-azabicvclof3.2.1loct-3- yll-1 H-benzimidazol-2-amine
1H NMR (300 MHz, CD3OD) δ 7.48-7.40 (m, 9H), 7.28 (m, 3H), 7.13 (m, 2H), 4.61 (pent, 1 H), 4.19 (m, 1 H), 3.59 (m, 1 H), 3.39-3.27 (m, 4H), 2.48- 1.65 (m, 16H). HRMS C34H39N5O m/z 534.3233 (M+H)Caι.; 534.3241 (M+H)obs,
Preparation of Amines 1-14:
Amine 1 : prepared by the literature procedure described in WO 00/38680.
Amine 2: Endo-1 -(8-azabicyclo[3.2.1]oct-3-yl)-2-ethyl-1 H-benzimidazole
Figure imgf000217_0001
Enc o-terf-butyl 3-[(2-aminophenyl)amino]-8-azabicyclo[3.2.1]octane-8- carboxylate (WO 00/38680) (2.5 g, 7.80 mmol) was treated with 20 mL 1 ,1 ,1- triethoxypropane at reflux for 3h. The reaction mixture was concentrated to dryness, redissolved in CH3OH (10 mL), and treated with 6 N HCl at reflux for 1 h. The reaction mixture was concentrated to dryness, chased with EtOH, and triturated with EtOH to give a solid that was filtered and dried to give the HCl salt of encfo-1-(8-azabicyclo[3.2.1]oct-3-yl)-2-ethyl-1 H-benzimidazole (1.35 g, 4.11 mmol, 53%) as a grey solid. 1H NMR (300 MHz, D2O) δ 7.72- 7.65 (m, 2H), 7.49-7.46 (m, 2H), 4.99 (m, 1H) 4.19 (m, 2H), 3.10 (q, 2H,
J=7.6Hz), 2.76-2.70 (m, 2H), 2.40-2.18 (m, 6H), 1.35 (t, 3H, J=7.6Hz). ES- LCMS m/z 256.07 (M+H).
Amine 3: Endo-1 -(8-azabicyclo[3.2.1]oct-3-yl)-2-[2-(phenylsulfonyl)ethyl]-1H- benzimidazole
Figure imgf000217_0002
Enofo-te/t-butyl 3-[(2-aminophenyl)amino]-8-azabicyclo[3.2.1]octane-8- carboxylate (WO 00/38680) (1.8 g, 5.70 mmol) was treated with 20 mL [(3,3,3-triethoxypropyl)sulfonyl]benzene at 150 °C for 3h. The reaction mixture was concentrated to dryness, redissolved in CH3OH (10 mL), and treated with 6 N HCl at reflux for 1 h. The reaction mixture was concentrated to dryness, chased with EtOH, and triturated with EtOH to give a solid that was filtered and dried to give the di-HCI salt of endb-1-(8-azabicyclo[3.2.1]oct- 3-yl)-2-[2-(phenylsulfonyl)ethyl]-1 H-benzimidazole (1.68 g, 3.59 mmol, 63%) as a grey solid. 1H NMR (300 MHz, D2O) δ 7.72-7.69 (m, 2H), 7.64 (m, 1 H), 7.58 (m, 1 H), 7.49-7.44 (m, 3H), 7.36 (m, 2H), 4.99 (m, 1 H) 4.19 (m, 2H), 3.93 (t, 2H, J=7.0Hz), 3.63 (t, 2H, J=7.0Hz), 2.75-2.65 (m, 2H), 2.33-2.15 (m, 6H). ES-LCMS m/z 396.14 (M+H).
Amine 4: Endo-1 -[(1 R,5S)-8-azabicyclo[3.2.1]oct-3-yl]-2-methyl-5- (methylsulfonyl)-l H-benzimidazole
Figure imgf000218_0001
Endo-tert-butyl (1R,5S)-3-{[4-(methylsulfonyl)-2-nitrophenyl]amino}-8- azabicyclo[3.2.1]octane-8-carboxylate
Figure imgf000218_0002
Endo-terf-butyl (1R,5S)-3-amino-8-azabicyclo[3.2.1]octane-8- carboxylate (WO 00/38680) (1.5 g, 6.66 mmoles) was treated with 1-fluoro-4- (methylsulfonyl)-2-nitrobenzene (1.46 g, 1 eq.) in 10 mL NMP with DIPEA (947 mg, 1.1 eq.) at 70°C for 3h. The reaction mixture was diluted with 5 mL NMP, cooled to ambient temperature, and water added to incipient cloudiness. The reaction mixture was stirred until a heavy precipitate formed. The precipitate was filtered off, washed successively with NMP/water (1 :1) and water, and air dried to give end -terf-butyl (1 £?,5S)-3-{[4-(methylsulfonyl)- 2-nitrophenyl]amino}-8-azabicyclo [3.2.1]octane-8-carboxylate (2.21 g, 78%) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 8.90 (d, 1 H, J=7.0Hz), 8.53 (d, 1 H, J=2.0Hz), 7.94 (dd, 1 H, J=9.2, 2.0Hz), 7.17 (d, 1 H, J=9.3Hz), 4.11 (m, 3H), 3.21 (s, 3H), 2.16 (m, 2H), 1.94 (m, 4H), 1.80 (m, 2H), 1.42 (s, 9H). Endo-tert-butyl (1R, 5S)-3-{[2-amino-4-(methylsulfonyl) phenyl]amino}-8- azabicyclo[3.2.1]octane-8-carboxylate
Figure imgf000219_0001
Endo-tert-buϊy\ (1 R,5S)-3-{[4-(methyl sulfonyl)-2-nitrophenyl]amino}-8- azabicyclo[3.2.1] octane-8-carboxylate (2.21 g, 5.19 mmoles) was subjected to catalytic hydrogenation with 10% Pd/C (260 mg) in EtOH/EtOAc (1 :1 , 100 mL) under 1atm H2(g) for 16h. The catalyst was filtered off and the filtrate concentrated to a purple oil which was carried on to the next step without further characterization.
Endo-1 -[(1R,5S)-8-azabicyclo[3.2.1]oct-3-yl]-2-methyl-5-(methylsulfonyl)-1H- benzimidazole
Figure imgf000219_0002
Endo-tert-buty\ (1R,5S)-3-{[2-amino-4-(methylsulfonyI)phenyl]amino}-8- azabicyclo[3.2.1] octane-8-carboxylate was treated with 1 ,1 ,1-triethoxyethane at reflux for 2h. The reaction mixture was concentrated to dryness, redissolved in CH3OH (10 mL), and treated with 6 N HCl at reflux for 1h. The reaction mixture was concentrated to dryness, chased with EtOH, and triturated with EtOH to give a solid that was filtered and dried to give the di- HCl salt of eπc/o-tert-butyl (1 R,5S)-3-{[2-amino-4-(methylsulfonyl) phenyl]amino}-8-azabicyclo[3.2.1]octane-8-carboxylate as a grey solid. 1H NMR (300 MHz, D2O) δ 8.27 (m, 1 H), 7.98-7.89 (m, 2H), 5.00 (m, 1H), 4.20 (m, 2H), 3.21 (s, 3H), 2.77 (s, 3H), 2.79-2.70 (m, 2H), 2.35-2.15 (6H).
Amine 5: Endo-1 -[(1 R,5S)-8-azabicyclo[3.2.1]oct-3-yl]-5-fluoro-2-methyl-1H- benzimidazole
Figure imgf000220_0001
Endo-tert-butyl (1R,5S)-3-[(4-fluoro-2-nitrophenyl) amino]-8- azabicyclo[3.2.1]octane-8-carboxylate
Figure imgf000220_0002
Enc/o-terf-butyl (1R,5S)-3-amino-8-azabicyclo[3.2.1]octane-8- carboxylate (WO 00/38680) (2.0 g, 8.88 mmoles) was treated with 1 ,4- difluoro-2-nitrobenzene (1.41 g, 1 eq.) in 10 mL NMP with DIPEA (1.26 g, 1.1 eq.) at 70 °C for 16h. The reaction mixture was cooled to ambient temperature, and water (4 mL) added to incipient cloudiness. The reaction mixture was stirred until a heavy precipitate formed. The precipitate was filtered off, washed successively with NMP/water (1 :1 ) and water, and air dried to give tert-butyl (1R,5S)-3-[(4-fluoro-2-nitrophenyl)amino]-8- azabicyclo[3.2.1]octane-8-carboxylate as an orange solid (2.74g , 7.50 mmoles, 84%). 1H NMR (300 MHz, CDCI3) δ 8.66 (d, 1 H, J=5.7Hz), 7.93 (m, 1 H), 7.27 (m, 1 H), 6.72 (m, 1 H), 4.29 (m, 3H), 3.91 (m, 1 H), 2.40-2.29 (m, 2H), 2.15-2.01 (m, 4H), 1.80 (m, 2H), 1.50 (s, 9H). Endo-tert-butyl (1R,5S)-3-[(2-amino-4-fluorophenyl) amino]-8- azabicycloβ.2.1]octane-8-carboxylate
Figure imgf000221_0001
Enc/o-terf-butyl (1 R,5S)-3-[(4-fluoro-2-nitrophenyl)amino]-8- azabicyclo[3.2.1]octane-8-carboxylate (2.74 g, 7.50 mmoles) was subjected to catalytic hydrogenation with 10% Pd/C (300 mg) in EtOH/EtOAc (1 :1 , 80 mL) under 1atm H2(g) for 16h. The catalyst was filtered off and the filtrate concentrated to give the title compound (2.57 g, 100%) as a white foam. ES- LCMS m/z 336.26 (M+H).
Endo-1 -[(1R,5S)-8-azabicyclo[3.2.1]oct-3-yl]-5-fluoro-2-methyl-1H- benzimidazole
Figure imgf000221_0002
Endo-tert-bu\y\ (1 R,5S)-3-[(2-amino-4-fluorophenyl)amino]-8- azabicyclo[3.2.1]octane-8-carboxylate was treated with 1 ,1 ,1-triethoxyethane and a catalytic amount of camphor sulphonic acid at reflux for 3h. The reaction mixture was concentrated to dryness, redissolved in CH3OH (10 mL), and treated with 6N HCl at reflux for 1h. The reaction mixture was concentrated to dryness, chased with EtOH, and triturated with EtOH to give a solid that was filtered and dried to give the di-HCI salt of enofo-1-[(1 R,5S)-8- azabicyclo[3.2.1]oct-3-yl]-5-fluoro-2-methyl-1 H-benzimidazole as a grey solid. ES-LCMS m/z 260.27 (M+H). Amine 6: Endo-1 -[(1R,5S)-8-azabicyclo[3.2.1]oct-3-yl]-4-fluoro-2-methyl-1H- benzimidazole
Figure imgf000222_0001
Prepared according to the method of Amine 5 from 1 ,3-difluoro-2- nitrobenzene. ES-LCMS m/z 260.24 (M+H).
Amine 7: Endo-3-[(1R,5S)-8-azabicyclo[3.2.1]oct-3-yl]-2-methyl-3H- imidazo[4, 5-b]pyridine
Figure imgf000222_0002
Prepared according to the method of Amine 5 from 2-chloro-3- nitropyridine. ES-LCMS m/z 243.22 (M+H).
Amine 8: Endo-1 -[(1 R,5S)-8-azabicyclo[3.2.1]oct-3-yl]-2-(trifluoromethyl)-1H- benzimidazole
Figure imgf000222_0003
Endo-tert-butyl (1R,5S)-3-[2-(trifluoromethyl)-1 H-benzimidazol-1 -yl]-8- azabicyclo[3.2.1]octane-8-carboxylate
Figure imgf000222_0004
To a solution of trifluoroacetic acid (496 mg, 4.35 mmoles) in 5 mL DMF was added CDI (4.35 mmoles, 1 eq.) and stirred 30 min at ambient temperature until CO2 evolution ceased. The reaction mixture was then cooled in an ice bath and Eπcfo-tetf-butyl 3-[(2-aminophenyl)amino]-8- azabicyclo[3.2.1 ] octane-8-carboxylate (WO 00/38680) (1.38 g, 4.35 mmoles, 1 eq.) dissolved in 10mL DMF was added slowly. The reaction mixture was stirred 30 min at 0°C and then warmed to ambient temperature and stirred for 30 min. The reaction mixture was then heated at 80°C for 16h. The reaction mixture was concentrated, dissolved in DCM, washed successively with saturated aqueous NaHCO3 and water (3x). The organic phase was separated, dried over MgSO4 and concentrated. A major impurity was removed by precipitation with Et2O, filtered off, and the filtrate concentrated to dryness. The crude product was purified by normal phase flash chromatography (SiO2, 10->40% EtOAc/Hexanes) to give EnαO-terf-butyl (1 R,5S)-3-[2-(trifluoromethyl)-1 H-benzimidazol-1 -yl]-8- azabicyclo[3.2.1]octane-8-carboxylate (0.36 g, 0.91 mmoles, 21%). ES- LCMS m/z 396.27 (M+H).
Endo-1 -[(1R,5S)-8-azabicyclo[3.2.1]oct-3-yl]-2-(trifluoromethyl)-1H- benzimidazole
Figure imgf000223_0001
Enc/o-ferf-butyl (1 R,5S)-3-[2-(trifluoro-methyl)-1 H-benzimidazol-1 -yl]-8- azabicyclo [3.2.1]octane-8-carboxylate (330 mg, 0.84 mmoles) was dissolved in 6 mL DCM and treated with 4 mL 4N HCl in Dioxane at ambient temperature for 30 minutes. A solid precipitated from the reaction mixture and was filtered off to give the HCl salt of Enc o-1 -[(1 R,5S)-8-azabicyclo[3.2.1]oct- 3-yl]-2-(trifluoromethyl)-1 H-benzimidazole (260 mg, 0.78 mmoles, 94%) as a pink solid. ES-LCMS m/z 295.67 (M+H). Amine 9: Endo-1 -[(1 R,5S)-8-azabicyclo[3.2.1]oct-3-yl]-2-chloro-1H- benzimidazole
Figure imgf000224_0001
Endo-1 -[(1R,5S)-8-azabicyclo[3.2.1]oct-3-yl]-1,3-dihydro-2H-benzimidazol-2- one
Figure imgf000224_0002
The title compound was obtained as a major by-product of the reaction of Endo-terf-butyl 3-[(2-aminophenyl)amino]-8-azabicyclo[3.2.1]octane-8- carboxylate (WO 00/38680) (1.7 g, 5.36 mmol) with 1-
(triethoxymethoxy)ethane (5 mL) at 150 °C for 3h, followed by concentration, dissolution in CH3OH (10 mL), and treatment with 6 N HCl at reflux for 1 h. The reaction mixture was concentrated to dryness, chased with EtOH, and triturated with EtOH to give a solid that was filtered and dried to give the HCl salt of Eπdo-1-[(1R,5S)-8-azabicyclo[3.2.1]oct-3-yl]-1 ,3-dihydro-2H- benzimidazol-2-one (0.73 g, 3.00 mmoles, 56%). ES-LCMS m/z 244.00 (M+H).
Endo-1 -[(1R,5S)-8-azabicyclo[3.2.1]oct-3-yl]-2-chloro-1 H-benzimidazole
Figure imgf000224_0003
Endo-1 -[(1 R,5S)-8-azabicyclo[3.2.1 ]oct-3-yl]-1 ,3-dihydro-2H- benzimidazol-2-one (0.73 g, 3.00 mmoles) was treated with 5 mL POCI3 with a catalytic amount of DMAP at reflux for 12h. The reaction was cooled and quenched with slow addition of 6N NaOH until pH was basic. The reaction mixture was extracted with DCM, dried over MgSO , filtered and concentrated to give impure Endo-1-[(1R,5S)-8-azabicyclo[3.2.1]oct-3-yl]-2-chloro-1H- benzimidazole as a tan foam. The crude amine was used as is. ES-LCMS m/z 262.23 (M+H).
Amine 10: Endo-1 -(8-azabicyclo[3.2.1]oct-3-yl)-2-methoxy-1 H-benzimidazole Endo-tert-butyl 3-(2-methoxy- 1 H-benzimidazol- 1 -yl)-8- azabicyclo[3.2.1]octane-8-carboxylate
Figure imgf000225_0001
Endo-tert-butyl 3-[(2-am nophenyl)amino]-8-azabicyclo[3.2.1]octane-8- carboxylate (WO 00/38680) (1.0 g, 3.15 mmol) was treated with 5 mL tetramethyl orthocarbonate at reflux for 40h. The reaction mixture was concentrated to dryness and purified by flash chromatography on silica gel eluted with 20% EtOAc in hexanes to give Endo-tert-butyl 3-(2-methoxy-1H- benzimidazol-1-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (0.50 g, 1.40 mmol, 44%) as an orange oil. ES-LCMS m/z 358.11 (M+H).
Endo-1 -(8-azabicyclo[3.2.1]oct-3-yl)-2-methoxy-1 H-benzimidazole
Figure imgf000225_0002
Tert-butyl 3-(2-methoxy-1 H-benzimidazol-1 -yl)-8- , azabicyclo[3.2.1]octane-8-carboxylate (0.50 g, 1.40 mmol) suspended in DCM (2 mL) was treated with TFA (1 mL) at ambient temperature for 5 min. The reaction mixture was concentrated to dryness and the product was crystalized from EtOAc/Et2O to give the di-TFA salt of Endo-1 -(8-azabicyclo[3.2.1]oct-3- yl)-2-methoxy-1 H-benzimidazole (340 mg, 0.722 mmol, 51%) as a tan solid. 1H NMR (300 MHz, D2O) δ 7.35 (m, 1 H), 7.26 (m, 1 H), 7.12 (m, 2H), 4.65 (m, 1 H), 4.08-4.00 (m, 2H), 4.03 (s, 3H), 2.55-2.45 (m, 2H), 2.17-2.02 (m, 6H). ES-LCMS m/z 258.02 (M+H).
Amine 11 : Endo-1 -(8-azabicyclo[3.2.1]oct-3-yl)-2-ethoxy-1 H-benzimidazole Endo-tert-butyl 3-(2-ethoxy- 1 H-benzimidazol- 1 -yl)-8-azabicyclo[3.2.1]octane- 8-carboxylate
Figure imgf000226_0001
Endo-tert-butyl 3-[(2-aminophenyl)amino]-8-azabicyclo[3.2.1]octane-8- carboxylate (WO 00/38680) (1.7 g, 5.36 mmol) was treated with 10 mL tetraethyl orthocarbonate at reflux for 16h. The reaction mixture was concentrated to dryness and purified by flash chromatography on silica gel eluted with DCM followed by 20% EtOAc in Hexanes to give Endo-tert-butyl 3- (2-ethoxy-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (1.15 g, 3.10 mmol, 58%) as an amber oil. ES-LCMS m/z 372.19 (M+H).
Endo- 1 -(8-azabicyclo[3.2.1]oct-3-yl)-2-ethoxy- 1 H-benzimidazole
Figure imgf000226_0002
Endo-tert-butyl 3-(2-ethoxy-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]octane-8-carboxylate (1.15 g, 3.10 mmol) suspended in DCM (4 mL) was treated with TFA (1 mL) at ambient temperature for 5 min. The reaction mixture was concentrated to dryness and the product crystalized from EtOAc/Et2O to give the di-TFA salt of Endo-1 -(8-azabicyclo[3.2.1]oct-3- yl)-2-ethoxy-1 H-benzimidazole (715 mg, 1.43 mmol, 46%) as a white powder. 1H NMR (300 MHz, D2O) δ 7.36 (m, 1 H), 7.27 (m, 1 H), 7.12 (m, 2H), 4.65 (m, 1 H), 4.43 (q, 2H, J=7.1 Hz), 4.00 (m, 2H), 2.54-2.43 (m, 2H), 2.16-2.00 (m, 6H). ES-LCMS m/z 272.05 (M+H).
Amine 12: Endo-1 -(8-azabicyclo[3.2.1]oct-3-yl)-1H-benzimidazol-2-amine
Endo-tert-butyl 3-(2-amino-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1]octane- 8-carboxylate
Figure imgf000227_0001
r
Endo-tert-butyl 3-[(2-aminophenyl)amino]-8-azabicyclo[3.2.1]octane-8- carboxylate (WO 00/38680) (2.5 g, 7.88 mmol) was treated with BrCN (0.92 g, 8.66 mmol) in CH3OH (30 mL) at reflux for 3h and concentrated to give endo- tert-butyl 3-(2-amino-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1]octane-8- carboxylate (2.30 g, 6.73 mmol, 85%). 1H NMR (300 MHz, DMSO-d6) δ 7.15 (d, 2H, J = 7.6 Hz), 6.97-6.86 (m, 2H), 6.21 (s, 2H), 4.34 (m, 2H), 4.22 (pent, 1 H), 2.42-2.32 (m, 2H), 1.98-1.85 (m, 6H), 1.44 (s, 9H). ES-LCMS m/z 343.12 (M+H).
Endo-1 -(8-azabicyclo[3.2.1]oct-3-yl)-1H-benzimidazol-2-amine
Endo-tert-butyl 3-(2-amin Xo-1 H-bxenziimidazol-1 -yl)-8- azabicyclo[3.2.1]octane-8-carboxylate (0.244 g, 0.713 mmol) suspended in DCM (2 mL) was treated with TFA (2 mL) at ambient temperature for 30 min. The reaction mixture was concentrated to dryness and the product crystalized from EtOAc to give the di-TFA salt of Endo-1 -(8-azabicyclo[3.2.1]oct-3-yl)-1H- benzimidazol-2-amine (320 mg, 0.681 mmol, 95%) as a white solid. 1H NMR (300 MHz, D2O) δ 7.40-7.20 (m, 4H), 4.66-4.49 (m, 1 H), 4.16 (m, 2H), 2.71- 2.60 (m, 2H), 2.29-2.11 (m, 6H). ES-LCMS m/z 243.04 (M+H).
Amine 13: Endo-1 -[(1 R,5S)-8-azabicyclo[3.2.1]oct-3-yl]-N-methyl-1H- benzimidazol-2-amine
Figure imgf000228_0001
Endo-tert-butyl (1R,5S)-3-[2-(methylamino)-1 H-benzimidazol-1 -yl]-8- azabicyclo[3.2.1]octane-8-carboxylate
Figure imgf000228_0002
Endo-tert-butyl 3-[(2-aminophenyl)amino]-8-azabicyclo[3.2.1]octane-8- carboxylate (WO 00/38680) (900 mg, 2.83 mmol) in THF was treated with methyl isothiocyanate (230 mg, 3.15 mmoles, 1.1 eq.) at 0°C for 1h followed by 16h at ambient temperature. The reaction mixture was concentrated, redissolved in 7mL DMF and treated with 1-[3-(dimethylamino)propyl]-3- ethylcarbodiimide hydrochloride (815 mg, 1.5 eq.) at ambient temperature for 16h. The reaction mixture was concentrated, dissolved in EtOAc, washed successively with saturated aqueous NaHCO , water (3x), and brine. The organic phase was separated, dried over MgSO and concentrated to give the desired product, endo-tert-butyl (1R,5S)-3-[2-(methylamino)-1H-benzimidazol- 1-yl]-8-azabicyclo[3.2.1]octane-8-carboxylate. ES-LCMS m/z 357.15 (M+H).
Endo-1 -[(1R,5S)-8-azabicyclo[3.2.1]oct-3-yl]-N-methyl-1H-benzimidazol-2- amine
Figure imgf000229_0001
Endo-tert-butyl (1 R,5S)-3-[2-(methylamino)-1 H-benzimidazol-1 -yl]-8- azabicyclo[3.2.1]octane-8-carboxylate was dissolved in 3 mL CH3OH and treated with 3 mL 4N HCl in Dioxane at ambient temperature for 30 minutes. The reaction mixture was concentrated and triturated with EtOH, filtered, and dried to give the di-HCI salt of Endo-1 -[(1 R,5S)-8-azabicyclo[3.2.1]oct-3-yl]-Λ/- methyl-1H-benzimidazol-2-amine (201 mg, 0.61 mmoles, 60%) as a pink solid. ES-LCMS m/z 257.04 (M+H).
Amine 14: Endo-3-[(1R, 5S)-8-azabicyclo[3.2.1]oct-3-yl]-2-methyl-3H- imidazo[4, 5-b]pyridine
Figure imgf000229_0002
Endo-tert-butyl (1 R,5S)-3-[(3-nitropyridin-2-yl)amino]-8- azabicyclo[3.2.1]octane-8-carboxylate
Figure imgf000229_0003
Endo-tert-butyl (1 R,5S)-3-amino-8-azabicyclo[3.2.1]octane-8- carboxylate (WO 00/38680) (8.64 g, 38.3 mmoles) was treated with 2-chloro- 3-nitropyridine (6.08 g, 1 eq.) in 50 mL NMP with DIPEA (10.9 g, 2.2 eq.) at 70°C for 16h. The reaction mixture was cooled to ambient temperature, and water (60 mL) added to incipient cloudiness. The reaction mixture was stirred until a heavy precipitate formed. The precipitate was filtered off, washed successively with NMP/water (1 :1) and water, and air dried to give endo-tert- butyl (1R,5S)-3-[(3-nitropyridin-2-yl)amino]-8-azabicyclo[3.2.1]octane-8- carboxylate as an brown solid (11.5 g, 33.0 mmoles, 86%).
Endo-tert-butyl (1 R, 5S)-3-[(3-aminopy din-2-yl)amino]-8- azabicyclo[3.2.1]octane-8-carboxylate
Figure imgf000230_0001
Endo-tert-butyl (1 R,5S)-3-[(3-nitropyridin-2-yl)amino]-8- azabicyclo[3.2.1]octane-8-carboxylate (5.17 g, 14.8 mmoles) was subjected to catalytic hydrogenation with 10% Pd/C (500 mg) in EtOH/EtOAc (1 :1 , 200 mL) under 1 atm H2(g) for 16h. The catalyst was filtered off and the filtrate was concentrated to give Endo-tert-butyl (1 ,5S)-3-[(3-aminopyridin-2-yl)amino]-8- azabicyclo[3.2.1]octane-8-carboxylate as a brown foam and was used in the next step without further characterization.
Endo-tert-butyl (1 R,5S)-3-(2-ethoxy-2-methyl-1 ,2-dihydro-3H-imidazo[4,5- b]pyridin-3-yl)-8-azabicyclo [3.2.1]octane-8-carboxylate
Figure imgf000230_0002
Endo-tert-butyl (1 R,5S)-3-[(3-aminopyridin-2-yl)amino]-8- azabicyclo[3.2.1]octane-8-carboxylate (2.85 g, 8.52 mmoles) was treated with 1 ,1 ,1-triethoxyethane and a catalytic amount of camphor sulphonic acid at reflux for 3h. The reaction mixture was concentrated to dryness, dissolved in EtOAc, washed with saturated aqueous NaHCO3, the organic phase separated, dried over MgSO4, filtered and concentrated. The crude product was purified by normal phase flash chromatography (SiO2, 10- 40% EtOAc/Hexanes) to give endo-tert-butyl (1R,5S)-3-(2-ethoxy-2-methyl-1 ,2- dihydro-3H-imidazo[4,5-b] pyridin-3-yl)-8-azabicyclo[3.2.1 ]octane-8- carboxylate (2.66 g, 6.84 mmoles, 80%). ES-LCMS m/z 411.08 (M+Na).
Endo-tert-butyl (1R,5S)-3-(2-methyl-3H-imidazo[4,5-b]pyridin-3-yl)-8- azabicyclo[3.2.1]octane-8-carboxylate
Figure imgf000231_0001
Endo-tert-butyl (1R,5S)-3-(2-ethoxy-2-methyl-1 ,2-dihydro-3H- imidazo[4,5-j ]pyridin-3-yl)-8-azabicyclo [3.2.1]octane-8-carboxylate (2.66 g, 6.84 mmoles) and a catalytic amount of camphor sulphonic acid were combined in NMP at 150 °C for 12h. The reaction mixture was cooled to ambient temperature, diluted with EtOAc, washed successively with saturated aqueous NaHCO3 and brine (5x). The organic phase was separated, dried over MgSO4, filtered and concentrated. The crude product was purified by normal phase flash chromatography (SiO2, EtOAc) to give Endo-tert-butyl
(1 R,5S)-3-(2-methyl-3H-imidazo[4,5-D]pyridin-3-yl)-8-azabicyclo[3.2.1 joctane- 8-carboxylate (1.60 g, 4.67 mmoles, 68%). ES-LCMS m/z 343.24 (M+H).
Endo-3-[(1R,5S)-8-azabicyclo[3.2.1]oct-3-yl]-2-methyl-3H-imidazo[4,5- bjpyridine
Figure imgf000231_0002
Endo-tert-butyl (1R,5S)-3-(2-methyl-3H-imidazo[4,5-i ]pyridin-3-yl)-8- azabicyclo[3.2.1]octane-8-carboxylate (1.60 g, 4.67 mmoles) was dissolved in 15 mL DCM and treated with 4 N HCl in dioxane at ambient temperature for 30 min. A precipitate formed directly from the reaction mixture and was filtered and dried to give the HCl salt of Endo-3-[(1R,5S)-8-azabicyclo [3.2.1]oct-3-yl]-2-methyl-3H-imidazo[4,5-jt)]pyridine as a brown solid. ES- LCMS m/z 243.22 (M+H).
Synthesis of the 5-(aminosulfonv0-2-chloronicotinic acid
Figure imgf000232_0001
2-Hydroxynicotinic acid (10.0 g, 71.8 mmol) was dissolved in 25 ml of chlorosulfonic acid and heated to 160°C overnight. After cooling the reaction was slowly poured into ice and stirred in an ice bath until a white precipitate formed. The solid was filtered off and dried under vacuum to afford 7.55 g of 5-(chlorosulfonyl)-2-hydroxynicotinic acid (44% yield). 1 H NMR (300 MHz, DMSO-d6) δ ppm 7.9 (dd, J=2.5, 0.7Hz, 1 H) 8.4 (dd, J=2.6, 0.7Hz, 1H).
5-(Chlorosulfonyl)-2-hydroxynicotinic acid (500 mg, 2.10 mmol) vas suspended in 5 ml of POCI3 in a sealed tube and heated to 130 °C until all solid had dissolved. The reaction was cooled to 0 °C and poured onto ice and stirred until a solid formed. The filtered white solid was dried to afford 2- chloro-5-(chlorosulfonyl)nicotinic acid. 1H NMR (400 MHz, Acetone-d6) δ ppm 8.9 (d, J=2.6Hz, 10H), 9.3 (d, J=2.6Hz, 10H).
2-Chloro-5-(chlorosulfonyl)nicotinic acid (400 mg, 1.56 mmol) was stirred in a slurry of ice and excess ammonium hydroxide was added at 0°C and stirred untill all of the ice had melted. The resulting solution was evaporated to afford a white solid 5-(aminosulfonyl)-2-chloronicotinic acid. MS ES+ 237 (M+H). 1H NMR (400 MHz, DMSO-D6) δ ppm 8.1 (dd, J=2.6, 0.9Hz, 1 H), 8.6 (m, 1 H). 2-{[(dimethylamino)sulfonyl]oxy}benzoic acid
Figure imgf000233_0001
Methyl 2-{[(dimethylamino)sulfonyl]oxy} benzoate (325.0 mg, 1.253 mmol) was dissolved in 2 ml of 1 ,4-dioxane and 2 ml of 1 M LiOH was added. The resulting solution was shaken overnight at 45°C. The reaction mixture was washed with DCE and separated using a hydrophobic frit. The aqueous layer was acidified to give a white solid which was filtered and dried to afford 244.4 mg (80% yield) of 2-{[(dimethyl-amino)sulfonyl]oxy}benzoic acid.
Figure imgf000233_0002
Example 386 1 -IT1 R.5S)-8-(2-f 1 -r(3-chlorophenvnsulfonvπ-4-phenyl-4-piperidinyltethyl)-8- azabicvclof3.2.11oct-3-yll-2-methyl-1 H-benzimidazole
Figure imgf000234_0001
3-Chlorobenzenesulfonyl chloride (31.6 mg, 0.122 mmol) was added to a solution of 2-methyl-1-{(1R,5S)-8-[2-(4-phenyl-4-piperidinyl)ethyl]-8- azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole (50.0 mg, 0.117 mmol) and diisopropyletheylamine (44.9 mg, 0.348 mmol) in DCM. The reactions were quenched with sat. NaHCO3 and separated with a hydrophobic frit. Flash chromatography on silica 0 to 10% MeOH in EtOAc afforded 1-[(1R,5S)-8-(2- {1-[(3-chlorophenyl)sulfonyl]-4-phenyl-4-piperidinyl}ethyl)-8- azabicyclo[3.2.1]oct-3-yl]-2-methyl-1 H-benzimidazole 14.7 mg (20% yield). MS ES+ 603(M+H). 1H NMR (300 MHz, chloroform-d) δ ppm 1.6 (m, 2H), 1.7 (m, 4H), 1.9 (m, 8H), 2.4 (m, 4H), 2.6 (s, 3H), 2.8 (m, 2H), 3.4 (m, 2H), 4.6 (m, 1 H), 7.2 (m, 5H), 7.3 (m, 3H), 7.4 (t, J=7.9Hz, 1 H), 7.5 (m, 1 H), 7.6 (d, J=7.8Hz, 1 H), 7.7 (m, 1 H), 7.7 (m, J=1.8, 1.8Hz, 1 H).
General Scheme Towards Pyrimidinyl and Tetrahvdro-biimidazolyl Derivatives of 2-Methyl-1-(8-r2-(4-Phenylpiperidin-4-vnethyl1-8-Azabicvclor3.2.1loct-3-ylV
1H-Benzimidazole
Figure imgf000234_0002
Example 388 Preparation of 2-methyl-1 ~f8-[2-(4-phenyl-1 -pyrimidin-2-ylpiperidin-4-v0ethyll- 8-azabicvclor3.2.1 loct-3-ylH H-benzimidazole
Figure imgf000235_0001
To a stirred solution of 2-methyl-1-{8-[2-(4-phenylpiperidin-4-yl)ethyl]-8- azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole dihydrochloride (25.3 mg, 0.05 mmol) in N, W-dimethylformade (2 mL) was added 2-chloropyrimidine (8.6 mg, 0.075 mmol) and triethylamine (21 μL, 0.15 mmol). The resulting mixture was stirred at 80 °C for 2.5 hours. After evaporation of the solvent, the crude product was directly purified by flash chromatography on silical gel, eluting with a gradient of 0-10% triethylamine in methanol to afford 2-methyl-1-{8-[2- (4-phenyl-1-pyrimidin-2-ylpiperidin-4-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1H- benzimidazole as amorphous solid (16.2 mg, 65%). 1H NMR (300 MHz, CDCI3) δ 8.30 (d, J=6.0Hz, 2H), 7.67 (dd, J=2.6, 7.0Hz, 1 H), 7.39-7.37 (m, 4H), 7.35-7.22 (m, 3H), 7.21-7.14 (m, 2H), 6.45 (t, J= 4.7Hz, 1 H), 4.64 (m, 1 H), 4.17-4.09 (m, 2H), 3.61-3.52 (m, 2H), 3.28-3.25 (m, 2H), 2.59 (s, 3H), 2.44-2.33 (m, 2H), 2.29-2.22 (m, 2H), 1.97-1.85 (m, 10H), 1.62 (d, J=7.7Hz, 2H). HRMS m/z (M+H)+ calcd: 507.3236; obsd: 507.3248.
Example 389 Preparation of 2-methyl-1-(8-(2-r4-phenyl-1-(4.4'.5.5'-tetrahvdro-1'H-1.2'- biimidazol-2-yl)piperidin-4-yllethyl)-8-azabicvclof3.2.11oct-3-yl)-1 H- benzimidazole
Figure imgf000236_0001
2-Methyl-1 -(8-{2-[4-phenyl-1 -(4,4',5,5'-tetrahydro-1 'H-1 ^'-biimidazol^- yl)piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-1 H-benzimidazole (16 mg, 58%) was obtained as amorphous solid from 2-methyl-1-{8-[2-(4- phenylpiperidin-4-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole dihydrochloride (25.3 mg, 0.05 mmol) and 2-methylthio-2-imidazoline hydroiodide (24.4 mg, 0.1 mmol) by the similar procedure outlined in example 388. 1H NMR (300 MHz, CDCI3) δ 7.68-7.65 (m, 1 H), 7.40-7.35 (m, 2H), 7.31- 7.25 (m, 4H), 7.21-7.12 (m, 2H), 5.87 (br, 1 H), 4.65-4.58 (m, 1H), 4.06-3.97 (m, 2H), 3.17-3.65 (m, 6H), 3.32-3.26 (m, 4H), 3.12-3.06 (m, 2H), 2.58 (s, 3H), 2.42-2.32 (m, 2H), 2.25-2.19 (m, 2H), 1.97-1.86 (m, 10H), 1.62 (d, J=7.9Hz, 2H). HRMS m/z (M+H)+ calcd: 565.3767, obsd: 565.3755.
Preparation of Carboximidoate, Carboximidamide and Carbimdo-thioate Derivatives of 2-Methyl-1-(8-f2-(4-Phenylpiperidin-4-yl)ethyl1 -8-Azabicvclo- I3.2.1 loct-3-yl)-1 H-Benzimidazole
Figure imgf000237_0001
Figure imgf000237_0002
Example 390 Preparation of 5-(4-{2-f3-(2-methyl-1 H-benzimidazol-1 -vπ-8-azabicvclo r3.2.noct-8-vnethyll-4-phenylpiperidin-1-vn-1H-1.2.4-triazol-3-amine
Figure imgf000238_0001
To a stirred solution of phenyl Λ/-cyano-4-{2-[3-(2-methyl-1H- benzimidazol-1-yl)-8-azabicyclo[3.2.1] oct-8-yl]ethyl}-4-phenylpiperidine-1- carboximidoate (18 mg, 0.031 mmol) in isopropyl alcohol (1 mL) was added hydrazine ( 3.6 μL, 0.11 mmol). The resulting mixture was then stirred at 80 °C for 4 hours. After evaporation of the solvents, the residue was purified by flash chromatography to afford 5-(4-{2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)-1H-1 ,2,4-triazol-3- amine as white solid (12.5 mg, 79%). 1H NMR (300 MHz, CDCI3) δ 7.67-7.64 (m, 2H), 7.39-7.29 (m, 5H), 7.25-7.13 (m, 3H), 4.66-4.55 (m, 2H), 4.28 (br, 2H), 3.56-3.49 (m, 3H), 3.27-3.21 (m, 4H), 2.57 (s, 3H), 2.42-2.22 (m, 4H), 1.96-1.82 (m, 9H), 1.64-1.62 (m, 2H). HRMS m/z (M+H)+ calcd: 511.3298, obsd: 511.3289.
Example 391
Preparation of isopropyl N-cvano-4-(2-r3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicvclof3.2.noct-8-vnethyl)-4-phenylpiperidine-1 -carboximidoate
Figure imgf000238_0002
Isopropyl Λ/-cyano-4-{2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidine-1 -carboximidoate (13 mg, 92%) was obtained as amorphous solid from phenyl Λ/-cyano-4-{2-[3-(2- methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1 ] oct-8-yl]ethyl}-4- phenylpiperidine-1 -carboximidoate (15 mg, 0.026 mmol) and sodium isopropoxide by the similar procedure outlined in example 7. 1H NMR (300 MHz, CDCI3) δ 7.67 (d, J=7.0Hz, 1 H), 7.42-7.35 (m, 2H), 7.29-7.21 (m, 4H), 7.19-7.13 (m, 2H), 5.30-5.22 (m, 1H), 4.69 (br, 1 H), 4.14-4.02 (m, 2H), 3.38- 3.20 (m, 4H), 2.59 (s, 3H), 2.41-2.14 (m, 4H), 1.94-1.68 (m, 12H), 1.32 (d, J=6.2Hz, 6H). HRMS m/z (M+H)+ calcd: 539.3498, obsd: 539.3503.
Example 392 Preparation of cyclopentyl N-cvano-4-{2-r3-(2-methyl-1 H-benzimidazol-1 -vO-8- azabicvcloF3.2.11oct-8-yllethyll-4-phenylpiperidine-1 -carboximidoate
Figure imgf000239_0001
Cyclopentyl Λ/-cyano-4-{2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidine-1 -carboximidoate (15 mg, 81 %) was obtained from phenyl Λ/-cyano-4-{2-[3-(2-methyl-1H-benzimidazol- 1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidine-1 -carboximidoate (19 mg, 0.033 mmol) and sodium cyclopentoxide by the similar procedure outlined in example 7. 1H NMR (CDCI3, 300 MHz): δ 7.67 (d, J=6.9Hz, 1 H), 7.42-7.31 (m, 2H), 7.29-7.24 (m, 4H), 7.19-7.12 (m, 2H), 5.51-5.47 (m, 1 H), 4.68 (br, 1 H), 3.99 (br, 2H), 3.35-3.28 (m, 4H), 2.59 (s, 3H), 2.42-2.28 (m, 4H), 1.97-1.81 (m, 14H), 1.75-1.62 (m, 6H). HRMS m/z (M+H)+ calcd: 565.3655, obsd: 565.3663.
Example 393A
Preparation of N'-cvano-4-(2-r3-(2-methyl-1 H-benzimidazol-1 -ylY-8-azabicvclo- r3.2.noct-8-vnethyl)-4-phenylpiperidine-1-carboximidamide
Figure imgf000239_0002
Phenyl Λ/-cyano-4-{2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidine-1 -carboximidoate (100 mg, 0.175 mmol) and a solution of ammonia in methanol (2 mL, 1.4 M) was stirred at ambient temperature for 20 hours. After evaporation of the excess ammonia and the solvent, the residue was subject to flash chromatography (Mega Bond Elut Si, MeOH/EtOAc, 10% to 40%) to afford /V-cyano-4-{2-[3-(2- methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4- phenylpiperidine-1-carboximidamide as amorphous solid (79 mg, 91%). 1H NMR (CDCI3, 300 MHz): δ 7.68-7.65 (m, 1 H), 7.42-7.34 (m, 2H), 7.30-7.24 (m, 4H), 7.20-7.18 (m, 2H), 6.11 (s, 2H), 4.65 (t, J=8.5Hz, 1 H), 3.82-3.78 (m, 2H), 3.27-3.20 (m, 4H), 2.53 (s, 3H), 2.45-2.25 (m, 4H), 1.96-1.84 (m, 10H), 1.64 (d, J=7.5Hz, 2H). HRMS m/z (M+H)+ calcd: 496.3189, obsd: 496.3181.
Example 393B
Preparation of N'-cvano-N-methyl-4-(2- 3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicvclor3.2.1 loct-8-vnethyl)-4-phenylpiperidine-1 -carboximidamide
Figure imgf000240_0001
Λ/'-cyano-Λ/-methyl-4-{2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidine-1 -carboximidamide (18 mg, quant.) was obtained from phenyl Λ/-cyano-4-{2-[3-(2-methyl-1H- benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidine-1- carboximidoate (20 mg, 0.035 mmol) and methylamine (0.7 mL, 2 M in EtOH) by the similar procedure outlined in example 393. 1H NMR (CDCI3, 300 MHz) δ 7.69 (d, J=7.3Hz, 1 H), 7.44-7.39 (m, 2H), 7.32-7.25 (m, 4H), 7.22-7.16 (m, 2H), 5.37 (s, 1 H), 4.83 (br, 1 H), 3.80-3.76 (m, 2H), 3.35-3.24 (m, 4H), 3.03 (d, J=4.6Hz, 3H), 2.63 (s, 3H), 2.56-2.29 (m, 4H), 2.08-1.89 (m, 10H), 1.73-1.71 (m, 2H). HRMS m/z (M+H)+ calcd: 510.3345, obsd: 510.3348. Example 394 Preparation of (4-(2-r3-(2-methyl-1 H-benzimidazol-1 -v -8- azabicvclor3.2.1 loct-8-yllethyl)-4-phenylpiperidin-1 -vπ(morpholin-4- vDmethylidene-cvanamide
Figure imgf000241_0001
(4-{2-[3-(2-Methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8- yl]ethyl}-4-phenylpiperidin-1 -yl)(morpholin-4-yl)methylidenecyanamide (5.1 mg, 26%) was obtained from phenyl Λ/-cyano-4-{2-[3-(2-methyl-1H- benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidine-1- carboximidoate (20 mg, 0.035 mmol) and morpholine (2 mL) by the similar procedure outlined in example 393. 1H NMR (CDCI3, 300 MHz) δ 7.67 (d, J=7.5Hz, 1 H), 7.41-7.37 (m, 2H), 7.29-7.25 (m, 4H), 7.21-7.13 (m, 2H), 3.71- 3.63 (m, 7H), 3.44-3.30 (m, 7H), 2.64 (s, 3H), 2.32-2.16 (m, 4H), 1.98 (br, 8H), 1.69 (br, 6H). HRMS m/z (M+H)+ calcd: 566.3607, obsd: 566.3610.
Example 395 Preparation of methyl N-cvano-4-(2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicvclo[3.2.1loct-8-yllethyl)-4-phenylpiperidine-1-carbimidothioate
Figure imgf000241_0002
To a stirred solution of 2-methyl-1 -{8-[2-(4-phenylpiperidin-4-yl)ethyl]-8- azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole dihydrochloride (25.3 mg, 0.05 mmol) in dichloromethane (2 mL) was added triethylamine (14 μL, 1 mmol) and dimethylcyanodithioiminocarbonate (8.8 mg, 0.06 mmol). The resulting mixture was stirred at ambient temperature for 3 hours before it was quenched with saturated sodium bicarbonate solution. The layers were separated and the aqueous layer was extracted with dichloromethane (2 x 10 mL). The combined organic extracts were dried over anhydrous sodium sulfate. After evaporation of the solvent, the crude product was purified by flash chromatography on silical gel, eluting with a gradient of 0-15% methanol in ethyl acetate to afford methyl Λ/-cyano-4-{2-[3-(2-methyl-1H-benzimidazol- 1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidine-1-carbimidothioate as amorphous solid (18 mg, 68%). 1H NMR (300 MHz, CDCI3) δ 7.70(d, J=7.0Hz, 1 H), 7.46-7.37 (m, 2H), 7.33-7.28 (m, 4H), 7.24-7.16 (m, 2H), 4.72 (br, 1 H), 4.29-4.24 (m, 2H), 3.46 (t, J=11.1 Hz, 2H), 3.31 (br, 2H), 2.78 (s, 3H), 2.62 (s, 3H), 2.54-2.35 (m, 4H), 2.08-1.86 (m, 10H), 1.69 (d, J=7.7Hz, 2H). HRMS m/z (M+H)+ calcd: 527.2957, obsd: 527.2933.
Example 396 Preparation of isopropyl N-cvano-4-(2-r3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicvclor3.2.1loct-8-yllethyl)-4-phenylpiperidine-1-carbimidothioate
Figure imgf000242_0001
To a stirred solution of phenyl Λ/-cyano-4-{2-[3-(2-methyl-1H- benzimidazol-1-yl)-8-azabicyclo[3.2.1] oct-8-yl]ethyl}-4-phenylpiperidine-1- carboximidoate (20 mg, 0.035 mmol) in THF (1 mL) was added sodium 2- propanethiolate (6.8 mg, 0.07 mmol). The resulting mixture was stirred at ambient temperature for 30 minutes before evaporation of the solvent. The crude product was then purified by flash chromatography on silical gel, eluting with a gradient of 0-10% methanol in ethyl acetate to afford isopropyl N- cyano-4-{2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo [3.2.1] oct-8- yl]ethyl}-4-phenylpiperidine-1-carbimidothioate as a white solid (14 mg, 72 %). 1H NMR (300 MHz, CDCI3) δ 7.69 (d, J=7.5Hz, 1 H), 7.45-7.40 (m, 2H), 7.32- 7.24 (m, 4H), 7.21-7.14 (m, 2H), 4.39-4.26 (m, 3H), 3.53 (br, 4H), 2.65 (s, 3H), 2.33-2.05 (m, 4H), 1.99-1.85 (m, 13H), 1.38 (d, J=6.4Hz, 6H). HRMS m/z (M+H)+ calcd: 555.3270, obsd: 555.3274.
Example 397 Preparation of cyclopentyl N-cvano-4-f2-r3-(2-methyl-1 H-benzimidazol-1 -ylV8- azabicvclor3.2.noct-8-vnethyl)-4-phenylpiperidine-1-carbimidothioate
Figure imgf000243_0001
Cyclopentyl Λ/-cyano-4-{2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidine-1-carbimidothioate (20 mg, quant.) was obtained as amorphous solid from phenyl Λ/-cyano-4-{2-[3-(2- methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo [3.2.1]oct-8-yl]ethyl}-4- phenylpiperidine-1 -carboximidoate (20 mg, 0.035 mmol) and sodium cyclopentanethiolate by the similar procedure outlined in example 396. 1H NMR (300 MHz, CDCI3) δ 7.68 (d, J=7.2Hz, 1 H), 7.44-7.39 (m, 2H), 7.31-7.22 (m, 4H), 7.20-7.13 (m, 2H), 4.46-4.42 (m, 1 H), 4.28-4.23 (m, 2H), 3.52-3.45 (m, 4H), 2.63 (s, 3H), 2.52 (br, 2H), 2.33-2.28 (m, 2H), 2.18-2.10 (m, 4H), 2.05-1.91 (m, 8H), 1.87-1.54 (m, 9H). HRMS m/z (M+H)+ calcd: 581.3426, obsd: 581.3438.
Preparation of Amide Derivatives Through HATU Promoted Amidation Method
Figure imgf000243_0002
Example 398 Preparation of 2-methyl-1-(8-(2-[4-phenyl-1-(1 H-pyrazol-4-ylcarbonyl) piperidin-4-yllethyll-8-azabicvclor3.2.1loct-3-v -1 H-benzimidazole
Figure imgf000244_0001
2-Methyl-1 -(8-{2-[4-phenyl-1 -(1 H-pyrazol-4-ylcarbonyl)piperidin-4- yl]ethyl}-8-azabicyclo[3.2.1] oct-3-yl)-1 H-benzimidazole (27 mg, quant.) was obtained as amorphous solid from 2-methyl-1-{8-[2-(4-phenyl piperidin-4- yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole dihydrochloride (25.3 mg, 0.05 mmol) and 4-pyrazoolecarboxylic acid ( 6 mg, 0.05 mmol) by the similar procedure outlined in example 5. 1H NMR (300 MHz, DMSO-d6100°C) δ 7.84 (s, 2H), 7.54-7.51 (m, 1 H), 7.47-7.38 (m, 5H), 7.28-7.24 (m, 1 H), 7.18- 7.11 (m, 2H), 3.91-3.86 (m, 3H), 3.46-3.40 (m, 4H), 3.08 (br, 3H), 2.53 (s, 3H), 2.16 (m, 2H), 2.08-1.74 (m, 12H). HRMS m/z (M+H)+ calcd: 523.3185, obsd: 523.3195.
Example 399 Preparation of 2-methyl-1-r(1 R.5S)-8-(2-(1-[(5-methyl-1 H-pyrazol-3- yl)carbonyll-4-phenylpiperidin-4-yllethyl)-8-azabicvclof3.2.1loct-3-vn-1 H- benzimidazole
Figure imgf000244_0002
2-Methyl-1 -[(1 R, 5S)-8-(2-{1 -[(5-methyl-1 H-pyrazol-3-yl)carbonyl]-4- phenylpiperidin-4-yl}ethyl)-8-azabicyclo[3.2.1]oct-3-yl]-1 H-benzimidazole (34 mg, 53%) was obtained as amorphous solid from 2-methyl-1-{8-[2-(4- phenylpiperidin-4-yl)ethyl]-8-azabicyclo [3.2.1]oct-3-yl}-1 H-benzimidazole (51 mg, 0.12 mmol), 5-methyl-1H-pyrazole-3-carboxylic acid (15 mg, 0.12 mmol) and HATU (47 mg, 0.12 mmol) by the similar procedure outlined in example 5. 1H NMR (300 MHz, DMSO-d6) δ 12.78 (s, 1 H), 7.49-7.47 (m, 1 H), 7.38-7.33 (m, 4H), 7.23-7.21 (m, 1 H), 7.11-7.05 (m, 3H), 6.24 (s, 1 H), 4.50 (br, 1 H), 4.12 (br, 1 H), 3.86 (br, 1 H), 3.60 (br, 1 H), 3.23 (br, 3H), 2.45 (s, 3H), 2.39-2.32 (m, 2H), 2.23 (s, 3H), 2.09 (br, 2H), 1.97-1.71 (m, 10H), 1.58-1.55 (m, 2H). HRMS m/z (M+H)+ calcd: 537.3342, obsd: 537.3367.
Example 400 Preparation of 6-methyl-3-r(4-(2-IY1 R.5SV3-(2-methyl-1 H-benzimidazol-1 -yl)- 8-azabicyclof3.2.1loct-8-yll ethyl)-4-phenylpiperidin-1-v0carbonyripyridin- 2(1 H)-one
Figure imgf000245_0001
6-Methyl-3-[(4-{2-[(1 R, 5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]pyridin-2(1H)- one (30 mg, 53%) was obtained as amorphous solid from 2-methyl-1-{8-[2-(4- phenylpiperidin-4-yl)ethyl]-8-azabicyclo [3.2.1]oct-3-yl}-1 H-benzimidazole dihydrochloride (51 mg, 0.10 mmol), 2-hydroxyl-6-methylpyridine-3-carboxylic acid (15 mg, 0.10 mmol) and HATU (38 mg, 0.10 mmol) by the similar procedure outlined in example 5. 1H NMR (400 MHz, CDCI3) δ 8.15 (d, J=7.5Hz, 1 H), 7.65 (d, J=7.3Hz, 1 H), 7.50-7.34 (m, 2H), 7.30-7.21 (m, 5H), 7.19-7.12 (m, 2H), 6.18 (d, J=7.5Hz, 1 H), 4.66-4.56 (m, 1 H), 4.14-4.07 (m, 1 H), 3.88 (br, 2H), 3.25 (br, 3H), 2.56 (s, 3H), 2.40-2.08 (m, 8H), 1.93-1.84 (m, 10H), 1.61 (d, J=6.5Hz, 2H). HRMS m/z (M+H)+ calcd: 564.3339, obsd: 564.3349. Example 401 Preparation of 5-r(4-(2-lϊ1 R.5S 3-(2-methyl-1 H-benzimidazol-1 -vh-8- azabicvclor3.2.noct-8-vnethylV4-phenylpiperidin-1-vπcarbonyllpyridin-2(1 H)- one
Figure imgf000246_0001
5-[(4-{2-[(1 R, 5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]pyridin-2(1H)- one (28 mg, 51 %) was obtained as amorphous solid from 2-methyl-1 -{8-[2-(4- phenylpiperidin-4-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole dihydrochloride (51 mg, 0.10 mmol), 6-hydroxynicotinic acid (14 mg, 0.10 mmol) and HATU (38 mg, 0.10 mmol) by the similar procedure outlined in example 5. 1H NMR (400 MHz, CDCI3) δ 7.66-7.62 (m, 2H), 7.54 (d, J=7.4Hz, 1 H), 7.40-7.36 (m, 2H), 7.35-7.23 (m, 4H), 7.19-7.12 (m, 2H), 6.57 (d, J=9.6Hz, 1 H), 4.64-4.59 (m, 1 H), 3.88 (br, 2H), 3.34-3.25 (m, 4H), 2.56 (s, 3H), 2.41-2.20 (m, 4H), 1.93-1.82 (m, 10H), 1.62 (d, J=6.2Hz, 2H). HRMS m/z (M+H)+ calcd: 550.3182, obsd: 550.3169.
Example 402 Preparation of 5-chloro-3-IT4-f2-r(1 R.5S)-3-(2-methyl-1 H-benzimidazol-1 -vh-8- azabicvclor3.2.noct-8-yll ethyl)-4-phenylpiperidin-1-yl)carbonyllpyridin-2(1 H one
Figure imgf000246_0002
5-Chloro-3-[(4-{2-[(1 R, 5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]pyridin-2(1H)- one (20 mg, 34%) was obtained as amorphous solid from 2-methyl-1-{8-[2-(4- phenylpiperidin-4-yl)ethyl]-8-azabicyclo [3.2.1]oct-3-yl}-1 H-benzimidazole dihydrochloride (51 mg, 0.10 mmol), 5-chloro-2-hydroxylpyridine-3-carboxylic acid (18 mg, 0.10 mmol) and HATU (38 mg, 0.10 mmol) by the similar procedure outlined in example 5. 1H NMR (400 MHz, CDCI3) δ 7.65 (d, J=8.4Hz, 1 H), 7.51-7.45 (m, 2H), 7.40-7.35 (m, 2H), 7.31-7.24 (m, 4H), 7.22- 7.12 (m, 2H), 4.64-4.58 (m, 1 H), 4.15-4.08 (m, 2H), 3.45-3.23 (m, 6H), 2.57 (s, 3H), 2.42-2.26 (m, 5H), 1.94-1.85 (m, 10H), 1.60 (d, J=6.8Hz, 2H). HRMS m/z (M+H)+ calcd: 584.2792, obsd: 584.2785.
Example 403 Preparation of 3-chloro-5-r(4-(2-lϊ1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicvclor3.2.noct-8-vnethyl)-4-phenylpiperidin-1-yl)carbonvnpyridin-2-(1 H)- one
Figure imgf000247_0001
3-Chloro-5-[(4-{2-[(1 R, 5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]pyridin-2(1H)- one (25 mg, 42%) was obtained as amorphous solid from 2-methyl-1-{8-[2-(4- phenylpiperidin-4-yl)ethyl]-8-azabicyclo [3.2.1]oct-3-yl}-1 H-benzimidazole dihydrochloride (51 mg, 0.10 mmol), 5-chloro-6-hydroxylnicotinic acid (18 mg, 0.10 mmol) and HATU (38 mg, 0.10 mmol) by the similar procedure outlined in example 5. 1H NMR (400 MHz, CDCI3) δ 7.76 (s, 1 H), 7.66-7.63 (m, 2H), 7.41-7.38 (m, 2H), 7.35-7.24 (m, 4H), 7.19-7.12 (m, 2H), 4.64-4.59 (m, 1 H), 3.89 (br, 2H), 3.35-3.26 (m, 4H), 2.57 (s, 3H), 2.41-2.28 (m, 4H), 1.94-1.83 (m, 11 H), 1.62 (d, J=7.9 Hz, 2H). HRMS m/z (M+H)+ calcd: 584.2792, obsd: 584.2787. Example 404 Preparation of (2S)-N1,N1-bisf4-f2-lϊ1 R.5S)-3-(2-methyl-1 H-benzimidazol-1- vn-8-azabicvclor3.2.1loct-8-yllethyl)-1-fN-(methylsulfonvn-L-seryll-4- phenylpiperidin-2-yl)-N2-(methylsulfonv -L-serinamide
Figure imgf000248_0001
{2S)-N1,N1-B\s{4-{2-[{ R, 5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-1-[Λ/-(methylsulfonyl)-- -seryl]-4- phenylpiperidin-2-yl}-Λ/2-(methylsulfonyl)-L-serinamide (43 mg, 50 %) was obtained as amorphous solid from 2-methyl-1-{8-[2-(4-phenylpiperidin-4- yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole dihydrochloride (70 mg, 0.14 mmol), Λ/-(methylsulfonyl)-L-serine (28 mg, 0.15 mmol, prepared from -serine and methanesulfonyl chloride) and HATU (57 mg, 0.15 mmol) by the similar procedure outlined in example 5. 1H NMR (400 MHz, CDCI3) δ 7.65 (d, J=8.4Hz, 1 H), 7.40-7.36 (m, 2H), 7.29-7.23 (m, 4H), 7.19-7.12 (m, 2H), 5.78 (dd, J=8.6, 16.5Hz, 1 H), 4.63-4.58 (m, 1 H), 4.56-4.45 (m, 1 H), 4.09- 4.04 (m, 1 H), 3.85-3.65 (m, 3H), 3.40-3.09 (m, 4H), 3.02 (s, 3/2H), 2.90 (s, 3/2H), 2.57 (s, 3H), 2.41-2.20 (m, 5H), 1.99-1.74 (m, 10H), 1.64-1.59 (m, 2H). HRMS m/z (M+H)+ calcd: 594.3114, obsd: 594.3114.
Example 405 Prearation of (2S,3R)-N1.N1-bisf4-(2-IT1 R.5S)-3-(2-methyl-1 H-benzimidazol-1- ylV8-azabicvclo[3.2.1 loct-8-yllethylH -rN-(methylsulfonvn-L-threonvn-4- phenylpiperidin-2-yl)-N2-(methylsulfonyl)-L-threoninamide
Figure imgf000249_0001
(2S, 3R)- ^,Λ/ -Bis{4-{2-[(1 R, 5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-1-[Λ/-(methylsulfonyl)- -threonyl]-4- phenylpiperidin-2-yl}-Λ/ -(methylsulfonyl)- -threoninamide (54 mg, 63%) was obtained as amorphous solid from 2-methyl-1-{8-[2-(4-phenylpiperidin-4- yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole dihydrochloride (70 mg, 0.14 mmol), Λ/-(methylsulfonyl)- -threonine (33 mg, 0.17 mmol, prepared from -threonine and methanesulfonyl chloride) and HATU (57 mg, 0.15 mmol) by the similar procedure outlined in example 5. 1H NMR (400 MHz, CDCIs) δ 7.64 (d, J=8.6Hz, 1 H), 7.38-7.35 (m, 2H), 7.28-7.22 (m, 4H), 7.18- 7.11 (m, 2H), 6.00 (br, 1 H), 4.64-4.54 (m, 1 H), 4.29 (d, J=9.7Hz, 1 H), 4.08- 4.00 (m, 1 H), 3.94-3.91 (m, 1 H), 3.77-3.71 (m, 1 H), 3.40-3.06 (m, 5H), 2.98 (s, 3/2H), 2.84 (s, 3/2H), 2.56 (s, 3H), 2.39-2.20 (m, 4H), 1.98-1.73 (m, 10H), 1.62-1.57 (m, 2H), 1.32 (d, J=6.2Hz, 3/2H), 1.25 (d, J=6.2Hz, 3/2H). HRMS m/z (M+H)+ calcd: 608.3271 , obsd: 608.3283.
Example 406 Preparation of 1 -(8-(2-H -flsoxazol-3-ylcarbonyl)-4-phenylpiperidin-4-vπethyl)- 8-azabicyclo[3.2.1loct-3-vπ-2-methyl-1 H-benzimidazole
Figure imgf000250_0001
To a pre-cooled (0 °C) solution of 2-methyl-1-{8-[2-(4-phenylpiperidin-
4-yl)ethyl]-8-azabicyclo [3.2.1]oct-3-yl}-1 H-benzimidazole dihydrochloride (25.3 mg, 0.05 mmol) in dichloromethane (3 mL) was added isoxazole-5- carbonyl chloride (7.2 mg, 0.055 mmol) and triethylamine (15 μL, 0.11 mmol). The resulting mixture was stirred overnight at ambient temperature and was then diluted with ethyl acetate (20 mL). After being washed with saturated sodium bicarbonate solution, the organic phase was dried over anhydrous sodium sulfate and evaporated. The crude product was purified by flash chromatography on silical gel, eluting with a gradient of 0-10% methanol in ethyl acetate to afford 1-(8-{2-[1-(isoxazol-3-ylcarbonyl)-4-phenylpiperidin-4- yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1 H-benzimidazole as amorphous solid (18.4 mg, 68%). 1H NMR (300 MHz, CDCI3) δ 8.32 (d, J=1.8Hz), 7.67 (dd, J=2.6, 7.0Hz, 1 H), 7.43-7.38 (m, 2H), 7.34-7.24 (m, 4H), 7.21-7.13 (m, 2H), 6.74 (d, J=1.8Hz), 4.64 (br, 1 H), 4.23-4.18 (m, 1H), 3.93- 3.89 (m, 1 H), 3.45-3.27 (m, 4H), 2.58 (s, 3H), 2.44-2.31 (m, 4H), 1.96-1.86 (m, 10H), 1.67-1.60 (m, 2H). HRMS m/z (M+H)+ calcd: 524.3026, obsd: 524.3024.
Preparation of the derivatives of 2-Methyl-1-f8-r2-(4-Phenylpiperidin-4- vDethvπ-8-Azabicvclor3.2.πoct-3-yl -1 H-benzimidazole with Heterocvcle- Methylene-Piperidine Linkages by Reductive Amination
Figure imgf000251_0001
Example 407 Preparation of 2-methyl-1-(8-(2-f4-phenyl-1-(1 ,3-thiazol-2-ylmethvπ-piperidin- 4-yl1ethyl)-8-azabicvclof3.2.1loct-3-vπ-1 H-benzimidazole
Figure imgf000251_0002
To a stirred solution of 2-methyl-1-{8-[2-(4-phenylpiperidin-4-yl)ethyl]-8- azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole dihydrochloride (25.3 mg, 0.05 mmol) in 1 ,2-dichloroethane (1 mL) was added triethylamine (14 μL, 0.1 mmol), 2-thiazole-carboxaldehyde (6.6 mg, 0.05 mmol) and sodium triacetoxylborohydride (10.6 mg, 0.05 mmol). The resulting mixture was stirred for 4 hours at ambient temperature before it was quenched with saturated sodium bicarbonate solution. The aqueous phase was extracted with ethyl acetate (2 x 10 mL). The combined extracts was washed with brine and dried over anhydrous sodium sulfate. After evaporation of the solvents, the residue was brought to a flash chromatography on silical gel, eluting with a gradient of 0-10% methanol in ethyl acetate to afford 2-methyl-1-(8-{2-[4- phenyl-1-(1 ,3-thiazol-2-ylmethyl)piperidin-4-yl]ethyl}-8-azabicyclo-[3.2.1]oct-3- yl)-1 H-benzimidazole (23 mg, 87%). 1H NMR (300 MHz, CDCI3) δ 7.79-7.65 (m, 2H), 7.46-7.37 (m, 2H), 7.34-7.15 (m, 7H), 5.32 (br, 1 H), 3.68 (s, 2H), 3.54 (br, 2H), 2.82-2.80 (m, 2H), 2.67 (s, 3H), 2.63-2.47 (m, 4H), 2.25 (br, 4H), 2.08-1.96 (m, 8H), 1.86 (br, 2H). HRMS m/z (M+H)+ calcd: 526.3004, obsd: 526.3008. Example 408 Preparation of 1-(8-(2-H-(1 H-imidazol-2-ylmethyl)-4-phenylpiperidin-4- vnethyl)-8-azabicvclo[3.2.1loct-3-vπ-2-methyl-1 H-benzimidazole
Figure imgf000252_0001
1 -(8-{2-[1 -(1 H-imidazol-2-ylmethyl)-4-phenylpiperidin-4-yl]ethyl}-8- azabicyclo[3.2.1]oct-3-yl)-2-methyl-1 H-benzimidazole (9.9 mg, 39%) was obtained as amorphous solid from 2-methyl-1-{8-[2-(4-phenylpiperidin-4- yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole dihydrochloride (25.3 mg, 0.05 mmol) and imidazol-2-carboxaldehyde (14.4 mg, 0.15 mmol) following the procedure outlined in example 407. 1H NMR (300 MHz, CDCI3) δ 9.78 (s, 10H), 7.69 (d, J=7.1 Hz, 2H), 7.41-7.27 (m, 5H), 7.25-7.17 (m, 3H), 7.03 (s, 2H), 4.68-4.63 (m, 1 H), 3.63 (s, 2H), 3.26 (br, 2H), 2.66-2.64 (m, 2H), 2.60 (s, 3H), 2.45-2.35 (m, 4H), 2.20-2.10 (m, 4H), 1.96-1.71 (m, 8H), 1 ,63 (d, J=7.7Hz, 2H). HRMS m/z (M+H)+ calcd: 509.3393, obsd: 509.3393.
Example 409 Preparation of 1 -(8-12-H -(2-fuiNlmethvO-4-phenylpiperidin-4-yl]ethyl)-8- azabicvclo[3.2.πoct-3-yl)-2-methyl-1 H-benzimidazole
Figure imgf000252_0002
1-(8-{2-[1-(2-Furylmethyl)-4-phenylpiperidin-4-yl]ethyl}-8- azabicyclo[3.2.1]oct-3-yl)-2-methyl-1 H-benzimidazole (18.4 mg, 72 %) was obtained as oil from 2-methyl-1-{8-[2-(4-phenylpiperidin-4-yl)ethyl]-8- azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole dihydrochloride (25.3 mg, 0.05 mmol) and 2-furaldehyde (4.8 mg, 0.05 mmol) following the procedure outlined in example 407. 1H NMR (300 MHz, CDCI3) δ 7.69 (d, J=7.0Hz, 1 H), 7.40-7.19 (m, 9H), 6.34 (s, 1H), 6.19 (s, 1H), 4.68-4.61 (m, 1H), 3.50 (s, 2H), 3.25 (br, 2H), 2.67 (br, 2H), 2.60 (s, 3H), 2.45-2.26 (m, 6H), 1.96-1.80 (m, 10H), 1.62 (d, J=7.8Hz, 2H). HRMS m/z (M+H)+ calcd: 509.3280, obsd: 509.3276.
Example 410 Preparation of (4-(2-r3-(2-methyl-1 H-benzimidazol-1 -ylV8- azabicvclo[3.2.11oct-8-vnethyll-4-phenylpiperidin-1-vπacetic acid
Figure imgf000253_0001
(4-{2-[3-(2-Methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8- yl]ethyl}-4-phenylpiperidin-1-yl)acetic acid (5.2 mg, 21 %) was obtained as oil from 2-methyl-1-{8-[2-(4-phenylpiperidin-4-yl)ethyl]-8-azabicyclo[3.2.1]oct-3- yl}-1 H-benzimidazole dihydro-chloride (25.3 mg, 0.05 mmol) and glyoxylic acid monohydrate (4.6 mg, 0.05 mmol) following the procedure outlined in example 407. 1H NMR (300 MHz, CDCI3) δ 7.69 (s, 1 H), 7.44 (d, J=7.3 Hz, 2H), 7.33-7.28 (m, 4H), 7.21 (br, 2H), 4.63 (m, 1 H), 3.93-3.85 (m, 3H), 3.32 (br, 2H), 3.10-3.06 (m, 2H), 2.63 (s, 3H), 2.54-2.33 (m, 4H), 2.01-1.90 (m, 11 H), 1.68 (d, J=7.7Hz, 2H). HRMS m/z (M+H)+ calcd: 487.3073, obsd: 487.3089.
Example 411
Preparation of 2,3-dimethoxy-6-r(4-f2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicvclo[3.2.11oct-8-yllethylV4-phenylpiperidin-1 -vDmethvnbenzoic acid
Figure imgf000253_0002
2,3-Dimethoxy-6-[(4-{2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo-[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)methyl]benzoic acid (14.4 mg, 46%)was obtained as oil from 2-methyl-1-{8-[2-(4-phenylpiperidin-4- yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole dihydrochloride (25.3 mg, 0.05 mmol) and 6-formyl-2,3-dimethoxybenzoic acid (10.5 mg, 0.05 mmol) following the procedure outlined in example 407. 1H NMR (300 MHz, CDCIs) δ 7.69 (d, J=7.4Hz, 1 H), 7.41-7.39 (m, 2H), 7.30-7.23 (m, 4H), 7.23- 7.14 (m, 2H), 6.81-6.77 (m, 2H), 4.63-4.58 (m, 1 H), 3.95 (s, 3H), 3.86 (s, 3H), 3.65 (s, 2H), 3.23 (br, 2H), 2.95 (br, 2H), 2.57 (s, 3H), 2.42-2.38 (m, 6H), 1.94- 1.81 (m, 10H), 1.62 (d, J=7.7Hz, 2H). HRMS m/z (M+H)+ calcd: 623.3597, obsd: 623.3585.
Preparation of Substituted Phenyl Acetic Acid Derivatives of 2-Methyl-1-{8-[2- (4-Phenylpiperidin-4-v0ethyll-8-Azabicvclor3.2.1 loct-3-yl)-1 H-benzimidazole by Petasis Coupling
Figure imgf000254_0001
Example 412 Preparation of (4-(2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8-azabicvclo- [3.2.1loct-8-yllethyl)-4-phenylpiperidin-1-yl)(phenyl)acetic acid
Figure imgf000254_0002
To a stirred solution of 2-methyl-1-{8-[2-(4-phenylpiperidin-4-yl)ethyl]-8- azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole dihydrochloride (25.3 mg, 0.05 mmol) in THF (3 mL) was added triethyl amine (14 μL), glyoxylic acid monohydrate (4.6 mg, 0.05 mmol) and phenyl boronic acid (6.1 mg, 0.05 mmol). The resulting mixture was then purged with nitrogen and sealed. After being heated to 60 °C for 3 hours, the solvent was evaporated and the residue was purified by flash chromatography on silical gel, eluting with a gradient of 10-80% methanol in ethyl acetate to afford (4-{2-[3-(2-methyl-1H- benzimidazol-1 -yl)-8-azabicyclo[3.2.1 ]oct-8-yl]ethyl}-4-phenylpiperidin-1 - yl)(phenyl)acetic acid (22 mg, 76%). 1H NMR (300 MHz,DMSO-d6) δ 9.41 (s, 1 H), 7.53-7.48 (m, 3H), 7.36-7.34 (m, 8H), 7.24-7.23 (m, 1 H), 7.17-7.09 (m, 2H), 4.58-4.45 (m, 1 H), 4.20 (s, 1 H), 3.24-3.21 (m, 2H), 3.08 (br, 1 H), 2.82- 2.65 (m, 2H), 2.82-2.65 (m, 2H), 2.44 (s, 3H), 2.39-2.05 (m, 7H), 1.83-1.68 (m, 8H), 1.59 (d, J=7.6Hz, 2H). HRMS m/z (M+H)+ calcd: 563.3386, obsd: 563.3390.
Example 413 Synthesis of methyl (4-{2-r3-(2-methyl-1 H-benzimidazol-1 -vH-8- azabicvclo[3.2.11oct-8-yllethyl)-4-phenylpiperidin-1 -yl)(phenvOacetate
Figure imgf000255_0001
To a stirred solution of (4-{2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo-[3.2.1 ]oct-8-yl]ethyl}-4-phenylpiperidin-1 -yl)(phenyl)acetic acid
(prepared above) (12 mg, 0.02 mmol) in methanol (2 mL) was added
(tirmethylsilyl)diazomethane (100 μL, 2.0 M in hexans). The reaction mixture was stirred for 30 minutes at room temperature. After evaporation of the solvents, the residue was purified by flash chromatography, eluting with a gradient of 0-10% methanol in ethyl acetate, to afford an oil (10 mg, 81%) as methyl (4-{2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1]oct-8- yl]ethyl}-4-phenylpiperidin-1-yl)(phenyl)acetate. 1H NMR (300 MHz, CDCI3) δ 7.67 (d, J=7.1 Hz, 1 H), 7.45-7.42 (m, 2H), 7.37-7.27 (m, 8H), 7.23-7.15 (m, 3H), 4.61 (m, 1 H), 3.89 (s, 1 H), 3.67 (s, 3H), 3.25-3.24 (m, 2H), 2.72-2.70 (m, 1H), 2.55 (s, 4H), 2.42-2.16 (m, 6H), 2.03-1.85 (m, 7H), 1.81-1.76 (m, 3H), 1.61-1.58 (m, 2H). HRMS m/z (M+H)+ calcd: 577.3543, obsd: 577.3557.
Example 414 Preparation of (5-chlorothien-2-v0(4-(2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicvclor3.2.11oct-8-vnethylV4-phenylpiperidin-1-yl)acetic acid
Figure imgf000256_0001
(5-Chlorothien-2-yl)(4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)acetic acid (29 mg, 96%) was obtained as amorphous solid from 2-methyl-1-{8-[2-(4- phenylpiperidin-4-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole dihydrochloride (25.3 mg, 0.05 mmol) and 5-chlorothiophene-2-boronic acid (8.1 mg, 0.05 mmol) following the procedure outlined in example 412. 1H NMR (300 MHz, DMSO-d6, 100°C) δ 7.50-7.45 (m, 1 H), 7.38-7.32 (m, 5H), 7.17-7.12 (m, 3H), 6.99-6.86 (m, 2H), 4.61-4.57 (m, 1 H), 4.30-4.24 (m, 1 H), 3.23 (br, 3H), 2.82-2.80 (m, 3H), 2.57-2.37 (m, 7H), 2.14 (br, 2H), 1.93-1.77 (m, 8H), 1.64-1.61 (m, 2H). HRMS m/z (M+H)+ calcd: 603.2561 , obsd: 603.2552. Example 415 Preparation of (4-methoχyphenγ0(4-f2-r3-(2-methyl-1 H-benzimidazol-1 -ylV8- azabicvclor3.2.1loct-8-vnethylV4-phenylpiperidin-1-vπacetic acid
Figure imgf000257_0001
(4-Methoxyphenyl)(4-{2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)acetic acid (25.6 mg, 86%) was obtained as amorphous solid from 2-methyl-1 -{8-[2-(4- phenylpiperidin-4-yl)ethyl]-8-azabicyclo[3.2.1 ]oct-3-yl}-1 H-benzimidazole dihydrochloride (25.3 mg, 0.05 mmol) and 4-methoxyphenylboronic acid (7.6 mg, 0.05 mmol) following the procedure outlined in example 412. 1H NMR (300 MHz, DMSO-de, 80°C) δ 9.44 (s, 1H), 7.52 (d, J=7.0Hz, 1H), 7.38-7.36 (m, 7H), 7.24-7.21 (m, 1 H), 7.17-7.12 (m, 2H), 6.92 (d, J=8.2Hz, 2H), 4.60- 4.51 (m, 1 H), 4.04 (s, 1 H), 3.78 (s, 3H), 3.26-3.22 (m, 3H), 2.97-2.90 (m, 2H), 2.75 (br, 1 H), 2.47 (s, 3H), 2.40-1.81 (m, 9H), 1.63 (d, J=7.3Hz, 2H). HRMS m/z (M+H)+ calcd: 593.3492, obsd: 593.3496.
Example 416 Preparation of (4-fluorophenyl)(4-f2-r3-(2-methyl-1 H-benzimidazol-1 -vD-8- azabicvclo[3.2.11oct-8-vπethylH-phenylpiperidin-1 -vOacetic acid
Figure imgf000257_0002
(4-Fluorophenyl)(4-{2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)acetic acid (24.5 mg, 84%) was obtained as amorphous solid from 2-methyl-1-{8-[2-(4- phenylpiperidin-4-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole dihydrochloride (25.3 mg, 0.05 mmol) and 4-fluorophenylboronic acid (7 mg, 0.05 mmol) following the procedure outlined in example 412. 1H NMR (300 MHz, DMSO-de) δ 7.52-7.48 (m, 3H), 7.37-7.35 (m, 4H), 7.24-7.05 (m, 6H), 4.54-4.48 (m, 1 H), 4.07 (s, 1 H), 3.23 (br, 2H), 2.98 (br, 1 H), 2.69-2.63 (m, 2H), 2.45 (s, 3H), 2.42-2.31 (m, 3H), 2.18 (br, 2H), 2.00 (br, 2H), 1.87-1.74 (m, 8H), 1 ,59 (d, J=7.3Hz, 2H). HRMS m/z (M+H)+ calcd: 581.3293, obsd: 581.3287.
Example 417
Synthesis of methyl (4-fluorophenyl)(4-{2-r3-(2-methyl-1 H-benzimidazol-1 -yl)- 8-azabicvclo[3.2.noct-8-yllethyl)-4-phenylpiperidin-1-yl)acetate
Figure imgf000258_0001
Methyl (4-fluorophenyl)(4-{2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)acetate (12 mg, 96%) was obtained as a solid from (4-fluorophenyl)(4-{2-[3-(2-methyl-1H- benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1- yl)acetic acid (12 mg, 0.02 mmol) and (trimethylsilyl)diazomethane (100 μL 2.0 M in hexanes) following the procedure outlined for example 9. 1H NMR (300 MHz, CDCIs) δ 7.67 (d, J=7.1 Hz, 1 H), 7.47-7.45 (m, 1 H), 7.41-7.38 (m, 2H), 7.32-7.29 (m, 5H), 7.17-7.11 (m, 3H), 7.09-7.06 (m, 2H), 4.60-4.40 (m, 1 H), 4.00 (s, 1 H), 3.54 (s, 3H), 3.17 (br, 2H), 2.60-2.43 (m, 1 H), 2.43-2.41 (m, 4H), 2.33-2.25 (m, 2H), 2.24-2.20 (m, 1 H), 2.19-2.00 (m, 3H), 1.78-1.69 (m, 10H), 1.54 (d, J=7.5Hz, 2H). HRMS m/z (M+H)+ calcd: 595.3448, obsd: 595.3467. Example 418 Preparation of 1 ,3-benzodioxol-5-yl(4-l2-[3-('2-methyl-1 H-benzimidazol-1 -yl .- 8-azabicvclo[3.2.1 loct-8-vnethyl)-4-phenylpiperidin-1 -vOacetic acid
Figure imgf000259_0001
1 ,3-Benzodioxol-5-yl(4-{2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)acetic acid (25 mg, 81%) was obtained as amorphous solid from 2-methyl-1-{8-[2-(4- phenylpiperidin-4-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole dihydrochloride (25.3 mg, 0.05 mmol) and 3,4-dioxolmethylenephenyl boronic acid (9.3 mg, 0.05 mmol) following the procedure outlined in example 412. 1H NMR (300 MHz, DMSO-d6) δ 9.40 (s, 1H), 7.52 (m, 1 H), 7.38-7.37 (m, 5H), 7.24 (m, 1 H), 7.17-7.08 (m, 3H), 6.96-6.87 (m, 2H), 6.03 (d, J=5.1Hz, 2H), 4.45.4.48 (m, 1 H), 4.16 (s, 1 H), 3.23-3.08 (m, 5H), 2.82 (br, 2H), 2.45 (s, 3H), 2.40-2.01 (m, 6H), 1.82-1.79 (m, 7H), 1.60 (d, J=7.4Hz, 2H). HRMS m/z (M+H)+ calcd: 607.3284, obsd: 607.3270.
Example 419 Preparation of (2.6-dimethylphenyl)(4-f2-[3-(2-methyl-1 H-benzimidazol-1 -ylV 8-azabicvclo[3.2.1 loct-8-yllethyl)-4-phenylpiperidin-1 -vDacetic acid
Figure imgf000259_0002
(2,6-Dimethylphenyl)(4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)acetic acid (26 mg, 90%) was obtained as amorphous solid from 2-methyl-1-{8-[2-(4- phenylpiperidin-4-yl)ethyl]-8-azabicyclo[3.2.1 ]oct-3-yl}-1 H-benzimidazole dihydrochloride (25.3 mg, 0.05 mmol) and 2,6-dimethylphenyl boronic acid (9 mg, 0.06 mmol) following the procedure outlined in example 412. 1H NMR (300 MHz, DMSO-de) δ 9.31 (s, 1 H), 7.48 (d, J=6.9Hz, 1H), 7.33-7.32 (m, 5H), 7.19-7.17 (m, 1 H), 7.13-6.96 (m, 5H), 4.5-4.49 (m, 1 H), 4.29 (s, 1 H), 3.24 (br, 2H), 2.83 (br, 1 H), 2.41 (s, 3H), 2.37 (m, 7H), 2.29-2.07 (m, 5H), 1.97-1.72 (m, 10H), 1.58 (d, J=7.2Hz, 2H). HRMS n7/z (M+H)+ calcd: 591.3699, obsd: 591.3690.
Example 420 Preparation of (2,3-dimethylphenvh(4-(2-r3-(2-methyl-1 H-benzimidazol-1 -yl)- 8-azabicvclo[3.2.1loct-8-yllethyl)-4-phenylpiperidin-1-yl)acetic acid
Figure imgf000260_0001
(2,3-Dimethylphenyl)(4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)acetic acid (35 mg, 99%) was obtained as amorphous solid from 2-methyl-1-{8-[2-(4- phenylpiperidin-4-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole dihydrochloride (30 mg, 0.06 mmol) and 2,3-dimethylphenyl boronic acid (10.5 mg, 0.07 mmol) following the procedure outlined in example 412. 1H NMR (300 MHz, DMSO-de) δ 9.37 (s, 1 H), 7.49-7.47 (m, 1 H), 7.39-7.32 (m, 6H), 7.22-7.18 (m, 1 H), 7.13-7.03 (m, 4H), 4.5-4.44 (m, 2H), 3.23 (br, 2H), 3.04-
2.88 (m, 2H), 2.71 (br, 1H), 2.56-2.51 (m, 1H), 2.39 (s, 3H), 2.36-2.29 (m, 2H), 2.25 (s, 3H), 2.22 (s, 3H), 2.15-1.93 (m, 5H), 1.81 (br, 7H), 1.58 (d, J=7.2Hz, 2H). HRMS m/z (M+H)+ calcd: 591.3699, obsd: 591.3706. Example 421 Synthesis of methyl (2.3-dimethylphenvD(4-l2-r3-(2-methyl-1 H-benzimidazol- 1-vπ-8-azabicvclo[3.2.1loct-8-yl1ethyl)-4-phenylpiperidin-1-vhacetate
Figure imgf000261_0001
Methyl (2,3-dimethylphenyl)(4-{2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)acetate (40 mg, 66%) was obtained as a solid from (2,3-Dimethylphenyl)(4-{2-[3-(2-methyl-1H- benzimidazol-1-yl)-8-azabicyclo[3.2.1] oct-8-yl]ethyl}-4-phenylpiperidin-1- yl)acetic acid (40 mg, 0.067 mmol) and (trimethylsilyl)diazomethane (300 μL 2.0 M in hexanes) following the procedure outlined for example 9. 1H NMR (300 MHz, CDCI3) δ 7.67 (d, J=7.8Hz, 1 H), 7.44-7.27 (m, 6H), 7.23-7.15 (m, 3H), 7.10-7.07 (m, 2H), 4.66-4.59 (m, 1 H), 4.30 (s, 1 H), 3.65 (s, 3H), 3.25 (br, 2H), 2.77 (br, 1 H), 2.67 (br, 1 H), 2.56 (s, 3H), 2.47-2.32 (m, 3H), 2.29 (s, 6H), 2.26-2.12 (m, 3H), 1.99-183 (m, 10H), 1.61-1.59 (m, 2H). HRMS m/z (M+H)+ calcd: 605.3856, obsd: 605.3863.
Example 422 Preparation of (3,5-dimethylphenyl)(4-{2-[3-(2-methyl-1 H-benzimidazol-1 -yl)- 8-azabicvclof3.2.1loct-8-yllethyl -4-phenylpiperidin-1-vπacetic acid
Figure imgf000261_0002
3,5-Dimethylphenyl)(4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl) acetic acid (28 mg, 94%) was obtained as amorphous solid from 2-methyl-1 -{8-[2-(4- phenylpiperidin-4-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole dihydrochloride (25 mg, 0.05 mmol) and 3,5-dimethylphenyl boronic acid (9.0 mg, 0.06 mmol) following the procedure outlined in example 412. 1H NMR (300 MHz, DMSO-de) δ 9.37 (s, 1H), 7.48-7.47 (m, 1H), 7.35-7.33 (m, 5H), 7.23-7.19 (m, 1 H), 7.11-7.07 (m, 4H), 6.94 (s, 1H), 4.53-4.47 (m, 1H), 4.13 (s, 1H), 3.23-3.15 (m, 4H), 2.83 (br, 2H), 2.39 (s, 3H), 2.36-2.25 (m, 3H), 2.21 (s, 6H), 2.14 (m, 4H), 1.81-1.70 (m, 8H), 1.58 (d, J=7.6Hz, 2H). HRMS m/z (M+H)+ calcd: 591.3699, obsd: 591.3707.
Preparation of ortho-, meta- and para-Carboxyl Benezamide Derivatives of 2- Methyl-1-(8-r2-(4-Phenylpiperidin-4-vnethvn-8-Azabicvclor3.2.noct-3-yl)-1H- Benzimidazole
Figure imgf000262_0001
Example 423 Preparation of ethyl 2-IY4-(2-r3-(2-methyl-1 H-benzimidazol-1 -vH-8- azabicvclor3.2.1loct-8-vnethylV4-phenylpiperidin-1-vπcarbonyllbenzoate
Figure imgf000263_0001
To a stirred solution of 2-[(4-{2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8- , azabicyclo-[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]benzoic acid (58 mg, 0.1 mmol) in dichloromethane (5 mL) was added ethanol (8.6 μL, 0.1 mmol) and triethyl amine (13 μL, 0.1 mmol). The resulting mixture was then cooled down on an ice-water bath before the addition of 1-[3- (dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (19 mg, 0.1 mmol) and 4-dimethylamino-pyridine (catalytic amount). After being stirred overnight at ambient temperature, the reaction mixture was diluted with dichloromethane (40 mL) and washed with saturated sodium bicarbonate solution. The organic phase was dried over anhydrous sodium sulfate. After evaporation of the solvent, the crude product was purified by flash chromatography on silical gel, eluting with a gradient of 0-10% methanol in ethyl acetate to afford methyl 4-[(4-{2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]benzoate as amorphous solid (29 mg, 50%). 1H NMR (300 MHz, CDCI3) δ 8.01 (d, J=7.9Hz, 1 H), 7.64 (d, J=7.6Hz, 1 H), 7.53 (br, 1 H), 7.42 (t, J=7.6Hz, 1 H), 7.37-7.33 (m, 2H), 7.28-7.20 (m, 4H), 7.17-7.10 (m, 3H), 4.61-4.53 (m, 1 H), 4.25 (br, 3H), 3.26-3.19 (m, 4H), 3.08 (br, 1 H), 2.52 (s, 3H), 2.39-2.30 (m, 3H), 1.98-1.76 (m, 11 H), 1.59 (d, J=7.8Hz, 2H), 1.37-1.18 (br, 3H). HRMS m/z (M+H)+ calcd: 605.3491 , obsd: 605.3496. Example 424 Preparation of isopropyl 2-r(4-{2-r3-.2-methyl-1 H-benzimidazol-1 -yl)-8- azabicvclor3.2.1loct-8-vnethyl)-4-phenylpiperidin-1-vπcarbonvnbenzoate
Figure imgf000264_0001
Isopropyl 2-[(4-{2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]benzoate (12 mg, 19%) was obtained as an oil from 2-[(4-{2-[3-(2-methyl-1H-benzimidazol- 1-yl)-8-azabicyclo-[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1- yl)carbonyl]benzoic acid (58 mg, 0.1 mmol), isopropyl alcohol (10 μL, 0.15 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (19 mg, 0.1 mmol) followed the procedure outlined in example 423. 1H NMR (400 MHz, CDCI3) δ 8.00 (d, J=7.7Hz, 1 H), 7.64 (d, J=7.7Hz, 1 H), 7.52 (br, 1 H), 7.42 (t, J=7.6Hz, 1 H), 7.37-7.33 (m, 2H), 7.28-7.20 (m, 4H), 7.18-7.10 (m, 3H), 5.22-5.08 (m, 1 H), 4.63-4.53 (m, 1 H), 4.34-3.67 (m, 2H), 3.26-3.00 (m, 4H), 2.53 (s, 3H), 2.48-2.30 (m, 2H), 2.17-2.07 (br, 2H), 1.96-1.62 (m, 10H), 1.59 (d, J=7.3Hz, 2H), 1.35-1.09 (m, 6H). HRMS m/z (M+H)+ calcd: 619.3648, obsd: 619.3637.
Example 425 Preparation of 2-IY4-(2-f3-(2-methyl-1 H-benzimidazol-1 -ylV8- azabicvclo[3.2.1 loct-8-yllethyl)-4-phenylpiperidin-1 -vDcarbonyllbenzamide
Figure imgf000264_0002
To a stirred solution of 2-[(4-{2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo-[3.2.1 ]oct-8-yl]ethyl}-4-phenylpiperidin-1 -yl)carbonyl]benzoic acid (69 mg, 0.12 mmol) in methylene chloride (4 mL) was added ammonia (1 mL, 0.5 M in dioxane), triethylamine (18 μL, 0.12 mmol) and HATU (46 mg, 0.12 mmol). The reaction mixture was stirred for 3 hours at ambient temperature before being diluted with methylene chloride and quenched with saturated sodium bicarbonate solution. The organic phase was dried over anhydrous sodium sulfate. After evaporation of the solvent, the crude product was purified by flash chromatography on silical gel, eluting with a gradient of 0- 20% methanol in ethyl acetate to afford 2-[(4-{2-[3-(2-methyl-1 H- benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1- yl)carbonyl]benzamide (57 mg, 83%) 1H NMR (400 MHz, CDCI3) δ 7.81 (d, J=8.6Hz, 1 H), 7.56 (d, J=7.3Hz, 1 H), 7.46-7.42 (m, 2H), 7.38-7.34 (m, 2H), 7.30-7.21 (m, 4H), 7.18-7.08 (m, 3H), 6.91 (br, 1 H), 5.74 (br, 1 H), 4.63-4.54 (m, 1 H), 4.26 (br, 1 H), 3.47-3.08 (m, 5H), 2.54 (s, 3H), 2.40-2.30 (m, 3H), 2.11-2.06 (m, 1H), 1.97-1.80 (m, 10H), 1.59 (d, J=7.9Hz, 2H). HRMS m/z (M+H)+ calcd: 576.3338, obsd: 576.3337.
Example 426
Preparation of 2-r(4-(2-f3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicvclo[3.2.noct-8-yllethyl)-4-phenylpiperidin-1-vπcarbonvn-N- propylbenzamide
Figure imgf000265_0001
2-[(4-{2-[3-(2-Methyl-1 H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8- yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]-/V-propylbenzamide (74 mg, quant.) was obtained as an oil from 2-[(4-{2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo-[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]benzoic acid (69 mg, 0.12 mmol), propylamine (14 mg, 0.24 mmol) and HATU (46 mg, 0.12 mmol) following the procedure outlined in example 425. 1H NMR (400 MHz, CDCI3) δ 7.76-7.74 (m, 1 H), 7.65 (d, J=7.3Hz, 1 H), 7.43 (br, 2H), 7.37-7.34 (m, 2H), 7.30-7.23 (m, 4H), 7.18-7.11 (m, 3H), 6.88-6.73 (br, 1 H), 4.63-4.54 (m, 1 H), 4.19 (br, 1 H), 3.36-3.06 (m, 7H), 2.54 (s, 3H), 2.40-2.29 (m, 3H), 2.11-2.08 (m, 1 H), 1.97-1.79 (m, 9H), 1.72-1.53 (m, 5H), 1.25-0.83 (m, 3H). HRMS m/z (M+H)+ calcd: 618.3808, obsd: 618.3811.
Example 427 Preparation of N-cvclopropyl-2--T4-f2-r3-(2-methyl-1 H-benzimidazol-1 -ylV8- azabicvclor3.2.noct-8-yllethylV4-phenylpiperidin-1-vπcarbonyllbenzamide
Figure imgf000266_0001
Λ/-Cyclopropyl-2-[(4-{2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]benzamide (61 mg, 83%) was obtained as an oil from 2-[(4-{2-[3-(2-methyl-1H-benzimidazol- 1-yl)-8-azabicyclo-[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1- yl)carbonyl]benzoic acid (69 mg, 0.12 mmol), cyclopropylamine (14 mg, 0.24 mmol) and HATU (46 mg, 0.12 mmol) following the procedure outlined in example 425. 1H NMR (400 MHz, CDCI3) δ 7.71 (d, J=7.9Hz, 1 H), 7.65 (d, J=7.3Hz), 7.41-7.33 (m, 4H), 7.29-7.23 (m, 4H), 7.21-7.09 (m, 3H), 7.03-6.84 (m, 1 H), 4.63-4.54 (m, 1 H), 4.20-4.17 (m, 1 H), 3.37-3.22 (m, 4H), 3.10-3.05 (m, 1 H), 2.92-2.70 (m, 1 H), 2.54 (s, 3H), 2.36-2.29 (m, 3H), 2.11 (br, 1 H), 1.98-1.61 (m, 10H), 1.59 (d, J=7.9Hz, 2H), 0.86-0.47 (m, 4H). HRMS m/z (M+H)+ calcd: 616.3651 , obsd: 616.3649.
Example 428 Preparation of 2-IT4-(2-r3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicvclo[3.2.1loct-8-vnethylV4-phenylpiperidin-1-yl)carbonyllnicotinamide
Figure imgf000266_0002
To a stirred solution of 2-methyl-1 -{8-[2-(4-phenylpiperidin-4-yl)ethyl]-8- azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole (51 mg, 0.12 mmol) in dichloro- methane (4 mL) was added 2.3-pyridinedicarboxylic anhydride (18 mg, 0.12 mmol) and triethylamine (17 μL, 0.12 mmol). The resulting mixture was stirred for 2 hours at ambient temperature before addition of ammonia (1 mL, 0.5 M in doxane) and 47 mg of HATU. The reaction mixture was then stirred for another 2 hours. After being diluted with methylene chloride and washed with saturated sodium bicarbonate solution, the organic phase was dried over anhydrous sodium sulfate. Evaporation of the solvent and purification by flash chromatography afforded 2-[(4-{2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1 ]oct-8-yl]ethyl}-4-phenylpiperidin-1 -yl)carbonyl]nicotinamide as a foam (51 mg, 69%). 1H NMR (300 MHz, CDCI3) δ 8.63-8.61 (m, 1 H), 8.17 (d, J=6.8Hz, 1 H), 7.66-7.64 (m, 2H), 7.38-7.33 (m, 3H), 7.30-7.22 (m, 4H), 7.20-7.10 (m, 2H), 5.79 (s, 1 H), 4.61-4.55 (m, 1 H), 4.27-4.22 (m, 1 H), 3.40-3.08 (m, 5H), 2.54 (s, 3H), 2.47-2.33 (m, 3H), 2.19-2.15 (m, 1 H), 1.97- 1.80 (m, 10H), 1.63-1.61 (m, 2H). HRMS m/z (M+H)+ calcd: 577.3291 , obsd: 577.3286.
Example 429 Preparation of 2-IT4-l2-r3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicvclor3.2.noct-8-vnethyl)-4-phenylpiperidin-1-vπcarbonvn-N- propylnicotinamide
Figure imgf000267_0001
2-[(4-{2-[3-(2-Methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1]oct-8- yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]-Λ/-propylnicotinamide (68 mg, 99%) was obtained as a foam from 2-methyl-1-{8-[2-(4-phenylpiperidin-4-yl)ethyl]-8- azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole (51 mg, 0.12 mmol), 2.3- pyridinedicarboxylic anhydride (18 mg, 0.12 mmol), propylamine (14 mg, 0.24 mmol) and HATU (47 mg, 0.12 mmol), following the procedure outlined in example 428. 1H NMR (400 MHz, CDCI3) δ 8.62-8.60 (m, 1 H), 8.16 (d, J=7.9Hz, 1 H), 7.65 (d, J=8.6Hz, 1 H), 7.57 (t, J=5.7Hz, 1H), 7.39-7.33 (m, 3H), 7.30-7.21 (m, 4H), 7.18-7.11 (m, 2H), 4.61-4.56 (m, 1 H), 4.27-4.22 (dt, J=13.2, 4.3Hz, 1 H), 3.38-3.31 (m, 3H), 3.22-3.06 (m, 4H), 2.54 (s, 3H), 2.40- 2.31 (m, 3H), 2.17-2.14 (m, 1 H), 1.92-1.80 (m, 10H), 1.62-1.52 (m, 4H), 0.93 (t, J=7.3Hz, 3H). HRMS m/z (M+H)+ calcd: 619.3761 , obsd: 619.3785.
Example 430 Preparation of N-cvclopropyl-2-r(4-(2-f3-(2-methyl-1 H-benzimidazol-1 -ylV8- azabicvclor3.2.1loct-8-yllethyl -4-phenylpiperidin-1-vπcarbonvnnicotinamide
Figure imgf000268_0001
Λ/-Cyclopropyl-2-[(4-{2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1 ]oct-8-yl]ethyl}-4-phenylpiperidin-1 -yl)carbonyl]nicotinamide (58 mg, 78%) was obtained as a foam from 2-methyl-1-{8-[2-(4- phenylpiperidin-4-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole (51 mg, 0.12 mmol), 2.3-pyridinedicarboxylic anhydride (18 mg, 0.12 mmol), cyclopropylamine (14 mg, 0.24 mmol) and HATU (47 mg, 0.12 mmol) following the procedure outlined in example 428. 1H NMR (400 MHz, CDCI3) δ 8.56-8.54 (m, 1 H), 8.03 (d, J=7.8Hz, 1 H), 7.80 (s, 1 H), 7.65 (d, J=7.0Hz, 1 H), 7.37-7.22 (m, 5H), 7.20-7.12 (m, 2H), 4.62-4.55 (m, 1 H), 4.23-4.19 (m, 1H), 3.35 (t, J=10.6Hz, 1 H), 3.22-3.06 (m, 4H), 2.89-2.87 (m, 1 H), 2.54 (s, 3H), 2.47-2.33 (m, 3H), 2.18-2.09 (m, 1 H), 1.88-1.83 (m, 10H), 1.61-1.58 (m, 2H), 0.84-0.62 (m, 2H), 0.59-0.56 (m, 2H). HRMS m/z (M+H)+ calcd: 617.3604, obsd: 617.3627. Example 431 Preparation of methyl 4-r 4-(2-[3-(2-methyl-1 H-benzimidazol-1 -vO-8- azabicvclor3.2.1 loct-8-yllethylV4-phenylpiperidin-1 -vDcarbonvnbenzoate
Figure imgf000269_0001
To a stirred solution of 2-methyl-1 -{8-[2-(4-phenylpiperidin-4-yl)ethyl]-8- azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole dihydrochloride (50.5 mg, 0.1 mmol) in dichloromethane (5 mL) was added terephthalic acid monomethyl ester (18 mg, 0.1 mmol) and triethyl amine (30 μL, 0.2 mmol). The resulting mixture was then cooled down on an ice-water bath before the addition of 1- [3-(dimethylamino)propyl]-3-ethylcarbo-diimide hydrochloride (19 mg, 0.1 mmol) and 4-dimethylaminopyridine (catalytic amount). After being stirred overnight at ambient temperature, the reaction mixture was diluted with dichloromethane (40 mL) and washed with saturated sodium bicarbonate solution. The organic phase was dried over anhydrous sodium sulfate. After evaporation of the solvent, the crude product was purified by flash chromatography on silical gel, eluting with a gradient of 0-10% methanol in ethyl acetate to afford methyl 4-[(4-{2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]benzoate as amorphous solid (65 mg, quant). 1H NMR (300 MHz, CDCI3) δ 8.11 (d, J=8.2Hz, 2H), 7.69 (d, J=7.2Hz, 1 H), 7.47 (d, J=8.2Hz, 2H), 7.41 (d, J=7.3Hz, 2H), 7.34-7.24 (m, 4H), 7.21-7.15 (m, 2H), 4.66 (br, 1 H), 4.26-4.21 (m, 1 H), 3.97 (s, 3H), 3.52-3.30 (m, 5H), 2.60 (s, 3H), 2.40 (br, 3H), 2.21-2.17 (br, 1 H), 1.99-1.79 (m, 10H), 1.68-1.66 (m, 2H). HRMS m/z (M+H)+ calcd: 591.3335, obsd: 591.3320. Example 432 Preparation of isopropyl 3-f(4-(2-r3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicvclor3.2.1loct-8-vnethyll-4-phenylpiperidin-1-vπcarbonyllbenzoate
Figure imgf000270_0001
Isopropyl 3-[(4-{2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]benzoate (10 mg, 16%) was obtained as an oil from 3-[(4-{2-[3-(2-methyl-1H-benzimidazol- 1 -yl)-8-azabicyclo-[3.2.1 ]oct-8-yl]ethyl}-4-phenylpiperidin-1 - yl)carbonyl]benzoic acid (70 mg, 0.12 mmol), isopropyl alcohol (10 μL, 0.12 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (23 mg, 0.12 mmol) following the procedure outlined in example 423. 1H NMR (400 MHz, CDCI3) δ 8.06 (d, J=7.9Hz, 1 H), 8.04 (s, 1 H), 7.64 (d, J=7.2Hz, 1 H), 7.54 (d, J=7.7Hz, 1 H), 7.46 (t, J=7.7Hz, 1 H), 7.39-7.35 (m, 1 H), 7.29- 7.26 (m, 4H), 7.18-7.11 (m, 3H), 5.25-5.22 (m, 1 H), 4.59 (br, 1 H), 4.20 (br, 1 H), 3.52 (br, 1 H), 3.35 (br, 1 H), 3.24 (br, 3H), 2.54 (s, 3H), 2.37-2.32 (m, 3H), 2.16 (br, 1 H), 1.92-1.75 (m, 10H), 1.60 (d, J=7.7Hz, 2H), 1.35 (d, J=6.2Hz, 6H). HRMS m/z (M+H)+ calcd: 619.3648, obsd: 619.3649.
Example 433 Preparation of 4-[(4-{2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8-azabicvclo- [3.2. noct-8-yl1ethyl)-4-phenylpiperidin-1-vπcarbonyllbenzoic acid
Figure imgf000270_0002
4-[(4-{2-[3-(2-Methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8- yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]benzoic acid (15 mg, 43 %) was obtained as white powder from methyl 4-[(4-{2-[3-(2-methyl-1 H-benzimidazol- 1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1- yl)carbonyl]benzoate following the procedure outlined in the previous example. HRMS m/z (M+H)+ calcd: 577.3179, obsd: 577.3189.
Preparation of Carboxamides and Carboxthioamides of 2-Methyl-1 -{8-[2-(4- Phenylpiperidin-4-vπethyll-8-Azabicvclor3.2.1loct-3-yl)-1 H-Benzimidazole
Figure imgf000271_0001
Example 434 Preparation of N-cvano-4-{2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.11oct-8-yllethyl)-4-phenylpiperidine-1-carboxamide
Figure imgf000272_0001
To a precooled (0 °C) solution of phenyl Λ/-cyano-4-{2-[3-(2-methyl-1H- benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidine-1- carboximidoate (27 mg, 0.047mmol) in a mixed solvent of THF-H2O (2 mL, 3:1) was added lithium hydroxide monhydrate (7.7 mg, 0.18 mmol). After stirring for 3 hours on an ice-water bath, the reaction mixture was diluted with dichloromethane (20 mL) and buffered with saturated sodium bicarbonate solution (10 mL). The aqueous phase was extracted with dichloromethane (3x 10 mL). The combined extracts were washed with brine and dried over anhydrous sodium sulfate. After evaporation of solvents, the residue was purified by flash chromatography on silical gel, eluting with a gradient of 10- 30% methanol in ethyl acetate to afford Λ/-cyano-4-{2-[3-(2-methyl-1 H- benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidine-1- carboxamide as a white solid (20 mg, 83%). 1H NMR (400 MHz, DMSO-d6) δ 7.46 (d, J=7.1 Hz, 1 H), 7.33-7.29 (m, 5H), 7.17-7.14 (m, 1 H), 7.11-7.04 (m, 2H), 4.53-4.48 (m, 1 H), 4.09 (br, 1 H), 3.55-3.51 (m, 2H), 3.21 (br, 2H), 3.06- 3.03 (m, 2H), 2.45 (s, 3H), 2.37-2.29 (m, 2H), 1.87-1.64 (m, 10H), 1.59-1.55 (m, 4H). 13C NMR (125 MHz, DMSO-d6) δ 165.0, 152.3, 146.7, 143.7, 134.0, 128.9, 127.3, 126.2, 125.0, 121.8, 121.4, 119.4, 111.6, 57.2, 55.6, 49.3, 48.0, 46.3, 36.3, 35.9, 30.0, 21.8, 14.9. HRMS m/z (M+H)+ calcd: 497.3029, obsd: 497.3026. Example 435 Preparation of N-isopropy|-4-{2-[3-(2-methyl-1 H-benzimidazol-1 -vh-8- azabicvclo [3.2. noct-8-yllethyl)-4-phenylpiperidine-1 -carboxamide
Figure imgf000273_0001
To a stirred solution of 2-methyl-1 -{8-[2-(4-phenylpiperidin-4-yl)ethyl]-8- azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole (20 mg, 0.047 mmol) in THF (2 mL) was added isopropyl isocyanate (4.3 mg, 0.047 mmol). The resulting mixture was stirred at ambient temperature overnight. After evaporation of the solvent, the residue was purified on silical gel, eluting with a gradient of 10-30% methanol in ethyl acetate to afford Λ/-isopropyl-4-{2-[3-(2-methyl-1 H- benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidine-1- carboxamide as white solid (15 mg, 63%). 1H NMR (300 MHz, CDCI3) δ 7.70 (d, J=7.2Hz, 1 H), 7.43-7.38 (m, 2H), 7.34-7.24 (m, 4H), 7.22-7.15 (m, 2H), 4.67 (br, 1 H), 4.24 (d, J=7.3Hz, 1 H), 3.99 (m, 1 H), 3.62-3.58 (m, 2H), 3.30 (br, 2H), 3.23-3.16 (m, 2H), 2.62 (s, 3H), 2.42 (br, 2H), 2.25-2.20 (m, 2H), 1.98- 1.83 (m, 9H), 1.68 (br, 2H), 1.17 (d, J=6.4Hz, 6H). HRMS m/z (M+H)+ calcd: 514.3546, obsd: 514.3530.
Example 436 Preparation of N-(tert-butvD-4-(2-r3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicvclo [3.2.1]oct-8-yl1ethyl)-4-phenylpiperidine-1 -carboxamide
Figure imgf000273_0002
Λ/-(fet -Butyl)-4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo- [3.2.1]oct-8-yl]ethyl}-4-phenylpiperidine-1 -carboxamide (39 mg, quant.) was obtained as syrup from 2-methyl-1-{8-[2-(4-phenyl piperidin-4-yl)ethyl]-8- azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole (30 mg, 0.07 mmol) and f-butyl isocyanate (6.9 mg, 0.07 mmol) following the procedure outlined in example 435. 1H NMR (300 MHz, CDCI3) δ 7.68 (d, J=7.5Hz, 1 H), 7.41-7.36 (m, 2H), 7.32-7.22 (m, 4H), 7.20-7.13 (m, 2H), 4.75 (br, 1 H), 4.31 (s, 1 H), 3.57-3.53 (m, 2H), 3.35 (br, 2H), 3.18-3.12 (m, 2H), 2.62 (s, 3H), 2.47 (br, 2H), 2.22- 2.17 (m, 2H), 1.97-1.81 (m, 10H), 1.71 (br, 2H), 1.34 (s, 9H). HRMS m/z (M+H)+ calcd: 528.3702, obsd: 528.3722.
Example 437 Preparation of ethyl N-F(4-(2-r3-(2-methyl-1 H-benzimidazol-1 -vO-8-azabicvclo [3.2.1loct-8-vnethyl>-4-phenylpiperidin-1-yl)carbonyllqlvcinate
Figure imgf000274_0001
Ethyl /V-[(4-{2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenyl piperidin-1-yl)carbonyl]glycinate (25 mg, 64%) was obtained as an oil from 2-methyl-1-{8-[2-(4-phenyl piperidin-4- yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole (30 mg, 0.07 mmol) and ethyl isocyanatoacetate (9 mg, 0.07 mmol) following the procedure outlined in example 435. 1H NMR (400 MHz, DMSO-d6) δ 7.46 (d, J=7.2Hz, 1 H), 7.37-7.32 (m, 5H), 7.20-7.17 (m, 1 H), 7.11-7.04 (m, 2H), 6.88 (t, J=5.6Hz, 1 H), 4.51-4.47 (m, 1 H), 4.02 (q, J=7.1 Hz, 2H), 3.66 (d, J=5.7Hz, 2H), 3.51-3.47 (m, 2H), 3.20 (br, 2H), 3.05 (t, J=9.7Hz, 2H), 2.46 (s, 3H), 2.36- 2.29 (m, 2H), 1.99 (br, 2H), 1.84-1.70 (m, 10H), 1.55 (d, J=7.5Hz, 2H), 1.13 (t, J=7.2Hz, 3H). HRMS m/z (M+H)+ calcd: 558.3444, obsd: 558.3445.
Example 438 Preparation of N-cvclohexyl-4-(2-r3-(2-methyl-1 H-benzimidazol-1 -vO-8- azabicvclo [3.2.11oct-8-vπethyl}-4-phenylpiperidine-1 -carboxamide
Figure imgf000274_0002
Λ/-Cyclohexyl-4-{2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidine-1 -carboxamide (34 mg, 88%) was obtained as an oil from 2-methyl-1-{8-[2-(4-phenylpiperidin-4- yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1H-benzimidazole (30 mg, 0.07 mmol) and cyclohexyl isocyanate (8.8 mg, 0.07 mmol) following the procedure outlined in example 435. 1H NMR (400 MHz, DMSO-d6) δ 7.46 (d, J=7.1 Hz, 1 H), 7.34-7.30 (m, 5H), 7.19-7.16 (m, 1 H), 7.11-7.04 (m, 2H), 6.03 (d, J=7.7Hz, 1H), 4.51-4.46 (m, 1 H), 3.47-3.43 (m, 2H), 3.35-3.34 (m, 1 H), 3.19 (br, 2H), 3.04-2.99 (m, 2H), 2.45 (s, 3H), 2.36-2.28 (m, 2H), 2.00-1.95 (m, 2H), 1.81-1.67 (m, 14H), 1.61-1.51 (m, 3H), 1.19-1.00 (m, 5H). HRMS m/z (M+H)+ calcd: 554.3859, obsd: 554.3863.
Example 439 Preparation of 4-(2-r3-(2-methyl-1 H-benzimidazol-1-ylV8-azabicvclof3.2.1loct- 8-yllethyl -4-phenyl-N-[4-(trifluoromethyl)phenyllpiperidine-1 -carboxamide
Figure imgf000275_0001
4-{2-[3-(2-Methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8- yl]ethyl}-4-phenyl-Λ/-[4-(trifluoromethyl)phenyl]piperidine-1 -carboxamide (27 mg, 88%) was obtained as an oil from 2-methyl-1-{8-[2-(4-phenylpiperidin-4- yl)ethyl]-8-azabicyclo[3.2.1]-oct-3-yl}-1 H-benzimidazole (22 mg, O.Oδmmol) and p-trifluoromethylphenyl isocyanate (9 mg, O.Oδmmol) following the procedure outlined in example 435. 1H NMR (400 MHz, DMSO-d6) δ 8.83 (s, 1 H), 7.65 (d, J=8.2Hz, 2H), 7.53 (d, J=8.2Hz, 2H), 7.45 (d, J=6.9Hz, 11-1), 7.39-7.32 (m, 5H), 7.20 (t, J=7.0Hz, 1 H), 7.10-7.06 (m, 2H), 4.50 (m, 1 H), 3.70-3.66 (m, 2H), 3.21 (br, 4H), 2.46 (s, 3H), 2.34-2.29 (m, 2H), 2.11-2.07
(m, 2H), 1.84-1.71 (m, 10H), 1.55 (d, J=7.5Hz, 2H). HRMS m/z (M+H)+ calcd: 616.3263, obsd: 616.3258. Example 440 Preparation of N-isopropy|-4-{2-r3-(2-methyl-1 H-benzimidazol-1 -ylV8- azabicvclo r3.2.1loct-8-vnethyl)-4-phenylpiperidine-1-carbothioamide
Figure imgf000276_0001
ΛMsopropyl-4-{2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1 ]oct-8-yl]ethyl}-4-phenylpiperidine-1 -carbothioamide (28 mg, quant.) was obtained as an oil from 2-methyl-1-{8-[2-(4-phenylpiperidin-4- yl)ethyl]-8-azabicyclo[3.2.1]-oct-3-yl}-1 H-benzimidazole (22 mg, 0.05 mmol) and isopropyl isothiocyanate (5.5 mg, 0.05 mmol) following the procedure outlined in example 435. 1H NMR (400 MHz, DMSO-d6) δ 7.46 (d, J=7.1 Hz, 1 H), 7.37-7.32 (m, 5 H), 7.20-7.15 (m, 2 H), 7.11-7.05 (m, 2 H), 4.53-4.45 (m, 1 H), 4.00-3.97 (m, 2 H), 3.48-3.43 (m, 2 H), 3.20 (br, 2 H), 2.46 (s, 3 H), 2.36- 2.28 (m, 2 H), 2.06-2.01 (m, 2 H), 1.82-1.70 (m, 10 H), 1.55 (d, J=7.5 Hz, 2 H). 1.09 (d, J=6.6 Hz, 6 H). HRMS m/z (M+H)+ calcd: 530.3317, obsd: 530.3310.
Example 441 Preparation of N-methyl-4-(2-[3-(2-methyl-1 H-benzimidazol-1 -vD-8-azabicvclo 3.2.11oct-8-yllethyl}-4-phenylpiperidine-1 -carbothioamide
Figure imgf000276_0002
Λ/-Methyl-4-{2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenyl piperidine-1 -carbothioamide (23 mg, 92%) was obtained as an oil from 2-methyl-1-{8-[2-(4-phenylpiperidin-4- yl)ethyl]-8-azabicyclo[3.2.1]-oct-3-yl}-1 H-benzimidazole (22 mg, 0.05 mmol) and methyl isothiocyanate (4 mg, 0.055 mmol) following the procedure outlined in example 435. 1H NMR (400 MHz, DMSO-d6) δ 7.57 (d, J=4.1 Hz, 1 H), 7.46 (d, J=7.1 Hz, 1H), 7.38-7.27 (m, δH), 7.19 (t, J=6.8Hz, 1 H), 7.11- 7.0δ (m, 2H), 4.δ4-4.44 (m, 1 H), 4.02-3.97 (m, 2H), 3.46-3.41 (m, 2H), 3.20 (br, 2H), 2.86 (d, J=3.9Hz, 3H), 2.46 (s, 3H), 2.41-2.28 (m, 2H), 2.07-2.03 (m, 2H), 1.91-1.70 (m, 10H), 1.55 (d, J=7.5Hz, 2H). HRMS m/z (M+H)+ calcd: 502.3004, obsd: 502.2994.
Example 442 Preparation of N-cvclohexyl-4-f2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicvclo [3.2.noct-8-yllethyl)-4-phenylpiperidine-1 -carbothioamide
Figure imgf000277_0001
Λ/-Cyclohexyl-4-{2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidine-1 -carbothioamide (26.9mg,
94%) was obtained as an oil from 2-methyl-1-{8-[2-(4-phenylpiperidin-4- yl)ethyl]-8-azabicyclo[3.2.1]-oct-3-yl}-1 H-benzimidazole (22mg, O.Oδmmol) and cyclohexyl isothiocyanate (7.7mg, O.Oδmmol) following the procedure outlined in example 436. 1H NMR (400 MHz, DMSO-d6) δ 7.46 (d, J=7.2 Hz, 1 H), 7.37-7.32 (m, 5 H), 7.20-7.17 (m, 1 H), 7.13-7.05 (m, 3 H), 4.51-4.47 (m, 1 H), 4.14 (br, 1 H), 4.00-3.97 (m, 2 H), 3.4δ (t, J=9.7 Hz, 2 H), 3.20 (br, 2 H), 2.46 (s, 3 H), 2.36-2.28 (m, 2 H), 2.05-2.01 (m, 2 H), 1.82-1.67 (m, 15 H), 1.55 (d, J=7.8 Hz, 2 H). 1.23-1.15 (m, 4 H). HRMS m/z (M+H)+ calcd: 670.3630, obsd: 670.3629.
Example 443 Preparation of N-(4-fluorobenzvD-4-(2-[3-(2-methyl-1 H-benzimidazol-1 -vh-8- azabicvclo[3.2.11oct-8-yr|ethyl)-4-phenylpiperidine-1 -carbothioamide
Figure imgf000278_0001
Λ/-(4-Fluorobenzyl)-4-{2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidine-1 -carbothioamide (27.6mg, 93%) was obtained as an oil from 2-methyl-1-{8-[2-(4-phenylpiperidin-4- yl)ethyl]-8-azabicyclo[3.2.1]-oct-3-yl}-1 H-benzimidazole (22mg, O.Oδmmol) and 4-fluorobenzyl isothiocyanate (9.0mg, 0.0δ4mmol) following the procedure outlined in example 435. 1H NMR (400 MHz, DMSO-d6) δ 8.13 (t, J=5.4 Hz, 1 H), 7.46 (d, J=7.δ Hz, 1 H), 7.39-7.30 (m, δ H), 7.29-7.26 (m, 2 H), 7.20 (t, J=6.8 Hz, 1 H), 7.11-7.06 (m, 4 H), 4.73 (d, J=δ.δ Hz, 2 H), 4.51- 4.47 (m, 1 H), 4.07 (br, 2 H), 3.51 (t, J=9.9 Hz, 2 H), 3.21 (br, 2 H), 2.46 (s, 3 H), 2.41-2.29 (m, 2 H), 2.09-2.05 (m, 2 H), 1.83-1.71 (m, 10 H), 1.56 (d, J=7.7 Hz, 2 H). HRMS m/z (M+H)+ calcd: 596.3223, obsd: 596.3232.
Example 444 Preparation of N,N-dimethyl-4-f2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicvclo[3.2.11oct-8-yl]ethyl)-4-phenylpiperidine-1 -carboxamide
Figure imgf000278_0002
At 0 °C, to a stirred solution of phosgen (0.25 mL, 2.0 in toluene) was added a solution of 2-methyl-1-{8-[2-(4-phenylpiperidin-4-yl)ethyl]-8- azabicyclo[3.2.1]-oct-3-yl}-1 H-benzimidazole (71 mg, 0.17mmol) in methylene chloride and triethylamine (excess). The mixture was stirred for 30 minutes at 0 °C and further one hour at room temperature. Nitrogene gas was then introduced to remove the excess phosgen. To this mixture was added excess dimethylamine and the resulting mixture was stirred overnight at ambient temperature. After being diluted with methylene chloride, the organic phase was washed with brine, dried over anhydrous sodium sulfate and purified by flash chromatography. Λ/,Λ/-dimethyl-4-{2-[3-(2-methyl-1H- benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl] ethyl}-4-phenylpiperidine-1- carboxamid was obtained as foam (52 mg, 63%). 1H NMR (400 MHz, CDCI3) δ 7.66 (d, J=7.3 Hz, 1 H), 7.37-7.34 (m, 2 H), 7.31-7.29 (m, 3 H), 7.23-7.12 (m, 3 H), 4.61 (br, 1 H), 3.44-3.38 (m, 2 H), 3.25 (br, 2 H), 3.12-3.06 (m, 2 H), 2.80 (s, 6 H), 2.58 (s, 3 H), 2.38-2.36 (m, 2 H), 2.19-2.15 (m, 2 H), 1.93-1.81 (m, 10 H), 1.61 (d, J=7.3 Hz, 2 H). HRMS m/z (M+H)+ calcd: 500.3389, obsd: 500.3386.
Example 445 Preparation of N,N-diethyl-4-f2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicvclor3.2.πoct-8-yllethyl)-4-phenylpiperidine-1 -carboxamide
Figure imgf000279_0001
N, Λ/-Diethyl-4-{2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1 ]oct-8-yl]ethyl}-4-phenylpiperidine-1 -carboxamide (50 mg, 57%) was obtained as an oil from 2-methyl-1-{8-[2-(4-phenyl piperidin-4- yl)ethyl]-8-azabicyclo[3.2.1]-oct-3-yl}-1 H-benzimidazole (71 mg, 0.17mmol), phosgen and diethylamine following the procedure outlined in example 444. 1H NMR (400 MHz, CDCI3) δ 7.66 (d, J=7.3 Hz, 1 H), 7.37-7.29 (m, δH), 7.23- 7.12 (m, 3 H), 4.64-4.68 (m, 1 H), 3.41-3.36 (m, 2 H), 3.24-3.23 (m, 2 H), 3.17 (q, J=7.2 Hz, 4 H), 3.10-3.04 (m, 2 H), 2.57 (s, 3 H), 2.40-2.32 (m, 2 H), 2.19- 2.15 (m, 2 H), 1.94-1.80 (m, 10 H), 1.60 (d, J=7.7 Hz, 2 H), 1.10 (t, J=7.0 Hz, 6 H). HRMS m/z (M+H)+ calcd: 528.3702, obsd: 528.3712. Example 446 Preparation of N. N-diallyl-4-f2-r3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1 loct-8-vnethyl)-4-phenylpiperidine-1 -carboxamide
Figure imgf000280_0001
N, Λ/-Diallyl-4-{2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1 ]oct-8-yl]ethyl}-4-phenylpiperidine-1 -carboxamide (42 mg, 46%) was obtained as an oil from 2-methyl-1-{8-[2-(4-phenylpiperidin-4- yl)ethyl]-8-azabicyclo[3.2.1]-oct-3-yl}-1 H-benzimidazole (71 mg, 0.17 mmol), phosgen and diallylamine following the procedure outlined in example 444. 1H NMR (400 MHz, CDCI3) δ 7.66 (d, J=7.1 Hz, 1 H), 7.37-7.33 (m, 2 H), 7.30- 7.29 (m, 3 H), 7.23-7.12 (m, 3 H), δ.86-δ.76 (m, 2 H), δ.18-δ.13 (m, 4 H), 4.61 (br, 1 H), 3.72 (d, J=δ.δHz, 4 H), 3.47-3.41 (m, 2 H), 3.24 (br, 2 H), 3.12-3.06 (m, 2 H), 2.67 (s, 3 H), 2.40-2.32 (m, 2 H), 2.20-2.16 (m, 2 H), 1.99-1.80 (m, 10 H), 1.60 (d, J=7.7 Hz, 2 H). HRMS m/z (M+H)+ calcd: 662.3702, obsd: 662.3701.
Example 447 Preparation of N-ethyl-N-methyl-4-{2- 3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicvclo[3.2.noct-8-vnethyl)-4-phenylpiperidine-1 -carboxamide
Figure imgf000280_0002
Λ/-Ethyl-Λ/-methyl-4-{2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidine-1 -carboxamide (63 mg,
62%) was obtained as an oil from 2-methyl-1-{8-[2-(4-phenylpiperidin-4- yl)ethyl]-8-azabicyclo[3.2.1]-oct-3-yl}-1 H-benzimidazole (71 mg, 0.17mmol), phosgen and Λ/-ethyl-Λ/-methylamine following the procedure outlined in example 444. 1H NMR (400 MHz, CDCI3) δ 7.66 (d, J=7.1 Hz, 1 H), 7.37-7.33 (m, 2 H), 7.31-7.29 (m, 3 H), 7.23-7.12 (m, 3 H), 4.63-4.59 (m, 1 H), 3.41-3.36 (m, 2 H), 3.24 (br, 2 H), 3.18 (q, J=7.1 Hz, 2 H), 3.11-3.04 (m, 2 H), 2,77 (s, 3 H), 2.57 (s, 3 H), 2.40-2.32 (m, 2 H), 2.19-2.15 (m, 2 H), 1.99-1.80 (m, 10 H), 1.60 (d, J=7.9 Hz, 2 H), 1.12 (t, J=7.1 Hz, 3 H). HRMS m/z (M+H)+ calcd: 514.3546, obsd: 514.3526.
Example 448 Prearation of N,N-diisopropyl-4-(2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicvclo[3.2.11oct-8-vπethyl)-4-phenylpiperidine-1 -carboxamide
Figure imgf000281_0001
To a flask containing phosgen (2 mL, 2 M in toluene) in methylene chloride (10 mL) was added triethylamine (75 μL, 0.5 mmol) and diisopropylamine (76 μL, 0.5 mmol). The mixture was stirred at room temperature for 4 hours before nitrogen gas was introduced to remove excess phosgen. To this freshly prepared chlorodiisopropyl carbamate was added 2- methyl-1-{8-[2-(4-phenylpiperidin-4-yl)ethyl]-8-azabicyclo[3.2.1]-oct-3-yl}-1H- benzimidazole (85 mg, 0.2 mmol) and triethylamin (60 μL, 0.4 mmol). The resulting mixture was stirred overnight at ambient temperature. The excess chlorocarbamate was quenched with 1 mL of methanol. After evaporation of solvent, the residue was directly purified by flash chromatography, eluting with a gradient of 0-5% methanol in ethyl acetate, to afford an oil (81 mg, 73%). 1H NMR (400 MHz, CDCI3) δ 7.66 (d, J=7.4 Hz, 1 H), 7.37-7.33 (m, 2 H), 7.31- 7.30 (m, 3 H), 7.22-7.12 (m, 3 H), 4.63-4.59 (m, 1 H), 3.62-3.55 (m, 2 H), 3.29-3.23 (m, 4 H), 3.03-2.97 (m, 2 H), 2.57 (s, 3 H), 2.40-2.32 (m, 2 H), 2.18- 2.14 (m, 2 H), 1.95-1.80 (m, 10 H), 1.60 (d, J=7.9 Hz, 2 H), 1.26 (d, J=6.6 Hz, 6 H). HRMS m/z (M+H)+ calcd: 556.4015, obsd: 556.4008. Example 449 Preparation of N. N-dimethyl-4-(2-r3-(2-methyl-1 H-benzimidazol-1-vπ-8- azabicvclor3.2.11oct-8-yllethyl)-4-phenylpiperidine-1-carbothioamide
Figure imgf000282_0001
N, Λ/-Dimethyl-4-{2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidine-1 -carbothioamide (58 mg, 75%) was obtained as a foam from 2-methyl-1-{8-[2-(4-phenylpiperidin-4- yl)ethyl]-8-azabicyclo[3.2.1 ]-oct-3-yl}-1 H-benzimidazole dihydrochloride (75 mg, 0.15mmol), thiophosgen and dimethylamine following the procedure outlined in example 444. 1H NMR (400 MHz, CDCI3) δ 7.65 (d, J=7.1 Hz, 1
H), 7.45-7.35 (m, 2 H), 7.32-7.29 (m, 3 H), 7.25-7.19 (m, 1 H), 7.17-7.12 (m, 2 H), 4.63-4.58 (m, 1 H), 3.75-3.70 (m, 2 H), 3.32-3.24 (m, 4 H), 3.10 (s, 6 H), 2.58 (s, 3 H), 2.40-2.33 (m, 2 H), 2.26-2.22 (m, 2 H), 1.97-1.82 (m, 10 H), 1.61 (d, J=7.9 Hz, 2 H). HRMS m/z (M+H)+ calcd: 516.3161 , obsd: 516.3158.
Example 450 Prearation of N-ethyl-N-methyl-4-(2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicvclo[3.2.noct-8-yllethyl)-4-phenylpiperidine-1 -carbothioamide
Figure imgf000282_0002
Λ/-Ethyl-Λ/-methyl-4-{2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidine-1 -carbothioamide (62 mg, 78%) was obtained as a foam from 2-methyl-1-{8-[2-(4-phenyl piperidin-4- yl)ethyl]-8-azabicyclo[3.2.1]-oct-3-yl}-1 H-benzimidazole dihydrochloride (75 mg, 0.15mmol), thiophosgen and Λ/-ethyl-Λ/-methylamine following the procedure outlined in example 444. 1H NMR (400 MHz, CDCI3) δ 7.65 (d, J=7.2 Hz, 1 H), 7.38-7.34 (m, 2 H), 7.31-7.29 (m, 3 H), 7.24-7.21 (m, 1 H), 7.18-7.12 (m, 2 H), 4.63-4.58 (m, 1 H), 3.72-3.66 (m, 2 H), 3.61 (q, J=7.0 Hz,
2 H), 3.31-3.24 (m, 4 H), 3.03 (s, 3 H), 2.57 (s, 3 H), 2.40-2.32 (m, 2 H), 2.26- 2.21 (m, 2 H), 1.97-1.82 (m, 10 H), 1.60 (d, J=7.8 Hz, 2 H), 1.21 (t, J=7.1 Hz,
3 H). HRMS m/z (M+H)+ calcd: 530.3317, obsd: 530.3301.
Example 451 Preparation of N. N-diethyl-4-f2-[3-(2-methyl-1 H-benzimidazol-1 -vB-8- azabicvclo[3.2.noct-8-vnethyll-4-phenylpiperidine-1 -carbothioamide
Figure imgf000283_0001
Λ/,Λ/-Diethyl-4-{2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidine-1 -carbothioamide (51 mg, 62%) was obtained as a foam from 2-methyl-1-{8-[2-(4-phenylpiperidin-4- yl)ethyl]-8-azabicyclo[3.2.1]-oct-3-yl}-1 H-benzimidazole dihydrochloride (75 mg, 0.15mmol), thiophosgen and diethylamine following the procedure outlined in example 444. 1H NMR (400 MHz, CDCI3) δ 7.65 (d, J=7.4 Hz, 1
H), 7.38-7.34 (m, 2 H), 7.32-7.29 (m, 3 H), 7.25-7.21 (m, 1 H), 7.19-7.12 (m, 2 H), 4.63-4.59 (m, 1 H), 3.72-3.68 (m, 2 H), 3.57 (q, J=7.1 Hz, 4 H), 3.30-3.25 (m, 4 H), 2.58 (s, 3 H), 2.40-2.33 (m, 2 H), 2.25-2.21 (m, 2 H), 1.97-1.82 (m, 10 H), 1.61 (d, J=7.7 Hz, 2 H), 1.18 (t, J=7.1 Hz, 6 H). HRMS m/z (M+H)+ calcd: 544.3474, obsd: 544.3482.
Example 452 Preparation of N, N-diallyl-4-(2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicvclor3.2.1loct-8-yllethyl}-4-phenylpiperidine-1 -carbothioamide
Figure imgf000283_0002
N, Λ/-Diallyl-4-{2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidine-1-carbothioamide (55 mg, 65%) was obtained as a foam from 2-methyl-1-{8-[2-(4-phenylpiperidin-4- yl)ethyl]-8-azabicyclo[3.2.1]-oct-3-yl}-1 H-benzimidazole dihydrochloride (75 mg, 0.15 mmol), thiophosgen and diallylamine following the procedure outlined in example 444. 1H NMR (400 MHz, CDCI3) δ 7.65 (d, J=7.1 Hz, 1 H), 7.38-7.35 (m, 2 H), 7.31-7.29 (m, 3 H), 7.25-7.21 (m, 1 H), 7.19-7.12 (m, 2 H), 5.91-5.81 (m, 2 H), 5.23-5.17 (m, 4 H), 4.63-4.58 (m, 1 H), 4.10 (d, J=5.6 Hz, 4 H), 3.82-3.79 (m, 2 H), 3.35-3.25 (m, 4 H), 2.59 (s, 3 H), 2.40-2.32 (m, 2 H), 2.27-2.23 (m, 2 H), 1.97-1.80 (m, 10 H), 1.61 (d, J=7.9 Hz, 2 H). HRMS m/z (M+H)+ calcd: 568.3474, obsd: 568.3470.
Example 453 Preparation of 1-((1 R,5S)-8-(2-[1-(1 H-imidazol-1 -ylcarbonothiovn-4- phenylpiperidin-4-yllethyll-8-azabicvclo[3.2.noct-3-yl)-2-methyl-1 H- benzimidazole
Figure imgf000284_0001
To a stirred solution of 2-methyl-1-{8-[2-(4-phenylpiperidin-4-yl)ethyl]-8- azabicyclo[3.2.1]-oct-3-yl}-1 H-benzimidazole (214 mg, 0.5 mmol) in methylene chloride was added 1-(1 H-imidazol-1 -ylcarbonothioyl)-1H- imidazole (89 mg, 0.5 mmol). The resulting mixture was stirred overnight. After evaporation of the solvents, the crude product was purified by flash chromatography, eluting with a gradient of 0-5% methanol in ethyl acetate, to afford 1 -((1 R, 5S)-8-{2-[1 -(1 H-imidazol-1 -ylcarbonothioyl)-4-phenylpiperidin-4- yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1 H-benzimidazole as a foam (200 mg, 74%). 1H NMR (400 MHz, CDCI3) δ 7.83 (s, 1 H), 7.65 (d, J=7.1 Hz, 1 H), 7.42-7.39 (m, 2 H), 7.31-7.28 (m, 4 H), 7.19-7.10 (m, 3 H), 7.07 (s, 1 H), 4.62-4.56 (m, 1 H), 3.53 (br, 1 H), 3.24-3.22 (m, 2 H), 2.56 (s, 3 H), 2.40-2.32 (m, 4 H), 1.99-1.81 (m, 10, H), 1.62 (d, J=7.9 Hz, 2 H). HRMS m/z (M+H)+ calcd: 539.2957, obsd: 539.2958. Preparation of N-acyl and N-sulfonyl αuanidine Derivatives of 2-Methyl-1-(8- r2-(4-Phenylpiperidin-4-vnethvn-8-Azabicvclor3.2.11-oct-3-yl)-1 H- benzimidazole
Synthesis of Acyl and Sulfonyl Derivatives
Figure imgf000285_0001
Example 454 Preparation of N-f(1 E)-[(4-chlorophenyl)aminol(4-(2-[3-(2-methyl-1 H- benzimidazol-1-vn-8-azabicvclo[3.2.1loct-8-yllethyl)-4-phenylpiperidin-1- yl)methylidene1-2.2-dimethylpropanamide
Figure imgf000285_0002
To a solution of trimethylacetamide (10 mg, 0.1 mmol) in DMF (0.5 mL) was added sodium hydride (60%, 5.2 mg, 0.13 mmol). After stirring for 5 minutes, 4-chlorophenylisothiocyanate (17 mg, 0.1 mmol) was added. The reaction mixture was stirred at 60 °C for one hour before being cooled down to room temperature. To this reaction mixture was then added 2-methyl-1 -{8-[2- (4-phenylpiperidin-4-yl)ethyl]-8-azabicyclo[3.2.1]-oct-3-yl}-1 H-benzimidazole (35 mg, O.Oδmmol), EDCI (19 mg, 0.1 mmol) and a catalytic amount of DMAP. After stirring at ambient temperature overnight, the reaction was quenched with water and extracted with dichloromethane (4x10 mL). The organic phase was washed with brine and dried over sodium sulfate. The solvent was removed and the residue was purified by flash chromatography on silical gel, eluting with a gradient of 0-15% methanol in ethyl acetate to afford Λ/-[(1£)- [(4-chlorophenyl)amino](4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-3-azabicyclo [3.2.1]oct-δ-yl]ethyl}-4-phenylpiperidin-1-yl) methylidene]-2,2- dimethylpropanamide as amorphous solid (20 mg, 3δ%). 1H NMR (400 MHz, DMSO-de) δ δ.9 (s, 1 H), 7.46 (d, J=8.8 Hz, 1 H), 7.39-7.33 (m, 6 H), 7.22- 7.19 (m, 1 H), 7.13-7.05 (m, 3 H), 6.61 (d, J=δ.6 Hz, 2 H), 4.51-4.47 (m, 1 H), 3.60-3.40 (m, 2 H), 3.26-3.13 (m, 4 H), 2.46 (s, 3 H), 2.37-2.30 (m, 2 H), 2.14 (br, 2 H), 1.65-1.71 (m, 10 H), 1.56 (d, J=7.4 Hz, 2 H), 0.68 (s, 9 H). HRMS m/z (M+H)+ calcd: 665.3735, obsd: 665.3741.
Example 455 Preparation of N- 1 EH(4-chlorophenyl)amino1(4-(2-r3-(2-methyl-1 H- benzimidazol-1-yl)-δ-azabicvclor3.2.noct-δ-vnethyl)-4-phenylpiperidin-1- vDmethylidenelmethane-sulfonamide
Figure imgf000286_0001
W-[(1 E)-[(4-Chlorophenyl)amino](4-{2-[3-(2-methyl-1 H-benzimidazol-1 - yl)-δ-azabicyclo[3.2.1 ]oct-8-yl]ethyl}-4-phenylpiperidin-1 -yl)methylidene] methanesulfonamide (38 mg, 73%) was obtained as amorphous solid from methanesulfonamide (9.5 mg, 0.1 mmol), 4-chloropheyl isothiocyanate (17 mg, 0.1 mmol) and 2-methyl-1-{8-[2-(4-phenylpiperidin-4-yl)ethyl]-δ- azabicyclo[3.2.1]-oct-3-yl}-1 H-benzimidazole (35 mg, O.Oδmmol) following the procedure outlined in example 454. 1H NMR (400 MHz, CDCI3) δ δ.39 (s, 1 H), 7.64 (d, J=7.1 Hz, 1 H), 7.37-7.33 (m, 2H), 7.30-7.21 (m, 6H), 7.19-7.10 (m, 2H), 6.δ9 (d, J=δ.6 Hz, 2H), 4.59-4.53 (m, 1H), 3.61 (d, J=13.5 Hz, 2H), 3.19 (br, 2H), 3.04 (t, J=11 Hz, 2H), 2.96 (s, 3H), 2.53 (s, 3H), 2.37-2.29 (m, 2 H), 2.20-2.16 (m, 2 H), 1.90-1.84 (m, 6H), 1.82-1.71 (m, 4H), 1.58 (d, J=7.4 Hz, 2H). HRMS m/z (M+H)+ calcd: 659.2935, obsd: 659.2935.
Figure imgf000287_0001
Example 456
Figure imgf000287_0002
To a stirred solution of 2-methyl-1 -{8-[2-(4-phenylpiperidin-4-yl)ethyl]-8- azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole dihydrochloride (505 mg, 1.0 mmol) in dichoromethane (20 mL) was added Boc-α-methyl alanine (203 mg, 1.0 mmol), triethylamine (470 μL, 3.0 mmol) and HATU (380 mg, 1.0 mmol). The resulting mixture was stirred at ambient temperature overnight before being quenched with saturated sodium bicarbonate. The layers were separated and the aqueous was extracted with dichloromethane. The combined organic phase was dried over anhydrous sodium sulfate. After evaporation of the solvent, the crude product was purified by flash chromatography on silical gel, eluting with a gradient of 0-8% methanol in ethyl acetate to afford compound 456 as amorphous solid (579 mg, 94%). 1H NMR (400 MHz, CDCI3) δ 7.65 (d, J=7.1 Hz, 1 H), 7.38-7.34 (m, 1 H), 7.30- 7.20 (m, 3 H), 7.19-7.13 (m, 3 H), 5.04 (s, 1 H), 4.65-4.61 (m, 1 H), 4.09-4.02 (m, 2H), 3.29-3.20 (m, 5 H), 2.58 (s, 3 H), 2.44-2.36 (m, 2 H), 2.22-2.20 (m, 2 H), 1.95-1.89 (m, 5 H), 1.84-1.78 (m, 4 H), 1.64 ( , J=7.8 Hz, 2 H), 1.49 (s, 5 H), 1.39-1.35 (m, 10 H). HRMS m/z (M+H)+ calcd: 614.4070, obsd: 614.4086. Example 457 Preparation of 2-methyl-1-(4-(2-lϊ1 R.5SV3-(2-methyl-1 H-benzimidazol-1-vn-8- azabicvclo[3.2.11oct-δ-yllethyl)-4-phenylpiperidin-1-vπ-1-oxopropan-2-amine
Figure imgf000288_0001
To a stirred solution of the product from example 456 (307 mg, 0.50 mmol) in methylene chloride was added HCl (2 mL, 4 M in dioxane). The reaction mixture was stirred for one hour at ambient temperature. Evaporation of solvents directly afforded 240 mg (99%) of white solid, which was then partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic phase was dried over anhydrous sodium sulfate. After removal of the solvent, the desired product was obtained as foam. 1H NMR (400 MHz, CDCIs) δ 7.66 (d, J=7.1 Hz, 1 H), 7.39-7.35 (m, 2 H), 7.31-7.22 (m, 4 H), 7.19-7.12 (m, 2 H), 4.64 (m, 1 H), 4.13-4.11 (m, 2 H), 3.40 (br, 2 H), 3.27 (br, 2 H), 2.57 (s, 3 H), 2.52-2.24 (m, 4 H), 1.94-1.91 (m, 4 H), 1.88-1.68 (m, 8 H), 1.63 (d, J=7.9 Hz, 2 H), 1.41 (s, 6 H). HRMS π?/z (M+H)+ calcd: 514.3546, obsd: 514.3561.
Example 458 Preparation of (2SVN.N-bis(4-{2-r(1 R.5S)-3-(2-methyl-1 H-benzimidazol-1 -vh- δ-azabicvclor3.2.noct-δ-yl1ethyl)-4-phenyl-1-D-prolylpiperidin-2-yl)-D- prolinamide
Figure imgf000288_0002
The Boc protected precursor was prepared from -Boc-proline (47 mg, 0.15 mmol), 2-methyl-1-{δ-[2-(4-phenylpiperidin-4-yl)ethyl]-δ- azabicyclo[3.2.1]oct-3-yl}-1H-benzimidazole (64 mg, 0.15 mmol) and HATU (57 mg, 0.15 mmol), following the procedure outlined in example 456. After removal of Boc protecting group with a solution of 4N HCl in dioxane, {2S)-N, N- bis(4-{2-[(1R, 5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-δ-yl]ethyl}-4-phenyl-1-D-prolyl-piperidin-2-yl)-D- prolinamide was obtained as an oil (80 mg, quant). 1H NMR (400 MHz, CDCI3) δ 7.66 (d, J=7.4 Hz, 1 H), 7.40-7.36 (m, 2 H), 7.30-7.28 (m, 3 H), 7.25- 7.23 (m, 1 H), 7.21-7.12 (m, 2 H), 4.65-4.55 (m, 1 H), 4.11-4.02 (m, 1 H), 3.93-3.34 (m, 1 H), 3.66-3.63 (m, 1 H), 3.32-3.14 (m, 5 H), 2.85-2.73 (m, 1 H), 2.57 (s, 3 H), 2.40-2.24 (m, 6 H), 2.15-1.50 (m, 5 H). HRMS m/z (M+H)+ calcd: 526.3546, obsd: 526.3565.
Example 459 Preparation of N2-acetyl-N1. N1-bis(1-(N-acetyl-2-methylalanyl)-4-(2-r(1 R,5S)- 3-(2-methyl-1 H-benzimidazol-1 -vn-8-azabicvclor3.2.11oct-8-yllethyl)-4- phenylpiperidin-2-ylV2-methylalaninamide
Figure imgf000289_0001
At 0 °C, to a stirred solution of 2-methyl-1-(4-{2-[(1R,5S)-3-(2-methyl- 1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1 - yl)-1-oxopropan-2-amine dihydrochloride (40 mg, 0.068mmol, obtained from compound 456 by removal of Boc protecting group with 4 M HCl in ether) in dichoromethane was added acetyl bromide (8.6 mg, 0.068 mmol), N,N- diethyl-isopropylamine (42 μL, 0.24 mmol) and DMAP (1 mg). The resulting mixture was stirred for 3 hours before being quenched with saturated sodium bicarbonate. The layers were separated and the aqueous layer was extracted with dichloromethane. The combined organic phase was dried over anhydrous sodium sulfate. After evaporation of the solvent, the crude product was purified by flash chromatography on silical gel, eluting with a gradient of 0-10% methanol in ethyl acetate to afford N2-acety\-N1 , Λ/ -bis(1- (Λ/-acetyl-2-methylalanyl)-4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-2-yl)-2-methylalaninamide as amorphous solid (34 mg, 90%). 1H NMR (400 MHz, CDCI3), δ 7.67 (d, J=6.5 Hz, 1 H), 7.40-7.37 (m, 2 H), 7.30-7.26 (m, 3 H), 7.24-7.13 (m, 3 H), 7.07 (s, 1 H), 4.03-4.00 (m, 1 H), 3.67-3.61 (m, 2 H), 3.34 (t, J=7.8 Hz, 1 H), 3.0δ (q, J=7.3 Hz, 1 H), 2.79-2.61 (m, 4 H), 2.43-2.06 (m, 6 H), 2.06-1.92 (m, 4 H), 1.65-1.80 (m, 2 H), 1.58 (s, 3 H), 1.54 (s, 3 H), 1.52-1.51 (m, 4 H), 1.43 (d, J=6.6 Hz, 4H). HRMS m/z (M+H)+ calcd: 556.3651 , obsd: 556.3647.
Example 460 Preparation of N2-(2.2-dimethylpropanoyl)-N1.N1-bis(1-rN-(2.2- dimethylpropanovn-2-methylalanvn-4-(2-r(1 R.5S)-3-(2-methyl-1 H- benzimidazol-1-yl)-8-azabicvclo[3.2.noct-8-yl1ethyll-4-phenylpiperidin-2-vπ-2- methylalaninamide
Figure imgf000290_0001
Λ/2-(2,2-dimethylpropanoyl)-Λ/ ,Λ/7-bis(1-[Λ/-(2,2-dimethylpropanoyl)-2- methylalanyl]-4-{2-[(1 R, 5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1] oct-δ-yl]ethyl}-4-phenylpiperidin-2-yl)-2-methyl alaninamide (17 mg, 42%) was obtained as an oil from 2-methyl-1-(4-{2-[(7R,5S)-3-(2- methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenyl piperidin-1-yl)-1-oxopropan-2-amine dihydrochloride (40 mg, 0.068 mmol) and pivaloyl chloride (8.4 μL, 0.068 mmol) following the procedure outlined in the example 459. 1H NMR (400 MHz, CDCI3), δ 7.66 (d, J=7.1 Hz, 1 H), 7.40- 7.36 (m, 2 H), 7.30-7.23 (m, 4 H), 7.19-7.12 (m, 2 H), 4.61 (br, 1 H), 3.99 (br, 2 H), 3.32-3.26 (m, 4 H), 2.57 (s, 3 H), 2.41-2.23 (m, 4 H), 1.93-1.76 (m, 9 H), 1.65 (s, 6 H), 1.63-1.61 (m, 2 H), 1.19 (s, 9 H). HRMS m/z (M+H)+ calcd: 598.4121 , obsd: 598.4116. Example 461
Figure imgf000291_0001
The product in example 461 (9 mg, 29 %) was obtained from 2-methyl- 1-(4-{2-[(1R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1]oct-8- yl]ethyl}-4-phenylpiperidin-1-yl)-1-oxopropan-2-amine dihydrochloride (26 mg, O.Oδmmol), 5-oxo-D-proline (6.5 mg, O.Oδmmol) and HATU (19 mg, O.Oδmmol) following the procedure outlined in example δ. 1H NMR (400 MHz, CDCI3) δ 7.79(s, 1 H), 7.6δ (d, J=7.2 Hz, 1 H), 7.40-7.36 (m, 2 H), 7.30-7.23 (m, 4 H), 7.19-7.12 (m, 2 H), 6.72 (s, 1 H), 4.63-4.δδ (m, 1 H), 4.14-4.09 (m, 1 H), 3.97 (br, 2 H), 3.31-3.26 (m, 4 H), 2.67 (s, 3 H), 2.64-2.10 (m, 9 H), 1.93- 1.76 (m, 10 H), 1.67-1.60 (m, 8 H). HRMS m/z (M+H)+ calcd: 626.3866, obsd: 626.3863.
Example 462
Preparation of 2-Methyl-1-(8-{2-[4-phenyl-1-(1 H-pyrrol-2-ylcarbonyl)piperidin- 4-vnethyl -δ-azabicvclor3.2.noct-3-vπ-1 H-benzimidazole
Figure imgf000291_0002
2-Methyl-1 -(δ-{2-[4-phenyl-1 -(1 H-pyrrol-2-ylcarbonyl)piperidin-4- yl]ethyl}-δ-azabicyclo[3.2.1 ] oct-3-yl)-1 H-benzimidazole (68.5 mg, 75%) was obtained as a white solid from 2-methyl-1 -{8-[2-(4-phenyl piperidin-4-yl)ethyl]- 8-azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole (64 mg, 0.15 mmol), 1H- pyrrole-2-carboxylic acid (16.6 mg, 0.15 mmol) and HATU (57 mg, 0.15 mmol), following the procedure outlined in example 5. 1H NMR (300 MHz, DMSO-de) δ 12.6 (br, 1 H), 7.68 (s, 1 H), 7.53-7.46 (m, 2 H), 7.41-7.32 (m, 5 H), 7.22-7.18 (m, 1 H), 7.13-7.04 (m, 3 H), 4.53-4.47 (m, 1 H), 4.11 (br, 1 H), 3.δ5 (br, 1 H), 3.27-3.09 (m, 4 H), 2.46 (s, 3 H), 2.39-2.29 (m, 2 H), 2.0 (br, 2 H), 1.97-1.70 (m, 10 H), 1.57-1.55 (m, 2 H). HRMS m/z (M+H)+ calcd: 522.3233, obsd: 522.3226.
Example 463 Preparation of (5R)-5-IT4-f2-r3-(2-methyl-1 H-benzimidazol-1 -yl)-δ- azabicvclo[3.2.noct-8-vnethyl)-4-phenylpiperidin-1-vπcarbonvnpyrrolidin-2- one
Figure imgf000292_0001
(5f?)-5-[(4-{2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1 ]oct- δ-yl]ethyl}-4-phenyl piperidin-1-yl)carbonyl]pyrrolidin-2-one (59 mg, δ5%) was obtained as white solid from 2-methyl-1-{8-[2-(4-phenylpiperidin-4-yl)ethyl]-δ- azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole (64 mg, 0.15 mmol), 5-oxo-D- proline (19 mg, 0.15 mmol) and HATU (57 mg, 0.15 mmol), following the procedure outlined in example 5. 1H NMR (400 MHz, CDCI3) δ 7.65 (d, J=3.δ Hz, 1 H), 7.40-7.36 (m, 2 H), 7.30-7.23 (m, 4 H), 7.13-7.11 (m, 2 H), 6.20 (s, Vz H), 6.09 (s, Vz H), 4.62-4.56 (m, 1 H), 4.50-4.42 (m, 1 H), 4.07-4.02 (m, 1 H), 3.5δ-3.55 (m, 1 H), 3.25-3.16 (m, 4 H), 2.56 (s, 3 H), 2.46-2.14 (m, 47 H), 2.03-1.73 (m, 11 H), 1.63-1.58 (m, 2 H). HRMS m/z (M+H)+ calcd: 540.3339, obsd: 540.3361.
Example 464 Preparation of 1-(δ-f2-M-(1 H-imidazol-5-ylcarbonvπ-4-phenylpiperidin-4- yllethyl)-δ-azabicvclo[3.2.1loct-3-vπ-2-methyl-1H-benzimidazole
Figure imgf000293_0001
1 -(δ-{2-[1 -(1 H-lmidazol-5-ylcarbonyl)-4-phenylpiperidin-4-yl]ethyl}-3- azabicyclo[3.2.1]oct-3-yl)-2-methyl-1 H-benzimidazole (18 mg, 23 %) was obtained from 2-methyl-1 -{8-[2-(4-phenylpiperidin-4-yl)ethyl]-8- azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole (64 mg, 0.15 mmol), 1 H- imidazole-5-carboxylic acid (17 mg, 0.15 mmol) and HATU (57 mg, 0.15 mmol), following the procedure outlined in example 5. 1H NMR (400 MHz, CDCIs) δ 9.68 (s, 1 H), 7.66 (d, J=8.6 Hz, 1 H), 7.41-7.23 (m, 6 H), 7.19-7.12 (m, 2 H), 6.90 (s, 1 H), 6.51 (s, 1 H), 6.24 (s, 1 H), 4.64-4.53 (m, 1 H), 4.20- 4.14 (m, 2 H), 3.43 (br, 1 H), 3.25 (br, 2 H), 2.56 (s, 3 H), 2.41-2.26 (m, 4 H), 2.01-1.81 (m, 10 H), 1.64-1.58 (m, 2 H). HRMS m/z (M+H)+ calcd: 523.3185, obsd: 523.3204.
Example 465 Preparation of 3-r(4-f2-f(1 R.5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicvclor3.2.noct-8-vnethyl)-4-phenylpiperidin-1-vπcarbonyllphenol
Figure imgf000293_0002
3-[(4-{2-[(1 R, 5S)-3-(2-Methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]phenol (70 mg,
84 %) was obtained from 2-methyl-1-{8-[2-(4-phenylpiperidin-4-yl)ethyl]-8- azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole (64 mg, 0.15 mmol), 3- hydroxybenzoic acid (21 mg, 0.15 mmol) and HATU (57 mg, 0.15 mmol), following the procedure outlined in example 5. 1H NMR (400 MHz, CDCI3) δ 7.66 (d, J=6.9 Hz, 1 H), 7.39-7.35 (m, 2 H), 7.31-7.24 (m, 4 H), 7.21-7.13 (m, 3 H), 6.94 (s, 1 H), 6.88-6.85 (m, 1 H), 6.81 (d, J=7.5 Hz, 1 H), 4.64-4.55 (m, 1 H), 4.13 (br, 1 H), 3.59-3.56 (m, 1 H), 3.40-3.37 (m, 1 H), 3.27-3.24 (m, 3 H), 2.49 (s, 3 H), 2.44-2.34 (m, 2 H), 2.26 (br, 1 H), 2.18-2.15 (m, 1 H), 1.99-1.79 (m, 10 H), 1.63-1.61 (m, 2 H). HRMS m/z (M+H)+ calcd: 549.3230, obsd: 549.3240.
Example 466 Preparation of 4-r.4-f2-f(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicvclo[3.2.11oct-8-vπethyll-4-phenylpiperidin-1 -vDcarbonyllphenyl acetate
Figure imgf000294_0001
4-[(4-{2-[(1 R, 5S)-3-(2-Methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-δ-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]phenyl acetate (6δ mg, 77 %) was obtained as a foam from 2-methyl-1-{8-[2-(4- phenylpiperidin-4-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole (64 mg, 0.15 mmol), 4-(acetyloxy) benzoic acid (27 mg, 0.15 mmol) and HATU (57 mg, 0.15 mmol), following the procedure outlined in example 5. 1H NMR (400 MHz, CDCIs) δ 7.65 (d, J=3.4 Hz, 1 H), 7.41-7.33 (m, 4 H), 7.30-7.22 (m, 4 H), 7.21-7.08 (m, 4 H), 4.64-4.54 (m, 1 H), 4.10 (br, 1 H), 3.58 (br, 1 H), 3.36-3.24 (m, 4 H), 2.54 (s, 3 H), 2.39-2.34 (m, 3 H), 2.30 (s, 3 H), 2.14 (br, 21 H), 1.98-1.82 (m, 10 H), 1.60 (d, J=7.8 Hz, 2 H). HRMS m/z (M+H)+ calcd: 591.3335, obsd: 591.3348. Example 467 Preparation of 4-r(4 2-lϊ1 R.5SV3-(2-methyl-1 H-benzimidazol-1 -vh-8- azabicvclo[3.2.11oct-δ-vnethyll-4-phenylpiperidin-1 -vDcarbonyllphenol
Figure imgf000295_0001
4-[(4.{2-[(1R, 5S)-3-(2-Methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1 ]oct-8-yl]ethyl}-4-phenylpiperidin-1 -yl)carbonyl]phenol (27 mg, 33%) was obtained as a foam from 2-methyl-1-{8-[2-(4-phenylpiperidin-4- yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole (64 mg, 0.15 mmol), 4- hydroxylbenzoic acid (21 mg, 0.15 mmol) and HATU (57 mg, 0.15 mmol), following the procedure outlined in example 5. 1H NMR (400 MHz, CDCI3) δ 7.67-7.64 (m, 1 H), 7.39-7.23 (m, 8 H), 7.23-7.13 (m, 2 H), 6.84 (d, J=8.4 Hz, 2 H), 4.67-4.54 (m, 1 H), 4.13 (br, 1 H), 3.71 (br, 1 H), 3.40-3.26 (m, 4 H), 2.51 (s, 3 H), 2.40-2.11 (m, 4 H), 1.95-1.82 (m, 10 H), 1.62 (d, J=8.0 Hz, 2 H). HRMS m/z (M+H)+ calcd: 549.3230, obsd: 548.3233.
Example 468 Preparation of 2-r(4-f2-f(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicvclo[3.2.11oct-8-vπethylH-phenylpiperidin-1 -vDcarbonyriphenol
Figure imgf000295_0002
2-[(4-{2-[(1 R, 5S)-3-(2-Methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1 ]oct-8-yl]ethyl}-4-phenylpiperidin-1 -yl)carbonyl]phenol (70 mg, 85%) was obtained as a syrupy from 2-methyl-1-{8-[2-(4-phenylpiperidin-4- yl)ethyl]-δ-azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole (64 mg, 0.15 mmol), 2- hydroxylbenzoic acid (21 mg, 0.15 mmol) and HATU (57 mg, 0.15 mmol), following the procedure outlined in example 5. 1H NMR (300 MHz, CDCI3) δ 9.61 (s, 1 H), 7.65 (d, J=7.δ Hz, 1 H), 7.42-7.31 (m, 2 H), 7.30-7.11 (m, δ H), 7.00 (d, J=δ.1 Hz, 1 H), 6.δ3 (t, J=7.4 Hz, 1 H), 4.67-4.53 (m, 1 H), 4.07-4.02 (m, 4 H), 3.40 (t, J=10.7 Hz, 1 H), 3.25 (br, 2 H), 2.55 (s, 3 H), 2.42-2.29 (m, 4 H), 1.94-1.60 (m, 10 H), 1.63-1.58 (m, 2 H). HRMS m/z (M+H)+ calcd: 549.3230, obsd: 548.3223.
Example 469 Preparation of 2-[(4-(2-lϊ1 R, 5S)-3-(2-methyl-1 H-benzimidazol-1 -vh-8- azabicvclo[3.2.noct-δ-yl1ethyl)-4-phenylpiperidin-1-yl)carbonvnphenyl acetate
Figure imgf000296_0001
2-[(4-{2-[(1R, 5S)-3-(2-Methyl-1 H-benzimidazol-1 -yl)-δ- azabicyclo[3.2.1]oct-δ-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]phenyl acetate (60 mg, 6δ%) was obtained as syrup from 2-methyl-1-{δ-[2-(4-phenylpiperidin- 4-yl)ethyl]-δ-azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole (64 mg, 0.15 mmol), 2-(acetyloxy)benzoic acid (27 mg, 0.15 mmol) and HATU (57 mg, 0.15 mmol), following the procedure outlined in example 5. 1H NMR (400 MHz, CDCI3) δ 7.66 (d, J=8.4 Hz, 1 H), 7.43-7.32 (m, 3 H), 7.30-7.23 (m, 6 H), 7.21-7.12 (m, 3 H), 4.62-4.56 (m, 1 H), 4.16-4.11 (m, 1 H), 3.46-3.34 (m, 2 H), 3.23-3.20 (m, 3 H), 2.53 (s, 3 H), 2.41-2.27 (m, 4 H), 2.16-2.13 (m, 2 H), 1.92-1.79 (m, 11 H), 1.62-1.57 (m, 2 H). HRMS m/z (M+H)+ calcd: 591.3335, obsd: 591.3341.
Example 470 Preparation of 4-fluoro-2-r(4-f2-r(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicvclo[3.2.11oct-δ-vπethyl)-4-phenylpiperidin-1 -vDcarbonyllphenol
Figure imgf000296_0002
4-Fluoro-2-[(4-{2-[(1 R, 5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-δ- azabicyclo[3.2.1]oct-δ-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]phenol (58 mg, 85%) was obtained as a foam from 2-methyl-1-{8-[2-(4-phenylpiperidin-4- yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1H-benzimidazole (51 mg, 0.12 mmol), 5- fluoro-2-hydroxybenzoic acid (19 mg, 0.12 mmol) and HATU (47mg, 0.12 mmol), following the procedure outlined in example 5. 1H NMR (400 MHz, CDCIs) δ 9.67 (br, 1 H), 7.65 (d, J=7.0 Hz, 1 H), 7.41-7.37 (m, 2 H), 7.32- 7.24(m, 4 H), 7.21-7.12 (m, 2 H), 7.05-7.01 (m, 1 H), 7.00-6.86 (m, 2 H), 4.61 (br, 1 H), 4.04-4.00 (m, 2 H), 3.38 (t, J=10.δ Hz, 2 H), 3.25 (br, 2 H), 2.55 (s, 3 H), 2.40-2.20 (m, 4 H), 1.94-1.63 (m, 10 H), 1.63-1.61 (m, 2 H). HRMS m/z (M+H)+ calcd: 567.3135, obsd: 567.3130.
Example 471 Preparation of 3-fluoro-2-r(4-f2-lϊ1 R.5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicvclor3.2.11dct-8-yl1ethyl}-4-phenylpiperidin-1-yl)carbonvπphenol
Figure imgf000297_0001
3-Fluoro-2-[(4-{2-[(1 R, 5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1 ]oct-δ-yl]ethyl}-4-phenylpiperidin-1 -yl)carbonyl]phenol (53 mg, 7δ%) was obtained as a foam from 2-methyl-1-{δ-[2-(4-phenyl piperidin-4- yl)ethyl]-δ-azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole (51 mg, 0.12 mmol), 6- fluoro-2-hydroxy-benzoic acid (19 mg, 0.12 mmol) and HATU (47mg, 0.12 mmol), following the procedure outlined in example 5. 1H NMR (400 MHz,
CDCI3) δ 7.65 (d, J=δ.6 Hz, 1 H), 7.44-7.36 (m, 2 H), 7.31-7.24(m, 3 H), 7.22- 7.12 (m, 4 H), 6.97 (d, J=3.4 Hz, 1 H), 6.5δ (t, J=9.0 Hz, 1 H), 4.64-4.55 (m, 1 H), 4.20 (br, 1 H), 3.59 (br, 1 H), 3.33 (br, 2 H), 2.54 (s, 3 H), 2.39-2.20 (m, 4 H), 1.99-1.31 (m, 10 H), 1.60 (d, J=7.1 Hz, 2 H). HRMS m/z (M+H)+ calcd: 567.3135, obsd: 567.3117. Example 472 Preparation of 5-chloro-2-IT4-(2-r(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -ylVδ- azabicvclor3.2.noct-δ-yl1ethyll-4-phenylpiperidin-1-vπcarbonvnphenol
Figure imgf000298_0001
5-Chloro-2-[(4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-δ- azabicyclo[3.2.1]oct-δ-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]phenol (46 mg, 66%) was obtained as a foam from 2-methyl-1-{δ-[2-(4-phenylpiperidin-4- yl)ethyl]-δ-azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole (51 mg, 0.12 mmol), 4- chloro-2-hydroxybenzoic acid (21 mg, 0.12 mmol) and HATU (47mg, 0.12 mmol), following the procedure outlined in example 5. 1H NMR (400 MHz,
CDCIs) δ 7.66 (d, J=7.3 Hz, 1 H), 7.41-7.37 (m, 2 H), 7.32-7.24 (m, 4 H), 7.21- 7.12 (m, 3 H), 7.02 (s, 1 H), 6.82 (d, J=6.4 Hz, 1 H), 4.60 (br, 1 H), 4.02-3.99 (m, 2 H), 3.41-3.35 (m, 2 H), 3.25 (br, 2 H), 2.56 (s, 3 H), 2.36-2.29 (m, 4 H), 1.94-1.84 (m, 10 H), 1.63-1.62 (m, 2 H). HRMS m/z (M+H)+ calcd: 583.2δ40, obsd: 583.2639.
Preparation of meta- and para- N-subsutituted sulfonamides
Figure imgf000298_0002
Figure imgf000299_0001
4-Chloro-3-(chlorosulfonyl)benzoic acid has been synthesized as described elsewhere in this application (Method G).
Figure imgf000299_0002
3-(Aminosulfonyl)-4-fluorobenzoic acid has been synthesized according to as Method G detailed elsewhere in this application.
Figure imgf000299_0003
2,6-Difluoro-3-(aminosulfonyl)benzoic acid, 2,6-dichloro-3- (aminosulfonyl)benzoic acid, 3,4-difluoro-5-(aminosulfonyl)benzoic acid and 2,6-methyl-3-(aminosulfonyl)benzoic acid were prepared with the similar procedure as above. Preparation of 3-fluoro-4-methylbenzenesulfonamide
Figure imgf000300_0001
To ~20 mL of liquid ammonia at -78°C was added 2.1g (10 mmol) of 3- fluoro-4-methyl benzenesulfonyl chloride. The excess ammonia was then naturally evaporated to dryness overnight at room temperature. The crude sulfonamide was partitioned methylene chloride (100mL) and water (100 mL). The aqueous phase was further extracted with methylene chloride. The combined organic extracts were dried over anhydrous sodium sulfate. Evaporation of the solvents afforded 1.9 g of 3-fluoro-4- methylbenzenesulfonamide as a solid.
Preparation of 4-(aminosulfonyl)-2-fluorobenzoic acid
Figure imgf000300_0002
To a stirred solution of 3-fluoro-4-methyl-benzenesulfonamide (prepared above) in 50 mL of water was added sodium carbonate (0.53g, 5 mmol) and potassium permanganate (3.16g, 20 mmol) portionwise over three hours at 50-60 °C. The resulting mixture was stirred for further 8 hours at this temperature before 0.2 mL of formic acid was added to quench the excess of potassium permanganate. The mixture was then filtered through celite while it was still hot and further washed with the hot water. The filtrate was concentrated to ~30 mL and adjusted to pH 9-10. The filtration was applied again to remove non-oxidized starting material. The final filtrate was acidified with HCl (cone.) to - pH 1 and 4-(aminosulfonyl)-2-fluorobenzoic acid was precipitated and collected by filtration as white solid (1.1 Og, 50%). The corresponding 4-(aminosulfonyl)-2-chlorobenzoic acid was prepared by the similar procedures. Exmple 473 Preparation of 2-chloro-5-r(4-(2-lϊ1 R.5S)-3-(2-methyl-1 H-benzimidazol-1 -ylVδ- azabicvclor3.2.1loct-8-vnethyl)-4-phenylpiperidin-1-vhcarbonvn-N- propylbenzenesulfonamide
Figure imgf000301_0001
To a stirred solution of 4-chloro-3-(chlorosulfonyl)benzoic acid (25.4 mg, 0.1 mmol) in dichloromethane (3 mL) was added propylamine (9 μL, 0.11 mmol), Λ/,Λ/-diisopropylethylamine (39mg, 0.3 mmol) and 4-N,N- dimethylaminopyridine (2 mg, 0.016 mmol). After the resultant mixture was stirred overnight, a solution of 2-methyl-1-{(1 R,5S)-8-[2-(4-phenyl piperidin-4- yl)ethyl]-δ-azabicyclo[3.2.1 ]oct-3-yl}-1 H-benzimidazole dihydrochloride (50 mg, 0.1 mmol) in W,Λ/-dimethylforamide (3 mL) was added and followed by addition of N, Λ/-diisopropylethylamine ( 39mg, 0.3 mmol) and HATU (33 mg. 0.1 mmol). The reaction mixture was stirred for further 4 hours before it was quenched with saturated sodium bicarbonate solution and extracted with dichloromethane. The combined organic extracts were dried over anhydrous sodium sulfate. After evaporation of solvents, the residue was purified by flash chromatography, eluting with a gradient of 0-3% methanol in ethyl acetate to afford 2-chloro-5-[(4-{2-[(7R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)- 8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]- - propylbenzenesulfonam.de as solid (30 mg, 43%). 1H NMR (400 MHz, CDCIs) δ δ.09 (s, 1 H), 7.65 (d, J=δ.4 Hz, 1 H), 7.65 (s, 2 H), 7.33 (t, J=7.5 Hz, 2 H), 7.30-7.23 (m, 4 H), 7.19-7.12 (m, 2 H), 5.10 (t, J=6.0 Hz, 1 H), 4.64-4.59 (m, 1 H), 4.19 (br, 1 H), 3.48 (br, 1 H), 3.34-3.35 (m, 4 H), 2.90 (q, J=6.3 Hz, 2 H), 2.57 (s, 3 H), 2.42-2.34 (m, 3 H), 2.20 (br, 1 H), 1.94-1.78 (m, 10 H), 1.62 (d, J=6.4 Hz, 2 H), 1.54-1.45 (m, 2 H), 0.88 (t, J=7.5 Hz, 3 H). HRMS m/z (M+H)+ calcd: 688.3088, obsd: 688.3063. Example 474 Preparation of 2-chloro-N-isopropyl-5-r(4-f2-[(1 R,5S)-3-(2-methyl-1 H- benzimidazol-1-yl)-8-azabicyclo[3.2.1l oct-8-yllethyll-4-phenylpiperidin-1- vπcarbonyllbenzene sulfonamide
Figure imgf000302_0001
2-Chloro-Λ/-isopropyl-5-[(4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 - yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]benzene sulfonamide (10 mg, 15%) was obtained as solid from 4-chloro-3- (chlorosulfonyl)benzoic acid (25.4 mg, 0.1 mmol), 2-methyl-1-{(1R,5S)-8-[2-(4- phenylpiperidin-4-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole dihydrochloride (50 mg, 0.1 mmol) and isopropylamine (9.4 μL, 0.11 mmol) following the procedure outlined in example 473. 1H NMR (300 MHz, CDCI3) δ 8.11 (s, 1 H), 7.67 (d, J=7.0 Hz, 1 H), 7.57 (s, 2 H), 7.42-7.37 (m, 2 H), 7.30- 7.20 (m, 4 H), 7.18-7.12 (m, 2 H), 4.89 (d, J=7.5 Hz, 1 H), 4.64-4.59 (m, 1 H), 4.18 (br, 1 H), 3.49-3.29 (m, 6 H), 2.58 (s, 3 H), 2.38-2.16 (m, 4 H), 1.95-1.88 (m, 10 H), 1.65-1.63 (m, 2 H), 1.10 (d, J=6.5 Hz, 6 H). HRMS m/z (M+H)+ calcd: 688.3088, obsd: 688.3093.
Example 475 Preparation of 2-chloro-N-cvclopropyl-5-r(4-f2-[(1 R,5S)-3-(2-methyl-1 H- benzimidazol-1-yl)-8-azabicvclo[3.2.1loct-8-vnethyl)-4-phenylpiperidin-1- vDcarbonvπbenzenesulfonamide
Figure imgf000302_0002
2-Chloro-Λ/-cyclopropyl-5-[(4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol- 1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1- yl)carbonyl]benzene sulfonamide (15 mg, 22%) was obtained as solid from 4- chloro-3-(chlorosulfonyl)benzoic acid (25.4 mg, 0.1 mmol), 2-methyl-1- {(1R,5S)-8-[2-(4-phenylpiperidin-4-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1H- benzimidazole dihydrochloride (50 mg, 0.1 mmole), cyclopropylamine (7.6 μL, 0.11 mmol) and HATU (38 mg, 0.1 mmol) following the procedure outlined in example 473. 1H NMR (400 MHz, CDCI3) δ 8.14 (s, 1 H), 7.66 (d, J=7.0 Hz, 1 H), 7.59 (s, 2 H), 7.41-7.37 (m, 2 H), 7.30-7.20 (m, 4 H), 7.18-7.13 (m, 2 H), 5.46 (s, 1 H), 4.65-4.60 (m, 1 H), 4.19 (br, 1 H), 3.50 (br, 1 H), 3.35-3.26 (m, 4 H), 2.57 (s, 3 H), 2.43-2.35 (m, 3 H), 2.19 (br, 2 H), 1.94-1.78 (m, 10 H), 1.63 (d, J=7.9 Hz, 2 H), 0.68-0.58 (m, 4 H). HRMS m/z (M+H)+ calcd: 686.2932, obsd: 686.2935.
Example 476 Preparation of N-acetyl-4-r(4-f2-r3-(2-methyl-1 H-benzimidazol-1 -vO-8- azabicvclor3.2.1loct-8-yllethyl}-4-phenylpiperidin-1-yl)carbonvnbenzene- sulfonamide
Figure imgf000303_0001
To a precooled (0 °C) solution of 4-[(4-{2-[3-(2-methyl-1H- benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1- yl)carbonyl]-benzene-sulfonamide (20 mg, 0.033 mmol) in dichloromethane (2 mL) was added acetyl bromide (4.2 mg, 0.034 mmol) and /V,/V-diisopropylethyl amine (12 μL, 0.66 mmol). The resulting mixture was stirred overnight at ambient temperature. After evaporation of the solvent, the crude product was purified by flash chromatography on silical gel, eluting with a gradient of 15- 30% methanol in ethyl acetate to afford -acetyl-4-[(4-{2-[3-(2-methyl-1H- benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1- yl)carbonyl]benzene-sulfonamide as amorphous solid (14 mg, 66%). 1H NMR (300 MHz, DMSO-cfe) δ 7.83 (d, J=8.1 Hz, 2 H), 7.48-7.46 (m, 3 H), 7.37-7.33 (m, 5 H), 7.21 (br, 1 H), 7.13 -7.05 (m, 2 H), 4.51 (t, J=8.1 , 1 H), 3.88 (br, 1 H), 3.67-3.15 (m, 6 H), 2.42 (s, 3 H), 2.37-2.30 (m, 2 H), 2.11-2.07 (br, 2 H), 1.96-1.72 (m, 13 H), 1.59 (d, J=7.4, 2 H). HRMS m/z (M+H)+ calcd: 654.3114, obsd: 654.3095.
Example 477 Preparation of 4-[Y4-(2-r3-(2-methyl-1 H-benzimidazol-1 -vπ-8-azabicyclo- f3.2.noct-8-vnethyl)-4-phenylpiperidin-1-yl)carbonyll-N-propionylbenzene- sulfonamide
Figure imgf000304_0001
4-[(4-{2-[3-(2-Methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1]oct-8- yl]ethyl}-4-phenylpiperidin-1 -yl)carbonyl]-Λ/-propionylbenzenesulfonamide (13 mg, 59%) was obtained from 4-[(4-{2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]- benzenesulfonamide (20 mg, 0.033 mmol) and propionyl chloride as amorphous solid by the similar procedure outlined in example 476. 1H NMR (300 MHz, DMSO-de) δ 7.87 (d, J=8.0 Hz, 2 H), 7.53-7.42 (m, 3 H), 7.39-7.35 (m, 5 H), 7.25-7.21 (m, 1 H), 7.15-7.07 (m, 2 H), 4.66 (br, 1 H), 3.90 (br, 1 H), 3.19-3.16 (m, 5 H), 2.45 (s, 3 H), 2.42-2.35 (m, 2 H), 2.22-2.09 (m, 5 H), 1.98- 1.78 (m, 10 H), 1.66 (d, J=7.3 Hz, 2 H), 1 ,17 (t, J=7.2 Hz, 3 H). HRMS m/z (M+H)+ calcd: 668.3271 , obsd: 668.3256.
Example 478 Preparation of N-butyryl-4-r(4-(2-r3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicvclo[3.2.noct-8-yllethyl}-4-phenylpiperidin-1-yl)carbonyllbenzene- sulfonamide
Figure imgf000304_0002
Λ/-butyryl-4-[(4-{2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo- [3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]benzenesulfonamide (15 mg, 68% ) was obtained from 4-[(4-{2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]- benzenesulfonamide (20 mg, 0.033 mmol) and butyryl chloride by the similar procedure outlined in example 476. 1H NMR (300 MHz, DMSO-c 6) δ 7.87 (d, J=8.1 Hz, 2 H), 7.52-7.4 (m, 3 H), 7.39-7.35 (m, 5 H), 7.25-7.21 (m, 1 H), 7.15-7.07 (m, 2 H), 4.69 (br, 1 H), 3.89 (br, 1 H), 3.16 (m, 5 H), 2.45 (s, 3 H), 2.42-2.35 (m, 2 H), 2.23-2.05 (m, 5 H), 1.98-1.78 (m, 10 H), 1.68-1.66 (m, 2 H), 1.40 (q, J=7.3 Hz, 2 H),17 (t, J=7.3 Hz, 3 H). HRMS m/z (M+H)+ calcd: 682.3427, obsd: 682.3426.
Example 479 Preparation of N-isobutyryl-4-[(4-{2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicvclo[3.2.noct-8-vnethyl)-4-phenylpiperidin-1-yl)carbonvnbenzene- sulfonamide
Figure imgf000305_0001
Λ/-isobutyryl-4-[(4-{2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo-
[3.2.1 ]oct-8-yl]ethyl}-4-phenylpiperidin-1 -yl)carbonyl]benzenesulfonamide (14 mg, 64% ) was obtained from 4-[(4-{2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]- benzenesulfonamide (20 mg, 0.033 mmol) and isobutyryl chloride by the similar procedure outlined in example 476. 1H NMR (300 MHz, DMSO-αe) δ 7.84 (d, J=8.2 Hz, 2 H), 7.50-7.47 (m, 3 H), 7.41-7.35 (m, 5 H), 7.25-7.21 (m, 1 H), 7.15-7.07 (m, 2 H), 4.60 (br, 1 H), 3.90 (br, 1 H), 3.75-3.16 (m, 5 H), 2.45 (s, 3 H), 2.42-2.23 (m, 3 H), 2.13-2.08(m, 2 H), 1.98-1.78 (m, 11 H), 1.65-1.62 (m, 2 H), 0.92 (d, J=6.8 Hz, 6 H). HRMS m/z (M+H)+ calcd: 682.3427, obsd: 682.3408. 305
Example 480 Preparation of N-acety|-2-chloro-5-[(4-(2-f3-(2-methyl-1 H-benzimidazol-1 -yl)- 8-azabicvclof3.2.noct-8-vnethyl)-4-phenylpiperidin-1-vncarbonyl1benzene- sulfonamide
Figure imgf000306_0001
Λ/-acetyl-2-chloro-5-[(4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl] benzenesulfonamide (21.8 mg, quant.) was obtained as amorphous solid from 2- chloro-5-[(4-{2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1]oct-8- yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl] benzenesulfonamide and acetyl bromide following the procedure outlined in example 476. 1H NMR (300 MHz, DMSO-de) δ 7.85-7.50 (m, 3 H), 7.49 (d, J=8.5 Hz, 1 H), 7.41-7.35 (m, 5 H), 7.25-7.21 (m, 1 H), 7.15-7.09 (m, 2 H), 4.54 (br, 1 H), 3.96 (br, 1 H), 3.42-3.29 ( m, 5 H), 3.06-3.03 (m, 1 H), 2.45-2.36 (m, 5 H), 2.17-2.07 (m, 2 H), 1.98- 1.75 (m, 10 H), 1.71-1.70 (m, 3 H), 1.63-1.61 (m, 2 H). HRMS m/z (M+H)+ calcd: 688.2724, obsd: 688.2745.
Example 481 Preparation of 2-chloro-5-[(4-{2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicvclo[3.2.11oct-8-yl1ethyl}-4-phenylpiperidin-1-yl)carbonvπ-N-propionyl benzenesulfonamide
Figure imgf000306_0002
2-Chloro-5-[(4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo- [3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]-/V-propionylbenzene- sulfonamide(16 mg, 73%) was obtained as amorphous solid from 2-chloro-5- [(4-{2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4- phenyl piperidin-1-yl)carbonyl] benzenesulfonamide and propionyl chloride following the procedure outlined in example 476. 1H NMR (300 MHz, DMSO- de) δ 7.81-7.56 (m, 3 H), 7.49 (d, J=8.4 Hz, 1 H), 7.39-7.26 (m, 5 H), 7.24-7.08 (m, 3 H), 4.80 (br, 1 H), 3.99-3.93 (m, 1 H), 3.58-3.38 (m, 5 H), 3.11-2.99 (m, 1 H), 2.47 (m, 4 H), 2.22-1.72 (m, 17 H), 0.89-0.81 (m, 3 H). HRMS m/z (M+H)+ calcd: 702.2881 , obsd: 702.2885.
Example 482 Preparation of 2-chloro-N-isobutyryl-5-[(4-(2-[3-(2-methyl-1 H-benzimidazol-1 - vπ-8-azabicvclor3.2.1loct-8-vnethyll-4-phenylpiperidin-1-vπcarbonvn benzenesulfonamide
Figure imgf000307_0001
2-Chloro-Λ/-isobutyryl-5-[(4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl] benzenesulfonamide (19 mg, 80%) was obtained as amorphous solid from 2-chloro-5- [(4-{2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4- phenylpiperidin-1-yl)carbonyl]benzenesulfonamide and isobutyryl chloride following the procedure outlined in example 476. 1H NMR (300 MHz, DMSO- de, 100 °C) δ 7.85-7.76 (m, 2 H), 7.60-7.50 (m, 2 H), 7.42-7.28 (m, 5 H), 7.26 (m, 1 H), 7.18-7.12 (m, 2 H), 4.76 (br, 1 H), 3.36-3.08 (m, 7 H), 2.53-2.27 (m, 7 H), 204-1.82 (m, 10 H), 1.69 (d, J=7.6 Hz, 2 H), 0.95 (d, J=6.6 Hz, 6 H). HRMS m z (M+H)+ calcd: 716.3037, obsd: 716.3013. Example 483 Preparation of 2-fluoro-5-IT4~(2-r(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -ylV8- azabicvclor3.2.noct-8-yllethyl}-4-phenylpiperidin-1-yl)carbonyllbenzene- sulfonamide
Figure imgf000308_0001
2-Fluoro-5-[(4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1- yl)carbonyl]benzenesulfonamide (20 mg, 32%) was obtained as solid from 3- (aminosulfonyl)-4-fluorobenzoic acid (22 mg, 0.1 mmol), 2-methyl-1-{(1R,5S)- 8-[2-(4-phenylpiρeridin-4-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1H- benzimidazole dihydrochloride (50 mg, 0.1 mmol) and HATU (38 mg, 0.1 mmol) following the procedure outlined in example 5. 1H NMR (400 MHz, CDCI3) δ 7.93-7.91 (m, 1 H), 7.64-7.58 (m, 2 H), 7.40-7.36 (m, 2 H), 7.30-7.21 (m, 5 H), 7.19-7.12 (m, 2 H), 5.61 (br, 1 H), 4.66-4.56 (m, 1 H), 4.20 (br, 1 H), 3.56 (br, 1 H), 3.26 (m, 4 H), 2.57 (s, 3 H), 2.42-2.34 (m, 4 H), 2.20 (br, 2 H), 1.99-1.83 (m, 9 H), 1.62 (m, 2 H). HRMS m/z (M+H)+ calcd: 630.2914, obsd: 630.2925.
Example 484 Preparation of 2-fluoro-N-methyl-5-r(4-f2-r(1 R.5S)-3-(2-methyl-1 H- benzimidazol-1-yl)-8-azabicvclo[3.2.1loct-8-yl1ethyll-4-phenylpiperidin-1- vOcarbonvπbenzene-sulfonamide
Figure imgf000308_0002
2-Fluoro-A/-methyl-5-[(4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)- 8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]benzene sulfonamide (53.8mg, 56%) was obtained as solid from 4-fluoro-3- (chlorosulfonyl)benzoic acid (48 mg, 0.2 mmol), 2-methyl-1-{(1R,5S)-8-[2-(4- phenylpiperidin-4-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole dihydrochloride (76 mg, 0.15 mmol) and methylamine (0.10 mL, 2.0 M in THF) following the procedure outlined in example 473. 1H NMR (400 MHz, CDCI3) δ 7.92-7.90(m, 1 H), 7.65-7.61 (m, 2 H), 7.40-7.36 (m, 2 H), 7.30-7.22 (m, 5 H), 7.18-7.12 (m, 2 H), 5.29 (d, J=4.9 Hz, 1 H), 4.63-4.58 (m, 1 H), 4.18 (br, 1 H), 3.50 (br, 1 H), 3.32-3.25 (m, 4 H), 2.71 (d, J=4.1 Hz, 3 H), 2.56 (s, 3 H), 2.41-2.33 (m, 3 H), 2.16 (br, 2 H), 1.92-1.81 (m, 10 H), 1.64-1.58 (m, 2 H). HRMS m/z (M+H)+ calcd: 644.3071 , obsd: 644.3061.
Example 485 Preparation of N-ethyl-2-fluoro-5-[(4-(2-r(1 R.5S)-3-(2-methyl-1 H- benzimidazol-1-yl)-8-azabicvclof3.2.1loct-8-yl]ethyl)-4-phenylpiperidin-1- vOcarbonyllbenzene-sulfonamide
Figure imgf000309_0001
Λ/-Ethyl-2-fluoro-5-[(4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]benzene sulfonamide (30.5 mg, 30%) was obtained as solid from 4-fluoro-3- (chlorosulfonyl)benzoic acid (48 mg, 0.2 mmol), 2-methyl-1 -{(1 R,5S)-8-[2-(4- phenylpiperidin-4-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole dihydrochloride (76 mg, 0.15 mmol) and ethylamine (0.10 mL, 2.0 M in THF) following the procedure outlined in example 473. 1H NMR (400 MHz, CDCI3) δ 7.93-7.90(m, 1 H), 7.66-7.61 (m, 2 H), 7.40-7.36 (m, 2 H), 7.30-7.22 (m, 5 H), 7.19-7.12 (m, 2 H), 4.94 (t, J=6.1 Hz, 1 H), 4.65-4.57 (m, 1 H), 4.17 (br, 1 H), 3.50 (br, 1 H), 3.26 (br, 4 H), 3.11-3.04 (m, 2 H), 2.56 (s, 3 H), 2.42-2.34 (m, 3 H), 2.20-2.17 (m, 1 H), 1.94-1.82 (m, 10 H), 1.64 (d, J=6.4 Hz, 2 H), 1.13 (t, J=7.1 Hz, 3 H). HRMS m/z (M+H)+ calcd: 658.3227, obsd: 658.3237. Example 486 Preparation of 2-fluoro-5-lϊ4-(2-lϊ1 R.5S)-3-(2-methyl-1 H-benzimidazol-1 -vh-8- azabicvclo[3.2.1 loct-8-vnethyl)-4-phenylpiperidin-1 -yl)carbonyll-N- propylbenzenesulfonam.de
Figure imgf000310_0001
2-Fluoro-5-[(4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]-Λ/- propylbenzene sulfonamide (41.8 mg, 41%) was obtained as solid from 4- fluoro-3-(chlorosulfonyl)benzoic acid (48 mg, 0.2 mmol), 2-methyl-1-{(1R,5S)- 8-[2-(4-phenylpiperidin-4-yl)ethyl]-8-azabicyclo[3.2.1 ]oct-3-yl}-1 H- benzimidazole dihydrochloride (76 mg, 0.15 mmol) and propylamine (16.5 μL, 0.2mmol) following the procedure outlined in example 473. 1H NMR (400 MHz, CDCI3) δ 7.92-7.90(m, 1 H), 7.66-7.61 (m, 2 H), 7.40-7.36 (m, 2 H), 7.30-7.22 (m, 5 H), 7.19-7.12 (m, 2 H), 5.03 (t, J=6.0 Hz, 1 H), 4.64-4.56 (m, 1 H), 4.18 (br, 1 H), 3.50 (br, 1 H), 3.33-3.25 (m, 4 H), 2.97 (q, J=6.8Hz, 2 H), 2.56 (s, 3 H), 2.42-2.34 (m, 3 H), 2.19 (br, 1 H), 2.10 (s, 1 H), 1.93-1.82 (m, 10 H), 1.62 (d, J=6.4 Hz, 2 H), 1.55-1.46 (m, 2 H), 0.88(t, J=7.5 Hz, 3 H). HRMS m/z (M+H)+ calcd: 672.3384, obsd: 672.3380.
Example 487 Preparation of 2-fluoro-N-isopropy|-5-lϊ4-f2-lϊ1 R,5SV3-(2-methyl-1 H- benzimidazol-1 -v0-8-azabicvclor3.2.11 oct-8-yllethyl)-4-phenylpiperidin-1 ■ vDcarbonyllbenzene sulfonamide
Figure imgf000311_0001
2-Fluoro- -isopropyl-5-[(4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 - yl)-8-azabicyclo[3.2.1 ]oct-8-yl]ethyl}-4-phenylpiperidin-1 -yl)carbonyl]benzene sulfonamide (35.6mg, 35%) was obtained as solid from 4-fluoro-3- (chlorosulfonyl)benzoic acid (48 mg, 0.2 mmol), 2-methyl-1-{(1R,5S)-8-[2-(4- phenylpiperidin-4-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole dihydrochloride (76 mg, 0.15 mmol) and isopropylamine (17 μL, 0.2mmol) following the procedure outlined in example 473. 1H NMR (400 MHz, CDCI3) δ 7.94-7.91 (m, 1 H), 7.67-7.61 (m, 2 H), 7.40-7.37 (m, 2 H), 7.30-7.22 (m, 5 H), 7.19-7.12 (m, 2 H), 4.75 (d, J=7.5 Hz, 1 H), 4.65-4.60 (m, 1 H), 4.19 (br, 1 H), 3.56-3.48 (m, 2 H), 3.33-3.26 (br, 4 H), 2.57 (s, 3 H), 2.41-2.34 (m, 3 H), 2.19-2.17 (br, 1 H), 1.94-1.82 (m, 11 H), 1.62 (d, J=7.9 Hz, 2 H), 1.11 (d, J=6.4 Hz, 6 H). HRMS m/z (M+H)+ calcd: 672.3384, obsd: 672.3398.
Example 488 Preparation of N-cvclopropyl-2-fluoro-5-f(4-(2-r(1 R,5S)-3-(2-methyl-1 H- benzimidazol-1-vπ-8-azabicvclor3.2.11oct-8-yl1ethyl}-4-phenylpiperidin-1- vDcarbonvnbenzenesulfonamide
Figure imgf000311_0002
Λ/-Cyclopropyl-2-fluoro-5-[(4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-
1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1- yl)carbonyl]benzene sulfonamide (43.0 mg, 43%) was obtained as solid from 4-fluoro-3-(chlorosulfonyl)benzoic acid (48 mg, 0.2 mmol), cyclopropyl amine (14 μL, 0.2mmol) and 2-methyl-1-{(1R,5S)-8-[2-(4-phenylpiperidin-4-yl)ethyl]- 8-azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole dihydrochloride (76 mg, 0.15 mmol) following the procedure outlined in example 473. 1H NMR (400 MHz, CDCIs) δ 7.97-7.95 (m, 1 H), 7.69-7.64 (m, 2 H), 7.40-7.36 (m, 2 H), 7.30-7.23 (m, 5 H), 7.19-7.12 (m, 2 H), 5.47 (s, 1 H), 4.64-4.56 (m, 1 H), 4.19 (br, 1 H), 3.51 (br, 1 H), 3.33-3.26 (m, 4 H), 2.56 (s, 3 H), 2.41-2.28 (m, 3 H), 2.27-2.17 (m, 2 H), 1.99-1.82 (m, 12 H), 1.62 (d, J=7.9 Hz, 2 H), 0.68-0.60 (m, 4 H). HRMS m/z (M+H)+ calcd: 670.3227, obsd: 670.3213.
Example 489 Preparation of 2-fluoro-5-r(4-(3-fluorophenyl)-4-f2-r(1 R,5SV3-(2-methyl-1 H- benzimidazol-1-vπ-8-azabicvclo[3.2.1loct-8-vnethyl)piperidin-1- vOcarbonvπbenzenesulfonamide
Figure imgf000312_0001
2-Fluoro-5-[(4-(3-fluorophenyl)-4-{2-[(1 R,5S)-3-(2-methyl-1 H- benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-1- yl)carbonyl]benzenesulfonamide (35 mg, 54%) was obtained as solid from 3- (aminosulfonyl)-4-fluorobenzoic acid (22 mg, 0.1 mmol), 1-((1 ,5S)-8-{2-[4-(3- fluorophenyl)piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H- benzimidazole dihydrochloride (52 mg, 0.1 mmol) and HATU (38mg, O.IOmmol) following the procedure outlined in example 473. 1H NMR (400 MHz, CDCI3), δ 7.96 (dd, J=6.8 Hz, 2.1 Hz, 1 H), 7.63-7.61 (m, 1 H), 7.59-7.55 (m, 1 H), 7.37-7.32 (m, 1 H), 7.29-7.20 (m, 2 H), 7.18-7.10 (m, 2 H), 7.06 (d, J=8.0 Hz, 1 H), 6.99-6.90 (m, 2 H), 6.04 (br, 2 H), 4.66 (t, J=8.8 Hz, 1 H), 4.14-4.08 (m, 1 H), 3.50 (br, 1 H), 3.9 (br, 4 H), 2.52 (s, 3 H), 2.44-2.36 (m, 2 H), 2.24 (br, 1 H), 2.09 (br, 1 H), 1.96-1.84 (m, 10 H), 1.65 (d, J=7.8 Hz, 2 H). HRMS m/z (M+H)+ calcd: 648.2820, obsd: 648.2822.
Example 490 Preparation of N-cvclopropyl-2-fluoro-5-f(4-(3-fluorophenvh-4-(2-r(1 R.5SV3- (2-methyl-1 H-benzimidazol-1 -yl)-8-azabicvclo[3.2.11oct-8-vπethyl)piperidin-1 - vDcarbonvπbenzenesulfonamide
Figure imgf000313_0001
Λ/-Cyclopropyl-2-fluoro-5-[(4-(3-fluoro phenyl)-4-{2-[(1R,5S)-3-(2- methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-1- yl)carbonyl]benzenesulfonamide (22 mg, 32%) was obtained as solid from 4- fluoro-3-(chlorosulfonyl) benzoic acid (48 mg, 0.2 mmol), cyclopropyl amine (14 μL, 0.2mmol) and 1-((1R,5S)-8-{2-[4-(3-fluorophenyl) piperidin-4-yl]ethyl}- 8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1 H-benzimidazole dihydrochloride (52 mg, 0.1 mmol) following the procedure outlined in example 473. 1H NMR (400 MHz, CDCIs), δ 7.96 (dd, J=6.7 Hz, 2.2 Hz, 1 H), 7.69-7.65 (m, 2 H), 7.39-7.33 (m, 1 H), 7.30-7.25 (m, 2 H), 7.19-7.12 (m, 2 H), 7.07 (d, J=8.0 Hz, 1 H), 7.01- 6.94 (m, 2 H), 5.39 (s, 1 H), 4.66 (br, 1 H), 4.16 (br, 1 H), 3.54 (br, 1 H), 3.48- 3.28 (m, 4 H), 2.58 (s, 3 H), 2.44-2.37 (m, 2 H), 2.29-2.20 (m, 2 H), 2.13 (br, 1 H), 1.97-1.81 (m, 10 H), 1.66 (d, J=7.9 Hz, 2 H), 0.68-0.61 (m, 4 H). HRMS /7?/z (M+H)+ calcd: 688.3133, obsd: 688.3146. Example 491 2.4-difluoro-3-r(4-(2-r(1 R.5S .-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicvclo[3.2.1 loct-8-vπethyll-4-phenylpiperidin-1 - vπcarbonvnbenzenesulfonamide Preparation of 3-(chlorosulfonvD-2,6-difluorobenzoic acid
Figure imgf000314_0001
3-(Chlorosulfonyl)-2,6-difluorobenzoic acid (8.6 g, 67%) was obtained as solid from 2,6-difluorobenzic acid (8 g, 50 mmol), following the procedure outlined in the preparation of 4-chloro-3-(chlorosulfonyl)benzoic acid.
Figure imgf000314_0002
2,4-Difluoro-3-[(4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]benzene sulfonamide (22mg, 34%) was obtained as solid from 3-(aminosulfonyl)-2,6- difluorobenzoic acid (24 mg, 0.1 mmol), 2-methyl-1-{(1R,5S)-8-[2-(4- phenylpiperidin-4-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole dihydrochloride (50 mg, 0.10 mmol) and HATU (38mg, 0.1 mmol) following the procedure outlined in example 473. 1H NMR (400 MHz, CDCI3) δ 8.00- 7.89 (m, 1 H), 7.64 (d, J=7.7 Hz, 1 H), 7.40-7.34 (m, 2 H), 7.30-7.24 (m, 4 H), 7.19-7.12 (m, 2 H), 7.07-6.97 (m, 1 H), 5.6 (br, 2 H), 4.66-4.55 (m, 1 H), 4.29- 4.24 (m, 1 H), 3.58-3.31 (m, 2 H), 3.25- 3.05 (m, 3 H), 2.54 (s, 3 H), 2.49-2.20 (m, 4 H), 1.99-1.76 (m, 10 H), 1.62 (d, J=7.7 Hz, 2 H). HRMS m/z (M+H)+ calcd: 648.2820, obsd: 648.2834. Example 492 Preparation of 2.4-difluoro-N-methyl-3- 4-(2-r(1 R.5S)-3-(2-methyl-1 H- benzimidazol-1-yl)-8-azabicvclo[3.2.1l oct-8-yllethyl)-4-phenylpiperidin-1- vDcarbonyll benzenesulfonamide
Figure imgf000315_0001
2,4-Difluoro-Λ/-methyl-3-[(4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 - yl)-8-azabicyclo[3.2.1 ]oct-8-yl]ethyl}-4-phenylpiperidin-1 -yl)carbonyl]benzene sulfonamide (90 mg, 40%) was obtained as solid from 3-(chlorosulfonyl)-2,6- difluorobenzoic acid (105 mg, 0.4 mmol), 2-methyl-1-{(1R,5S)-8-[2-(4-phenyl piperidin-4-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole dihydrochloride (177 mg, 0.35 mmol) and methylamine (230 μL, 2.0 M in THF) following the procedure outlined in example 473. 1H NMR (400 MHz, CDCI3) δ 7.98-7.92 (m, 1 H), 7.67-7.65 (d, 1 H), 7.41-7.37 (m, 2 H), 7.30-7.28 (m, 4 H), 7.21-7.03 (m, 3 H), 4.84(m, Vz H, rotamer), 4.75-4.71 (m, Vz H, rotamer), 4.66-4.58 (m, 1 H), 3.41- 3.20 (m, 5 H), 2.74 (d, J=5.1 Hz, 3/2 H, rotamer), 2.69 (d, J=5.1 Hz, 3/2 H, rotamer), 2.57 (s, 3/2 H, rotamer), 2.56 (s, 3/2 H, rotamer), 2.41-2.37 (m, 3 H), 2.26-2.23 (m, 2 H), 1.99-1.77 (m, 9 H), 1.69-1.62 (m, 4 H). HRMS m/z (M+H)+ calcd: 662.2976, obsd: 662.2982.
Example 493 Preparation of N-ethyl-2. 4-difluoro-3-r(4-(2-r(1 R.5S)-3-(2-methyl-1 H- benzimidazol-1-vπ-8-azabicvclor3.2.noct-8-yllethyl)-4-phenylpiperidin-1- vDcarbonvHbenzenesulfonamide
Figure imgf000316_0001
Λ/-Ethyl-2, 4-difluoro-3-[(4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 - yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]benzene sulfonamide (92 mg, 45%) was obtained as solid from 3-(chlorosulfonyl)-2,6- difluorobenzoic acid (105 mg, 0.4 mmol), 2-methyl-1-{(1R,5S)-8-[2-(4- phenylpiperidin-4-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole dihydrochloride (150 mg, 0.30 mmol) and ethylamine (230 μL, 2.0 M in THF) following the procedure outlined in example 473. 1H NMR (400 MHz, CDCI3) δ 8.01-7.92 (m, 1 H), 7.70 (m, Vz H, rotamer), 7.66 (d, J=7.1 Hz, 1 H), 7.54- 7.52 (m, Vz H, rotamer ), 7.41-7.32 (m, 2 H), 7.30-7.25 (m, 4 H), 7.20-7.13 (m, 2 H), 7.11-7.02 (m, 1 H), 4.90-4.59 (m, 2 H), 4.35-4.27 (m, 2 H), 3.42- 3.20 (m, 5 H), 3.18-2.96 (m, 2 H), 2.57 (s, 3/2 H, rotamer), 2.56 (s, 3/2 H, rotamer), 2.42-2.35 (m, 3 H), 2.26-2.23 (m, 1 H), 1.99-1.76 (m, 9 H), 1.68-1.62 (m, 2 H), 0.89-0.82 (m, 3 H). HRMS m/z (M+H)+ calcd: 676.3133, obsd: 676.3154.
Example 494 Preparation of 2.4-difluoro-N-isopropyl-3-lϊ4-f2-lϊ1 R.5S 3-(2-methyl-1 H- benzimidazol-1-yl)-8-azabicvclor3.2.1loct-8-yllethyl)-4-phenylpiperidin-1- vDcarbonvHbenzenesulfonamide
Figure imgf000317_0001
2,4-Difluoro-Λ/-isopropyl-3-[(4-{2-[(1 R,5S)-3-(2-methyl-1 H- benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1- yl)carbonyl]benzene sulfonamide (100 mg, 41%) was obtained as solid from 3-(chlorosulfonyl)-2,6-difluorobenzoic acid (105 mg, 0.4 mmol), 2-methyl-1- {(1 R,5S)-8-[2-(4-phenylpiperidin-4-yl)ethyl]-8-azabicyclo[3.2.1 ]oct-3-yl}-1 H- benzimidazole dihydrochloride (177 mg, 0.35 mmol) and isopropylamine (40 μL, 0.45 mmol) following the procedure outlined in example 473. 1H NMR (400 MHz, CDCIs) δ 8.01-7.93 (m, 1 H), 7.66 (d, J=7.5 Hz, 1 H), 7.41-7.37 (m, 2 H), 7.30-7.25 (m, 5 H), 7.20-7.14(m, 2 H), 7.12-7.01 (m, 1 H), 4.80-4.65 (m, 2 H), 4.29-4.23 (m, 1 H), 3.55-3.49 (m. 1 H), 3.40- 3.18 (m, 5 H), 2.58 (s, 3/2 H, rotamer), 2.57 (s, 3/2 H, rotamer), 2.40 (br, 3 H), 2.24-2.23 (m, 1 H), 1.96- 1.73 (m, 10 H), 1.67-1.65 (m, 2 H), 1.21-1.16 (m, 3 H), 1.10-1.04 (m, 3 H). HRMS /77/z (M+H)+ calcd: 690.3289, obsd: 690.3276.
Example 495 Preparation of N-cvclopropy|-2.4-difluoro-3-r(4-(2-[(1 R,5S)-3-(2-methyl-1 H- benzimidazol-1-vπ-8-azabicvclor3.2.noct-8-yllethyl)-4-phenylpiperidin-1- vDcarbonvnbenzenesulfonamide
Figure imgf000318_0001
Λ/-Cyclopropyl-2,4-difluoro-3-[(4-{2-[(1 R,5S)-3-(2-methyl-1 H- benzimidazol-1-yl)-8-azabicyclo[3.2.1] oct-8-yl]ethyl}-4-phenylpiperidin-1- yl)carbonyl]benzene sulfonamide (110 mg, 48%) was obtained as solid from 3-(chlorosulfonyl)-2,6-difluorobenzoic acid (105 mg, 0.4 mmol), 2-methyl-1- {(1R,5S)-8-[2-(4-phenylpiperidin-4-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1H- benzimidazole dihydrochloride (150 mg, 0.30 mmol) and cyclopropylamine (32 μL, 0.45 mmol) following the procedure outlined in example 473. 1H NMR (400 MHz, CDCIs) δ 8.02-7.97 (m, 1 H), 7.65 (d, J=7.2 Hz, 1 H), 7.41-7.37 (m, 2 H), 7.30-7.24 (m, 4 H), 7.20-7.04 (m, 2 H), 5,43 (s, Vz H, rotamer), 5.31 (s, Vz H, rotamer), 4.65-4.59 (m, 1 H), 4.30-4.27 (m, 1 H), 3.39-3.20 (m. 5H), 2.57 (s, 3/2 H, rotamer), 2.56 (s, 3/2 H, rotamer), 2.42-2.24 (m, 4H), 1.99-1.77 (m, 11 H), 1.65-1.60 (m, 2 H), 0.80-0.76 (m, 1 H), 0.75-0.55 (m, 3 H). HRMS m/z (M+H)+ calcd: 688.3133, obsd: 688.3135.
Example 496 Preparation of 2.4-difluoro-3--T4-f2--ϊ1R.5SV3-(2-methyl-1 H-benzimidazol-1 - yl)-8-azabicvclof3.2.11oct-8-yl]ethyl)-4-phenylpiperidin-1 -vπcarbonyll-N- propylbenzenesulfonamide
Figure imgf000319_0001
2,4-Difluoro-3-[(4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1 ]oct-8-yl]ethyl}-4-phenylpiperidin-1 -yl)carbonyl]-/V- propylbenzenesulfonamide (34.6mg, 34%) was obtained as solid from 3- (chlorosulfonyl)-2,6-difluorobenzoic acid (52 mg, 0.2 mmol), 2-methyl-1- {(1R,5S)-8-[2-(4-phenylpiperidin-4-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1H- benzimidazole dihydrochloride (76 mg, 0.15 mmol) and propylamine (16.5 μL, 0.2 mmol) following the procedure outlined in example 473. 1H NMR (400 MHz, CDCI3), δ 8.01-7.91 (m, 1 H), 7.65 (d, J=7.1 Hz, 1 H), 7.41-7.37 (m, 2 H), 7.30-7.28 (m, 4 H), 7.19-7.01 (m, 3 H), 4.96 (t, J=5.8 Hz, Vz H, rotamer), 4.87 (t, J=6.2 Hz, Vz H, rotamer), 4.65-4.58 (m, 1 H), 4.31-4.25 (m, 1 H), 3.40- 3.23 (m, 5 H), 2.57 (s, 3/2 H, rotamer), 2.56 (s, 3/2 H, rotamer), 2.39-2.37 (m, 3 H), 2.25-2.22 (m, 1 H), 1.97-1.76 (m, 10 H), 1.65-1.63 (m, 2 H), 1.56-1.47 (m, 2 H), 0.92-0.85 (m, 3 H). HRMS m/z (M+H)+ calcd: 690.3289, obsd: 690.3301.
Example 497 Preparation of 2,4-difluoro-3--Y4-(3-fluorophenvn-4-(2-r(1 R,5S)-3-(2-methyl- 1 H-benzimidazol-1 -yl)-8-azabicvclor3.2. noct-8-vnethyllpiperidin-1- vπcarbonvnbenzenesulfonamide
Figure imgf000320_0001
2,4-Difluoro-3-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H- benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-1- yl)carbonyl]benzenesulfonamide (10 mg, 15%) was obtained as solid from 3- (aminosulfonyl)-2,6-difluorobenzoic acid (24 mg, 0.1 mmol), 1-((1R,5S)-8-{2- [4-(3-fluorophenyl)piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl- 1 H-benzimidazole dihydrochloride (52mg, 0.10 mmol) and HATU (38mg, 0.1 mmol) following the procedure outlined in example 473. 1H NMR (400 MHz, CDCIs) δ 8.01-7.92 (m, 1 H), 7.65 (d, J=7.7 Hz, 1 H), 7.39-7.34 (m, 1 H), 7.30- 7.26 (m, 1 H), 7.21-7.13 (m, 2 H), 7.08-6.95 (m, 4 H), 5.35 (br, 2 H), 4.64-4.60 (m, 1 H), 4.26-4.23 (m, 1 H), 3.48-3.20 (m, 5 H), 2.56 (s, 3 H), 2.46-2.17 (m, 4 H), 1.99-1.64 (m, 12 H). HRMS m/z (M+H)+ calcd: 666.2725, obsd: 666.2746.
Example 498 Preparation of 2.4-difluoro-3-r(4-(3-fluorophenvn-4-(2-r(1 R.5S)-3-(2-methyl- 1 H-benzimidazol-1 -yl)-8-azabicvclo[3.2.noct-8-vnethyl|piperidin-1- yl)carbonvn-N-methylbenzenesulfonamide
Figure imgf000320_0002
2,4-Difluoro-3-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H- benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-1-yl)carbonyl]-/V- methylbenzenesulfonamide (14 mg, 21%) was obtained as solid from 2,6- difluoro-3-(chlorosulfonyl)benzoic acid (52 mg, 0.2 mmol), methylamine (120 μL, 2.0 M in THF) and 1-((1 ,5S)-8-{2-[4-(3-fluorophenyl)piperidin-4-yl]ethyl}- 8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1 H-benzimidazole dihydrochloride (52 mg, 0.1 mmol) following the procedure outlined in example 473. 1H NMR (400 MHz, CDCIs), δ 7.94 (q, J=8.0 Hz, 1 H), 7.65 (d, J=7.3 Hz, 1 H), 7.35 (q, J=8.0 Hz, 1 H), 7.29 (d, J=8.0 Hz, 1 H), 7.19-7.12 (m, 2 H), 7.09-7.02 (m, 2 H), 6.98- 6.94 (m, 2 H), 4.99-4.86 (two sets of multiplets, 1 H, rotamers), 4.63-4.61 (m, 1 H), 4.27-4.23 (m, 1 H), 3.41-3.34 (m, 2 H), 3.25-3.18 (m, 3 H), 2.73 (d, J=5.0 Hz, 3/2 H, rotamer), 2.70 (d, J=4.9 Hz, 3/2 H, rotamer), 2.57 (s, 3/2 H, rotamer), 2.56 (s, 3/2 H, rotamer), 2.43-2.28 (m, 3 H), 2.22-2.17 (m, 1 H),
1.94-1.77 (m, 10 H), 1.66-1.63 (m, 2 H). HRMS m/z (M+H)+ calcd: 680.2882, obsd: 680.2881.
Example 499 Preparation of N-ethyl-2,4-difluoro-3-[(4-(3-fluorophenyl)-4-f2-[(1 R,5S)-3-(2- methyl-1 H-benzimidazol-1 -yl)-8-azabicvclo[3.2.11oct-8-yl1ethyl|piperidin-1 - vDcarbonyllbenzenesulfonamide
Figure imgf000321_0001
Λ/-Ethyl-2,4-difluoro-3-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl- 1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1 ]oct-8-yl]ethyl}piperidin-1 - yl)carbonyl]benzenesulfonamide (16 mg, 23%) was obtained as solid from 2,6-difluoro-3-(chlorosulfonyl) benzoic acid (52 mg, 0.2 mmol), ethylamine (120 μL, 2.0 M in THF) and 1-((1R,5S)-8-{2-[4-(3-fluorophenyl) piperidin-4- yl]ethyl}-8-azabicyclo[3.2.1 ]oct-3-yl)-2-methyl-1 H-benzimidazole dihydrochloride (52 mg, 0.1 mmol) following the procedure outlined in example 473. 1H NMR (400 MHz, CDCI3) δ 7.95 (q, J=8.0 Hz, 1 H), 7.66 (d, J=8.0 Hz, 1 H), 7.36 (q, J=8.0 Hz, 1 H), 7.30-7.28 (m, 1 H), 7.19-7.12 (m, 2 H), 7.09-7.04 (m, 2 H), 7.01-6.95 (m, 2 H), 4.93-4.84 (two sets of multiplets, 1 H, rotamers), 4.64 (br, 1 H), 4.27-4.24 (m, 1 H), 3.41-3.37 (m, 2 H), 3.26-3.25 (m, 3 H), 3.22-2.95 (m, 2 H), 2.58 (s, 3/2 H, rotamer), 2.56 (s, 3/2 H, rotamer), 2.43-2.30 (m, 3 H), 2.20-2.10 (m, 1 H), 1.95-1.78 (m, 10 H), 1.66-1.64 (m, 2 H), 1.16-1.10 (m, 3 H). HRMS m/z (M+H)+ calcd: 694.3039, obsd: 694.3051.
Example 500 Preparation of 2,4-difluoro-3-.T4-(3-fluorophenvn-4-f2-.T1 R.5S)-3-(2-methyl- 1 H-benzimidazol-1 -vπ-8-azabicvclo[3.2.noct-8-vnethyl)piperidin-1- yl)carbonyll-N-propylbenzenesulfonamide
Figure imgf000322_0001
2,4-Difluoro-3-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H- benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-1-yl)carbonyl]-/V- propylbenzenesulfonamide (42mg, 59%) was obtained as solid from 2,6- difluoro-3-(chlorosulfonyl) benzoic acid (52 mg, 0.2 mmol), propylamine (18 μL,0.22mmol) and 1-((1 R,5S)-8-{2-[4-(3-fluorophenyl) piperidin-4-yl]ethyl}-8- azabicyclo[3.2.1]oct-3-yl)-2-methyl-1 H-benzimidazole dihydrochloride (52 mg, 0.1 mmol) following the procedure outlined in example 473. 1H NMR (400 MHz, CDCI3) δ 7.95-7.91 (m, 1 H), 7.65 (d, J=8.0 Hz, 1 H), 7.39-7.35 (m, 1 H), 7.30 -7.29 (m, 1 H), 7.16-7.14 (m, 2 H), 7.12-7.04 (m, 2 H), 6.96-6.95 (m, 2 H), 5.05-4.97 (two sets of multiplets, 1 H, rotamers), 4.63-4.57 (m, 1 H), 4.26- 4.23 (m, 1 H ), 3.41-3.35 (m, 2 H), 3.25-3.21 (m, 4 H), 3.04-2.90 (m, 2 H), 2.57 (s, 3/2 H, rotamer), 2.56 (s, 3/2 H, rotamer), 2.39-2.34 (m, 3 H), 2.20- 2.10 (m, 1 H), 1.97-1.80 (m, 10 H), 1.65-1.63 (m, 2 H), 1.54-1.49 (m, 2 H), 0.90-0.85 (m, 3 H). HRMS m/z (M+H)+ calcd: 708.3195, obsd: 708.3189. Example 501 Preparation of 2.4-difluoro-3-lϊ4-(3-fluorophenvn-4-(2-lϊ1 R.5SV3-(2-methyl- 1 H-benzimidazol-1 -vπ-8-azabicvclor3.2.noct-8-vnethyl>piperidin-1- vPcarbonvπ-N-isopropylbenzenesulfonamide
Figure imgf000323_0001
2,4-Difluoro-3-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H- benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-1-yl)carbonyl]-V- isopropylbenzenesulfonamide (40 mg, 56%) was obtained as solid from 2,6- difluoro-3-(chloro sulfonyl)benzoic acid (52 mg, 0.2 mmol), isopropylamine (19 μL,0.22mmol) and 1 -((1 R,5S)-8-{2-[4-(3-fluorophenyl)piperidin-4-yl]ethyl}-8- azabicyclo [3.2.1]oct-3-yl)-2-methyl-1 H-benzimidazole dihydrochloride (52 mg, 0.1 mmol) following the procedure outlined in example 473. 1H NMR (400 MHz, CDCIs) δ 7.95 (q, J=7.3 Hz, 1 H), 7.65 (d, J=7.1 Hz, 1 H), 7.36 (q, J=7.7 Hz, 1 H), 7.29 (d, J=7.7 Hz, 1 H), 7.19-7.12 (m, 2 H), 7.10-7.04 (m, 2 H), 7.00- 6.94 (m, 2 H), 4.91 (d, J=7.7 Hz, Vz H, rotamer), 4.86 (d, J=7.7 Hz, Vz H, rotamers), 4.62-4.59 (m, 1 H), 4.26-4.22 (m, 1 H), 3.55-3.50 (m, 1 H), 3.41- 3.37 (m, 2 H), 3.24-3.19 (m, 3 H), 2.57 (s, 3/2 H, rotamer), 2.56 (s, 3/2 H, rotamer), 2.42-2.29 (m, 3 H), 2.17-2.14 (m, 1 H), 1.96-1.77 (m, 10 H), 1.66- 1.65 (m, 2 H), 1.18 (dd, J=15, 6.6 Hz, 3 H, rotamer), 1.06 (dd, J=15, 6.6 Hz, 3 H, rotamer). HRMS m/z (M+H)+ calcd: 708.3195, obsd: 708.3201.
Example 502 Preparation of N-cvclopropyl-2.4-difluoro-3-r(4-(3-fluorophenvn-4-(2-r(1 R.5S)- 3-(2-methyl-1 H-benzimidazol-1 -yl)-8-azabicvclor3.2.1loct-8-vnethyl)piperidin- 1-yl)carbonyr|benzenesulfonamide
Figure imgf000324_0001
/V-Cyclopropyl-2,4-difluoro-3-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2- methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-1- yl)carbonyl]benzenesulfonamide (40 mg, 53%) was obtained as solid from 2,6-difluoro-3-(chlorosulfonyl)benzoic acid (52 mg, 0.2 mmol), cyclopropyl amine (14 μL, 0.2mmol) and 1-((1R,5S)-8-{2-[4-(3-fluorophenyl)piperidin-4- yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1 H-benzimidazole dihydrochloride (52 mg, 0.1 mmol) following the procedure outlined in example 473. 1H NMR (400 MHz, CDCI3), δ 7.98-7.96 (m, 1 H), 7.65 (d, J=8.8 Hz, 1 H), 7.38-7.33 (m, 1 H), 7.31-7.26 (m, 1 H), 7.19-7.12 (m, 2 H), 7.10-7.06 (m, 2 H), 7.04-6.94 (m, 2 H), 5.55 (s, Vz H, rotamer), 5.49 (s, Vz H, rotamer), 4.64-4.58 (m, 1 H), 4.27-4.22 (m, 1 H), 3.42-3.35 (m, 2 H), 3.25-3.19 (m, 3 H), 2.57 (s, 3/2 H, rotamer), 2.56 (s, 3/2 H, rotamer), 2.41-2.14 (m, 5 H), 2.03- 1.77 (m, 10 HO, 1.64 (J=7.9 Hz, 2 H), 0.78-0.73 (m, 1 H), 0.66-0.54 (m, 3 H). HRMS m/z (M+H)+ calcd: 706.3038, obsd: 706.3044.
Example 503 Preparation of 3-fluoro-4-IY4-{2-IY1 R.5S)-3-(2-methyl-1 H-benzimidazol-1 -vh-8- azabicvclor3.2.1loct-8-yllethyl}-4-phenylpiperidin-1-yl)carbonyllbenzene sulfonamide
Figure imgf000325_0001
3-Fluoro-4-[(4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1- yl)carbonyl]benzenesulfonamide (41 mg, 77%) was obtained as solid from 4- (aminosulfonyl)-2-fluorobenzoic acid (22 mg, 0.1 mmol), 2-methyl-1-{(1R,5S)- 8-[2-(4-phenylpiperidin-4-yl)ethyl]-8-azabicyclo[3.2.1 ]oct-3-yl}-1 H- benzimidazole dihydrochloride (51 mg, 0.1 mmol) and HATU (38mg, 0.1 mmol) following the procedure outlined in example 5. 1H NMR (400 MHz, CDCI3) δ 7.68 (d, J=7.9 Hz, 1 H), 7.63-7.60 (m, 2 H), 7.40-7.36 (m, 2 H), 7.29- 7.23 (m, 5 H), 7.18-7.12 (m, 2 H), 6.18 (br, 2 H), 4.61 (t, J=9 Hz, H), 4.21-4.18 (m, 1 H), 3.36- 3.18 (m, 5 H), 2.49 (s, 3 H), 2.39-2.19 (m, 4 H), 1.96-1.81 (m, 10 H), 1.62 (d, J=7.9 Hz, 2 H). HRMS m/z (M+H)+ calcd: 630.2914, obsd: 630.2907.
Example 504 Preparation of 3-chloro-4-lϊ4 2-r(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicvclo[3.2.noct-8-vnethyl)-4-phenylpiperidin-1-yl)carbonvnbenzene sulfonamide
Figure imgf000325_0002
3-Chloro-4-[(4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1- yl)carbonyl]benzenesulfonamide (27mg, 42%) was obtained as solid from 4- (amino sulfonyl)-2-chlorobenzoic acid (24 mg, 0.1 mmol), 2-methyl-1- {(1R,5S)-8-[2-(4-phenylpiperidin-4-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1H- benzimidazole dihydrochloride (51 mg, 0.1 mmol) and HATU (38mg, 0.1 mmol) following the procedure outlined in example 5. 1H NMR (400 MHz, CDCIs), δ 7.95 (s, Vz H, rotamer), 7.91 (s, Vz H, rotamer ), 7.81-7.76 (m, 1 H), 7.64-7.62 (m, 1 H), 7.41-7.36 (m, 2 H), 7.30-7.23 (m, 5 H), 7.19-7.09 (m, 2 H), 6.05 (br, 2 H), 4.62 (br, 1 H), 4.26-4.17 (m, 1 H), 3.48- 3.07 (m, 5 H), 2.50 (s, 3/2 H, rotamer ), 2.49 (s, 3/2 H, rotamer ), 2.37-2.08 (m, 4 H), 1.94-1.71 (m, 10 H), 1.62 (d, 2 H). HRMS m/z (M+H)+ calcd: 646.2619, obsd: 646.2626.
Example 505 Preparation of 3,4-difluoro-5-.T4 2-r(1 R.5S)-3-(2-methyl-1 H-benzimidazol-1 - yl)-8-azabicvclo[3.2.noct-8-yllethyl)-4-phenylpiperidin-1-yl)carbonyllbenzene sulfonamide
Figure imgf000326_0001
3,4-Difluoro-5-[(4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1 ]oct-8-yl]ethyl}-4-phenylpiperidin-1 -yl)carbonyl]benzene sulfonamide (26mg, 40%) was obtained from 5-(aminosulfonyl)-2,3- difluorobenzoic acid (0.15mmol), 2-methyl-1-{(1R,5S)-8-[2-(4-phenylpiperidin- 4-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole dihydrochloride (51 mg, 0.1 mmol) and HATU (38mg, 0.1 mmol) following the procedure outlined in example 473. 1H NMR (400 MHz, CDCI3) δ 7.70-7.65 (m, 2 H), 7.47-7.37 (m, 3 H), 7.29-7.25 (m 4 H), 7.20-7.13 (m, 2 H), 4.84 (br, 1 H), 4.14-4.11 (m, 1 H), 3.65-3.20 (m, 6 H), 2.57 (s, 3 H), 2.53-2.48 (m, 2 H), 2.30-2.11 (m, 3 H), 1.97-1.71 (m, 11 H). HRMS m/z (M+H)+ calcd: 648.2820, obsd: 648.2828. Example 506 Preparation of 3,4-difluoro-5-r(4-(3-fluorophenvn-4-(2-r(1 R.5SV3-(2-methyl- 1 H-benzimidazol-1 -vπ-8-azabicvclor3.2.noct-8-vnethyl)piperidin-1- vOcarbonyr|benzenesulfonamide
Figure imgf000327_0001
3,4-Difluoro-5-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H- benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-1- yl)carbonyl]benzenesulfonamide (20mg, 30%) was obtained from 5- (aminosulfonyl)-2,3-difluorobenzoic acid (0.15mmol), 1-((1R,5S)-8-{2-[4-(3- fluorophenyl) piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1 H- benzimidazoledihydrochloride (52 mg, 0.1 mmol) and HATU (38mg, 0.1 mmol) following the procedure outlined in example 5. 1H NMR (400 MHz, CDCI3) δ 7.69-7.62 (m, 2 H), 7.46-7.42 (m, 1 H), 7.39-7.33 (m, 1 H), 7.30-7.26 (m, 1 H), 7.21-7.13 (m, 2 H), 7.06 (d, J=7.9 Hz), 7.00-6.95 (m, 2 H), 5.86 (br, 2 H), 4.66-4.61 (m, 1 H), 4.14-4.09 (m, 1 H), 3.51 (br, 1 H), 3.29 (br, 4 H), 2.54 (s, 3 H), 2.49-2.13 (m, 5 H), 1.95-1.83 (m, 9 H), 1.67-1.65 (m, 2 H). HRMS m/z (M+H)+ calcd: 666.2726, obsd: 666.2719.
Example 507 Preparation of 2.3-Difluoro-N-methyl-5-r(4-(2-[(1 R.5S)-3-(2-methyl-1 H- benzimidazol-1 -yl)-8-azabicyclo[3.2.11 oct-8-yl1ethyl)-4-phenylpiperidin-1 - vDcarbonvnbenzene sulfonamide
Figure imgf000327_0002
2,3-Difluoro-Λ/-methyl-5-[(4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 ■ yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]benzene sulfonamide (31 mg, 47%) was obtained as solid from 3-(chlorosulfonyl)-4,5- difluorobenzoic acid (52 mg, 0.2 mmol), methylamine (110 μL, 2.0 M in THF), 2-methyl-1-{(1R,5S)-8-[2-(4-phenylpiperidin-4-yl)ethyl]-8-azabicyclo[3.2.1]oct- 3-yl}-1 H-benzimidazole dihydro chloride (51 mg, 0.1 mmol) and HATU (38mg, 0.1 mmol) following the procedure outlined in example 473. 1H NMR (400 MHz, CDCIs) δ 7.68-7.64 (m, 2 H), 7.50-7.45 (m, 1 H), 7.41-7.37 (m, 2 H), 7.30-7.24 (m 4 H), 7.19-7.12 (m, 2 H), 5.26t(br, 1 H), 4.66-4.6- (m, 1 H), 4.17 (br, 1 H), 3.51 (br, 1 H), 3.27 (br, 4 H), 2.75 (d, J=2.3 Hz, 3 H), 2.57 (s, 3 H), 2.42-2.34 (m, 3 H), 2.20 (br, 1 H), 2.01-1.75 (m, 10 H), 1.63 (d, J=7.90 Hz, 2 H). HRMS m/z (M+H)+ calcd: 662.2976, obsd: 672.2985.
Example 508 Preparation of 2.3-difluoro-N-isopropyl-5-f(4-(2-r(1 R,5S)-3-(2-methyl-1 H- benzimidazol-1-yl)-8-azabicvclo[3.2.1loct-8-yllethyl)-4-phenylpiperidin-1- vPcarbonvπbenzenesulfonamide
Figure imgf000328_0001
2,3-Difluoro-Λ/-isopropyl-5-[(4-{2-[(1 R,5S)-3-(2-methyl-1 H- benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1- yl)carbonyl]benzene-sulfonamide (25 mg, 36%) was obtained as solid from 3- (chlorosulfonyl)-4,5-difluorobenzoic acid (52 mg, 0.2 mmol), isopropylamine (19 μL, 0.2 mmol), 2-methyl-1-{(1R,5S)-8-[2-(4-phenylpiperidin-4-yl)ethyl]-8- azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole dihydrochloride (51 mg, 0.1 mmol) and HATU (38mg, 0.1 mmol) following the procedure outlined in example 473. 1H NMR (400 MHz, CDCI3) δ 7.69-7.65 (m, 2 H), 7.50-7.45 (m, 1 H), 7.41-7.37 (m, 2 H), 7.30-7.24 (m 4 H), 7.19-7.12 (m, 2 H), 4.90 (d, J=7.7 Hz, 1 H), 4.65 (m, 1 H), 4.18 (br, 1 H), 3.61-3.51 (m, 2 H), 3.26 (br, 4 H), 2.57 (s, 3 H), 2.43-2.35 (m, 3 H), 2.201-2.19 (m, 1 H), 1.94-1.85 (m, 10 H), 1.63 (d, J=7.90 Hz, 2 H), 1.14 (d, J=6.6 Hz, 6 H). HRMS m/z (M+H)+ calcd: 690.3289, obsd: 690.3309.
Example 509 Preparation of N-cvclopropy|-2.3-difluoro-5-r(4-(2-r(1 R.5S)-3-(2-methyl-1 H- benzimidazol-1-vπ-8-azabicvclor3.2.noct-8-vnethyl)-4-phenylpiperidin-1- vDcarbonv-lbenzenesulfonanπide
Figure imgf000329_0001
A/-Cyclopropyl-2, 3-difluoro-5-[(4-{2-[(1 R,5S)-3-(2-methyl-1 H- benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1- yl)carbonyl]benzenesulfonamide (29 mg, 42%) was obtained as solid from 3- (chlorosulfonyl)-4,5-difluorobenzoic acid (52 mg, 0.2 mmol), isopropylamine (15 μL, 0.2 mmol), 2-methyl-1-{(1R,5S)-8-[2-(4-phenylpiperidin-4-yl)ethyl]-8- azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole dihydrochloride (51 mg, 0.1 mmol) and HATU (38mg, 0.1 mmol) following the procedure outlined in example 473. 1H NMR (400 MHz, CDCI3) δ 7.72-7.71 (m, 1 H), 7.66-7.64 (m,
1 H), 7.53-7.48 (m, 1 H), 7.41-7.37 (m, 2 H), 7.30-7.24 (m 4 H), 7.19-7.12 (m,
2 H), 5.61 (s, 1 H), 4.67-4.57 (m, 1 H), 4.18 (br, 1 H), 3.51 (br, 1 H), 3.27 (br, 4 H), 2.57 (s, 3 H), 2.42 -2.28 (m, 4H), 2.221-2.20 (m, 1 H), 1.94-1.76 (m, 10 H), 1.65-1.60 (m, 2 H), 0.71-0.61 (m, 4 H). HRMS m/z (M+H )+ calcd: 688.3133, obsd: 688.3123. Example 510 Preparation of N-cyclopentyl-2.3-difluoro-5-r(4-(2-r.1 R.5S)-3-(2-methyl-1 H- benzimidazol-1-yl)-8-azabicvclo[3.2.noct-8-vnethyl)-4-phenylpiperidin-1- vDcarbonvnbenzenesulfonamide
Figure imgf000330_0001
Λ/-Cyclopentyl-2,3-difluoro-5-[(4-{2-[(1 R,5S)-3-(2-methyl-1 H- benzimidazol-1-yl)-8-azabicyclo[3.2.1] oct-8-yl]ethyl}-4-phenylpiperidin-1- yl)carbonyl] benzenesulfonamide (29 mg, 40%) was obtained as solid from 3- (chlorosulfonyl)-4,5-difluorobenzoic acid (52 mg, 0.2 mmol), isopentylamine (22 μL, 0.2 mmol), 2-methyl-1 -{(1 R,5S)-8-[2-(4-phenylpiperidin-4-yl)ethyl]-8- azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole dihydrochloride (51 mg, 0.1 mmol) and HATU (38mg, 0.1 mmol) following the procedure outlined in example 473. 1H NMR (400 MHz, CDCI3) δ 7.69-7.65 (m, 2 H), 7.50-7.46 (m, 1 H), 7.41-7.37 (m, 2 H), 7.30-7.24 (m 4 H), 7.19-7.12 (m, 2 H), 5.01 (d, J=7.3 Hz, 1 H), 4.68-4.64 (m, 1 H), 4.18 (br, 1 H), 3.69-3.64 (m, 1 H), 3.51 (br, 1 H), 3.29 (br, 4 H), 2.57 (s, 3 H), 2.44-2.36 (m, 3 H), 2.20-2.18 (m, 1 H), 1.97-1.70 (m, 12 H), 1.69-1.60 (m, 4 H), 1.57-1.47 (m, 2 H), 1.45-1.24 (m, 2 H). HRMS m/z (M+H)+ calcd: 716.3446, obsd: 716.3456.
Example 511 ■ Preparation of 4-fluoro-N-methyl-2-fmethylamino)-3-IT4-f2-IY1 R.5S 3-(2- methyl-1 H-benzimidazol-1-vπ-8-azabicvclo[3.2.noct-8-vnethyl}-4- phenylpiperidin-1-yl)carbonvnbenzenesulfonamide
Figure imgf000331_0001
4-Fluoro-Λ/-methyl-2-(methylamino)-3-[(4-{2-[(1R,5S)-3-(2-methyl-1H- benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1- yl)carbonyl]benzenesulfonamide (20mg, 30%) was obtained as solid from 6- fluoro-2-(methylamino)-3-[(methyl amino)sulfonyl]benzoic acid (205 mg, 0.8 mmol), 2-methyl-1 -{(1 R,5S)-8-[2-(4-phenylpiperidin-4-yl)ethyl]-8- azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole dihydro- chloride (51 mg, 0.1 mmol) and HATU (38mg, 0.1 mmol) following the procedure outlined in example 473. 1H NMR (400 MHz, CDCI3) δ 7.79-7.74 (m, 1 H), 7.66-7.64 (m, 1 H), 7.41-7.34 (m, 2 H), 7.30-7.21 (m 4 H), 7.19-7.04 (m, 3 H), 6.95-6.40 (m, 1 H), 6.29-6.18 (m, 1 H), 5.07-4.93 (m, 1 H), 4.64 (br, 1 H), 4.37-4.08 (m, 1 H), 3.57-3.34 (m, 1 H), 3.39-3.12 (m, 4 H), 3.00 (d, J=5.4 Hz, 3/2 H, rotamer), 2.75 (d, J=5.2 Hz, 3/2 H, rotamer), 2.58-2.56 (m, 3 H), 2.41-2.07 (m, 4 H), 1.93-1.68 (m, 12 H), 1.63-1.61 (m, 2 H). HRMS m/z (M+H)+ calcd: 673.3336, obsd: 673.3345.
Example 512 Preparation of 2,4-dichloro-3-IT4-f2--Y1 R.5S)-3-(2-methvH H-benzimidazol-1 - v0-8-azabicvclor3.2.1 loct-8-vnethylV4-phenylpiperidin-1 -yl .carbonyllbenzene- sulfonamide
Figure imgf000332_0001
2,4-Dichloro-3-[(4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]benzene sulfonamide (36mg, 53%) was obtained as solid from 3-(aminosulfonyl)-2,6- dichlorobenzoic acid (51 mg, 0.15 mmol), 2-methyl-1-{(1 ,5S)-8-[2-(4- phenylpiperidin-4-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole dihydrochloride (51 mg, 0.1 mmol) and HATU (38mg, 0.1 mmol) following the procedure outlined in example 473.
1H NMR (400 MHz, CDCIs) δ 7.99-7.94 (d, J=8.4 Hz, 1 H), 7.63-7.61 (d, J=7.2 Hz, 1 H), 7.43-7.36 (m, 3 H), 7.29-7.26 (m, 4 H), 7.18-7.08 (m, 2 H), 5.96 (br, 2 H), 4.63 (br, 1 H), 4.29-4.24 (m, 1 H), 3.40-3.12 (m, 5 H), 2.53 (s, 3 H),
2.48-2.36 (m, 3 H), 2.24-2.21 (m, 1 H), 1.99-1.84 (m, 9 H), 1.64-1.61 (m, 2 H). HRMS m/z (M+H)+ calcd: 680.2229, obsd: 680.2228.
Example 513 Preparation of 2,4-dichloro-3-r(4-(3-fluorophenyl)-4-f2-r(1 R.5S)-3-(2-methyl- 1 H-benzimidazol-1 -yl)-8-azabicvclof3.2.11oct-8-yllethyl|piperidin-1 - vOcarbonvπbenzenesulfonamide
Figure imgf000332_0002
2,4-Dichloro-3-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H- benzimidazol-1-yl)-8-azabicyclo [3.2.1]oct-8-yl]ethyl}piperidin-1- yl)carbonyl]benzene sulfonamide (30mg, 43%) was obtained as solid from 3- (aminosulfonyl)-2,6-dichlorobenzoic acid (51 mg, 0.15 mmol), 2-methyl-1- {(1R,5S)-8-[2-(4-(3-fluorophenyl) piperidin-4-yl)ethyl]-8-azabicyclo[3.2.1]oct-3- yl}-1 H-benzimidazole dihydrochloride (52 mg, 0.1 mmol) and HATU (38mg, 0.1 mmol) following the procedure outlined in example 473. 1H NMR (400 MHz, CDCI3) δ 8.01-7.99 (m, 1 H), 7.64-7.62 (m, 1 H), 7.45-7.35 (m, 2 H), 7.34-7.28 (m, 1 H), 7.22-7.12 (m, 2 H), 7.08-7.06 (m, 1 H), 6.99-6.95 (m, 2 H), 5.79 (br, 2 H), 4.65-4.55 (m, 1 H), 4.27-4.23 (m, 1 H), 3.43-3.12 (m, 5 H), 2.54 (s, 3 H), 2.41-2.37 (m, 4 H), 2.19-2.16 (m, 1 H), 1.94-1.83 (m, 9 H), 1.66-1.65 (m, 2 H). HRMS m/z (M+H)+ calcd: 698.2135, obsd: 698.2141.
Example 514 Preparation of 2.4-dichloro-N-methyl-3-r(4-f2-r(1 R.5S)-3-(2-methyl-1 H- benzimidazol-1-yl)-8-azabicvclo[3.2.11 oct-8-yr|ethyl)-4-phenylpiperidin-1- vDcarbonvnbenzene sulfonamide
Figure imgf000333_0001
2,4-Dichloro-Λ/-methyl-3-[(4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-
1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1- yl)carbonyl]benzene sulfonamide (33mg, 48%) was obtained as solid from
2,6-dichloro-3-(chlorosulfonyl)benzoic acid (58 mg, 0.20 mmol), methylamine (120 μL, 2.0 M in THF), 2-methyl-1 -{(1 R,5S)-8-[2-(4-phenylpiperidin-4- yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole dihydrochloride (51 mg, 0.1 mmol) and HATU (38mg, 0.1 mmol) following the procedure outlined in example 473. 1H NMR (400 MHz, CDCI3) δ 8.06-8.03 (m, 1 H), 7.66-7.64 (m, 1 H), 7.52-7.44 (m, 1 H), 7.41-7.37 (m, 2 H), 7.30-7.24 (m, 4 H), 7.19-7.12 (m, 2 H), 5.31-5.13 (m, 1 H), 4.64 (br, 1 H), 4.34-4.25 (m, 1 H), 3.43-3.12 (m, 5 H), 2.68-2.63 (m, 3 H), 2.57-2.55 (m, 3 H), 2.39-2.34 (m, 3 H), 2.26-2.20 (m, 1 H), 1.99-1.82 (m, 10 H), 1.63-1.62(m, 2 H). HRMS m/z (M+H)+ calcd: 694.2385, obsd: 694.2391. Example 515 Preparationo of 2.4-dichloro-3--Y4~f2--Y1 R,5S)-3-(2-methyl-1 H-benzimidazol-1- vπ-8-azabicvclor3.2.1loct-8-yllethyl 4-phenylpiperidin-1-yl)carbonvn-N- propylbenzenesulfonamide
Figure imgf000334_0001
2,4-Dichloro-3-[(4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]-/V- propylbenzenesulfonamide (19mg, 26%) was obtained as solid from 2,6- dichloro-3-(chlorosulfonyl)benzoic acid (58 mg, 0.20 mmol), propylamine (20 μL, 0.24 mmol), 2-methyl-1-{(1R,5S)-8-[2-(4-phenylpiperidin-4-yl)ethyl]-8- azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole dihydrochloride (51 mg, 0.1 mmol) and HATU (38mg, 0.1 mmol) following the procedure outlined in example 473. 1H NMR (400 MHz, CDCIs) δ 8.06-8.04 (m, 1 H), 7.65 (d, 1 H), 7.52-7.41 (m, 1 H), 7.39-7.32 (m, 2 H), 7.29-7.21 (m, 4 H), 7.19-7.12 (m, 2 H), 5.29-4.98 (m, 1 H), 4.63 (br, 1 H), 4.33-4.27 (m, 1 H), 3.42-3.12 (m, 5 H), 3.04-2.88 (m, 2 H), 2.86-2.77 (m, 1 H), 2.58-2.56 (m, 3 H), 2.40-2.37 (m, 3 H), 2.26-2.19 (m, 1 H), 1.93-1.63 (m, 14 H), 1.57-1.51(m, 2 H), 0.92-0.85 (m, 3 H). HRMS m/z (M+H)+ calcd: 722.2698, obsd: 722.2686.
Example 516 Preparation of 2.4-dichloro-N-isopropyl-3-IT4-f2-r(1 R.5S)-3-(2-methyl-1 H- benzimidazol-1-vπ-8-azabicvclor3.2.1loct-8-yllethyl)-4-phenylpiperidin-1- vDcarbonyllbenzenesulfonamide
Figure imgf000335_0001
2,4-Dichloro-/V-isopropyl-3-[(4-{2-[(1 R,5S)-3-(2-methyl-1 H- benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1- yl)carbonyl]benzene sulfonamide (20 mg, 28%) was obtained as solid from 2,6-dichloro-3-(chlorosulfonyl)benzoic acid (58 mg, 0.20 mmol), isopropylamine (20.5 μL, 0.24 mmol), 2-methyl-1-{(1R,5S)-8-[2-(4- phenylpiperidin-4-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole dihydrochloride (51 mg, 0.1 mmol) and HATU (38mg, 0.1 mmol) following the procedure outlined in example 473. 1H NMR (400 MHz, CDCI3) δ 8.08-8.05 (m, 1 H), 7.66-7.65 (m, 1 H), 7.51-7.44 (m, 1 H), 7.41-7.37 (m, 2 H), 7.30-7.25 (m, 4 H), 7.20-7.12 (m, 2 H), 4.95-4.83 (m, 1 H), 4.64-4.62 (m, 1 H), 4.32-4.27 (m, 1 H), 3.49-3.34 (m, 2 H), 3.27-3.24 (m, 3 H), 3.19-3.14 (m, 1 H), 2.57-2.56 (m, 3 H), 2.40-2.37 (m, 3 H), 2.26-2.18 (m, 1 H), 1.96-1.82 (m, 10 H), 1.64- 1.62 (m, 2 H), 1.21-1.02 (m, 6 H). HRMS m/z (M+H)+ calcd: 722.2698, obsd: 722.2702.
Example 517 Preparation of 2.4-dichloro-N-cvclopropyl-3-[(4-(2-[(1 R.5S)-3-(2-methyl-1 H- benzimidazol-1-vπ-8-azabicvclo[3.2.noct-8-vnethyl)-4-phenylpiperidin-1- vDcarbonyllbenzenesulfonamide
Figure imgf000336_0001
2,4-Dichloro-Λ/-cyclopropyl-3-[(4-{2-[(1 R,5S)-3-(2-methyl-1 H- benzimidazol-1-yl)-8-azabicyclo[3.2.1] oct-8-yl]ethyl}-4-phenylpiperidin-1- yl)carbonyl]benzene sulfonamide (35 mg, 49%) was obtained as solid from 2,6-dichloro-3-(chlorosulfonyl)benzoic acid (58 mg, 0.20 mmol), cyclopropylamine (17 μL, 0.24 mmol), 2-methyl-1 -{(1 R,5S)-8-[2-(4- phenylpiperidin-4-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole dihydrochloride (51 mg, 0.1 mmol) and HATU (38mg, 0.1 mmol) following the procedure outlined in example 473. 1H NMR (400 MHz, CDCI3) δ 8.12-8.09 (m, 1 H), 7.66-7.65 (m, 1 H), 7.54-7.46 (m, 1 H), 7.41-7.37 (m, 2 H), 7.30-7.25 (m, 4 H), 7.19-7.12 (m, 2 H), 5.67-5.54 (m, 1 H), 4.64 (br, 1 H), 4.33-4.27 (m,
1 H), 3.43-3.12 (m, 5 H), 2.58-2.56 (m, 3 H), 2.40-2.37 (m, 3 H), 2.26-2.19 (m,
2 H), 2.04-1.82 (m, 10 H), 1.64-1.63 (m, 2 H), 0.85-0.76 (m, 1 H), 0.67-0.54 (m, 3 H). HRMS m/z (M+H)+ calcd: 720.2542, obsd: 720.2558.
Example 518 Preparation of 2.4-dichloro-N-cvclopentyl-3-r(4-(2-[(1 R.5SV3-(2-methyl-1 H- benzimidazol-1-yl)-8-azabicvclor3.2.1loct-8-yllethyl)-4-phenylpiperidin-1- vπcarbonyllbenzenesulfonamide
Figure imgf000337_0001
2,4-Dichloro-Λ/-cyclopentyl-3-[(4-{2-[(1 R,5S)-3-(2-methyl-1 H- benzimidazol-1-yl)-8-azabicyclo[3.2.1] oct-8-yl]ethyl}-4-phenylpiperidin-1- yl)carbonyl] benzenesulfonamide (28mg, 37%) was obtained as solid from 2,6-dichloro-3-(chlorosulfonyl)benzoic acid (58 mg, 0.20 mmol), cyclopentylamine (20 μL, 0.24 mmol), 2-methyl-1-{(1R,5S)-8-[2-(4- phenylpiperidin-4-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole dihydrochloride (51 mg, 0.1 mmol) and HATU (38mg, 0.1 mmol) following the procedure outlined in example 473. 1H NMR (400 MHz, CDCI3) δ 8.08-8.06 (m, 1 H), 7.67-7.65 (m, 1 H), 7.52-7.44 (m, 1 H), 7.41-7.34 (m, 2 H), 7.29-7.25 (m, 4 H), 7.19-7.12 (m, 2 H), 5.09-4.96 (m, 1 H), 4.62 (br, 1 H), 4.31-4.28 (m, 1 H), 3.60-3.50 (m. 1 H), 3.42-3.11 (m, 5 H), 2.58-2.53 (m, 3 H), 2.40-2.37 (m, 4 H), 2.25-2.18 (m, 1 H), 1.99-1.75 (m, 11 H), 1.73-1.49 (m, 8 H). HRMS m/z (M+H)+ calcd: 748.2855, obsd: 748.2863.
Example 519 Preparation of 2-chloro-N-methoxy-5-IY4-(2-[(1 R.5S)-3-(2-methyl-1 H- benzimidazol-1-yl)-8-azabicvclo[3.2.noct-8-vnethyll-4-phenylpiperidin-1- vDcarbonyllbenzene sulfonamide
Figure imgf000338_0001
2-Chloro-Λ/-methoxy-5-[(4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 - yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]benzene sulfonamide (17 mg, 25%) was obtained as solid from 4-chloro-3- (chlorosulfonyl)benzoic acid (50 mg, 0.2 mmol), methoxyamine hydrochloride (21 mg, 0.20 mmol), 2-methyl-1-{(1R,5S)-8-[2-(4-phenylpiperidin-4-yl)ethyl]-8- azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole dihydrochloride (51 mg, 0.1 mmol) and HATU (38mg, 0.1 mmol) following the procedure outlined in example 473. 1H NMR (400 MHz, CDCI3) δ 8.14 (d, J= 2.0 Hz, 1 H), 8.09 (br, 1 , H), 7.67-7.57 (m, 3 H), 7.41-7.37 (m, 2 H), 7.30-7.24 (m, 4 H), 7.19-7.09 (m, 2 H), 4.67 (br, 1 H), 4.21-4.19 (m, 1 H), 3.77 (s, 3 H), 3.53-3.50 (m, 1 H), 3.35-3.28 (m, 4 H), 2.57 (s, 3 H), 2.39 (br, 3 H), 2.20-2.17 (m, 1 H), 1.95-1.77 (m, 10 H), 1.66-1.64 (m, 2 H). HRMS m/z (M+H)+ calcd: 676.2724, obsd: 676.2727.
Example 520 Preparation of 2-chloro-5-IT4-(3-fluorophenvn-4-(2-r(1 R.5SV3-(2-methyl-1 H- benzimidazol-1-vπ-8-azabicvclor3.2.noct-8-vnethyl)piperidin-1-vπcarbonvn-N- methoxybenzenesulfonamide
Figure imgf000339_0001
2-Chloro-5-[(4-(3-fluorophenyl)-4-{2-[(1 R,5S)-3-(2-methyl-1 H- benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-1-yl)carbonyl]-/V- methoxybenzenesulfonamide (10 mg, 14%) was obtained as solid from 4- chloro-3-(chloro sulfonyl)benzoic acid (50 mg, 0.2 mmol), methoxyamine hydrochloride (21 mg, 0.20 mmol), 1-((1R,5S)-8-{2-[4-(3- fluorophenyl)piperidin-4-yl]ethyl}-8-azabicyclo [3.2.1]oct-3-yl)-2-methyl-1H- benzimidazole dihydrochloride (52 mg, 0.1 mmol) and HATU (38mg, 0.1 mmol) following the procedure outlined in example 473. 1H NMR (400 MHz, CDCIs) δ 8.14 (d, J= 1.6 Hz, 1 H), 7.92 (br, 1 , H), 7.71-7.59 (m, 3 H), 7.38 (q, J=7.7 Hz, 1 H), 7.30-7.26 (m, 1 H), 7.20-7.13 (m, 2 H), 7.08 (d, J=8.1 Hz, 1 H), 7.01-6.96 (m, 2 H), 4.67 (br, 1 H), 4.14-4.11 (m, 1 H), 3.78 (s, 3 H), 3.59 (br, 1 H), 3.54-3.31 (br, 4 H), 2.59 (s, 3 H), 2.44 (br, 2 H), 2.28 (br, 2 H), 2.11 (br, 2 H), 1.97-1.65 (m, 10 H). HRMS m/z (M+H)+ calcd: 694.2630, obsd: 694.2630.
Example 521 Preparation of 2-chloro-N-ethoxy-5-lϊ4-f2-r(1 R.5S)-3-(2-methyl-1 H- benzimidazol-1-yl)-8-azabicvclo[3.2.11oct-8-vnethyl)-4-phenylpiperidin-1- vDcarbonyllbenzene sulfonamide
Figure imgf000340_0001
2-Chloro-/V-ethoxy-5-[(4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)- 8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]benzene- sulfonamide (6 mg, 8%) was obtained as solid from 4-chloro-3- (chlorosulfonyl)benzoic acid (50 mg, 0.2 mmol), ethoxyamine hydrochloride (29 mg, 0.20 mmol), 2-methyl-1 -{(1 R,5S)-8-[2-(4-phenylpiperidin-4-yl)ethyl]-8- azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole dihydrochloride (51 mg, 0.1 mmol) and HATU (38mg, 0.1 mmol) following the procedure outlined in example 473. 1H NMR (400 MHz, CDCI3) δ 8.12 (s, 1 H), 7.80 (s, 1 H), 7.67- 7.59 (m, 3 H), 7.41-7.38 (m, 2 H), 7.30-7.26 (m, 3 H), 7.20-7.12 (m, 2 H), 4.69 (br, 1 H), 4.21 (br, 1 H), 4.03 (q, J=7.0 Hz, 2 H), 3.51 (br, 1 H), 3.29 (br, 4 H), 2.58 (s, 3 H), 2.42-2.39 (m, 3 H), 2.16 (br, 1 H), 1.94 (br, 7 H), 1.69 (br, 5 H), 1.16 (t, J=7.0 Hz, 3 H). HRMS m/z (M+H)+ calcd: 690.2881 , obsd: 690.2878.
Example 522 Preparation of 2-chloro-N-ethoxy-5-r(4-.3-fluoro phenv0-4-(2-r(1 R,5S)-3-(2- methyl-1 H-benzimidazol-1 -yl)-8-azabicvclor3.2.1loct-8-yllethyl>piperidin-1- vDcarbonv-lbenzenesulfonamide
Figure imgf000340_0002
2-Chloro-Λ/-ethoxy-5-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H- benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-1-yl) carbonyl]benzenesulfonamide (12mg, 17%) was obtained as solid from 4- chloro-3-(chlorosulfonyl)benzoic acid (50 mg, 0.2 mmol), ethoxyamine hydrochloride (29 mg, 0.20 mmol), 1-((1R,5S)-8-{2-[4-(3- fluorophenyl)piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H- benzimidazole dihydrochloride (52 mg, 0.1 mmol) and HATU (38mg, 0.1 mmol) following the procedure outlined in example 473. 1H NMR (400 MHz, CDCIs) δ 8.13 (d, J= 1.8 Hz, 1 H), 7.82 (br, 1 , H), 7.67-7.59 (m, 3 H), 7.37 (q, J=7.8 Hz, 1 H), 7.29 (d, J=7.7 Hz, 1 H), 7.20-7.13 (m, 2 H), 7.08 (d, J=8.1 Hz, 1 H), 7.01-6.96 (m, 2 H), 4.81 (br, 1 H), 4.17 (br, 1 H), 4.04 ( q, J=7.1 Hz, 2 H), 3.53 (br, 1 H), 3.39-3.31 (br, 4 H), 2.59 (s, 3 H), 2.43 (br, 2 H), 2.29 (br, 1 H), 2.10 (br, 2 H), 1.97-1.93 (m, 8 H), 1.71 (br, 4 H), 1.16 (t, J=7.0 Hz, 3 H). HRMS m/z (M+H)+ calcd: 708.2787, obsd: 708.2797.
Example 523 Preparation of 4-chloro-N-methoxy-3-r(4-f2-[(1 R,5S)-3-(2-methyl-1 H- benzimidazol-1-vπ-8-azabicvclo[3.2.noct-8-vπethyl}-4-phenylpiperidin-1- vDcarbonyllbenzene-sulfonamide
Figure imgf000341_0001
4-Chloro-Λ/-methoxy-3-[(4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 - yl)-8-azabicyclo[3.2.1 ]oct-8-yl]ethyl}-4-phenylpiperidin-1 -yl)carbonyl]benzene sulfonamide (2mg) was obtained as solid from 2-chloro-5- (chlorosulfonyl)benzoic acid (50 mg, 0.2 mmol), methoxyamine hydrochloride (21 mg, 0.20 mmol), 2-methyl-1-{(1 ,5S)-8-[2-(4-phenylpiperidin-4-yl)ethyl]-8- azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole dihydrochloride (51 mg, 0.1 mmol) and HATU (38mg, 0.1 mmol) following the procedure outlined in example 473. 1H NMR (400 MHz, CDCI3) δ 7.90-7.85 (m, 2 H), 7.66 (d, J=7.5 Hz, 1 H), 7.57 (m, 1 H), 7.42-7.33 (m, 2 H), 7.30-7.26 (m, 4 H), 7.20-7.12 (m, 3 H), 4.70 (br, 1 H), 4.30-4.22 (m, 1 H), 3.80 (d, J=7.1 Hz, 3 H), 3.42-3.09 (m, 7 H), 2.56 (s, 3 H), 2.43 -2.08 (m, 4 H), 1.95-1.90 (m, 8 H), 1.89-1.75 (m, 3 H). HRMS m/z (M+H)+ calcd: 676.2724, obsd: 676.2722.
Example 524 Preparation of 4-chloro-3-IT4-(3-fluorophenviy4-(2-r(1 R.5SV3-(2-methyl-1 H- benzimidazol-1 -yl)-8-azabicvclor3.2.11oct-8-vπethyl|piperidin-1 -vOcarbonyll-N- methoxybenzenesulfonamide
Figure imgf000342_0001
4-Chloro-3-[(4-(3-fluorophenyl)-4-{2-[(1 R,5S) -3-(2-methyl-1 H- benzimidazol-1-yl)-8-azabicyclo[3.2.1] oct-8-yl]ethyl}piperidin-1-yl)carbonyl]-V- methoxy benzenesulfonamide (3.9 mg) was obtained as solid from 2-chloro-5- (chlorosulfonyl)benzoic acid (50 mg, 0.2 mmol), ethoxyamine hydrochloride (29 mg, 0.20 mmol), 1-((1 ,5S)-8-{2-[4-(3-fluorophenyl)piperidin-4-yl]ethyl}-8- azabicyclo[3.2.1]oct-3-yl)-2-methyl-1 H-benzimidazole dihydrochloride (52 mg, 0.1 mmol) and HATU (38rhg, 0.1 mmol) following the procedure outlined in example 473. 1H NMR (400 MHz, CDCI3) δ 7.89-7.85 (m, 2 H), 7.66 (d, J=7.7 Hz, 1 H), 7.61-7.55 (m, 1 H), 7.38-7.36 (m, 1 H), 7.31-7.29 (m, 1 H), 7.21-7.14 (m, 3 H), 7.10-7.05 (m, 1 H), 6.99-6.97 (m, 2 H), 4.68 -4.63 (m, 1 H), 4.27- 4.23 (m, 1 H), 3.80 (d, J=4 Hz, 3 H), 3.43-3.20 (m, 5 H), 3.18-3.09 (m, 1 H), 2.56 (s, 3 H), 2.43-2.30 (m, 4 H ), 2.16-2.13 (m, 1 H), 1.96-1.89 (m, 10 H). HRMS m/z (M+H)+ calcd: 694.2630, obsd: 694.2625. Example 525 Preparation of 4-chloro-N-ethoxy-3-IT4-f2-r(1 R,5S)-3-(2-methyl-1 H- benzimidazol-1-yl)-8-azabicvclo[3.2.noct-8-yllethyl)-4-phenylpiperidin-1- vDcarbonvπbenzene-sulfonamide
Figure imgf000343_0001
4-Chloro-Λ/-ethoxy-3-[(4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)- 8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]benzene- sulfonamide (3.1 mg) was obtained as solid from 2-chloro-5- (chlorosulfonyl)benzoic acid (50 mg, 0.2 mmol), ethoxyamine hydrochloride (29 mg, 0.20 mmol), 2-methyl-1-{(1R,5S)-8-[2-(4-phenylpiperidin-4-yl)ethyl]-8- azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole dihydrochloride (51 mg, 0.1 mmol) and HATU (38mg, 0.1 mmol) following the procedure outlined in example 473. 1H NMR (400 MHz, CDCI3) δ 7.90-7.84 (m, 1 H), 7.65 (d, J=7.5 Hz, 1 H), 7.60-7.53 (m, 1 H), 7.41-7.32 (m, 2 H), 7.30-7.26 (m, 5 H), 7.19-7.14 (m, 3 H), 4.65 (br, 1 H), 4.30-4.22 (m, 1 H), 4.06-4.02 (m, 2 H), 3.33-3.25 (m, 5 H), 2.55 (s, 3 H), 2.38 (br, 3 H), 2.11-2.08 (m, 1 H), 1.99-1.89 (m, 9 H), 1.87- 1.64 (m, 2 H), 1.22- 1.15 (m, 3 H). HRMS m/z {M+H)+ calcd: 690.2881, obsd: 690.2880.
Example 526
Preparation of 3-r(4-(3-fluorophenyl)-4-f2-f(1 R,5S)-3-(2-methyl-1 H- benzimidazol-1-yl)-8-azabicvclo[3.2.noct-8-vnethyl|piperidin-1-vπcarbonyl1- 2,4-dimethylbenzene sulfonamide
Figure imgf000343_0002
3-[(4-(3-Fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1 H-benzimidazol-1 ■ yl)-8-azabicyclo[3.2.1 ]oct-8-yl]ethyl}piρeridin-1 -yl)carbonyl]-2,4- dimethylbenzene sulfonamide (25 mg, 38%) was obtained as solid from 3- (aminosulfonyl)-2,6-dimethylbenzoic acid (23 mg, 0.1 mmol), 1-((1R,5S)-8-{2- [4-(3-fluorophenyl)piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl- 1 H-benzimidazole dihydrochloride (52 mg, 0.1 mmol) and HATU (38mg, 0.1 mmol) following the procedure outlined in example 5. 1H NMR (400 MHz, CDCI3) δ 7.89 (d, J=8.2 Hz, 1 H), 7.64 (d, J=7.2 Hz, 1 H), 7.36 (q, J=7.9 HZ, 1 H), 7.29 (d, J=7.4 Hz, 1 H), 7.19-7.10 (m, 3 H), 7.05 (d, J=7.9 HZ, 1 H), 6.99- 6.95 (m, 2 H), 5.20 (br, 2 H), 4.61-4.56 (m, 1 H), 4.27-4.23 (m, 1 H), 3.46-3.41 (m, 1 H), 3.23 (br, 3 H), 3.10-3.05 (m, 1 H), 2.60 (s, 3/2 H, rotamer), 2.53 (s, 3 H), 2.41 (s, 3/2 H, rotamer), 2.37 (s, 3/2 H, rotamer), 2.33-2.29 (m, 2 H), 2.19 (s, 3/2 H, rotamer), 2.11-2.08 (m, 1 H), 1.94-1.82 (m, 10 H), 1.74-1.62 (m, 3 H). HRMS m/z (M+H)+ calcd: 658.3227, obsd: 658.3223.
Example 527 Preparation of 3-r(4-(3-fluorophenyl)-4-(2-r(1 R.5S)-3-(2-methyl-1 H- benzimidazol-1-yl)-8-azabicvclo[3.2.1loct-8-vnethyl>piperidin-1-yl)carbonvn- N,2,4-trimethyl benzenesulfonamide
Figure imgf000344_0001
3-[(4-(3-Fluorophenyl)-4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 - yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-1-yl)carbonyl]-Λ/-2,4-trimethyl benzenesulfonamide (10 mg, 15%) was obtained as solid from 3- (chlorosulfonyl)-2,6-dimethylbenzoic acid (50 mg, 0.2 mmol), methylamine (120 μL, 2.0 M in THF), 1-((1R,5S)-8-{2-[4-(3-fluorophenyl)piperidin-4- yl]ethyl}-8-azabicyclo[3.2.1 ]oct-3-yl)-2-methyl-1 H-benzimidazole dihydrochloride (52 mg, 0.1 mmol) and HATU (38mg, 0.1 mmol) following the procedure outlined in example 473. 1H NMR (400 MHz, CDCI3) δ 7.91-7.88 (m, 1 H), 7.66 (d, J=7.7 Hz, 1 H), 7.36 (q, J=7.7 HZ, 1 H), 7.29 (d, J=7.5 Hz, 1 H), 7.22-7.14 (m, 3 H), 7.05 (d, J=7.9 HZ, 1 H), 6.99-6.95 (m, 2 H), 4.63-4.52 (m, 2 H), 4.33-4.29 (m, 1 H), 3.43-3.34 (m, 1 H), 3.25 (br, 3 H), 3.05 (q, J=10.6 Hz, 1 H), 2.64-2.55 (m, 8 H), 2.42-4.21 (m, 7 H), 2.08 (br, 1 H), 1.95- 1.88 (m, 6 H), 1.84-1.63 (m, 6 H). HRMS m/z (M+H)+ calcd: 672.3384, obsd: 672.3400.
Example 528 Preparation of N-ethyl-3-r(4-(3-fluorophenvn-4-(2-[(1 R,5S)-3-(2-methyl-1 H- benzimidazol-1-vπ-8-azabicvclor3.2.noct-8-vnethyl)piperidin-1-yl)carbonvn- 2,4-dimethylbenzenesulfonamide
Figure imgf000345_0001
N-Ethyl-3-[(4-(3-fluorophenyl)-4-{2-[(1 R,5S)-3-(2-methyl-1 H- benzimidazol-1-yl)-8-azabicyclo[3.2.1] oct-8-yl]ethyl}piperidin-1-yl)carbonyl]-
2,4-dimethyl benzenesulfonamide (9.2mg, 14%) was obtained as solid from 3-
(chlorosulfonyl)-2,6-dimethylbenzoic acid (50 mg, 0.2 mmol), ethylamine (120 μL, 2.0 M in THF), 1-((1R,5S)-8-{2-[4-(3-fluorophenyl)piperidin-4-yl]ethyl}-8- azabicyclo[3.2.1]oct-3-yl)-2-methyl-1 H-benzimidazole dihydrochloride (52 mg, 0.1 mmol) and HATU (38mg, 0.1 mmol) following the procedure outlined in example 473. 1H NMR (400 MHz, CDCI3) δ 7.89 (d, J=8.0 Hz, 1 H), 7.66 (d, J=7.3 Hz, 1 H), 7.36 (q, J=7.7 Hz, 1 H), 7.30 (d, J=8.1 Hz, 1 H), 7.21-7.13 (m, 3 H), 7.06 (d, J=7.9 HZ, 1 H), 6.99-6.95 (m, 2 H), 4.63-4.59 (m, 1 H), 4.51- 4.49 (m, 1 H), 4.33-4.29 (m, 1 H), 3.40-3.34 (m, 1 H), 3.25-3.21 (m, 3 H), 3.11-3.05 (m, 1 H), 2.94-2.87 (m, 1 H), 2.62 (s, 3 H), 2.57 (s, 3 H), 2.55-2.30 (m, 3 H), 2.20 (s, 3 H), 2.09-2.06 (m, 1 H), 1.95-1.88 (m, 6 H), 1.84-1.63 (m, 6 H), 1.12 (t, J=7.2 Hz, 3 H). HRMS m/z (M+H)+ calcd: 686.3540, obsd: 686.3522. Example 529 Preparation of 3-r(4-.3-fluorophenvn-4-f2-r(1 R.5S)-3-(2-methyl-1 H- benzimidazol-1-yl)-8-azabicvclor3.2.1loct-8-vnethyl)piperidin-1-yl)carbonyll- 2,4-dimethyl-N-propylbenzenesulfonamide
Figure imgf000346_0001
3-[(4-(3-Fluorophenyl)-4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 - yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-1-yl)carbonyl]-2,4-dimethyl-Λ/- propylbenzenesulfonamide (8 mg, 12%) was obtained as solid from 3- (chlorosulfonyl)-2,6-dimethylbenzoic acid (50 mg, 0.2 mmol), propylamine (18μL, 0.22 mmol), 1 -((1 R,5S)-8-{2-[4-(3-fluorophenyl)piperidin-4-yl]ethyl}-8- azabicyclo[3.2.1]oct-3-yl)-2-methyl-1 H-benzimidazole dihydrochloride (52 mg, 0.1 mmol) and HATU (38mg, 0.1 mmol) following the procedure outlined in example 473. 1H NMR (400 MHz, CDCI3) δ 7.91-7.88 (m, 1 H), 7.66 (d, J=7.7 Hz, 1 H), 7.36 (q, J=7.6 HZ, 1 H), 7.33-7.31 (m, 1 H), 7.21-7.13 (m, 3 H), 7.06 (d, J=7.3 HZ, 1 H), 6.99-6.95 (m, 2 H), 4.63-4.59 (m, 1 H), 4.53-4.42 (m, 1 H), 4.33-4.24 (m, 1 H), 3.43-3.34 (m, 1 H), 3.25-3.21 (m, 3 H), 3.09-2.88 (m, 2 H), 2.84-2.76 (m, 1 H), 2.62 -2.56 (m, 6 H), 2.42-2.20 (m, 6 H), 2.08-2.06 (m, 1 H), 1.95-1.88 (m, 6 H), 1.84-1.63 (m, 6 H), 1.53-1.46 (m, 2 H), 0.90-0.84 (m, 3 H). HRMS m/z (M+H)+ calcd: 700.3697, obsd: 700.3696.
Example 530 Preparation of 3-r(4-(3-fluorophenvn-4-f2-lϊ1 R, 5S)-3-(2-methyl-1 H- benzimidazol-1-vπ-8-azabicvclor3.2.noct-8-vnethyl|piperidin-1-yl)carbonvn-N- isopropyl-2,4-dimethylbenzenesulfonamide
Figure imgf000347_0001
3-[(4-(3-Fluorophenyl)-4-{2-[(1 R, 5S)-3-(2-methyl-1 H-benzimidazol-1 - yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-1-yl)carbonyl]-Λ/-isopropyl-2,4- dimethylbenzenesulfonamide (8 mg, 12%) was obtained as solid from 3- (chlorosulfonyl)-2,6-dimethylbenzoic acid (50 mg, 0.2 mmol), isopropylamine (19 μL, 0.22 mmol), 1-((1R,5S)-8-{2-[4-(3-fluorophenyl)piperidin-4-yl]ethyl}-8- azabicyclo[3.2.1]oct-3-yl)-2-methyl-1 H-benzimidazole dihydrochloride (52 mg, 0.1 mmol) and HATU (38mg, 0.1 mmol) following the procedure outlined in example 473. 1H NMR (400 MHz, CDCI3) δ 7.94-7.92 (m, 1 H), 7.66 (d, J=7.1 Hz, 1 H), 7.36 (q, J=7.7 HZ, 1 H), 7.30-7.29 (m, 1 H), 7.21-7.14 (m, 3 H), 7.06 (d, J=7.9 HZ, 1 H), 6.99-6.95 (m, 2 H), 4.64-4.60 (m, 1 H), 4.34-4.24 (m, 2 H), 3.46-3.35 (m, 2 H), 3.25-3.20 (m, 3 H), 3.06-2.95 (m, 1 H), 2..61 (s, 3 H), 2.58 (s, 3 H), 2.44-2.30 (m, 3 H), 2.20 (s, 3 H), 2.08-2.06 (m, 1 H), 1.95-1.86 (m, 6 H), 1.85-1.64 (m, 6 H), 1.19-1.15 (m, 3H), 1.05-1.01 (m, 3 H). HRMS m/z (M+H)+ calcd: 700.3697, obsd: 700.3711.
Example 531 Preparation of N-cvclopropyl-3-IY4-(3-fluorophenyl)-4-(2-[(1 R.5S)-3-(2-methyl- 1 H-benzimidazol-1 -yl)-8-azabicvclor3.2.11oct-8-vπethyl)piperidin-1 - v0carbonvπ-2.4-dimethylbenzenesulfonamide
Figure imgf000348_0001
W-Cyclopropyl-3-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H- benzimidazol-1-yl)-8-azabicyclo [3.2.1]oct-8-yl]ethyl}piperidin-1-yl)carbonyl]- 2,4-dimethylbenzenesulfonamide (12 mg, 17%) was obtained as solid from 3- (chlorosulfonyl)-2,6-dimethylbenzoic acid (50 mg, 0.2 mmol), cyclopropylamine (15μL, 0.22 mmol), 1 -((1 R,5S)-8-{2-[4-(3- fluorophenyl)piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H- benzimidazole dihydrochloride (52 mg, 0.1 mmol) and HATU (38mg, 0.1 mmol) following the procedure outlined in example 473. 1H NMR (400 MHz, CDCIs) δ 7.96 (d, J=8.0 Hz, 1 H), 7.66 (d, J=8.0 Hz, 1 H), 7.38-7.34 (m, 1 H), 7.31-7.29 (m, 1 H), 7.21-7.13 (m, 3 H), 7.06 (d, J=8.0 Hz, 1 H), 6.99-6.95 (m, 2 H), 5.29-5.14 (m, 1 H), 4.61 (br, 1 H), 4.32-4.29 (m, 1 H), 3.60-3.37 (m, 2 H), 3.24-3.20 (m, 3 H), 3.06-3.01 (m, 2 H), 2.60 -2.57 (m, 6 H), 2.40-2.30 (m, 3 H), 2.21 (s, 3 H), 2.08-2.06 (m, 1 H), 1.94-1.81 (m, 9 H), 1.69-1.63 (m, 3 H), 0.60-0.53 (m, 4 H). HRMS m/z (M+H)+ calcd: 698.3540, obsd: 698.3567.
Example 532 Preparation of N-cvclopentyl-3-lϊ4-f3-fluorophenvn-4-f2-IT1 R.5S)-3-(2-methyl- 1 H-benzimidazol-1 -yl)-8-azabicvclor3.2.noct-8-vnethyl}piperidin-1- v0carbonvπ-2.4-dimethylbenzenesulfonamide
Figure imgf000349_0001
Λ/-Cyclopentyl-3-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H- benzimidazol-1-yl)-8-azabicyclo [3.2.1]oct-8-yl]ethyl}piperidin-1-yl)carbonyl]- 2,4-dimethylbenzenesulfonamide (24 mg, 33%) was obtained as solid from 3- [(cyclopentyl amino)sulfonyl]-2,6-dimethyl benzoic acid (30 mg, 0.1 mmol), 1- ((1R,5S)-8-{2-[4-(3-fluorophenyl)piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1] oct-3- yl)-2-methyl-1 H-benzimidazole dihydrochloride (52 mg, 0.1 mmol) and HATU (38mg, 0.1 mmol) following the procedure outlined in example 5. 1H NMR (400 MHz, CDCI3) δ 7.93-7.91 (m, 1 H), 7.67-7.64 (m, 1 H), 7.36 (q. J=8.0 Hz, 1 H), 7.30-7.28 (m, 1 H), 7.21-7.12 (m, 3H), 7.07-7.05 (m, 1 H), 6.99-6.95 (m, 2 H), 4.63-4.53 (m, 2 H), 4.31-4.28 (m, 1 H), 3.59-3.50 (m, 1 H), 3.44-3.34 (m, 1 H), 3.24 (br, 3 H), 3.08 -3.00 (m, 1 H), 2.61 (s, 3/2H, rotamer), 2.57 (s, 3/2 H, rotamer), 2.56 (s, 3/2 H, rotamer), 2.41 (s, 3/2 H, rotamer), 2.39 (s, 3/2 H, rotamer), 2.36-2.34 (m, 3 H), 2.20 (s, 3/2 H, rotamer), 2.08 (br, 1 H), 1.95-1.76 (m, 10 H), 1.69-1.56 (m, 5 H), 1.52-1.45 (m, 3 H), 1.32-1.27 (m, 1 H). HRMS m/z (M+H)+ calcd: 726.3853, obsd: 726.3824.
Example 533 Preparation of 4-hvdroxy-3--Y4--2-[(1 R.5S)-3-(2-methyl-1 H-benzimidazol-1 -vH- 8-azabicvclor3.2.11oct-8-vnethyl}-4-phenylpiperidin-1-vπcarbonvnbenzene sulfonamide
Figure imgf000350_0001
4-Hydroxy-3-[(4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1- yl)carbonyl]benzenesulfonamide (20 mg) was obtained as solid from 5- (aminosulfonyl)-2-hydroxybenzoic acid (43 mg, 0.2 mmol), 2-methyl-1- {(1 R,5S)-8-[2-(4-phenylpiperidin-4-yl)ethyl]-8-aza bicyclo[3.2.1]oct-3-yl}-1 H- benzimidazole (100mg, 0.2 mmol) and HATU (76mg, 0.2 mmol) following the procedure outlined in example 5. 1H NMR (400 MHz, DMSO-of6) δ 10.66 (s, 1 H), 7.74 (s, 1 H), 7.65 (dd, J=2.4, 8.2 Hz, 1 H), 7.54 (d, J=2.2 Hz, 1 H), 7.49- 7.47 (m, 1 H), 7.38 (br, 5 H), 7.22-7.10 (m, 5 H), 6.96 (d, 8.6 Hz, 1 H), 4.48 (br, 1 H), 3.90 (br, 1 H), 3.24 (br, 1 H), 3.09-3.03 (m, 4 H), 2.47-2.45 (m, 6 H), 2.09 (br, 5 H), 1.81 (br, 6 H), 1.57 (br, 1 H). HRMS m/z (M+H)+ calcd: 628.2958, obsd: 628.2958.
Example 534 Preparation of 6-IT4-f2-IT1 R.5S)-3-(2-methyl-1 H-benzimidazol-1 -vh-8- azabicvclor3.2.1loct-8-yl1ethyl|-4-phenylpiperidin-1-vπcarbonvn-1 ,2- benzisothiazol-3(2H)-one 1 ,1 -dioxide
Figure imgf000350_0002
6-[(4-{2-[(1 R, 5S)-3-(2-Methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]-1 ,2- benzisothiazol-3(2H)-one 1 ,1-dioxide (78mg, 61 %) was obtained as solid from 3-oxo-2,3-dihydro-1 ,2-benzisothiazole-6-carboxylic acid 1 ,1-dioxide (46 mg, 0.2 mmol), 2-methyl-1-{(1R, 5S)-8-[2-(4-phenylpiperidin-4-yl)ethyl]-8- azabicyclo [3.2.1]oct-3-yl}-1H-benzimidazole (100mg, 0.2 mmol) and HATU (76mg, 0.2 mmol) following the procedure outlined in example 5. 1H NMR (400 MHz, DMSO-c e) δ 7.63-7.61 (m, 2 H), 7.57-7.54 (m, 1 H), 7.50-7.47 (m, 1 H), 7.44-7.33 (m, 5 H), 7.25-7.20 (m, 1 H), 7.15-7.07 (m, 3, H), 4.69-4.63 (m, 1 H), 3.93(br, 1 H), 3.47 (br, 3 H), 3.39-3.30 (m, 1 H), 2.48 (s, 3 H), 2.43- 2.38 (m, 4 H), 2.27-2.20 (m, 4 H), 1.97-1.78 (m, 7 H), 1.78-1.66 (m, 2 H). HRMS m/z (M+H)+ calcd: 638.2801 , obsd: 638.2796.
Synthesis of amides via EDCI coupling - Method P
Acid, EDCI, base
Figure imgf000351_0002
Figure imgf000351_0001
Synthesis of amides via HATU-mediated coupling - Method A
Figure imgf000351_0003
Synthesis of amides via anhydride - Method B
Figure imgf000351_0004
Synthesis of amides via Isatoic Anhydride opening - Method U
Figure imgf000352_0001
The following table includes compounds of the present invention that were prepared by the methods depicted above.
Figure imgf000352_0002
Figure imgf000352_0003
Figure imgf000353_0001
Figure imgf000354_0001
Figure imgf000355_0001
004/054974
355
Figure imgf000356_0001
Figure imgf000357_0001
Notes:
I . Compound was synthesized according to WO 00/66558, Schering Corporation, 2000. 2. Compound was synthesized according to procedure outlined for example 572.
3. Compound was synthesized according to the literature procedure described by M. H. Chen et al., Org. Prep. Proced. Int., 2000, v32, pp. 381- 384. 4. Compound was synthesized according to the literature procedure described in J. Heterocycl. Chem. 26(5), 1461-8 (1989).
5. Compound was synthesized according to the literature procedure described in J. Chem. Res. Synop. 12, 400-1 (1984).
6. Compound was synthesized according to the literature procedure described in Chem. Ber., 109(1), 268-73 (1976).
7. Compound was synthesized according to the procedure described in EP 0016565A1 , 1980.
8. Compound was synthesized according to procedure outlined for example 572. 9. Compound was synthesized according to the literature procedure described in J. Org. Chem., 41 (6), 1041-51 (1976). 10. Compound was synthesized according to the literature procedure described in J. Med. Chem., 33(2), 781-9 (1990).
I I . Compound was synthesized according to the literature procedure described in Bioorganic & Medicinal Chemistry Letters, 9(18), 2679-2684
(1999). Example 571
Figure imgf000358_0001
Ethyl 1 -[(4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenyl piperidin-1- yl)carbonyl]cyclohexanecarboxylate was synthesized via EDCI-HOBt acylation method P. 1H NMR (300MHz, CDCI3) δ 7.66(d, 1 H), 7.43-7.12(m, 8H), 4.61 (m, 1 H), 4.22-4.09(m, 2H), 3.65(m, 1 H), 3.33-3.05(m, 4H), 2.88(m, 1 H), 2.58(s, 3H), 2.46-2.11(m, 4H), 2.05(s, 1 H),2.00-1.83(m, 12H), 1.63- 1.52(m, 6H), 1.50-1.37(m, 2H),1.07-1.32 (m, 4H). HRMS C38H5oN4O3 m/z 611.3961 (M+H)cai., 611.3973 (M+H)0bs.
Figure imgf000358_0002
2,2-Dimethyl-3-(4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)-3-oxopropanoic acid was prepared by treating title compound from example 628 with NaOH. 1H NMR (300 MHz, CDCI3) δ 7.75 (d, 1 H), 7.43-7.12 (m, 8H), 4.68 (m, 1H), 4.07 (m, 1 H), 3.69 (m, 1 H), 3.30-3.14 (m, 2H), 2.70-2.58 (m, 3H), 2.20 (m, 2H), 2.05-1.73 (m, 7H), 1.50-1.07 (m, 12H), 1.02-0.74 (m, 3H). HRMS C33HΛO3 m/z 543.3335 (M+H)Caι. 543.3337 (M+H)obs. Example 573
Figure imgf000359_0001
1 -[(4-{2-[(1 R,5S)-3-(2-Methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1- yl)carbonyl]cyclopropanecarboxylic acid was prepared by treating title compound from example 573 with NaOH. 1H NMR (300 MHz, CDCI3) δ 7.66 (d, 1 H), 7.40-7.10 (m, 8H), 4.62 (m, 1 H), 4.14 (m, 1 H), 3.25 (m, 2H), 3.08 (m, 2H), 2.58 (s, 3H), 2.43-2.19(m, 3H), 2.05-1.78(m, 8H), 1.27(s, 6H) 0.92- 0.78(m, 2H). HRMS C33H4oN4O3 m/z 541.3179 (M+H)Caι.. 541.3163 (M+H)0bs,
Example 574 2-Methyl-1 -IΪ1 R,5S)-8-(2-(1 -r(5-methylpyrazin-2-vncarbonvn-4- phenylpiperidin-4-yl)ethyl)-8-azabicvclor3.2.noct-3-yll-1 H-benzimidazole
Figure imgf000359_0002
Method A (HATU). 1H NMR (300 MHz, CDCI3) δ 8.78(s, 1 H), 8.41 (s,
1H), 7.67(d, 1H), 7.45-7.09(m, 8H), 4.61 (m, 1H), 4.25(m, 1H), 3.75(m, 1H), 3.42-3.19(m, 4H), 2.62(s, 3H), 2.57(s, 3H), 2.40-2.19(m, 4H), 2.00-1.79(m, 10H), 1.63(m, 2H). ES-LCMS m/z 548(M+H). Example 575 2-Methyl-1-[(1 R.5S)-8-(2-f1-r(1-oxidoPyridin-3-yl)carbonyll-4-phenylpiperidin- -yllethvh-8-azabicvclor3.2.noct-3-yl1-1 H-benzimidazole
Figure imgf000360_0001
Method A (HATU). 1H NMR (300 MHz, CDCI3) δ 8.23 (d, 1 H), 7.68 (d, 1H), 7.45-7.10 (m, 11H), 4.61 (m, 1H), 4.24 (m, 1 H), 3.53 (m, 1H), 3.30-3.18 (m, 4H), 2.58 (s, 3H), 2.40-2.29 (m, 3H), 2.01-1.80 (m, 9H), 1.65 (m, 4H). ES- LCMS m/z 549(M+H).
Example 576 1 -IΪ1 R,5S)-8-(2-(1 -f(1 ,5-dimethyl-l H-pyrazol-3-yl)carbonyll-4-phenylpiperidin- 4-yl)ethv0-8-azabicvclo[3.2.11oct-3-yll-2-methyl-1 H-benzimidazole
Figure imgf000360_0002
Method A (HATU). 1H NMR (300 MHz, CDCI3) δ 7.68 (d, 1 H), 7.45- 7.10 (m, 8H), 6.36 (s, 1 H), 4.63 (m, 1 H), 4.30-4.10 (m, 2H), 3.79 (s, 3H), 3.62 (m, 1 H), 3.40-3.21 (m, 3H), 2.57 (s, 3H), 2.45-2.20 (m, 7H), 2.02-1.78 (m, 10H), 1.64-1.57 (m, 2H). ES-LCMS m/z 550(M+H). Example 577 1 -[(1 R.5S)-8-(2-(1 -[(5-chlorothien-2-vncarbonvn-4-phenylpiperidin-4-yl)ethylV 8-azabicvclor3.2.1loct-3-yl1-2-methyl-1 H-benzimidazole
Figure imgf000361_0001
Method A (HATU). 1H NMR (300 MHz, CDCI3) δ 7.68 (d, 1H), 7.45- 7.01 (m, 9H), 6.86 (d, 1 H), 4.61 (m, 1 H), 4.15-3.97 (m, 2H), 3.41 (m, 2H), 3.25 (m, 2H), 2.57 (s, 3H), 2.45-2.25 (m, 4H), 2.00-1.77 (m, 10H), 1.61-1.58 (m, 2H). ES-LCMS m/z 572(M+H).
Example 578 5-r.4-(2-lϊ1 R.5SV3-(2-methyl-1 H-benzimidazol-1 -vn-8-azabicvclor3.2.11oct-8- yllethyl)-4-phenylpiperidin-1 -vDcarbonyll-l H-1 ,2,3-benzotriazole
Figure imgf000361_0002
Method A (HATU). 1H NMR (300 MHz, CDCI3) δ 7.94 (s, 1 H), 7.84 (d, 1 H), 7.69 (d, 1 H), 7.48-7.14(m,10H), 4.64 (m, 1 H), 4.27 (m, 1H), 3.61 (m, 1 H), 3.49-3.22 (m, 4H), 2.54 (s, 3H), 2.45-2.30 (m, 3H), 2.22 (m, 1H), 2.05-1.73 (m, 10H), 1.68-1.57 (m, 2H). ES-LCMS m/z 573(M+H). Example 579 1 -IT1 R,5S)-8-(2-f 1 -[(2-chloro-6-methylpyridin-3-vπcarbonvn-4-pheny|piperidin- 4-yltethyl)-8-azabicvclor3.2.1 loct-3-vn-2-methyl-1 H-benzimidazole
Figure imgf000362_0001
Method A (HATU). 1H NMR (300 MHz, CDCI3) δ 7.70-7.55 (m, 1 H), 7.47-7.08 (m, 10H), 4.61 (m, 1 H), 4.23 (m, 1 H), 3.49-3.17 (m, 5H), 2.57 (s, 6H), 2.45-2.29 (m, 3H), 2.13 (m, 1 H), 2.02-1.78 (m, 10H), 1.68-1.56 (m, 2H). ES-LCMS m/z 581 (M+H)
Example 580 6-lϊ4-(2-IT1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8-azabicvclor3.2.1 loct-8- yllethyl)-4-Phenylpiperidin-1 -vPcarbonyll-l ,3-benzothiazole
Figure imgf000362_0002
Method A (HATU). 1H NMR (300 MHz, CDCI3) δ 9.08 (s, 1 H), 8.20 (d, 1 H), 8.03 (s, 1 H), 7.69 (d, 1 H), 7.55 (d, 1 H), 7.41-7.09 (m, 8H), 4.61 (m, 1 H), 4.23 (m, 1 H), 3.62 (m, 1 H), 3.48-3.17 (m, 4H), 2.55 (s, 3H), 2.45-2.28 (m, 3H), 2.25-2.09 (m, 2H), 2.01-1.78 (m, 9H), 1.63 (d, 2H). ES-LCMS m/z 589(M+H). Example 581 methyl 6-K4-<2-K1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.11oct-8-vπethyl)-4-phenylpiperidin-1 -vDcarbonyllnicotinate
Figure imgf000363_0001
Method A (HATU). 1H NMR (300 MHz, CDCI3) δ 9.19 (s, 1H), 8.38 (d, 1 H), 7.65 (d, 1 H), 7.45-7.09 (m, 8H), 4.61 (m, 1 H), 4.21 (m, 1 H), 3.98 (s, 3H), 3.64 (m, 1 H), 3.48-3.21 (m, 4H), 2.57 (s, 3H), 2.48-2.29 (m, 3H), 2.25-2.15 (m, 1 H), 2.02-1.79 (m, 10H), 1.62-1.55 (m, 2H). ES-LCMS m/z 591 (M+H).
Example 582 1 -IΪ1 R,5S)-8-(2-(1 -r(4.5-dichloroisothiazol-3-vπcarbonyl1-4-phenylpiperidin-4- yl)ethvπ-8-azabicvclor3.2.noct-3-vn-2-methyl-1 H-benzimidazole
Figure imgf000363_0002
Method A (HATU). 1H NMR (300 MHz, CDCI3) δ 7.68 (d, 1H), 7.43- 7.09 (m, 8H), 4.65 (m, 1H), 4.30-4.13 (m, 1H), 3.60-3.17 (m, 5H), 2.58 (s, 3H), 2.46-2.19 (m, 4H), 2.05-1.81 (m, 10H), 1.69-1.59 (m, 2H). ES-LCMS m/z 607(M+H). Example 583 1 -K1 R.5S)-8-(2-(1 -r(2.4-dimethyl-1.3-thiazol-5-vncarbonyll-4-phenylpiperidin- -yl)ethyl)-8-azabicvclor3.2.11oct-3-vn-2-methyl-1 H-benzimidazole
Figure imgf000364_0001
Method A (HATU). 1H NMR (300 MHz, CDCI3) δ 7.65 (d, 1 H), 7.46- 7.18 (m, 8H), 4.61 (m, 1 H), 3.98 (m, 1 H), 3.42-3.19 (m, 4H), 2.67 (s, 3H), 2.56 (s, 3H), 2.41-2.19 (m, 7H), 2.05-1.75 (m, 10H), 1.70-1.55 (m, 2H). ES-LCMS m/z 567(M+H).
Example 584 1 -in R.5S)-8-f2-π -(2.5-dimethyl-3-furoyl)-4-phenylpiperidin-4-vnethyl)-8- azabicvclo[3.2.11oct-3-yl)-2-methyl-1 H-benzimidazole
Figure imgf000364_0002
Method A (HATU). H NMR (300 MHz, CDCI3) δ 7.68 (d, 1 H), 7.42- 7.11 (m, 8H), 5.91 (s, 1H), 4.61 (m, 1H), 4.06 (m, 1H), 3.76 (m, 1H), 3.40-3.18 (m, 4H), 2.57 (s, 3H), 2.44-2.33 (m, 4H), 2.31 (s, 3H), 2.24 (s, 3H), 2.00-1.72 (m, 10H), 1.62-1.53 (m, 2H). ES-LCMS m/z 550(M+H). 364
Example 585 2-methyl-1 -((1 R,5S)-8-(2-r4-phenyl-1 -fthien-2-ylacetvn piperidin-4-vπethyl 8- azabicvclor3.2.noct-3-yl)-1 H-benzimidazole
Figure imgf000365_0001
Method A (HATU). 1H NMR (300 MHz, CDCI3) δ 7.71 (d, 1H), 7.43- 7.09 (m, 9H), 7.01-6.83 (m, 2H), 4.75 (m,1 H), 4.10-3.97 (m, 1 H), 3.90 (s, 2H), 3.84 (s, 1H), 3.75-3.59 (m, 4H), 2.54 (s, 3H), 2.52-2.36 (m, 1H), 2.25-1.57 (m, 14H). ES-LCMS m/z 552(M+H).
Example 586 2-methyl-1 -((1 R,5S)-8-(2-[1 -(3-methyl-2-furoyl)-4-phenylpiperidin-4-yllethyl)-8- azabicvclo[3.2.1foct-3-y0-1 H-benzimidazole
Figure imgf000365_0002
Method A (HATU). 1H NMR (300 MHz, CDCI3) δ 7.66 (d, 1 H), 7.43- 7.09 (m, 9H), 6.32 (s, 1H), 4.63(m,1H), 3.98 (m, 1H), 3.48-3.20 (m, 4H), 2.58 (s, 3H), 2.48-2.20 (m, 7H), 2.02-1.78 (m, 10H), 1.70-1.55 (m, 2H). ES-LCMS m/z 536(M+H). O 2004/054974
365
Example 587 1 -((1 R,5S)-8-(2-π -(4,5-dimethyl-2-furoyl)-4-phenylpiperidin-4-vπethyl -8- azabicyclor3.2.11oct-3-yl)-2-methyl-1 H-benzimidazole
Figure imgf000366_0001
Method A (HATU). 1H NMR (300 MHz, CDCI3) δ 7.68 (d, 1 H), 7.44-
7.13 (m, 8H), 6.73 (s, 1 H), 4.64(m,1 H), 4.20-4.07 (m, 2H), 3.55-3.21 (m, 4H), 2.58 (s, 3H), 2.48-2.21 (m, 7H), 2.03-1.80 (m, 13H), 1.70-1.59 (m, 2H). ES- LCMS m/z 550(M+H).
Example 588
1 -[(1 R,5S)-8-(2-f 1 -[(1 -tert-butyl-3-methyl-1 H-pyrazol-5-yl)carbonvn-4- phenylpiperidin-4-yl)ethyl)-8-azabicvclo|'3.2.11oct-3-yll-2-methyl-1 H- benzimidazole
Figure imgf000366_0002
Method A (HATU). 1H NMR (300 MHz, CDCI3) δ 7.66 (d, 1 H), 7.46-
7.13 (m, 8H), 5.95 (s, 1H), 4.63 (m, 1H), 4.20-4.13 (m, 1 H), 3.62-3.48 (m, 1 H), 3.41-3.13 (m, 4H), 2.58 (s, 3H), 2.48-2.28 (m, 3H), 2.26 (s, 1H), 2.24-2.10 (m, 1H), 2.00-1.65 (m, 12H), 1.59 (s, 10H). ES-LCMS m/z 592(M+H). O 2004/054
366
Example 589 2-methyl-1 -((1 R,5S)-8-f2-[1 -M -oxidoisonicotinoyl)-4-phenylpiperidin-4- vnethyl)-8-azabicvclo[3.2.11oct-3-yl)-1 H-benzimidazole
Figure imgf000367_0001
Method A (HATU). 1H NMR (300 MHz, CDCI3) δ 8.25 (d, 2H), 8.18 (d, 1 H), 7.42-7.12 (m, 10H), 4.63 (m, 1 H), 3.39-3.20 (m, 4H), 2.58 (s, 3H), 2.41- 2.30 (m, 3H), 1.97-1.77 (m, 10H), 1.68-1.49 (m, 5H). ES-LCMS m/z 549(M+H).
Example 590 2-methyl-1-r(1R.5S)-8-(2-(1-[(5-methylthien-2-yl)carbonvn-4-phenylpiperidin-4- yl)ethyl)-8-azabicvclof3.2.noct-3-yl1-1 H-benzimidazole
Figure imgf000367_0002
Method A (HATU). 1H NMR (300 MHz, CDCI3) δ 7.68 (d, 1 H), 7.45- 7.06 (m, 9H), 6.69 (m, 1H), 4.64 (m, 1H), 4.19-4.00 (m, 2H), 3.44 (m, 2H), 3.30 (m, 2H), 2.58 (s, 3H), 2.51 (s, 3H), 2.48-2.23 (m, 4H), 2.04-1.81 (m, 10H), 1.70-1.60 (m, 2H). ES-LCMS m/z 552(M+H). Example 591 1-((1R.5SV8-f2-ri-(5-bromo-2-furoyl)-4-phenylpiperidin-4-vnethyl)-8- azabicvclo[3.2.1loct-3-yl)-2-methyl-1 H-benzimidazole
Figure imgf000368_0001
Method A (HATU). 1H NMR (300 MHz, CDCI3) δ 7.69 (d, 1H), 7.47- 7.13 (m, 8H), 6.96 (d, 1H), 6.43 (d, 1H), 4.66 (m, 1H), 4.20-4.07 (m, 2H), 3.52- 3.22 (m, 4H), 2.59 (s, 3H), 2.49-2.24 (m, 4H), 2.04-1.81 (m, 10H), 1.70-1.60 (m, 2H). ES-LCMS m/z 600(M+H).
Example 592 1 -IΪ1 R.5S)-8-(2-( 1 -r.5-bromothien-2-v0carbonyll-4-phenylpiperidin-4-yl)ethyl)- 8-azabicvclor3.2.1loct-3-vn-2-methyl-1 H-benzimidazole
Figure imgf000368_0002
Method A (HATU). 1H NMR (300 MHz, CDCI3) δ 7.66 (d, 1 H), 7.48- 7.13 (m, 9H), 7.07-6.95 (m, 1H), 4.64 (m, 1H), 4.10-3.94 (m, 2H), 3.53-3.21 (m, 4H), 2.58 (s, 3H), 2.46-2.25 (m, 4H), 2.04-1.79 (m, 10H), 1.71-1.57 (m, 2H). ES-LCMS m/z 616(M+H). Example 593 2-methyl-1-f(1R,5S)-8-r2-(4-phenyl-1 4-
[(trifluoromethvπthio1benzoyl piperidin-4-yl)ethvn-8-azabicvclor3.2.noct-3-yll- 1 H-benzimidazole
Figure imgf000369_0001
Method A (HATU). 1H NMR (300 MHz, CDCI3) δ 7.80-7.62 (m, 3H), 7.50-7.11 (m, 11H), 4.63 (m, 1 H), 4.25-4.13 (m, 1H), 3.60-3.17 (m, 4H), 2.57 (s, 1H), 2.44-2.29 (m, 3H), 2.20-2.08 (m, 1H), 2.02-1.70 (m, 10H), 1.62-1.57 (m, 2H). ES-LCMS m/z 632(M+H).
Example 594 2-methyl-1-r(1R.5S)-8-(2-f1-[(5-methyl-3-phenylisoxazol-4-vncarbonvn-4- phenylpiperidin-4-yl)ethyl)-8-azabicvclor3.2.11oct-3-ylM H-benzimidazole
Figure imgf000369_0002
Method A (HATU). 1H NMR (300 MHz, CDCI3) δ 7.74-7.65 (m, 2H),
7.51-7.14 (m, 12H), 4.59 (m, 1H), 4.18 (m, 1H), 3.38-3.17 (m, 4H), 2.57 (s, 3H), 2.48 (s, 3H), 2.44-2.17 (m, 4H), 2.01-1.54 (m, 12H). ES-LCMS m/z 613(M+H). Example 595 1 -R1 R,5S)-8-(2-(1 -r(2,6-dichloropyridin-3-yl)carbonvn-4-phenylpiperidin-4- yl)ethyl)-8-azabicvclor3.2.1 loct-3-vn-2-methyl-1 H-benzimidazole
Figure imgf000370_0001
Method A (HATU). 1H NMR (300 MHz, CDCI3) δ 7.74-7.60 (m, 2H), 7.54-7.05 (m, 9H), 4.61 (m, 1 H), 4.23 (m, 1 H), 3.45-3.02 (m, 5H), 2.56 (s, 3H), 2.47-2.09 (m, 4H), 2.00-1.75 (m, 8H), 1.70-1.53 (m, 2H), 1.28-1.20 (m, 2H). ES-LCMS m/z 601 (M+H).
Example 596 N-(4-r(4-(2-r(1 R.5S)-3-(2-methyl-1 H-benzimidazol-1-yl)-8-azabicvclor3.2.noct- 8-vnethyl)-4-phenylpiperidin-1-yl)carbonvnphenyl)thiourea
Figure imgf000370_0002
Method A (HATU). 1H NMR (300 MHz, CDCI3) δ 8.95 (s, 1H), 7.67 (d, 1 H), 7.45-7.06 (m, 10H), 6.35 (s, 1 H), 4.61 (m, 1 H), 4.20-4.09 (m, 1 H), 3.71- 3.51 (m, 1 H), 3.48-3.16 (m, 4H), 2.56 (s, 3H), 2.46-2.13 (m, 4H), 2.04-1.55 (m, 13H), 1.27 (s, 2H). ES-LCMS m/z 606(M+H). Example 597 methyl 3-fluoro-5-IT4-(2-IT1 R.5SV3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicvclo[3.2.1loct-8-yl1ethyll-4-phenylpiperidin-1-yl)carbonvnbenzoate
Figure imgf000371_0001
Method A (HATU). 1H NMR (300 MHz, CDCI3) δ 7.85-7.63 (m, 2H), 7.42-7.09 (m, 10H), 4.62 (m, 1H), 4.30-4.15 (m, 1H), 3.94 (s, 3H), 3.62-3.19 (m, 5H), 2.57 (s, 3H), 2.46-2.12 (m, 4H), 2.00-1.75 (m, 10H), 1.73-1.55 (m, 2H). ES-LCMS m/z 608(M+H).
Example 598 1-r(1R,5S)-8-(2-f1-[(2.4-dimethylpyridin-3-yl)carbonyll-4-phenylpiperidin-4- yl)ethyl)-8-azabicvclor3.2.noct-3-vn-2-methyl-1 H-benzimidazole
Figure imgf000371_0002
Method A (HATU). 1H NMR (300 MHz, CDCI3) δ 8.36 (d, 1 H), 7.65 (d, 1 H), 7.44-7.23 (m, 8H), 7.05-6.93 (m, 1 H), 4.61 (m, 1 H), 4.36-4.25 (m, 1 H), 3.50-3.03 (m, 7H), 2.56 (m, 4H), 2.37 (m, 4H), 2.15 (s, 3H), 1.97-1.54 (m, 12H). ES-LCMS m/z 561 (M+H). Example 599 methyl 2.5-dimethyl-4-r(4-(2-IY1 R.5S)-3-(2-methyl-1 H-benzimidazol-1 -ylV-8- azabicvclor3.2.noct-8-vnethyl}-4-phenylpiperidin-1-vπcarbonvnbenzoate
Figure imgf000372_0001
Method A (HATU). 1H NMR (300 MHz, CDCI3) δ 7.83-7.60 (m, 2H),
7.50-7.08 (m, 9H), 4.62 (m, 1 H), 4.30-4.11 (m, 1 H), 3.91 (s, 2H), 3.42-3.08 (m, 6H), 2.94 (s, 3H), 2.81 (s, 3H), 2.57 (s, 3H), 2.40-2.14 (m, 4H), 2.05-1.75 (m, 10H), 2.20-1.57 (m, 2H). ES-LCMS m/z 618(M+H).
Example 600
1 -((1 R,5S)-8-(2-f 1 -(3,5-dichloro-1 -oxidoisonicotinovπ-4-phenylpiperidin-4- vnethyl)-8-azabicvclo[3.2.noct-3-yl)-2-methyl-1 H-benzimidazole
Figure imgf000372_0002
Method A (HATU). 1H NMR (300 MHz, CDCI3) δ 8.23-8.10 (m, 1 H), 7.70-7.61 (m, 1 H), 7.45-7.08 (m, 9H), 4.61 (m, 1 H), 4.35-4.24 (m, 1 H), 2.58 (s, 3H), 2.48-2.22 (m, 4H), 2.04-1.77 (m, 10H), 1.70-1.57 (m, 2H). ES-LCMS m/z 617(M+H). Example 601 N-f2-r(4-(2-r(1 R.5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8-azabicvclor3.2.noct- 8-vnethyl)-4-phenylpiperidin-1-vπcarbonvπphenyl)methanesulfonamide
Figure imgf000373_0001
Method A (HATU). 1H NMR (300 MHz, methanol-d4) δ 7.90-7.75 (m, 2H), 7.71-7.41 (m, 10H), 7.36-7.24 (m, 1H), 5.31 (m, 1H), 4.25-4.04 (m, 3H), 3.62-3.53 (m, 1H), 3.51-3.26 (m, 8H), 3.04-2.90 (m, 1 H), 2.84 (s, 3H), 2.78- 2.69 (m, 1H), 2.52-2.13 (m, 10H), 2.10-1.82 (m, 2H). ES-LCMS m/z 625(M+H).
Example 602 4-chloro-2-lϊ4-f2-r(1 R.5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicvclo[3.2.noct-8-yl1ethyl)-4-phenylpiperidin-1-yl)carbonvnaniline
Figure imgf000373_0002
Method B (Anhydride). 1H NMR (300 MHz, methanol-d4) δ 7.81-7.73 (m, 2H), 7.63-7.57 (m, 2H), 7.46 (s, 1H), 7.31 (m, 1H), 7.20-7.03 (m, 2H), 6.79(d,1H), 5.27 (m, 1H), 4.11-4.03 (m, 2H), 3.30 (m, 6H), 2.97-2.86 (m, 2H), 2.82 (s, 3H), 2.77-2.70 (m, 2H), 2.45-2.11 (m, 10H), 1.95-1.83 (m, 2H). ES- LCMS m/z 581 (M+H). Example 603 4-bromo-2-r(4-(2-IT1 R.5SV3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicvclo[3.2.1 loct-8-yllethyl)-4-phenylpiperidin-1 -yl)carbonv-]aniline
Figure imgf000374_0001
Method B (Anhydride). 1H NMR (300 MHz, methanol-d4) δ 8.08-7.93 (m, 2H), 7.85-7.72 (m, 2H), 7.64-7.55 (m, 2H), 7.50-7.42 (m, 4H), 7.34-7.27 (m, 1 H), 6.80 (d, 1 H), 5.31 (m, 1 H), 4.14-4.00 (m, 1 H), 3.38-3.27 (m, 6H), 2.98-2.87 (m, 2H), 2.86 (s, 3H), 2.83-2.71 (m, 2H), 2.44-2.14 (m, 10H), 2.00- 1.85 (m, 2H). ES-LCMS m/z 625(M+H).
Example 604 1 -1(1 R.5S)-8-(2-f 1 -Iϊ5-ethyl-1 -phenyl-1 H-1 ,2,3-triazol-4-yl)carbonvn-4- phenylpiperidin-4-yl>ethyl)-8-azabicvclo[3.2.noct-3-vn-2-methyl-1 H- benzimidazole
Figure imgf000374_0002
Method A (HATU). Acid precursor synthesized according to procedure outlined in J. Chem. Res. Synop., 12, 400-1 (1984). 1H NMR (300 MHz, CDCIs) δ 7.70-7.54 (m, 4H), 7.50-7.13 (m, 10H), 4.64 (m, 1 H), 4.40-4.35 (m, 1 H), 4.28-4.15 (m, 1 H), 3.82-3.65 (m, 1 H), 3.48-3.22 (m, 4H), 3.00-2.85 (m, 2H), 2.46-2.30 (m, 4H), 2.04-1.78 (m, 13H), 1.68-1.57 (m, 2H), 1.18-1.05 (m, 3H). ES-LCMS m/z 627(M+H). O 2004/054974
374
Example 605 4-(f5-IY4-f2-IT1 R.5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicvclo[3.2.noct-8-vπethyl}-4-Phenylpiperidin-1-yl)carbonvn-1H-1 ,2.3- triazol-4-yl)oxy)phenol
Figure imgf000375_0001
Method A (HATU). Acid precursor synthesized according to procedure outlined in J. Chem. Res. Synop., 12, 400-1 (1984). 1H NMR (400 MHz, CDCI3) δ 7.66 (d, 1H), 7.58-7.11 (m, 10H), 6.92-6.88 (m, 1H), 6.75-6.69 (m, 1H), 4.76 (m, 1H), 4.20-3.95 (m, 2H), 3.52-3.21 (m, 4H), 2.52-2.29 (m, 6H), 2.19-1.55 (m, 12H), 1.25 (s, 2H). ES-LCMS m/z 631 (M+H).
Example 606 2-methyl-1-r(1 R,5S)-8-(2-f1-r(1-methyl-1 H-1.2,3-triazol-5-yl)carbonvπ-4- phenylpiperidin-4-yl}ethv0-8-azabicvclo[3.2.11oct-3-yl1-1 H-benzimidazole
Figure imgf000375_0002
Method A (HATU). Acid precursor synthesized according to procedure outlined in J. Org. Chem. 41(6), 1041-51 (1976). 1H NMR (300 MHz, CDCI3) δ 7.75-7.62 (m, 2H), 7.46-7.11 (m, 8H), 4.67-4.53 (m, 1H), 4.16 (s, 3H), 3.85- 3.71 (m, 1H), 3.46-3.18 (m, H), 2.45-2.22 (m, 4H), 1.98-1.58 (m, 16H). ES- LCMS m/z 537(M+H). Example 607 (1R.5S)-8-(2-ri-(2.2-dimethylpropanovn-4-phenylρiperidin-4-vnethyll-3-(3- isopropyl-5-methyl-4H-1 ,2,4-triazol-4-yl)-8-azabicvclo[3.2.1loctane
Figure imgf000376_0001
Method A (HATU). Amine portion synthesized according to the procedure described in WO01109106A2, Pfizer Corp. 1H NMR (300 MHz, CDCI3) δ 7.44-7.20 (m, 5H), 4.53 (m, 1 H), 3.96-3.88 (m, 2H), 3.35-2.89 (m, 8H), 2.44 (s, 3H), 2.22-2.15 (m, 2H), 2.01-1.71 (m, 8H), 1.59-1.49 (m, 4H), 1.36 (d, 5H), 1.29 (s, 9H). ES-LCMS m/z 505(M+H).
Example 608 2-bromo-N-ethyl-5-r(4-(2-r(1 R.5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.11oct-8-yl1ethyl}-4-phenylpiperidin-1- vDcarbonyllbenzenesulfonamide
Figure imgf000376_0002
Method A (HATU). 1H NMR (300 MHz, CDCI3) δ 8.14 (s, 1H), 7.80 (d, 1 H), 7.68 (d, 1 H), 7.48-7.15 (m, 9H), 5.19 (m, 1 H), 4.63 (m, 1 H), 4.24 (m, 1 H), 3.57-3.49 (m, 1 H), 3.38-3.19 (m, 4H), 3.04-2.95 (m, 2H), 2.58 (s, 3H), 2.44- 2.33 (m, 3H), 2.22-2.17 (m, 1H), 1.95-1.75 (m, 10H), 1.61 (m, 2H), 1.12 (m, 3H). ES-LCMS m/z 717(M+H). Example 609 2-bromo-5-lϊ4-f2-lϊ1 R,5SK3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicvclof3.2.1loct-8-vnethyl)-4-phenyl piperidin-1-vOcarbonvH-N- propylbenzenesulfonamide
Figure imgf000377_0001
Method A (HATU). 1H NMR (300 MHz, CDCI3) δ 8.14 (s, 1 H), 7.80 (d, 1 H), 7.68 (d, 1 H), 7.48-7.15 (m, 9H), 5.22 (m, 1 H), 4.62 (m, 1 H), 4.26 (m, 1 H), 3.49 (m, 2H), 3.35-3.25 (m, 4H), 2.92-2.85 (m, 2H), 2.58 (s, 3H), 2.44-2.33 (m, 3H), 2.21-2.17 (m, 1 H), 1.95-1.75 (m, 10H), 1.61 (m, 2H), 1.52 (m, 2H), 0.89 (m, 3H). ES-LCMS m/z 731 (M+H).
Example 610 2-bromo-N-cvclopropyl-5-r.4-(2-lϊ1 R.5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicvclor3.2.11oct-8-vπethyll-4-phenylpiperidin-1 - vQcarbonyllbenzenesulfonamide
Figure imgf000377_0002
Method A (HATU). 1H NMR (300 MHz, CDCI3) δ 8.19 (s, 1 H), 7.79 (d, 1 H), 7.68 (d, 1 H), 7.51-7.16 (m, 9H), 5.68 (m, 1 H), 4.66 (m, 1 H), 4.20 (m, 1 H), 4.26 (m, 1 H), 3.54-3.27 (m, 5H), 2.58 (s, 3H), 2.41-2.36 (m, 3H), 2.17 (m, 2H), 1.95-1.75 (m, 10H), 1.64 (m, 2H), 0.68 (m, 4H). ES-LCMS m/z 729(M+H). Example 611 2-methyl-1 -K1 R.5S)-8-(2-f4-phenyl-1 -f(1 -phenyl-1 H-1 ,2,3-triazol-5- yl)carbonvnpiperidin-4-yl)ethvπ-8-azabicvclor3.2.noct-3-vn-1 H-benzimidazole
Figure imgf000378_0001
Method A (HATU). 1H NMR (300 MHz, CDCI3) δ 7.84 (s, 1 H), 7.70- 7.48 (m, 5H), 7.43-7.11 (m, 8H), 4.58 (m, 1H), 4.20-4.10 (m, 1 H), 3.22 (m, 4H), 3.01 (m, 1H), 2.40-2.23 (m, 3H), 1.96-1.60 (m, 15H), 1.26 (m, 2H). ES- LCMS m/z 599(M+H).
Example 612 2-methyl-1-((1 R,5S)-8-(2-r4-phenyl-1-(1 H-1 ,2,3-triazol-5-ylcarbonyl)piperidin- 4-vnethyl)-8-azabicvclor3.2.n oct-3-yl)-1 H-benzimidazole
Figure imgf000378_0002
Method A (HATU). 1H NMR (300 MHz, CDCI3) δ 8.13 (s, 1 H), 7.70 (d, 1H), 7.40-7.15 (m, 8H), 4.67 (m, 1H), 4.40 (m, 1H), 4.19 (m, 1H), 3.72 (m, 1H), 3.44-3.26 (m, 1H), 2.49-2.21 (m, 8H), 2.01-1.85 (m, 10H), 1.66 (m, 2H), 1.26 (s, 1 H). ES-LCMS m/z 523(M+H). Example 613 2-methyl-1 -f(1 R,5S)-8-(2-(4-phenyl-1 -[(3-phenyloxiran-2-yl)carbonyllpiperidin- 4-yllethvπ-8-azabicvclor3.2.noct-3-vn-1 H-benzimidazole
Figure imgf000379_0001
Method A (HATU). 1H NMR (300 MHz, CDCI3) δ 7.66 (m, 1 H), 7.38- 7.16 (m, 13H), 4.59 (m, 1 H), 4.08 (m, 1 H), 3.62 (m, 1 H), 3.24 (m, 2H), 2.59 (s, 3H), 2.55 (m, 1 H), 2.34 (m, 2H), 1.93-1.82 (m, 5H), 1.70-1.52 (m, 10H), 1.25 (s, 2H). ES-LCMS m/z 574(M+H).
Example 614 N-ethyl-2.4-difluoro-5-f(4-f2-[(1 R.5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicvclo[3.2.11oct-8-vnethyl}-4-phenylpiperidin-1- vDcarbonyllbenzenesulfonamide
Figure imgf000379_0002
Method A (HATU). 1H NMR (300 MHz, methanol-d4) δ 7.60-7.37 (m, 7H), 7.22 (m, 3H), 6.59 (d, 1H), 4.79 (m, 1H), 3.63 (m, 1H), 3.44 (m, 2H), 3.24 (m, 2H), 2.96 (m, 2H), 2.55 (s, 3H), 2.50-2.33 (m, 2H), 2.12-1.90 (m, 10H), 1.79 (m, 2H), 1.20 (m, 3H), 1.07 (m, 3H). ES-LCMS m/z 675(M+H). Example 615 2-methoxy-N-methyl-5-IY4-{2-r(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicvclor3.2.1loct-8-vnethyll-4-phenylpiperidin-1- vDcarbonvnbenzenesulfonamide
Figure imgf000380_0001
Method A (HATU). 1H NMR (300 MHz, methanol-d4) δ 7.90 (d, 1 H), 7.69 (d, 1 H), 7.56 (d, 1H), 7.48-7.37 (m, 5H), 7.32-7.19 (m, 4H), 4.78 (m, 1 H), 4.03 (s, 3H), 3.39-3.31 (m, 4H), 2.55 (d, 6H), 2.45 (m, 2H), 2.29 (m, 2H), 2.11- 1.82 (m, 10H), 1.73 (m, 2H), 1.30 (s, 3H). ES-LCMS m/z 655(M+H).
Example 616
N-ethyl-2-methoxy-5-r(4-(2-IT1 R.5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicvclo[3.2.11oct-8-yl1ethyll-4-phenylpiperidin-1 - vDcarbonyllbenzenesulfonamide
Figure imgf000380_0002
Method A (HATU). 1H NMR (300 MHz, methanol-d4) δ 7.91 (s, 1H), 7.68 (m, 1H), 7.52 (m, 1H), 7.48-7.36 (m, 5H), 7.32-7.19 (m, 4H), 4.76 (m, 1H), 4.03 (s, 3H), 3.39-3.31 (m, 4H), 2.94 (m, 2H), 2.55 (s, 3H), 2.48-2.39 (m, 4H), 2.09-1.88 (m, 10H), 1.71 (m, 2H), 1.30 (s, 3H), 1.05 (m, 3H). ES-LCMS m/z 669(M+H). Example 617 N-isopropyl-2-methoxy-5-r.4-(2-lϊ1 R.5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicvclo[3.2.11oct-8-vnethyl)-4-phenylpiperidin-1 - vDcarbonyllbenzenesulfonamide
Figure imgf000381_0001
Method A (HATU). 1H NMR (300 MHz, methanol-d4) δ 7.92 (d, 1H), 7.70 (m, 1H), 7.52 (m, 1 H), 7.43-7.36 (m, 5H), 7.32-7.13 (m, 4H), 4.75 (m, 1 H), 4.12 (m, 1 H), 4.03 (s, 3H), 3.66 (m, 1 H), 3.40-3.31 (m, 6H), 2.54 (s, 3H), 2.48-2.36 (m, 4H), 2.04-1.90 (m, 10H), 1.70 (m, 2H), 1.06 (d, 6H). ES-LCMS m/z 683(M+H).
Example 618 N-cvclopropyl-2-methoxy-5-f(4-(2-f(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)- 8-azabicvclo[3.2.1")oct-8-v-1 ethyl)-4-phenylpiperidin-1-vDcarbonyr|benzene sulfonamide
Figure imgf000381_0002
Method A (HATU). 1H NMR (300 MHz, methanol-d4) δ 7.95 (m, 1 H), 7.73 (m, 1 H), 7.52 (m, 1 H), 7.48-7.39 (m, 5H), 7.30-7.15 (m, 4H), 4.76 (m, 1 H), 4.17 (m, 1 H), 4.03 (s, 3H), 3.69 (m, 1 H), 3.40-3.31 (m, 6H), 2.54 (s, 3H), 2.48-2.36 (m, 4H), 2.21-1.90 (m, 10H), 1.71 (m, 2H), 0.55 (m, 4H). ES-LCMS m/z 681 (M+H). Example 619 2-chloro-5-IY4-(2-IT1 R.5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicvclor3.2.11oct-8-vnethyl)-4-phenylpiperidin-1 -vDcarbonyllaniline
Figure imgf000382_0001
Method A (HATU). 1H NMR (300 MHz, methanol-d4) δ 7.53 (m, 1 H),
7.41 (m, 5H), 7.27-7.17 (m, 4H), 6.82 (s, 1 H), 6.62 (d, 1 H), 4.74 (m, 1 H), 4.70 (m, 1 H), 3.66 (m, 1 H), 3.36-3.24 (m, 6H), 2.52 (s, 3H), 2.45-2.40 (m, 2H), 2.22 (m, 1H), 2.02-1.83 (m, 10H), 1.70 (m, 2H). ES-LCMS m/z 581 (M+H).
Example 620
N-(2-chloro-5-[(4-(2-r(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -ylV-8- azabicvclor3.2.11oct-8-vπethyl)-4-phenylpiperidin-1 - vPcarbonvπphenvDmethane sulfonamide
Figure imgf000382_0002
Method A (HATU). Intermediate 4-chloro-3-
[(methylsulfonyl)amino]benzoic acid was synthesized in same fashion as described in example 639 from precursor example 619. 1H NMR (300 MHz, methanol-d- δ 7.72-7.68 (m, 2H), 7.53 (m, 2H), 7.41 (m, 5H), 7.27-7.17 (m, 3H), 4.73 (m, 1 H), 4.14 (m, 1 H), 3.53 (m, 7H), 3.30 (m, 2H), 2.51 (s, 3H), 2.45-2.29 (m, 4H), 2.01-1.89 (m, 10H), 1.69 (m, 2H). ES-LCMS m/z 659(M+H). Example 621 1 -((1 R.5S)-8-(2-π -(2.6-dimethoxybenzoyl)-4-phenylpiperidin-4-vnethyl)-8- azabicvclof3.2.1 loct-3-yl)-2-methyl-1 H-benzimidazole
Figure imgf000383_0001
Acylation via EDCI-HOBt Method P using 2,6-dimethoxybenzoic acid (Aldrich) on 0.21 mmol scale yielded 50 mg (40%) product. 1H NMR (300 MHz, CDCI3) δ 7.68 (d, 1 H), 7.42-7.15 (m, 9H), 6.68-6.47 (m, 2H), 4.67 (m, 1 H), 4.23 (m, 1 H), 3.85 (s, 3H), 3.72 (s, 3H), 3.47-3.35 (m, 4H), 3.15-3.04 (m, 1H), 2.55 (s, 3H), 2.48-2.25 (m, 3H), 2.20-2.07 (m, 1 H), 2.03-1.72 (m, 10H), 1.65 (m, 2H). HRMS C37H44N4O3 m/z 593.3492 (M+H)Caι.. 593.3478 (M+H)obs-
Example 622 1 -((1 R,5S)-8-(2-π -(2,6-dimethylbenzovn-4-phenylpiperidin-4-vnethyl)-8- azabicvclo[3.2.1 loct-3-yl)-2-methyl-1 H-benzimidazole
Figure imgf000383_0002
Acylation via EDCI-HOBt Method P using 2,6-dimethylbenzoic acid (Aldrich) on 0.14 mmol scale yielded 53 mg (67%) product. 1H NMR (300 MHz, CDCI3) δ 7.87 (m, 1H), 7.51-6.97 (m, 11H), 5.51 (m, 2H), 4.22 (m, 1H), 4.05-3.88 (m, 2H), 3.50 (m, 1H), 3.28 (m, 1H), 3.09 (m, 3H), 2.82 (s, 3H), 2.62 (m, 1 H), 2.30 (s, 6H), 2.20-2.02 (m, 10H), 1.88 (m, 1 H), 1.71 (m, 1 H). HRMS C37H4 N4O m/z 561.3593 (M+H)Caι-. 561.3585 (M+H)0bs-
Example 623 3-chloro-2-[(4-{2-r(1 R,5SV3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicvclo[3.2.11oct-8-vnethyl)-4-phenylpiperidin-1-yl)carbonvnaniline
Figure imgf000384_0001
Acylation via EDCI-HOBt Method P using 2-amino-6-chlorobenzoic acid (Aldrich) on 0.14 mmol scale yielded 41 mg (50%) product. 1H NMR (300 MHz, CDCI3) δ 7.92 (m, 1 H), 7.58-7.25 (m, 8H), 7.07 (m, 1 H), 6.80-6.55 (m, 2H), 5.50 (m, 1 H), 4.26 (m, 5H), 3.99 (m, 3H), 3.50-3.29 (m, 2H), 3.25-3.09 (m, 1 H), 2.99 (m, 2H), 2.83 (s, 3H), 2.20-2.58 (m, 2H), 2.42-2.02 (m, 9H). HRMS C35H4oCIN5O m/z 582.3000 (M+H)Caι.. 582.3002 (M+H)0 s.
Example 624
1 -[(1 R.5S)-8-(2-f 1 -[(4,6-dimethylpyrimidin-5-yl)carbonyl1-4-phenylpiperidin-4- yl)ethyl)-8-azabicvclor3.2.noct-3-yll-2-methyl-1 H-benzimidazole
Figure imgf000384_0002
4,6-Dimethylpyrimidine-5-carboxylic acid was synthesized according to the procedure outlined in WO 00/66558, Schering Corporation, 2000, pages
67-69. Overall yield was 12% (3 steps).
Figure imgf000385_0001
Acylation via EDCI-HOBt Method P using 4,6-dimethylpyrimidine-5- carboxylic acid on 0.16 mmol scale yielded 46 mg (51%) of the product. 1H NMR (300 MHz, CDCI3) δ 8.92 (s, 1H), 7.55 (m, 1H), 7.43 (m, 5H), 7.20 (m, 3H), 4.88 (s, 1H), 4.74 (m, 1H), 4.27 (m, 1H), 3.51-3.07 (m, 5H), 2.54 (s, 6H), 2.50-2.20 (m, 7H), 2.05-1.84 (m, 9H), 1.69 (m, 2H). HRMS CasH^NeO m/z 563.3498 (M+H)Caι.. 563.3483 (M+H)0bs.
Example 625 N-((1 R,5S)-8-(2-π-(3.5-dichloroisonicotinovn-4-phenylpiperidin-4-yllethyll-8- azabicvclo[3.2.1loct-3-yl)-N-[(2Z,4Z)-hexa-2,4-dienyllethanimidamide
Figure imgf000385_0002
Acylation via EDCI-HOBt Method P using 4,6-dichloroisonicotinic acid (TCI America) on 0.16 mmol scale yielded 53 mg (55%) of the product. 1H NMR (300 MHz, CDCI3) δ 8.66 (s, 1H), 8.61 (s, 1H), 7.54 (d, 1H), 7.42 (m, 5H), 7.30-7.1 (m, 3H), 4.75 (m, 1H), 4.26 (m, 1H), 3.48-3.30 (m, 5H), 3.19 (m, 1 H), 2.54 (s, 3H), 2.45-2.26 (m, 4H), 2.10-1.84 (m, 10H), 1.71(m, 2H). HRMS C34H37CI2N5O m/z 602.2453 (M+H)Caι. 602.2476 (M+H)obs. Example 626 3-methyl-2-r(4-f2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicvclo[3.2.noct-8-vnethyl)-4-phenylpiperidin-1-vncarbonvnaniline
Figure imgf000386_0001
Acylation via EDCI-HOBt Method P using 2-amino-6-methylbrnzoic acid (Aldrich) on 0.1 6mmol scale yielded 39 mg (43%) of the product. 1H NMR (300 MHz, CDCI3) δ 7.55 (m, 1 H), 7.42 (m, 5H), 7.20 (m, 3H), 7.03 (m, 1 H), 6.70-6.53 (m, 2H), 4.88 (s, 3H), 4.74 (m, 1 H), 4.20 (m, 1 H), 3.55-3.26 (m, 3H), 2.27 (m, 2H), 2.10-1.84 (m, 10H), 1.71 (m, 2H), 1.30 (s, 1 H). HRMS C-36H43N5O m/z 562.3546 (M+H)Caι. 562.3544 (M+H)obs.
Example 627 ethyl 2-ethyl-2-IT4-f2-r(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicvclo[3.2.11oct-8-vπethylH-phenylpiperdin-1 -vDcarbonyllbutonate
Figure imgf000386_0002
Preparation of 2-(ethoxycarbonyl)-2-ethylbutanoic acid
Figure imgf000386_0003
A solution of diethyl-malonic acid diethyl ester (3.0 g, 13.89 mmol) and potassium hydroxide (0.778 g, 13.89 mmol) in ethanol (50 ml) was stirred at room temperature for 18 hrs. The solvent was evaporated off and the residue was dissolved in water (20 ml) and extracted with dichloromethane (20 ml). This organic layer was discarded. The aqueous layer was then acidified with concentrated HCl and extracted with dichloromethane (3 x 20 ml). The combined organic layers were dried over magnesium sulfate and concentrated to give a colorless oil (1.9 g, 72%). 1H NMR (300 MHz, methanol-d4) δ 4.17 (m, 2H), 1.89 (m, 4H), 1.25 (m, 3H), 0.83 (m, 6H). ES- LCMS m/z 188 (M+H).
Preparation of ethyl 2-ethyl-2-[(4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 - yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperdin-1-yl)carbonyl]butonate (example 627)
Acylation via EDCI-HOBt Method P using 2-(ethoxycarbonyl)-2- ethylbutanoic acid on 0.21 mmol scale yielded 115 mg (91 %) of colorless oil. H NMR (300 MHz, CDCI3) δ 7.88 (d, 1 H), 7.67 (m, 2H), 7.40-7.18 (m, 6H), 4.87 (m, 1 H), 4.75-4.40 (m, 2H), 4.22 (m, 3H), 3.41 (m, 2H), 3.12 (m, 2H), 2.55 (s, 3H), 2.45 (m, 1 H), 2.20-1.61 (m, 16H), 1.44 (s, 1 H), 1.21 (m, 3H), 0.92-0.70 (m, 6H). HRMS C37H50N4O3 m/z 599.3961 (M+H)Caι. 599.3981 (M+H)obs-
Example 628 ethyl 2,2-dimethyl-3-(4-(2-r(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicvclo[3.2.1 loct-8-vπethyl}-4-phenylpiperidin-1 -yl)-3-oxopropanoate
Figure imgf000387_0001
3-Ethoxy-2,2-dimethyl-3-oxopropanoic acid was prepared as in the case of diethyl dimethylmalonate on 15.96 mmol scale to give product as a colorless oil (1.8 g, 70%). 1H NMR (300 MHz, methanol-d4) δ 4.17 (m, 2H), 1.43 (s, 6H), 1.25 (m, 3H). ES-LCMS m/z 160 (M+H).
Figure imgf000388_0001
The ompound in example 628 was prepared via acylation (EDCI-HOBt Method P) using 3-ethoxy-2,2-dimethyl-3-oxopropanoic acid on 0.21 mmol scale, yielding 98 mg (82%) of the product as a colorless oil. 1H NMR (300 MHz, CDCI3) δ 7.69 (d, 1 H), 7.38 (m, 2H), 7.28 (m, 4H), 7.17 (m, 2H), 4.69 (m, 1H), 4.17 (m, 2H), 3.30 (m, 2H), 3.08 (m, 1H), 2.58 (s, 3H), 2.39 (m, 2H), 2.20 (m, 2H), 1.97-1.60 (m, 12H), 1.50-1.37 (m, 4H), 1.30-1.18 (m, 5H), 0.87 (m, 2H). HRMS C35H46N4O3 m/z 571.3648 (M+H)Caι. 571.3646 (M+H)0bs.
Example 629 ethyl 1 -r(4-{2-IT1 R.5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicvclo[3.2.11oct-8-yllethylH~phenylpiperidin-1 - vDcarbonyllcvclopropanecarboxylate
Figure imgf000388_0002
1-(Ethoxycarbonyl)cyclopropanecarboxylic acid was prepared as described in in case of diethyl 1 ,1-cyclopropanedicarboxylate on 16.13 mmol scale to give product as a colorless oil (2.1 g, 82%). 1H NMR (300 MHz, methanol-d4) δ 3.95 (m, 2H), 1.43 (s, 4H), 0.98 (m, 3H). ES-LCMS m/z 158 (M+H).
Figure imgf000388_0003
The compound in example 629 was prepared by acylation via EDCI- HOBt Method P using 1 -(ethoxy carbonyhcyclopropanecarboxylic acid on 0.21 mmol scale, yielding 82 mg (68%) product as a colorless oil. 1H NMR (300 MHz, CDCI3) δ 7.67 (m, 1 H), 7.45-7.10 (m, 8H), 4.62 (m, 1 H), 4.15 (m, 2H), 3.69 (m, 1 H), 3.26 (m, 4H), 2.58 (s, 3H), 2.44-2.15 (m, 5H), 1.97-1.76 (m, 10H), 1.63 (m, 2H), 1.45 (m, 3H), 1.35-1.16 (m, 5H). HRMS C35H44N4O3 m/z 569.3492 (M+H)Caι. 569.3503 (M+H)0bs.
Example 630 2-methyl-1 -((1 R.5S)-8-(2-r4-phenyl-1 -(pyrazin-2-ylcarbonyl)piperidin-4- vnethyl)-8-azabicvclor3.2.11oct-3-yl)-1 H-benzimidazole
Figure imgf000389_0001
The title compound was obtained by method A (HATU) using 2- pyrizinecarboxylic acid on 0.16 mmol scale. 1H NMR (300 MHz, CDCI3) δ 8.89 (s, 1 H), 8.59 (dd, 2H), 7.67 (m, 1 H), 7.45-7.10 (m, 8H), 4.61 (m, 1 H), 4.32-4.05 (m, 1H), 3.71 (m, 1H), 3.44-3.21 (m, 4H), 2.56 (s, 3H), 2.42-2.22 (m, 4H), 2.00-1.79 (m, 10H), 1.63 (m, 2H). ES-LCMS m/z 534(M+H).
Example 631 2-methyl-1-r(1R.5S)-8-(2-f1-rπ-methyl-1H-pyrrol-2-yl)carbonyll-4- phenylpiperidin-4-yl)ethvπ-8-azabicvclor3.2.noct-3-yll-1 H-benzimidazole
Figure imgf000390_0001
The title compound in example 631 was synthesized using method A (HATU) with 1 -methyl-1 H-pyrrole-2-carboxylic acid on 0.16 mmol scale. 1H NMR (300 MHz, CDCI3) δ 7.65 (d, 1H), 7.45-7.12 (m, 8H), 6.68 (s, 1H), 6.30 (d, 1 H), 6.08 (m, 1 H), 4.62 (m, 1 H), 4.04 (m, 2H), 3.76 (s, 3H), 3.44 (m, 2H), 3.26 (m, 2H), 2.57 (s, 3H), 2.44-2.18 (m, 4H), 2.03-1.78 (m, 10H), 1.63 (m, 2H). ES-LCMS m/z 535(M+H).
Example 632 2-methyl-1 -((1 R.5SV8 2-[4-phenyl-1 -(1 ,2.3-thiadiazol-4-ylcarbonvnpiperidin- 4-vπethyl)-8-azabicvclor3.2.πoct-3-vD-1 H-benzimidazole
Figure imgf000390_0002
The title compound in example 632 was synthesized using method A (HATU) utilizing 1 ,2,3-thiadiazole-4-carboxylic acid on 0.16 mmol scale. 1H NMR (300 MHz, CDCI3) δ 8.97 (m, 1 H), 7.72-7.51 (m, 1 H), 7.45-7.00 (m, 8H), 5.25 (m, 2H), 4.55 (m, 1 H), 4.21 (m, 2H), 3.68-3.09 (m, 4H), 2.60-2.20 (m, 5H), 2.02-1.72 (m, 10H), 1.53 (m, 2H). ES-LCMS m/z 540(M+H). Example 633 2-methyl-1 -[(1 R,5S)-8-(2-f 1 -r(2-methylpyridin-3-yl)carbonvπ-4-phenylpiperidin- 4-yl}ethvπ-8-azabicvclo[3.2.1loct-3-vn-1 H-benzimidazole
Figure imgf000391_0001
The title compound in example 633 was synthesized using method A (HATU) utilizing 2-methylnicotinic acid on 0.16 mmol scale. 1H NMR (300 MHz, CDCI3) δ 8.54 (d, 1 H), 7.65 (m, 1 H), 7.45-7.08 (m, 10H), 4.61 (m, 1 H), 4.28 (m, 1 H), 3.45-3.07 (m, 5H), 2.65-2.48 (m, 4H), 2.43-2.30 (m, 5H), 2.22- 2.03 (m, 2H), 1.97-1.77 (m, 8H), 1.63 (m, 2H). ES-LCMS m/z 547(M+H).
Example 634 2-methyl-1 -f(1 R,5S)-8-(2-{1 -[(6-methylpyridin-2-yl)carbonyll-4-phenylpiperidin- 4-yl)ethvπ-8-azabicvclo[3.2.11oct-3-vn-1 H-benzimidazole
Figure imgf000391_0002
The title compound in example 634 was synthesized using method A (HATU) utilizing 6-methylpyridine-2-carboxylic acid on 0.16 mmol scale. 1H NMR (300 MHz, CDCI3) δ 7.66 (m, 2H), 7.45-7.09 (m, 10H), 4.62 (m, 1 H), 4.22 (m, 1 H), 3.65 (m, 1 H), 3.50-3.20 (m, 4H), 2.56 (m, 6H), 2.36 (m, 3H), 2.17 (m, 1 H), 2.0-1.80 (m, 10H), 1.63 (m, 2H). ES-LCMS m/z 547(M+H). Example 635 1 -f(1 R.5S 8-(2-f 1 -rf2-fluoropyridin-3-vncarbonvn-4-phenylpiperidin-4-yl)ethyl)- 8-azabicvclor3.2.11oct-3-vn-2-methyl-1 H-benzimidazole
Figure imgf000392_0001
The title compound in example 635 was synthesized using method A (HATU) utilizing 2-fluoronicotinic acid on 0.16 mmol scale. 1H NMR (300 MHz, CDCIs) δ 8.28 (d, 1 H), 7.84 (m, 1 H), 7.68 (m, 1 H), 7.45-7.20 (m, 9H), 4.61 (m, 1 H), 4.27 (m, 1 H), 3.45-3.15 (m, 5H), 2.56 (s, 3H), 2.35 (m, 3H), 2.20 (m, 1 H), 1.98-1.73 (m, 10H), 1.67-1.5 5(m, 2H). ES-LCMS m/z 551 (M+H).
Example 636 1 -rd R.5S)-8-(2-f 1 -lϊ4-bromo-1 -ethyl-3-methyl-1 H-Pyrazol-5-yl)carbonyll-4- phenylpiperidin-4-yl)ethyl)-8-azabicvclo[3.2.1loct-3-vn-2-methyl-1H- benzimidazole
Figure imgf000392_0002
The title compound in example 636 was synthesized using method A (HATU) utilizing 4-bromo-1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid on 0.16 mmol scale. 1H NMR (300 MHz, CDCI3) δ 7.66 (d, 1 H), 7.50-7.05 (m, 8H), 4.64 (m, 1 H), 4.30-2.86 (m, 2H), 3.55 (m, 1 H), 3.40-3.28 (m, 4H), 2.58 (s, 3H), 2.37 (m, 3H), 2.25 (m, 3H), 2.12-1.78 (m, 10H), 1.65 (m, 2H), 1.46 (m, 2H), 1.33 (m, 3H). ES-LCMS m/z 642(M+H).
Example 637 2-methyl-1-( R,5S)-8-(2-r4-phenv]-1-(thien-3-ylcarbonyl)piperidin-4-vnethyl)- 8-azabicvclo[3.2.1 loct-3-yl)-1 H-benzimidazole
Figure imgf000393_0001
The title compound in example 637 was synthesized using method A (HATU) utilizing thiophene-3-carboxylic acid on 0.16 mmol scale. 1H NMR (300 MHz, CDCI3) δ 7.66 (d, 1 H), 7.54-7.20 (m, 11 H), 4.62 (m, 1 H), 4.15 (m, 1 H), 3.74 (m, 1 H), 3.42-3.20 (m, 4H), 2.57 (s, 3H), 2.45-2.12 (m, 4H), 2.05- 1.25 (m, 10H), 1.64 (m, 2H). ES-LCMS m/z 538(M+H).
Example 638 1-r R,5S)-8-(2-f1-r(3-bromothien-2-vncarbonyll-4-phenylpiperidin-4-yl)ethvn- 8-azabicvclor3.2.1loct-3-vn-2-methyl-1 H-benzimidazole
Figure imgf000393_0002
The title compound in example 638 was synthesized using method A (HATU) utilizing 3-bromothiophene-2-carboxylic acid on 0.16 mmol scale. 1H NMR (300 MHz, CDCI3) δ 7.68 (d, 1 H), 7.45-7.10 (m, 9H), 6.97 (d, 1H), 4.63 (m, 1 H), 4.15 (m, 1 H), 3.63 (m, 1 H), 3.37-3.28 (m, 4H), 2.57 (s, 3H), 2.48-2.22 (m, 4H), 2.05-1.80 (m, 10H), 1.65 (m, 2H). ES-LCMS m/z 616(M+H).
Example 639
Figure imgf000394_0001
N-{3-[(4-{2-[(1 R,5S)-3-(2-Methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1 ]oct-8-yl]ethyl}-4-phenylpiperidin-1 - yl)carbonyl]phenyl}methane sulfonamide was synthesized as in the following scheme.
Figure imgf000394_0002
tert-butyl 3-[(4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1 ]oct-8-yl]ethyl}-4-phenylpiperidin-1 - yl)carbonyl]phenylcarbamate was prepared by Method A (HATU) using 3- [(tetf-butoxycarbonyl)amino]benzoic acid on 1.64 mmol scale. Purification by reverse phase chromatography on C18 using Acetonitrile:water 10:90 to 90:10 and removal of solvent gave 635 mg of product (60%). ES-LCMS m/z 647(M+H).
Figure imgf000394_0003
3-[(4-{2-[(1R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1]oct-8- yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]phenylamine was obtained by dissolving of Boc-derivative coupling product in 20 ml dichloromethane and treatment with 2 ml of trifluoroacetic acid at room temperature for 2 hrs. Removal of solvent gave product in quantative yield. ES-LCMS m/z 547(M+H).
Figure imgf000395_0001
N-{3-[(4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1 ]oct-8-yl]ethyl}-4-phenylpiperidin-1 - yl)carbonyl]phenyl}methane sulfonamide was synthesized by dissolving the amine precursor (60 mg, 0.11 mmol) in 3 ml dichloromethane cooled to 0°C, followed by addition of 2 eq of Hunig base and methane sulfonyl chloride (12 mg, 0.11 mmol) and stirring overnight at room temperature. The solution was then diluted with DCM and washed with Na2CO3, dried organic layer with MgSO4 and rotovapped to dryness. Purified by reverse phase chromatography on C18 using Acetonitrile:water 10:90 to 90:10. Removal of solvent gave 38 mg (56%) of the product. 1H NMR (300 MHz, methanol-d4) δ 7.83 (m, 2H), 7.68-7.43 (m, 9H), 7.33 (m, 1 H), 5.34 (m, 1 H), 4.21-4.11 (m, 3H), 3.63 (m, 1 H), 3.46 (s, 3H), 3.38-3.27 (m, 4H), 2.97 (m, 2H), 2.85 (s, 3H), 2.79 (m, 2H), 2.46 (m, 3H), 2.29-2.19(m, 7H), 1.99-1.87 (m, 2H). ES-LCMS m/z 625(M+H).
Example 640 N-{4-[(4-{2-[(1 R,5S)-3-(2-Methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1- yl)carbonyl]phenyl}methane sulfonamide was synthesized similarly to the title compound in example 639.
Figure imgf000396_0001
Tert-butyl 4-[(4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1 ]oct-8-yl]ethyl}-4-phenylpiperidin-1 - yl)carbonyl]phenylcarbamate was prepared as described in example 639 using 4-[(tert-butoxycarbonyl)amino]benzoic acid to give 545 mg (53%) of product. ES-LCMS m/z 647(M+H).
Figure imgf000396_0002
4r[(4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1 ]oct-8- yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]phenylamine was prepared as in example 639. ES-LCMS m/z 547(M+H).
Figure imgf000396_0003
The title compound in example 640 (N-{4-[(4-{2-[(1 R,5S)-3-(2-methyl- 1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1- yl)carbonyl]phenyl}methanesulfonamide) was prepared as described for example 639 to give 28 mg (40%) of the title product of example 640. 1H NMR (300 MHz, methanol-d4) δ 7.85 (m, 2H), 7.66-7.41 (m, 10H), 7.33 (m, 1 H), 5.39 (m, 1 H), 4.21-4.09 (m, 3H), 3.63 (m, 1 H), 3.46 (s, 6H), 2.97-2.92 (m, 2H), 2.85 (s, 3H), 2.73( m, 2H), 2.46-2.37 (m, 3H), 2.24 (m, 7H), 1.97-1.90 (m, 2H). ES-LCMS m/z 625(M+H).
Example 641
Figure imgf000397_0001
2-[(4-{2-[(1 R,5S)-3-(2-Methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]-6- nitrophenylamine was synthesized by method B (Anhydride) using 4- nitroisatoic anhydride on 0.16 mmol scale. 1H NMR (300 MHz, methanol-d ) δ 7.80 (m, 1 H), 7.60 (m, 3H), 7.46 (m, 5H), 7.31-7.25 (m, 2H), 5.31 (m, 1 H), 4.20-4.10 (m, 2H), 3.52 (m, 1 H), 3.35-3.22 (m, 3H), 2.94 (m, 2H), 2.82 (s, 3H), 2.75 (m, 2H), 2.40 (m, 3H), 2.20 (m, 7H), 1.93-1.86 (m, 2H). ES-LCMS m/z 592(M+H).
Example 642
Figure imgf000397_0002
2-[(4-{2-[(1 R,5S)-3-(2-Methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]-5- nitrophenylamine was synthesized by method B (Anhydride) using 5- nitroisatoic anhydride on 0.16 mmol scale. 1H NMR (300 MHz, methanol-d4) δ 8.00 (d, 2H), 7.78 (m, 2H), 7.60 (m, 2H), 7.45 (m, 4H), 7.31 (m, 1H) 6.79 (d, 1 H), 5.30 (m, 1H), 4.10 (m, 2H), 3.40-3.22 (m, 4H), 2.94 (m, 2H), 2.81 (m, 3H), 2.75 (m, 2H), 2.45-2.14 (m, 10H), 1.92-1.90 (m, 2H). ES-LCMS m/z 592(M+H).
Example 643
Figure imgf000398_0001
2-Methyl-1-((1 R,5S)-8-{2-[4-phenyl-1-(1 H-1 ,2,4-triazol-3- ylcarbonyl)piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-1 H-benzimidazole was synthesized by method A (HATU) using 1H-1 ,2,4-triazole-3-carboxylic acid on 0.16 mmol scale. 1H NMR (300 MHz, CDCI3) δ 8.09 (s, 1H), 7.68 (m, 1 H), 7.45-7.11 (m, 8H), 4.93 (m, 1 H), 4.64 (m, 1 H), 4.21 (m, 1H), 3.83 (m, 1H), 3.37-3.25 (m, 2H), 2.37 (m, 3H), 2.05-1.81 (m, 7H), 1.78-1.55 (m, 11H). ES-LCMS m/z 523(M+H).
Example 644
Figure imgf000398_0002
2-Methyl-1-[(1 R,5S)-8-(2-{4-phenyl-1-[(1 -phenyl-1 H-1 ,2,4-triazol-3- yl)carbonyl]piperidin-4-yl}ethyl)-8-azabicyclo[3.2.1]oct-3-yl]-1 H-benzimidazole was synthesized by method A (HATU) using 1 -phenyl-1 H-1 , 2,4-triazole-3- carboxylic acid on 0.16 mmol scale. 1H NMR (300 MHz, CDCI3) δ 7.75-7.61 (m, 2H), 7.57-7.10 (m, 12H), 4.63 (m, 1H), 4.31 (m, 1H), 4.06 (m, 1 H), 3.55- 398
3.38 (m, 2H), 3.25 (m, 2H), 2.37 (m, 4H), 2.04-1.61 (m, 14H), 1.26 (m, 2H). ES-LCMS m/z 599(M+H).
Example 645
Figure imgf000399_0001
2-Bromo-N-methyl-5-[(4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)- 8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]benzene sulfonamide was obtained by method A (HATU) using acid 38 on 0.09 mmol scale. 1H NMR (300 MHz, CDCI3) δ 8.14 (s, 1H), 7.79 (d, 1H), 7.66 (d, 1H), 7.52-7.08 (m, 9H), 5.47 (m, 1H), 4.62 (m, 1H), 4.25 (m, 1H), 3.50 (m, 1H),
3.26 (m, 4H), 2.57 (s, 3H), 2.39 (m, 3H), 2.18 (m, 1H), 2.04-1.58 (m, 12H),
1.27 (s, 3H). ES-LCMS m/z 703(M+H).
Example 646
Figure imgf000399_0002
2-Bromo-N-isopropyl-5-[(4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 - yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]benzene sulfonamide was obtained by method A (HATU) using Acid 41 on 0.09 mmol scale. 1H NMR (300 MHz, CDCI3) δ 8.16 (s, 1H), 7.80 (d, 1H), 7.65 (d, 1H), 7.50-7.08 (m, 9H), 5.09 (m, 1H), 4.63 (m, 1H), 4.23 (m, 1H), 3.46 (m, 1H), 3.26 (m, 4H), 2.58 (s, 3H), 2.36 (m, 3H), 2.18 (m, 1 H), 2.00-1.75 (m, 10H), 1.65-1.58 (m, 2H), 1.12 (m, 6H). ES-LCMS m/z 731 (M+H). Example 647
Figure imgf000400_0001
2,4-Difluoro-5-[(4-{2-[(1R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]benzene sulfonamide was obtained by method A (HATU) using Acid 31 on 0.14 mmol scale. 1H NMR (300 MHz, CDCI3) δ 7.40 (m, 2H), 7.30-7.10 (m, 9H), 4.84 (m, 1H), 4.24 (m, 1 H), 3.40 (m, 2H), 2.98 (s, 3H), 2.30 (m, 5H), 2.15-1.72 (m, 12H). ES-LCMS m/z 647(M+H).
Example 648
Figure imgf000400_0002
2,4-Difluoro-5-[(4-{2-[(1R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]-N- propylbenzenesulfonamide was obtained by method A (HATU) using Acid 34 on 0.14 mmol scale. 1H NMR (300 MHz, CDCI3) δ 7.56 (m, 1H), 7.45-7.15 (m, 10H), 4.74 (m, 1H), 4.23 (m, 1H), 3.50-3.16 (m, 6H), 2.94 (m, 2H), 2.55 (s, 3H), 2.43 (m, 4H), 2.12-1.86 (m, 10H), 1.74 (m, 2H), 1.51 (m, 2H), 0.89 (m, 3H). ES-LCMS m/z 689(M+H). Example 649
Figure imgf000401_0001
2,4-Difluoro-N-isopropyl-5-[(4-{2-[(1 R,5S)-3-(2-methyl-1 H- benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1- yl)carbonyl] benzenesulfonamide was obtained by method A (HATU) using Acid 35 on 0.14 mmol scale. 1H NMR (300 MHz, CDCI3) δ 7.68 (m, 1H), 7.45- 7.15 (m, 9H), 7.00 (m, 1 H), 4.83 (m, 1H), 4.62 (m, 1 H), 4.28 (m, 1 H), 3.60- 3.18 (m, 6H), 2.58 (s, 3H), 2.44-2.15 (m, 4H), 2.00-1.76 (m, 10H), 1.62 (m, 2H), 1.13 (m, 6H). ES-LCMS m/z 689(M+H).
Example 650
Figure imgf000401_0002
N-Cyclopropyl-2,4-difluoro-5-[(4-{2-[(1 R,5S)-3-(2-methyl-1 H- benzimidazol-1-yl)-8-azabicyclo[3.2.1] oct-8-yl]ethyl}-4-phenylpiperidin-1- yl)carbonyl]benzene sulfonamide was obtained by Method A (HATU) using Acid 36 on 0.14 mmol scale. 1H NMR (300 MHz, CDCI3) δ 7.67 (m, 1H), 7.45- 7.22 (m, 8H), 7.10 (m, 2H), 4.61 (m, 1H), 4.24 (m, 1H), 3.36-3.24 (m, 5H), 2.57 (s, 3H), 2.29 (m, 5H), 1.95-1.60 (m, 10H), 1.62 (m, 2H), 1.25 (s, 4H). ES-LCMS m/z 687(M+H). Example 651
Figure imgf000402_0001
Ethyl 3-(4-(3-fluorophenyl)-4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol- 1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-1-yl)-2,2-dimethyl-3- oxopropanoate was obtained by Method A (HATU) using 3-ethoxy-2,2- dimethyl-3-oxopropanoic acid on 0.21 mmol scale. 1H NMR (300 MHz, methanol-d4) δ 7.55 (m, 1 H), 7.43 (m, 2H), 7.19 (m, 4H), 7.00 (m, 1 H), 4.72 (m, 1 H), 4.19 (m, 2H), 3.32 (m, 4H), 2.56 (s, 3H), 2.41 (m, 2H), 2.20 (m, 2H), 2.08-1.79 (m, 10H), 1.69 (m, 2H), 1.40 (s, 5H), 1.25 (m, 6H). ES-LCMS m/z 588(M+H).
Figure imgf000402_0002
Ethyl 1-[(4-(3-fluorophenyl)-4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol- 1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-1-yl)carbonyl]cyclopropane carboxylate was obtained by Method A (HATU) using 1 - (ethoxycarbonyl)cyclopropanecarboxylic acid on 0.21 mmol scale. 1H NMR (300 MHz, methanol-d4) δ 7.55 (m, 1H), 7.44 (m, 2H), 7.19 (m, 4H), 7.00 (m, 1H), 4.75 (m, 1H), 4.16 (m, 2H), 4.00 (m, 1H), 3.83 (m, 1H), 3.32 (m, 3H), 2.56 (s, 3H), 2.46 (m, 2H), 2.29 (m, 2H), 2.10-1.83 (m, 10H), 1.69 (m, 2H), 1.47 (s, 2H), 1.27 (m, 6H). ES-LCMS m/z 586(M+H). 402
Figure imgf000403_0001
Ethyl 1-[(4-(3-fluorophenyl)-4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol- 1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-1-yl)carbonyl]cyclobutane carboxylate was obtained by Method A (HATU) using 1 - (ethoxycarbonyl)cyclobutanecarboxylic acid on 0.21 mmol scale. 1H NMR (300 MHz, methanol-d4) δ 7.55 (m, 1H), 7.40 (m, 2H), 7.20 (m, 4H), 7.00 (m, 1 H), 4.74 (m, 1 H), 4.19 (m, 2H), 3.95 (m, 1 H), 3.32 (m, 5H), 3.04 (m, 1 H), 2.56 (s, 3H), 2.44 (m, 4H), 2.05-1.78 (m, 10H), 1.70 (m, 2H), 1.27 (m, 6H). ES-LCMS m/z 600(M+H).
Example 653B
Figure imgf000403_0002
Ethyl 2-ethyl-2-[(4-(3-fluorophenyl)-4-{2-[(1 R,5S)-3-(2-methyl-1 H- benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-1- yl)carbonyl]butanoate was obtained by Method A (HATU) using 2- (ethoxycarbonyl)-2-ethylbutanoic acid on 0.21 mmol scale. 1H NMR (300 MHz, CDCI3) δ 7.70 (d, 1 H), 7.33 (m, 3H), 7.07 (m, 4H), 4.64 (m, 1 H), 4.18 (m, 2H), 3.50 (m, 1H), 3.24 (m, 4H), 2.57 (s, 3H), 2.38 (m, 2H), 2.14 (m, 2H), 1.94-1.69 (m, 10H), 1.62 (m, 2H), 1.24 (m, 7H), 0.77 (m, 5H). ES-LCMS m/z 616(M+H). 403
Example 654 2-Chloro-5-[(4-(3-chlorophenyl)-4-(2-rd R.5S 3-(2-methyl-1 H-benzimidazol-1 - vn-8-azabicvclo[3.2.11oct-8-vπethyl}piperidin-1 - vDcarbonyllbenzenesulfonamide
Figure imgf000404_0001
A mixture of 1-((1 ,5S)-8-{2-[4-(3-chlorophenyl)piperidin-4-yl]ethyl}-8- azabicyclo[3.2.1] oct-3-yl)-2-methyl-1H-benzimidazole dihydrochloride (0.15 g, 0.32 mmol), 4-chloro-3-sulfamoylbenzoic acid (0.076 g, 0.32 mmol) and triethylamine (0.14 mL, 1 mmol) in dimethylformamide (1 mL) was treated with O-(7-azabenzotriazol-1-yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate (0.133 g, 0.35 mmol) and the resulting mixture was stirred for 1 h at rt. The mixture was diluted with water and the resulting precipitate was collected, washed with saturated sodium bicarbonate and water, dried and purified by chromatography on silica gel eluting with a 120:15:1 to 60:15:1 gradient of chloroform:methanol:ammonium hydroxide to give 2-chloro-5-[(4-(3- chlorophenyl)-4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-1-yl)carbonyl]benzenesulfonamide as a white solid (0.052 g, 24%). 1H NMR (400 MHz, CD3OD3) δ 8.09 (s, 1 H), 7.90 (s, 1 H), 7.69 (m, 1 H), 7.62 (m, 1 H), 7.53 (m, 1 H), 7.38-7.46 (m, 3H), 7.27-7.38 (m, 1H), 7.17-7.20 (m, 2H), 4.74 (m, 1H), 4.11 (m, 1H), 3.58 (m, 2H), 3.40 (m, 2H), 3.16-3.22 (m, 1H), 2.54 (s, 3H), 2.41-2.49 (m, 2H), 2.33- 2.38 (m, 1 H), 2.20-2.26 (m, 1H), 1.94-2.12 (m, 10H), 1.68-1.74 (m, 2H). HRMS C35H39CI2N5O3S /z 680.2229 (M+H)Caι.. 680.2239 (M+H)0bs, Example 655 1 -((1 R.5S 8-f2-π -(2,2-Dimethylpropanovn-4-(2-methylphenvnpiperidin-4- vπethyl}-8-azabicvclor3.2.11oct-3-v0-2-methyl-1 H-benzimidazole
Figure imgf000405_0001
Tert-butyl 4-(1-cyano-2-ethoxy-2-oxoethyl)-4-(2- methylphenyl)piperidine-1-carboxylate. Using the same procedure as in Example 16b 1-bromo-2-methylbenzene (5.1 g, 30 mmol) was used in place of 1-chloro-3-iodobenzene to give tert-butyl 4-(1-cyano-2-ethoxy-2-oxoethyl)- 4-(2-methylphenyl)piperidine-1 -carboxylate as an oil that was used without further purification.
[1-(tert-Butoxycarbonyl)-4-(2-methylphenyl)piperidin-4-yl](cyano)acetic Acid. tert-Butyl 4-(1-cyano-2-ethoxy-2-oxoethyl)-4-(2- methylphenyl)piperidine-1 -carboxylate was hydrolysed using the same procedure as in Example 16c to give [1 -(fert-butoxycarbonyl)-4-(2- methylphenyl) piperidin-4-yl](cyano)acetic acid as an amber foam that was used without further purification. tert-Butyl 4-(Cyanomethyl)-4-(2-methylphenyl) piperidine-1 -carboxylate. [1-(te/f-Butoxycarbonyl)-4-(2-methylphenyl)piperidin-4-yl](cyano)acetic acid was subjected to the same decarboxylation conditions used in Example 16d and purified by chromatography on silica gel eluting with a 1 :9 to 1 :1 ethyl acetate:hexane gradient to give tert-butyl 4-(cyanomethyl)-4-(2- methylphenyl)piperidine-1 -carboxylate as a solid (2.4 g, 76% overall yield). 1H NMR (400 MHz, CDCI3) δ 7.33 (m, 1H), 7.19 (m, 3H), 3.72 (m, 2H), 3.15 (m, 2H), 2.76 (s, 2H), 2.50-2.55 (m, 2H), 2.48 (s, 3H), 1.93 (m, 2H), 1.44 (s, 9H). ES-LCMS m/z 337 (M+23). tert-Butyl 4-(2-methylphenyl)-4-(2-oxoethyl)piperidine-1 -carboxylate. Using the same procedure as in Example 16e using tert-butyl 4- (cyanomethyl)-4-(2-methylphenyl) piperidine-1 -carboxylate (2.4 g, 7.5 mmol) gave tert-butyl 4-(2-methylphenyl)-4-(2-oxoethyl)piperidine-1 -carboxylate as a foam (1.6 g, 69%). 1H NMR (400 MHz, CDCI3) δ 9.32 (t, 1 H), 7.31 (m, 1 H), 7.18 (m, 3H), 3.51-3.58 (m, 2H), 3.37-3.44 (m, 2H), 2.83 (s, 2H), 2.53 (s, 3H), 2.33 (m, 2H), 1.96 (m, 2H), 1.44 (s, 9H). ES-LCMS m/z 340 (M+23). tert-Butyl 4-{2-[3-(2-Methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-(2-methylphenyl)piperidine-1-carboxylate. Using the same procedure as in Example 16f using tert-butyl 4-(2- methylphenyl)-4-(2-oxoethyl)piperidine-1 -carboxylate (1.6 g, 5 mmol) gave tert-butyl 4-{2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1]oct-8- yl]ethyl}-4-(2-methylphenyl)piperidine-1 -carboxylate as a solid (2.5 g, 94%). 1H NMR (400 MHz, CDCI3) δ 7.67 (m, 1H), 7.13-7.32 (m, 7H), 4.63 (m, 1H), 3.61 (m, 2H), 3.28 (m, 4H), 2.88 (m, 2H), 2.59 (s, 3H), 2.54 (s, 3H), 2.34-2.40 (m, 4H), 1.82-1.96 (m, 8H), 1.63 (m, 2H), 1.44 (s, 9H). ES-LCMS m/z 543 (M+1).
2-Methyl-1-(8-{2-[4-(2-methylphenyl) piperidin-4-yl]ethyl}-8- azabicyclo[3.2.1]oct-3-yl)-1 H-benzimidazole Dihydrochloride. Using the same procedure as in Example 16g using tert-butyl 4-{2-[3-(2-methyl-1H- benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-(2- methylphenyl)piperidine-1 -carboxylate (2.5 g, 4.6 mmol) gave 2-methyl-1-(8- {2-[4-(2-methylphenyl)piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1] oct-3-yl)-1 H- benzimidazole dihydrochloride as a solid (2.2 g, 100%). 1H NMR (400 MHz, DMSO-de) δ 11.28 (s, 1 H), 9.02 (m, 2H), 7.89 (m, 1 H), 7.80 (m, 1 H), 7.55 (m, 2H), 7.20 (m, 4H), 6.05 (m, 1H), 4.11 (m, 2H), 3.26 (m, 2H), 3.05 (m, 1H), 2.88 (s, 4H), 2.81 (m, 3H), 2.53 (s, 3H), 2.33 (m, 2H), 2.13-2.23 (m, 8H), 2.08 (m, 2H). ES-LCMS m/z 443 (M+1).
1-((1R,5S)-8-{2-[1-(2,2-Dimethylpropanoyl)-4-(2- methylphenyl)piperidin-4-yl]ethyl}-8-azabicyclo [3.2.1]oct-3-yl)-2-methyl-1 H- benzimidazole (example 655). A mixture of 2-methyl-1 -(8-{2-[4-(2- methylphenyl)piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1] oct-3-yl)-1 H- benzimidazole dihydrochloride (0.15 g, 0.31 mmol), triethylamine (0.087 mL, 0.62 mmol) and trimethylacetyl chloride (0.043 mL, 0.34 mmol) in O 2004 0
406
dichloromethane (3 mL) was stirred at rt for 1h. The reaction mixture was diluted with dichloromethane, washed with saturated sodium bicarbonate solution, dried, concentrated and purified by chromatography on silica gel eluting with 33:1 dichloromethane:methanol to give 1-((1R,5S)-8-{2-[1-(2,2- dimethylpropanoyl)-4-(2-methylphenyl)piperidin-4-yl]ethyl}-8-azabicyclo [3.2.1]oct-3-yl)-2-methyl-1 H-benzimidazole as a white solid (0.073 g, 45%). 1H NMR (400 MHz, CDCI3) δ 7.67 (m, 1H), 7.13-7.31 (m, 7H), 4.62 (m, 1H), 3.86 (m, 2H), 3.48 (m, 2H), 3.24 (m, 2H), 2.56 (m, 6H), 2.34 (m, 4H), 1.93 (m, 8H), 1.60 (m, 4H), 1.27 (s, 9H). HRMS C34H46N4O m/z 527.3750 (M+H)Caι., 527.3749 (M+H)obs,
Example 656 2-Chloro-5 1442-111 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicvclo 3.2.11oct-8-vπethyl}-4-(2-methylphenyl)piperidin-1 - yl]carbonyl}benzenesulfonamide
Figure imgf000407_0001
A mixture of 2-methyl-1-(8-{2-[4-(2-methylphenyl)piperidin-4-yl]ethyl}-8- azabicyclo[3.2.1]oct-3-yl)-1 H-benzimidazole dihydrochloride (0.30 g, 0.63 mmol), 4-chloro-3-sulfamoylbenzoic acid (0.15 g, 0.63 mmol) and triethylamine (0.3 mL, 2 mmol) in dimethylformamide (2 mL) was treated with O-(7-azabenzotriazol-1-yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate (0.26 g, 0.69 mmol) and the resulting mixture was stirred for 1 h at rt. The mixture was diluted with water and the resulting precipitate was collected, washed with saturated sodium bicarbonate solution and water, dried and purified by chromatography on silica gel eluting with a gradient of 310:15:1 to 200:15:1 of chloroform:methanol:ammonium hydroxide to give 2-chloro-5-{[4- {2-[(1R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1]oct-8- O 2004/05497
407
yl]ethyl}-4-(2-methylphenyl)piperidin-1 -yljcarbonyljbenzenesulfonamide as a white solid (0.089 g, 21%). 1H NMR (400 MHz, CD3OD) δ 8.08 (s, 1H), 7.68 (m, 1H), 7.60 (m, 1H), 7.52 (m, 1H), 7.41 (m, 1H), 7.33 (m, 1H), 7.13-7.21 (m, 5H), 4.75 (m, 1 H), 4.08 (m, 1H), 3.49 - 3.58 (m, 2H), 3.31 (m, 5H), 2.55 (m, 7H), 2.46 (m, 3H), 1.90-2.09 (m, 10H), 1.65 (m, 2H). HRMS C36H42CIN5O3S m/z 660.2775 (M+H)Caι.. 660.2764 (M+H)0bs,
Example 657 Methyl 3-f 14-12-1/1 R,5S)-3-(2-Methyl-1 H-benzimidazol-1 -yl)-8- azabicvclor3.2.11oct-8-vπethyl)-4-(2-methylphenyl)piperidin-1 - yllcarbonyllbenzoate
Figure imgf000408_0001
A mixture of 2-methyl-1-(8-{2-[4-(2-methyl phenyl)piperidin-4-yl]ethyl}- 8-azabicyclo[3.2.1]oct-3-yl)-1 H-benzimidazole dihydrochloride (0.40 g, 0.84 mmol), monomethyl isophthalate (0.15 g, 0.84 mmol) and triethylamine (0.4 mL, 2.9 mmol) in dimethylformamide (3 mL) was treated with O-(7- azabenzotriazol-1-yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate (0.35 g, 0.92 mmol) and stirred at rt for 1 h. The mixture was diluted with water and the resultant precipitate was collected, washed with water, dried and purified by chromatography on silica gel eluting with 1 :33 methanol:dichloromethane to give methyl 3-{[4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-(2-methylphenyl) piperidin-1- yl]carbonyl}benzoate as a glass (0.240 g, 47%). H NMR (400 MHz, CDCI3) δ 8.08 (m, 2H), 7.67 (m, 2H), 7.59 (m, 1H), 7.49 (t, 1 H), 7.13-7.29 (m, 6H), 4.62 (m, 1H), 4.11 (m, 1H), 3.93 (s, 3H), 3.56 (m, 2H), 3.26 (m, 2H), 2.54 (m, 5H), 2.36 (m, 4H), 1.95 (m, 10H), 1.64 (m, 4H). HRMS C38H44N4O3 m/z 605.3492 (M+H)Cai. 605.3497 (M+H)0bs, O 2004 0
408
Example 658 3-{r4-(2-IT1R.5S)-3-(2-Methv--1 H-benzimidazol-1 -yl)-8-azabicvclo[3.2.11oct-8- vπethyl)-4-C2-methylphenvπpiperidin-1-vncarbonyl}benzoic Acid
Figure imgf000409_0001
A solution of methyl 3-{[4-{2-[(1R,5S)-3-(2-methyl-1 H-benzimidazol-1 - yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-(2-methylphenyl)piperidin-1-yl]carbonyl} benzoate (0.15 g, 0.29 mmol) in methanol (1 mL) was treated with 2N sodium hydroxide solution (1.5 mL) and let stir at rt for 4 h. The mixture was concentrated to remove methanol and acidified by adding 1 N hydrochloric acid. The resulting precipitate was collected, washed with water and dried to give 3-{[4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-(2-methylphenyl) piperidin-1- yl]carbonyl}benzoic acid as a pale pink solid (0.04 g, 31%). 1H NMR (400 MHz, CD3OD) δ 8.11 (m, 1 H), 8.02 (s, 1 H), 7.54 (m, 3H), 7.48 (m, 1H), 7.34 (m, 1H), 7.17-7.28 (m, 5H), 5.08 (m, 1H), 4.07 (m, 1H), 3.87 (m, 2H), 3.54 (m, 2H), 3.30 (m, 1 H), 2.71 (m, 2H), 2.39-2.55 (m, 10H), 2.22-2.30 (m, 6H), 2.09 (m, 3H), 1.92 (m, 1H). HRMS C37H42N4O3 m/z 591.3335 (M+H)Ca... 591.3350 (M+H)obs..
Example 659 1-(dR.5S)-8-f2-r4-d .3-Benzodioxol-5-yl)-1-(2.2-dimethylpropanovnpiperidin- 4-vπethylV-8-azabicvclor3.2.11oct-3-yl)-2-methyl-1 H-benzimidazole
Figure imgf000410_0001
tert-Butyl 4-(1,3-benzodioxol-5-yl)-4-(1-cyano-2-ethoxy-2- oxoethyl)piperidine-1-carboxylate. Using the same procedure as in Example 16b 4-bromo-1 ,2-(methylenedioxy)benzene (10.2 g, 51 mmol) was used in place of 1-chloro-3-iodobenzene and purified by chromatography on silica gel eluting with a 1 :9 to 1 :2 ethyl acetate:hexane gradient to give tert-butyl 4-(1 ,3- benzodioxol-5-yl)-4-(1 -cyano-2-ethoxy-2-oxoethyl)piperidine-1 -carboxylate as a foam (4.6 g, 65%). 1H NMR (400 MHz, CDCI3) δ 6.80 (m, 3H), 5.96 (s, 2H), 4.01 (m, 2H), 3.90 (m, 2H), 3.53 (s, 1 H), 2.88 (m, 2H), 2.41-2.51 (m, 2H), 1.94-2 02 (m, 2H), 1.43 (s, 9H), 1.08 (t, 3H). ES-LCMS m/z 415 (M-1). [4-(1,3-Benzodioxol-5-yl)-1-(tert-butoxycarbonyl)piperidin-4- yl](cyano)acetic Acid. tert-Butyl 4-(1 ,3-benzodioxol-5-yl)-4-(1-cyano-2-ethoxy- 2-oxoethyl)piperidine-1 -carboxylate (4.6 g, 11 mmol) was hydrolysed using the same procedure as in Example 16c to give [4-(1 ,3-benzodioxol-5-yl)-1- (tert-butoxycarbonyl)piperidin-4-yl](cyano)acetic acid as an amber foam (4.2 g, 100%). 1H NMR (400 MHz, CDCI3) δ 6.82 (m, 3H), 5.97 (s, 2H), 3.88 (m, 2H), 3.55 (s, 1 H), 2.88 (m, 2H), 2.48 (m, 2H), 1.89-2.03 (m, 2H), 1.41 (s, 9H). ES-LCMS m/z 387 (M-1). tert-Butyl 4-(1 ,3-benzodioxol-5-yl)-4-(cyano methyl) piperidine-1 - carboxylate. [4-(1 ,3-Benzodioxol-5-yl)-1 -(tert-butoxycarbonyl)piperidin-4- yl](cyano) acetic acid (4.2 g, 11 mmol) was subjected to the same decarboxylation conditions used in Example 16d and purified by chromatography on silica gel eluting with a 1 :9 to 1 :2 ethyl acetate:hexane gradient to give tert-butyl 4-(1 ,3-benzodioxol-5-yl)-4-(cyanomethyl) piperidine- 1 -carboxylate as a foam (2.9 g, 80%). 1H NMR (400 MHz, CDCI3) δ 6.82 (m, 3H), 5.97 (s, 2H), 3.74 (m, 2H), 3.07 (m, 2H), 2.50 (s, 2H), 2.21 (m, 2H), 1.76- 1.83 (m, 2H), 1.43 (s, 9H). ES-LCMS m/z 245 (M-99). tert-Butyl 4-(1 ,3-benzodioxol-5-yl)-4-(2-oxoethyl)piperidine-1 - carboxylate. Using the same procedure as in Example 16e tert-butyl 4-(1 ,3- benzodioxol-5-yl)-4-(cyanomethyl)piperidine-1 -carboxylate (2.9 g, 8.6 mmol) gave tert-butyl 4-(1 ,3-benzodioxol-5-yl)-4-(2-oxoethyl)piperidine-1 -carboxylate (2.0 g, 69%). 1H NMR (400 MHz, CDCI3) δ 9.39 (t, 1 H), 6.79-6.84 (m, 3H), 5.96 (s, 2H), 3.57-3.63 (m, 2H), 3.21-3.27 (m, 2H), 2.58 (s, 2H), 2.10-2.16 (m, 2H), 1.77-1.84 (m, 2H), 1.43 (s, 9H). tert-Butyl 4-(1 ,3-benzodioxol-5-yl)-4-{2-[3-(2-methyl-1 H-benzimidazol- 1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}piperidine-1 -carboxylate. Using the same procedure as in Example 16f tert-butyl 4-(1 ,3-benzodioxol-5-yl)-4-(2- oxoethyl)piperidine-1 -carboxylate (2.0 g, 5.8 mmol) gave tert-butyl 4-(1 ,3- benzodioxol-5-yl)-4-{2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}piperidine-1 -carboxylate after chromatography on silica gel eluting with a dichloromethane to 1 :9 methanol:dichloromethane gradient as a foam (2.4 g, 73%). 1H NMR (400 MHz, CDCI3) δ 7.66 (m, 1 H), 7.28 (m, 1H), 7.12-7.20 (m, 2H), 6.79 (m, 2H), 6.72 (m, 1H), 5.96 (s, 2H), 4.64 (m, 2H), 3.63 (m, 2H), 3.30 (m, 2H), 3.19 (m, 4H), 2.60 (s, 3H), 2.43 (m, 2H), 1.71-2.08 (m, 11H), 1.44 (s, 9H). ES-LCMS m/z 573 (M+1).
1-(8-{2-[4-(1,3-Benzodioxol-5-yl)piperidin-4-yl]ethyl}-8- azabicyclo[3.2.1]oct-3-yl)-2-methyl-1 H-benzimidazole dihydrochloride. Using the same procedure as in Example 16g tert-butyl 4-(1 ,3-benzo-dioxol-5-yl)-4- {2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1 ]oct-8- yl]ethyl}piperidine-1 -carboxylate (2.4 g, 4.2 mmol) gave 1-(8-{2-[4-(1 ,3- benzodioxol-5-yl)piperidin-4-yl]ethyl}-8-azabicyclo [3.2.1]oct-3-yl)-2-methyl- 1 H-benzimidazole dihydro-chloride as a solid (2.1 g, 100%). 1H NMR (400 MHz, DMSO-d6) δ 11.22 (s, 1 H), 9.06-9.13 (m, 2H), 7.88 (m, 1H), 7.80 (m, 1 H), 7.56 (m, 2H), 7.02 (s, 1 H), 6.91 (m, 1 H), 6.82 (m, 1 H), 6.02 (s, 2H), 4.07 (m, 2H), 3.19 (m, 2H), 2.88 (s, 3H), 2.78-2.83 (m, 4H), 2.52 (m, 2H), 1.95- 2.26 (m, 11 H). ES-LCMS m/z 473 (M+1).
Title compound in example 659. A mixture of 1-(8-{2-[4-(1 ,3- benzodioxol-5-yl)piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H- benzimidazole dihydrochloride (0.2 g, 0.39 mmol), triethylamine (0.11 mL, 0.78 mmol) and trimethylacetyl chloride (0.053 mL, 0.43 mmol) in dichloromethane (4 mL) was stirred at rt for 1 h before the reaction mixture was quenched with saturated sodium bicarbonate solution. The organic layer was separated, dried and concentrated to give 1-((1 R,5S)-8-{2-[4-(1 ,3- benzodioxol-5-yl)-1-(2,2-dimethylpropanoyl)piperidin-4-yl]ethyl}-8-azabicyclo [3.2.1]oct-3-yl)-2-methyl-1 H-benzimidazole as a foam (0.18 g, 82%). 1H NMR (400 MHz, CDCI3) δ 7.81 (m, 1 H), 7.29 (m, 3H), 6.83 (m, 2H), 6.75 (m, 1 H), 6.21 (m, 1H), 6.00 (s, 2H), 3.95 (m, 2H), 3.84 (m, 2H), 3.38 (m, 2H), 2.98 (m, 2H), 2.86 (s, 3H), 2.56 (m, 2H), 2.31 (m, 4H), 2.07-2.21 (m, 4H), 1.82 (m, 4H), 1.26 (s, 9H). HRMS C^H Ws m/z 557.3492 (M+H)Caι., 557.3495 (M+H)0bs,
Example 660 5-r(4-d .3-Benzodioxol-5-yl)-4-f2-fd R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)- 8-azabicvclo[3.2.noct-8-yl1ethyl)piperidin-1-yl)carbonyl1-2-chlorobenzene sulfonamide
Figure imgf000412_0001
A mixture of 1-(8-{2-[4-(1 ,3-benzodioxol-5-yl)piperidin-4-yl]ethyl}-8- azabicyclo[3.2.1]oct-3-yl)-2-methyl-1 H-benzimidazole dihydrochloride (0.40 g, 0.78 mmol), triethylamine (0.35 mL, 2.5 mmol) and 4-chloro-3- sulfamoylbenzoic acid (184 mg, 0.78 mmol) in dimethylformamide (2.5 mL) was treated with O-(7-azabenzotriazol-1-yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate (327 mg, 0.86 mmol) and the resulting mixture was stirred for 1 h at rt. The mixture was diluted with water and the resulting precipitate was collected, washed with saturated sodium bicarbonate solution and water, dried and purified by chromatography on silica gel eluting with a chloroform:methanol:ammonium hydroxide 400:15:1 to 200:15:1 gradient to give 5-[(4-(1 ,3-benzodioxol-5-yl)-4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol- 1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-1-yl) carbonyl]-2- chlorobenzenesulfonamide as a solid (0.09 g, 17%). 1H NMR (400 MHz, CDsOD) δ 8.08 (s, 1H), 7.67 (m, 1H), 7.59 (m, 1H), 7.51 (m, 1H), 7.41 (m, 1H), 7.17 (m, 2H), 6.94 (s, 1H), 6.81-6.86 (m, 2H), 5.93 (s, 2H), 4.74 (m, 1H), 4.11 (m, 1H), 3.52 (m, 1H), 3.30 (m, 4H), 2.52 (s, 3H), 2.44 (m, 2H), 2.39 (m, 1H), 2.18 (m, 1H), 1.80-2.04 (m, 12H), 1.70 (m, 2H). HRMS C36H40CIN5O5 m/z 690.2517 (M+H)Caι., 690.2538 (M+H)obs..
Example 661 1-rdR,5S)-8-(2-d-Benzyl-4-r3-(trifluoromethyl)phenvn piperidin-4-yl)ethyl)-8- azabicyclor3.2.noct-3-vn-2-methyl-1 H-benzimidazole
Figure imgf000413_0001
The following compounds were prepared according to the procedures in Example 16. Ethyl (1-Benzylpiperidin-4-ylidene)(cyano)acetate. Using the same procedure as in Example 16a 1-benzylpiperidin-4-one (47.3 g, 0.25 mol) was used in place of tert-butyl 4-oxo-1 -piperidine carboxylate to give ethyl (1- benzylpiperidin-4-ylidene)(cyano)acetate as a solid (72.2 g, 100%). 1H NMR (400 MHz, CDCI3) δ 7.25-7.35 (m, 5H), 4.26 (q, 2H), 3.54 (s, 2H), 3.14 (m, 2H), 2.78 (m, 2H), 2.64 (m, 2H), 2.59 (m, 2H), 1.33 (t, 3H). ES-LCMS m/z 283 (M-1).
Ethyl {1-Benzyl-4-[3-(trifluoromethyl)phenyl] piperidin-4- yl}(cyano)acetate. Using the same procedure as in Example 16b 3- bromobenzotrifluoride (20.2 g, 0.09 mol) was used in place of 1-chloro-3- iodobenzene to give ethyl {1 -benzyl-4-[3-(trifluoro methyl)phenyl]piperidin-4- yl}(cyano)acetate as a solid (5.6 g, 37%). 1H NMR (400 MHz, CDCI3) δ 7.51- 7.63 (m, 4H), 7.22-7.35 (m, 5H), 3.92 (m, 2H), 3.69 (s, 1 H), 3.40 (s, 2H), 2.67 (m, 2H), 2.51 (m, 2H), 2.18-2.29 (m, 4H), 0.99 (t, 3H). ES-LCMS m/z 431 (M+1).
{1 -Benzyl-4-[3-(trifluoromethyl)phenyl] piperidin-4-yl}(cyano)acetic Acid. Ethyl {1-benzyl-4-[3-(trifluoromethyl)phenyl]piperidin-4-yl}(cyano) acetate (5.6 g, 0.013 mol) was hydrolysed using the same procedure as in Example 16c to give an amber foam (5.2 g, 100%) that was used without further purification. {1-Benzyl-4-[3-(trifluoromethyl)phenyl] piperidin-4-yl}acetonitrile. {1 - Benzyl-4-[3-(trifluoromethyl)phenyl]piperidin-4-yl}(cyano)acetic acid (5.2 g, 0.013 mol) was subjected to the same decarboxylation conditions used in Example 16d and purified by column chromatography on silica gel eluting with 1:1 hexane:ethyl acetate to give {1-benzyl-4-[3-
(trifluoromethyl)phenyl]piperidin-4-yl}acetonitrile as a solid (2.9 g, 63%). 1H NMR (400 MHz, CDCI3) δ 7.51-7.58 (m, 4H), 7.25-7.36 (m, 5H), 3.49 (s, 2H), 2.60 (m, 4H), 2.35 (m, 4H), 2.10 (s, 2H). ES-LCMS m/z 359 (M+1).
{1-Benzyl-4-[3-(trifluoromethyl)phenyl] piperidin-4-yl}acetaldehyde. Using the same procedure as in Example 16e {1-benzyl-4-[3-(trifluoromethyl) phenyl]piperidin-4-yl}acetonitrile (2.4 g, 6.7 mmol) gave {1-benzyl-4-[3- (trifluoromethyl)phenyl]piperidin-4-yl}acetaldehyde as a tan foam (2.0 g, 83%). 1H NMR (400 MHz, CDCI3) δ 9.38 (t, 1H), 7.48-7.60 (m, 4H), 7.25-7.32 (m, 5H), 3.45 (s, 2H), 2.70 (s, 2H), 2.56 (m, 2H), 2.38 (m, 2H), 2.25 (m, 2H), 2.01 (m, 2H). ES-LCMS m/z 360 (M-1).
Title compound in example 661: 1-[(1R,5S)-8-(2-{1-Benzyl-4-[3- (trifluoromethyl)phenyl]piperidin-4-yl}ethyl)-8-azabicyclo[3.2.1]oct-3-yl]-2- methyl-1 H-benzimidazole. Using the same procedure as in Example 16f {1 - benzyl-4-[3-(trifluoromethyl)phenyl]piperidin-4-yl}acetaldehyde (0.23 g, 0.64 mmol) was used in place of tert-butyl 4-(3-chlorophenyl)-4-(2-oxoethyl) piperidine-1 -carboxylate to give 1-[(1R,5S)-8-(2-{1-benzyl-4-[3- (trifluoromethyl)phenyl]piperidin-4-yl}ethyl)-8-azabicyclo[3.2.1]oct-3-yl]-2- methyl-1 H-benzimidazole as a glass (0.10 g, 27%). 1H NMR (400 MHz, CDCI3) δ 7.67 (m, 1 H), 7.55 (s, 1 H), 7.49 (s, 3H), 7.26-7.33 (m, 6H), 7.12- 7.20 (m, 2H), 4.63 (m, 1H), 3.53 (m, 2H), 3.25 (m, 2H), 2.72 (m, 2H), 2.56 (s, 3H), 2.38 (m, 4H), 2.24 (m, 2H), 1.84-1.94 (m, 10H), 1.63 (m, 2H). HRMS C36H4ι F3N4 m/z 587.3362 (M+H)Caι., 587.3375 (M+H)obs..
Example 662 1 -rd R.5SV8-f2-d -(2.2-Dimethylpropanoyl)-4-[3- (trifluoromethvπphenvnpiperidin-4-yl)ethyl)-8-azabicvclo[3.2.1loct-3-vn-2- methyl-1 H-benzimidazole
Figure imgf000415_0001
2-Methyl-1-[8-(2-{4-[3-(trifluoromethyl) phenyl]piperidin-4-yl}ethyl)-8- azabicyclo[3.2.1]oct-3-yl]-1 H-benzimidazole dihydrochloride. A mixture of 1- [(1 R,5S)-8-(2-{1 -benzyl-4-[3-(trifluoromethyl)phenyl] piperidin-4-yl}ethyl)-8- azabicyclo[3.2.1]oct-3-yl]-2-methyl-1 H-benzimidazole (0.2 g, 0.34 mmol), 1 N hydrochloric acid (0.34 mL) and 10% Palladium on carbon (50 mg) in methanol (10 mL) was hydrogenated overnight at rt and atmospheric pressure. The mixture was filtered through celite and concentrated to give 2- methyl-1-[8-(2-{4-[3-(trifluoromethyl)phenyl] piperidin-4-yl}ethyl)-8- azabicyclo[3.2.1]oct-3-yl]-1 H-benzimidazole dihydrochloride as a solid (0.15 g, 89%) that was used without further purification.
Title compound in example 662: 1-[(1R,5S)-8-(2-{1-(2,2- Dimethylpropanoyl)-4-[3-(trifluoromethyl) phenyl]piperidin-4-yl}ethyl)-8- azabicyclo[3.2.1]oct-3-yl]-2-methyl-1 H-benzimidazole. A mixture of 2-methyl- 1 -[8-(2-{4-[3-(trifluoromethyl)phenyl]piperidin-4-yl}ethyl)-8- azabicyclo[3.2.1]oct-3-yl]-1 H-benzimidazole dihydrochloride (0.05 g, 0.1 mmol), triethylamine (0.028 mL, 0.2 mmol) and trimethylacetyl chloride (0.014 mL, 0.11 mmol) in dichloromethane (1 mL) was stirred 1 h at rt before the reaction mixture was quenched with saturated sodium bicarbonate solution. The organic layer was separated, dried, concentrated and purified by chromatography on silica gel eluting with 1 :33 methanokdichloromethane to give 1 -[(1 R,5S)-8-(2-{1 -(2,2-dimethylpropanoyl)-4-[3-(trifluoro methyl)phenyl]piperidin-4-yl}ethyl)-8-azabicyclo[3.2.1] oct-3-yl]-2-methyl-1H- benzimidazole as a glass (0.025 g, 43%). 1H NMR (400 MHz, CDCI3) δ 7.68 (m, 1 H), 7.54 (m, 4H), 7.13-7.21 (m, 3H), 4.62 (m, 1 H), 3.95 (m, 2H), 3.25 - 3.37 (m, 3H), 2.61 (s, 3H), 2.40 (m, 2H), 2.18 (m, 3H), 1.88 (m, 10H), 1.64 (m, 2H), 1.27 (s, 9H). HRMS C^sFsON-t m/z 581.3467 (M+H)Caι., 581.3476 (M+H)obs..
Example 663 2-Chloro-5-α4-f2-rd R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicvclor3.2.noct-8-yllethyl)-4-[3-(tri-fluoromethvπphenvnpiperidin-1- vDcarbonvDbenzene-sulfonamide
Figure imgf000416_0001
A mixture of 2-methyl-1-[8-(2-{4-[3-(trifluoromethyl)phenyl]piperidin-4- yl}ethyl)-8-azabicyclo[3.2.1]oct-3-yl]-1 H-benzimidazole dihydrochloride (0.1 g, 0.2 mmol), triethylamine (0.056 mL, 0.4 mmol) and 3-(aminosulfonyl)-4- chlorobenzoyl chloride (0.056 g, 0.22 mmol) in dichloromethane (2 mL) was stirred at rt for 1.5 h. The reaction mixture was diluted with dichloromethane, washed with saturated sodium bicarbonate solution, dried, concentrated and purified by three successive chromatographies on silica gel eluting with mixtures of methanol in dichloromethane to give 2-chloro-5-({4-{2-[(1 R,5S)-3- (2-methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1 ]oct-8-yl]ethyl}-4-[3- (trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)benzenesulfonamide as a wax (0.002 g, 2%). 1H NMR (400 MHz, CD3OD3) δ 7.79-7.94 (m, 2H), 7.57-7.71 (m, 5H), 7.40-7.54 (m, 2H), 7.15-7.21 (m, 2H), 4.73 (m, 1 H), 4.15 (m, 1 H), 3.39-3.55 (m, 4H), 3.16-3.22 (m, 1 H), 2.52 (s, 3H), 2.34-2.50 (m, 3H), 2.22- 2.32 (m, 1 H), 1.94-2.12 (m, 10H), 1.68-1.74 (m, 2H). HRMS C36H39CIF3N5O3S m/z 714.2492 (M+H)Caι., 714.2496 (M+H)0bs,
Example 664 1 -(d R,5S)-8-(2-r4-(3-Chloro-5-fluorophenvn-1 -(2.2- dimethylpropanoyl)piperidin-4-yllethyl)-8-azabicvclor3.2.noct-3-vπ-2-methyl-
1 H-benzimidazole
Figure imgf000417_0001
tert-Butyl 4-(3-chloro-5-fluorophenyl)-4-(1 -cyano-2-ethoxy-2- oxoethyl)piperidine-1-carboxylate. Using the same procedure as in Example
16b 1-bromo-3-chloro-5-fluorobenzene (10.7 g, 51 mmol) was used in place of 1-chloro-3-iodobenzene to give tert-butyl 4-(3-chloro-5-fluorophenyl)-4-(1- cyano-2-ethoxy-2-oxoethyl)piperidine-1 -carboxylate as an amber foam that was used without further purification.
[1-(tert-Butoxycarbonyl)-4-(3-chloro-5-fluorophenyl)piperidin-4- yl](cyano)acetic Acid. tert-Butyl 4-(3-chloro-5-fluorophenyl)-4-(1 -cyano-2- ethoxy-2-oxoethyl)piperidine-1 -carboxylate was hydrolysed using the same procedure as in Example 16c to give [1 -(tert-butoxycarbonyl)-4-(3-chloro-5- fluorophenyl) piperidin-4-yl](cyano)acetic acid as an amber foam that was used without further purification. tert-Butyl 4-(3-chloro-5-fluorophenyl)-4-(cyanomethyl)piperidine-1- carboxylate. [1-(tert-Butoxycarbonyl)-4-(3-chloro-5-fluorophenyl)piperidin-4- yl](cyano)acetic acid was subjected to the same decarboxylation conditions used in Example 16d and purified by chromatography on silica gel eluting with 1 :4 ethyl acetate:hexane to give tert-butyl 4-(3-chloro-5-fluorophenyl)-4- (cyanomethyl)piperidine-l -carboxylate as a solid (2.3 g, 38% overall). 1H NMR (400 MHz, CDCI3) δ 7.13 (s, 1H), 7.05 (m, 1H), 6.98 (m, 1H), 3.71 (m, 2H), 3.11 (m, 2H), 2.55 (s, 2H), 2.20 (m, 2H), 1.86 (m, 2H), 1.43 (s, 9H). ES- LCMS m/z 253 (M-99). tert-Butyl 4-(3-chloro-5-fluorophenyl)-4-(2-oxoethyl)piperidine-1- carboxylate. Using the same procedure as in Example 16e tert-butyl 4-(3- chloro-5-fluorophenyl)-4-(cyanomethyl)piperidine-1 -carboxylate (2.3 g, 6.5 mmol) gave tert-butyl 4-(3-chloro-5-fluorophenyl)-4-(2-oxoethyl)piperidine-1- carboxylate as an amber foam (1.5 g, 65%). 1H NMR (400 MHz, CDCI3) δ 9.43 (t, 1 H), 7.12 (s, 1H), 6.95-7.01 (m, 2H), 3.55-3.62 (m, 2H), 3.24-3.30 (m, 2H), 2.63 (s, 2H), 2.04-2.17 (m, 2H), 1.80-1.91 (m, 2H), 1.42 (s, 9H). ES-LCMS m/z 354 (M-1). tert-Butyl 4-(3-chloro-5-fluorophenyl)-4-{2-[3-(2-methyl-1 H- benzimidazol-1 -yl)-8-azabicyclo[3.2.1] oct-8-yl]ethyl}piperidine-1 -carboxylate. Using the same procedure as in Example 16f tert-butyl 4-(3-chloro-5- fluorophenyl)-4-(2-oxoethyl)piperidine-1-carboxylate (1.5 g, 4.2 mmol) gave tert-butyl 4-(3-chloro-5-fluorophenyl)-4-{2-[3-(2-methyl-1 H-benzimidazol-1 -yl)- 8-azabicyclo[3.2.1]oct-8-yl]ethyl}piperidine-1 -carboxylate as a solid (1.7 g, 71%). 1H NMR (400 MHz, CDCI3) δ 7.66 (m, 1H), 7.29 (m, 1H), 7.17 (m, 2H), 7.08 (s, 1 H), 6.98 (m, 1 H), 6.91 (m, 1 H), 4.66 (m, 2H), 3.83 (m, 2H), 3.62 (m, 2H), 3.25 (4H), 3.01 (m, 1 H), 2.60 (s, 3H), 2.44 (m, 2H), 2.02 (m, 4H), 1.71- 1.86 (m, 6H), 1.43 (s, 9H). ES-LCMS m/z 581 (M+1).
1-((1R,5S)-8-{2-[4-(3-Chloro-5-fluorophenyl) piperidin-4-yl]ethyl}-8- azabicyclo[3.2.1]oct-3-yl)-2-methyl-1 H-benzimidazole dihydrochloride. Using the same procedure as in Example 16g tert-butyl 4-(3-chloro-5-fluorophenyl)- 4-{2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl} piperidine-1 -carboxylate (1.7g, 2.9 mmol) gave 1-((1R,5S)-8-{2-[4-(3-chloro-5- fluorophenyl)piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H- benzimidazole dihydrochloride as a solid (1.5 g, 100%). 1H NMR (400 MHz, DMSO-de) δ 11.26 (s, 1 H), 9.14 (s, 2H), 7.89 (m, 1 H), 7.80 (m, 1 H), 7.55 (m, 2H), 7.37 (m, 1H), 7.30 (m, 2H), 6.03 (m, 1H), 4.11 (m, 2H), 3.22 (m, 2H), 3.11 (m, 1 H), 2.88 (s, 3H), 2.75-2.90 (m, 4H), 2.30 (m, 2H), 2.10-2.25 (m, 8H), 2.08 (m, 2H). ES-LCMS m/z 481 (M+1).
1-((1R,5S)-8-{2-[4-(3-Chloro-5-fluorophenyl)-1-(2,2- dimethylpropanoyl)piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl- 1 H-benzimidazole (example 664). A mixture of 1-((1f?,5S)-8-{2-[4-(3-chloro-5- fluorophenyl)piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H- benzimidazole dihydrochloride (0.2 g, 0.39 mmol), triethylamine (0.11 mL, 0.78 mmol) and trimethylacetyl chloride (0.053 mL, 0.43 mmol) in dichloromethane (4 mL) was stirred at rt for 1 h before the reaction mixture was quenched with saturated sodium bicarbonate solution. The organic layer was separated, dried, concentrated and purified by two successive chromatographies on silica gel using a dichloromethane to methano dichloromethane 1 :20 gradient to give 1-((1 R,5S)-8-{2-[4-(3-chloro- 5-fluorophenyl)-1-(2,2-dimethylpropanoyl)piperidin-4-yl]ethyl}-8- azabicyclo[3.2.1]oct-3-yl)-2-methyl-1 H-benzimidazole as a glass (0.06 g,
27%). 1H NMR (400 MHz, CDCI3) δ 7.67 (m, 1H), 7.29 (m, 1H), 7.17 (m, 2H), 7.09 (m, 1H), 7.00 (m, 1H), 6.93 (m, 1 H), 4.72 (m, 1H), 3.90 (m, 2H), 3.37 (m, 4H), 2.61 (s, 3H), 2.47 (m, 2H), 1.89-2.11 (m, 8H), 1.78 (m, 6H), 1.27 (s, 9H). HRMS C33H42CIFN4O m/z 565.3109 (M+H)Caι., 565.3095 (M+H)0bs,
Example 665 2-Chloro-5-r(4-(3-chloro-5-fluorophenyl)-4-f2-[dR,5S)-3-(2-methyl-1H- benzimidazol-1-yl)-8-azabicvclo r3.2.πoct-8-yllethyl}piperidin-1- vDcarbonyllbenzene sulfonamide
Figure imgf000420_0001
A mixture of 1-((1R,5S)-8-{2-[4-(3-chloro-5-fluorophenyl)piperidin-4- yl]ethyl}-8-azabicyclo[3.2.1] oct-3-yl)-2-methyl-1 H-benzimidazole dihydrochloride (0.40 g, 0.78 mmol), triethylamine (0.35 mL, 2.5 mmol) and 4- chloro-3-sulfamoylbenzoic acid (184 mg, 0.78 mmol) in dimethylformamide (2.5 mL) was treated with O-(7-azabenzotriazol-1-yl)-1 , 1 ,3,3- tetramethyluronium hexafluorophosphate (327 mg, 0.86 mmol) and the resulting mixture was stirred for 1 h at rt. The mixture was diluted with water and the resulting precipitate was collected, washed with saturated sodium bicarbonate solution and water, dried and purified by chromatography on silica gel eluting with a gradient of chloroform:methanol:ammonium hydroxide 400:15:1 to 200:15:1 to give 2-chloro-5-[(4-(3-chloro-5-fluoro phenyl)-4-{2- [(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1]oct-8- yl]ethyl}piperidin-1-yl)carbonyl]benzenesulfonamide as a solid (0.20 g, 36%). 1H NMR (400 MHz, CD3OD) δ 8.09 (s, 1 H), 7.67 (m, 1 H), 7.60 (m, 1 H), 7.51 (m, 1 H), 7.42 (m, 1 H) 7.30 (s, 1 H), 7.10-7.21 (m, 4H), 4.72 (m, 1 H), 4.06 (m, 1H), 3.57 (m, 1H), 3.47 (m, 1H), 3.30 (m, 3H), 2.52 (s, 3H), 2.40-2.48 (m, 4H), 2.27 (m, 1H), 2.14 (m, 1H), 1.83-2.04 (m, 10H), 1.70 (m, 2H). HRMS C35H38CI2FN5O3S m/z 698.2134 (M+H)Caι., 698.2161 (M+H)0bs, Example 666 1-(d R,5S)-8-f2-π-(2,2-Dimethylpropanovn-4-(3-ethoxyphenvnpiperidin-4- vnethyl)-8-azabicvclof3.2.11oct-3-v0-2-methyl-1 H-benzimidazole
Figure imgf000421_0001
tert-Butyl 4-(1-cyano-2-ethoxy-2-oxoethyl)-4-(3- ethoxyphenyl)piperidine-1-carboxylate. Using the same procedure as in Example 16b 3-bromophenetole (10.2 g, 51 mmol) was used in place of 1- chloro-3-iodobenzene and purified by chromatography on silica gel eluting with a 1 :9 to 1 :2 ethyl acetate:hexane gradient to give tert-butyl 4-(1-cyano-2- ethoxy-2-oxoethyl)-4-(3-ethoxyphenyl)piperidine-1 -carboxylate as an oil (5.4 g, 77%). 1H NMR (400 MHz, CDCI3) δ 7.29 (m, 1 H), 6.81-6.91 (m, 3H), 3.90- 4.04 (m, 4H), 3.55 (s, 1 H), 2.86 (m, 2H), 2.54 (m, 2H), 1.95-2.05 (m, 4H), 1.43 (s, 9H), 1.40 (t, 3H), 1.04 (t, 3H). ES-LCMS m/z 317 (M-99).
[1-(tert-Butoxycarbonyl)-4-(3-ethoxyphenyl)piperidin-4-yl](cyano)acetic Acid. tert-Butyl 4-(1-cyano-2-ethoxy-2-oxoethyl)-4-(3-ethoxy phenyl)piperidine-1 -carboxylate was hydrolysed using the same procedure as in Example 16c to give [1 -(tert-butoxycarbonyl)-4-(3-ethoxyphenyl)piperidin-4- yl](cyano)acetic acid as a pale yellow foam that was used without further purification. tert-Butyl 4-(cyanomethyl)-4-(3-ethoxyphenyl) piperidine-1 -carboxylate.
[1-(tert-Butoxycarbonyl)-4-(3-ethoxyphenyl)piperidin-4-yl](cyano)acetic acid was subjected to the same decarboxylation conditions used in Example 16d and purified by chromatography on silica gel eluting with a 1 :9 to 1:2 ethyl acetate:hexane gradient to give tert-butyl 4-(cyanomethyl)-4-(3- ethoxyphenyl)piperidine-1 -carboxylate as a solid (3.1 g, 72%). 1H NMR (400 MHz, CDCI3) δ 7.31 (m, 1H), 6.80-6.94 (m, 3H), 4.04 (m, 2H), 3.74-3.80 (m, 2H), 3.06 (m, 2H), 2.53 (s, 2H), 2.30 (m, 2H), 1.83 (m, 2H), 1.43 (s, 9H), 1.40 (t, 3H). ES-LCMS m/z 245 (M-99). tert-Butyl 4-(3-ethoxyphenyl)-4-(2-oxoethyl) piperidine- 1 -carboxylate. Using the same procedure as in Example 16e tert-butyl 4-(cyanomethyl)-4-(3- ethoxyphenyl)piperidine-1 -carboxylate (3.1 g, 9 mmol) gave tert-butyl 4-(3- ethoxyphenyl)-4-(2-oxoethyl) piperidine-1 -carboxylate as a solid (2.1 g, 68%). 1H NMR (400 MHz, CDCI3) δ 9.37 (t, 1H), 7.30 (m, 1H), 6.89 -6.92 (m, 2H), 6.76 (m, 1 H), 4.02 (m, 2H), 3.59-3.65 (m, 2H), 3.19-3.26 (m, 2H), 2.60 (s, 2H), 2.17-2.22 (m, 2H), 1.85 (m, 2H), 1.43 (s, 9H), 1.40 (m, 3H). tert-Butyl 4-(3-ethoxyphenyl)-4-{2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-
8-azabicyclo[3.2.1]oct-8-yl]ethyl}piperidine-1 -carboxylate. Using the same procedure as in Example 16f tert-butyl 4-(3-ethoxy phenyl)-4-(2- oxoethyl)piperidine-1 -carboxylate (2.1 g, 6 mmol) gave tert-butyl 4-(3- ethoxyphenyl)-4-{2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1]oct- 8-yl]ethyl}piperidine-1 -carboxylate after chromatography on silica gel eluting with a dichloromethane to 1 :9 methanol:dichloromethane gradient as a solid (3.0 g, 88%). 1H NMR (400 MHz, CDCI3) δ 7.66 (m, 1H), 7.26 (m, 2H), 7.13- 7.19 (m, 2H), 6.85 (m, 2H), 6.75 (m, 1 H), 4.66 (m, 2H), 4.03 (m, 2H), 3.65 (m, 2H), 3.30 (m, 2H), 3.17 (m, 4H), 2.60 (s, 3H), 2.40 (m, 2H), 1.65-2.16 (m, 11 H), 1.43 (s, 9H), 1.40 (m, 3H). ES-LCMS m/z 573 (M+1 ).
1 -(8-{2-[4-(3-Ethoxyphenyl)piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct- 3-yl)-2-methyl-1 H-benzimidazole dihydrochloride. Using the same procedure as in Example 16g tert-butyl 4-(3-ethoxy phenyl)-4-{2-[3-(2-methyl-1 H- benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}piperidine-1 -carboxylate (3.0 g, 5.2 mmol) gave 1 -(8-{2-[4-(3-ethoxyphenyl)piperidin-4-yl]ethyl}-8- azabicyclo[3.2.1] oct-3-yl)-2-methyl-1 H-benzimidazole dihydrochloride as a solid (2.6 g, 100%). 1H NMR (400 MHz, DMSO-d6) δ 11.21 (s, 1H), 9.04 (s, 2H), 7.88 (m, 1 H), 7.80 (m, 1H), 7.55 (m, 2H), 7.31 (m, 1 H), 6.83-6.94 (m, 3H), 6.02 (m, 1 H), 4.07 (m, 2H), 3.21 (m, 2H), 2.88 (s, 3H), 2.75-2.83 (m, 4H), 2.52 (m, 2H), 2.18-2.34 (m, 8H), 2.08 (m, 4H), 1.33 (t, 3H). ES-LCMS m/z 473 (M+1). 422
1-((1R,5S)-8-{2-[1-(2,2-Dimethylpropanoyl)-4-(3- ethoxyphenyl)piperidin-4-yl]ethyl}-8-azabicyclo [3.2.1]oct-3-yl)-2-methyl-1 H- benzimidazole (example 666). A mixture of 1-(8-{2-[4-(3-ethoxyphenyl) piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole dihydrochloride (0.2 g, 0.39 mmol), triethylamine (0.11 mL, 0.78 mmol) and trimethylacetyl chloride (0.053 mL, 0.43 mmol) in dichloromethane (4 mL) was stirred at rt for 1 h before the reaction mixture was quenched with saturated sodium bicarbonate solution. The organic layer was separated, dried, concentrated and purified by chromatography on silica gel eluting with a dichloromethane to 1 :9 methanol.-dichloromethane gradient to give 1- ((1 R,5S)-8-{2-[1-(2,2-dimethylpropanoyl)-4-(3-ethoxyphenyl) piperidin-4- yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1 H-benzimidazole as a foam (0.14 g, 65%). 1H NMR (400 MHz, CDCI3) δ 7.65 (m, 1H), 7.28 (m, 2H), 7.16 (m, 2H), 6.86 (m, 2H), 6.76 (m, 1 H), 4.63 (m, 1H), 4.04 (m, 2H), 3.94 (m, 2H), 3.29 (m, 4H), 2.59 (s, 3H), 2.40 (m, 2H), 2.19 (m, 2H), 1.66-1.95 (m, 12H), 1.43 (t, 3H), 1.26 (s, 9H). HRMS C35H48N4O2 m/z 557.3856 (M+H)Caι., 557.3840 (M+H) obs.
Example 667 2-Chloro-5-r(4-(3-ethoχyphenyl)-4-f2-rd R,5S)-3-(2-methyl-1 H-benzimidazol-1 ■ yl)-8-azabicvclo[3.2.noct-8-vnethyl)piperidin-1- vDcarbonvπbenzenesulfonamide
Figure imgf000423_0001
A mixture of 1 -(8-{2-[4-(3-ethoxyphenyl) piperidin-4-yl]ethyl}-8- azabicyclo[3.2.1]oct-3-yl)-2-methyl-1 H-benzimidazole dihydrochloride (0.40 g, 0.78 mmol), triethylamine (0.35 mL, 2.5 mmol) and 4-chloro-3- sulfamoylbenzoic acid (184 mg, 0.78 mmol) in dimethylformamide (2.5 mL) was treated with O-(7-azabenzotriazol-1-yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate (327 mg, 0.86 mmol) and the resulting mixture was stirred for 1 h at rt. The mixture was diluted with water and the resulting precipitate was collected, washed with saturated sodium bicarbonate solution and water, dried and purified by chromatography on silica gel eluting with a chloroform:methanol:ammonium hydroxide 400:15:1 to 200:15:1 gradient to give 2-chloro-5-[(4-(3-ethoxy phenyl)-4-{2-[(1 R,5S)-3-(2-methyl-1 H- benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-1- yl)carbonyl]benzenesulfonamide as a solid (0.34 g, 62%). 1H NMR (400 MHz, CD3OD) δ 8.08 (s, 1H), 7.67 (m, 1H), 7.59 (m, 1H), 7.51 (m, 1H), 7.41 (m, 1 H), 7.29 (m, 1H), 7.17 (m, 2H), 6.93-6.98 (m, 2H), 6.81 (m, 1 H), 4.74 (m, 1H), 4.17 (m, 1H), 4.04 (m, 2H), 3.54 (m, 1 H), 3.30 (m, 4H), 2.52 (s, 3H), 2.40-2.48 (m, 4H), 2.27 (m, 1 H), 2.14 (m, 1 H), 1.83-2.04 (m, 10H), 1.70 (m, 2H), 1.40 (t, 3H). HRMS C37H44CIN5O4S m/z 690.2881 (M+H)Caι., 690.2901 (M+H)o s..
Example 668 3-d -(2,2-Dimethylpropanovn-4-(2-rd R.5S)-3-(2-methyl-1 H-benzimidazol-1 - yl)-8-azabicvclo[3.2.1 ]oct-8-vπethyl}piperidin-4-yl)phenol
Figure imgf000424_0001
tert-Butyl 4-(cyanomethyl)-4-(3-methoxyphenyl)piperidine-1 - carboxylate was prepared using the same procedures used in Example 16a-d using 1 -bromo-3-methoxybenzene in the place of 1 -chloro-3-iodobenzene in Example 16b. tert-Butyl 4-(3-methoxyphenyl)-4-(2-oxoethyl)piperidine-1 '-carboxylate.
Using the same procedure as in Example 16e tert-butyl 4-(cyanomethyl)-4-(3- methoxyphenyl)piperidine-1 -carboxylate (1.2 g, 3.8 mmol) gave tert-butyl 4-(3- methoxyphenyl)-4-(2-oxoethyl)piperidine-1 -carboxylate as a foam (0.9 g, 69%). 1H NMR (400 MHz, CDCI3) δ 9.38 (t, 1H), 7.30 (m, 1H), 6.88-6.95 (m, 2H), 6.78 (m, 1 H), 3.80 (s, 3H), 3.60 (m, 2H), 3.21-3.27 (m, 2H), 2.61 (s, 2H), 2.21 (m, 2H), 1.83 (m, 2H), 1.43 (s, 9H). tert-Butyl 4-(3-methoxyphenyl)-4-{2-[3-(2-methyl- 1 H-benzimidazol- 1 -yl)-
8-azabicyclo[3.2.1]oct-8-yl]ethyl}piperidine-1 -carboxylate. Using the same procedure as in Example 16f tert-butyl 4-(3-methoxy phenyl)-4-(2- oxoethyl)piperidine-1 -carboxylate (0.9 g, 2.5 mmol) gave tert-butyl 4-(3- methoxyphenyl)-4-{2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}piperidine-1 -carboxylate as a foam (1.2 g,
85%). 1H NMR (400 MHz, CDCI3) δ 7.66 (m, 1 H), 7.28 (m, 2H), 7.16 (m, 2H), 6.88 (m, 2H), 6.76 (m, 1 H), 4.62 (m, 1H), 3.82 (s, 3H), 3.65 (m, 2H), 3.16- 3.26 (m, 4H), 3.08 (m, 1 H), 2.58 (s, 3H), 2.37 (m, 2H), 2.13 (m, 2H), 1.83-1 97 (m, 6H), 1.78 (m, 3H), 1.61 (m, 2H), 1.43 (s, 9H). 3-(4-{2-[3-(2-Methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1]oct-8- yl]ethyl}piperidin-4-yl)phenol Hydrobromide. A mixture of tert-butyl 4-(3- methoxy phenyl)-4-{2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}piperidine-1 -carboxylate (235 mg, 0.42 mmol) and 48% hydrobromic acid was heated at 100°C for 6 h. The mixture was concentrated and used without further purification.
3-(1-(2,2-Dimethylpropanoyl)-4-{2-[(1R,5S)-3-(2-methyl-1H- benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-4-yl)phenol (example 668). A mixture of 3-(4-{2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-4-yl)phenol hydrobromide (0.22 g, 0.42 mmol), triethylamine (0.117 mL, 0.84 mmol) and trimethylacetyl chloride (0.057 mL, 0.462 mmol) in dichloromethane (2 mL) was stirred at rt for 3h. The reaction mixture was diluted with dichloromethane, washed with saturated sodium bicarbonate solution, dried, concentrated and purified by chromatography on silica gel eluting with 33:1 dichloromethane:methanol to give 3-(1 -(2,2-dimethyl propanoyl)-4-{2-[(1 R,5S)-3-(2-methyl-1 H- benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-4-yl)phenol as a white solid (0.070 g, 32%). 1H NMR (400 MHz, DMSO-d6) δ 9.25 (s, 1H), 7.47 (m, 1H), 7.34 (m, 1H), 7.05-7.15 (m, 3H), 6.77 (m, 1H), 6.73 (s, 1H), 6.59 (m, 1 H), 4.51 (m, 1 H), 3.74 (m, 2H), 3.24 (m, 4H), 2.47 (s, 3H), 2.36 (m, 2H), 1.97 (m, 2H), 1.86 (m, 4H), 1.75 (m, 6H), 1.58 (m, 2H), 1.15 (s, 9H). HRMS C33H44N4O2 m/z 529.3543 (M+H)Caι., 529.3542 (M+H)0bs,
Example 669 2-Chloro-5-f(4-(3-hvdroχyphenyl)-4-{2-rdR,5S)-3-(2-methyl-1H-benzimidazol- 1-yl)-8-azabicvclo[3.2.11oct-8-yl1ethyl}piperidin-1- yl)carbonvπbenzenesulfonamide
Figure imgf000426_0001
A mixture of 3-(4-{2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl} piperidin-4-yl)phenol hydrobromide (0.25 g, 0.48 mmol), triethylamine (0.212 mL, 1.5 mmol) and 4-chloro-3- sulfamoylbenzoic acid (0.113 g, 0.48 mmol) in dimethylformamide (1.5 mL) was treated with O-(7-azabenzotriazol-1-yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate (0.2 g, 0.53 mmol) and the resulting mixture was stirred for 1 h at rt. The mixture was diluted with water and the resulting precipitate was collected, washed with saturated sodium bicarbonate solution and water, dried and purified by column chromatography on silica gel eluting with 200:15:1 chloroform:methanol:ammonium hydroxide to give 2-chloro-5-[(4-(3- hydroxyphenyl)-4-{2-[(1R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-1-yl)carbonyl]benzenesulfonamide as a pink solid (0.022 g, 7%). 1H NMR (400 MHz, CD3OD) δ 8.08 (s, 1H), 7.67 (m, 1H), 7.60 (m, 1H), 7.51 (m, 1H), 7.41 (m, 1H), 7.18 (m, 3H), 6.84 (m, 2H), 6.67 (m, 1H), 4.74 (m, 1H), 4.15 (m, 1H), 3.54 (m, 1H), 3.32 (m, 7H), 2.52 (s, 3H), 2.34-2.50 (m, 3H), 2.20-2.30 (m, 1H), 1.78-2.10 (m, 10H), 1.65-1.72 (m, 2H). HRMS C35H40CIN5O4S m/z 662.2568 (M+H)Caι., 662.2571 (M+H)obs, Example 670 1 -(U R.5SV8-f2-[4-(4-Chloro-3-fluorophenvn-1 -(2.2- dimethylpropanoyl)piperidin-4-vnethyl)-8-azabicvclo[3.2.noct-3-vπ-2-methyl- 1 H-benzimidazole
Figure imgf000427_0001
tert-Butyl 4-(4-chloro-3-fluorophenyl)-4-(1 -cyano-2-ethoxy-2- oxoethyl)piperidine-1 -carboxylate. Using the same procedure as in Example 16b 1-bromo-4-chloro-5-fluorobenzene (10.7 g, 51 mmol) was used in place of 1 -chloro-3-iodobenzene to give tert-butyl 4-(4-chloro-3-fluorophenyl)-4-(1- cyano-2-ethoxy-2-oxoethyl)piperidine-1 -carboxylate as an amber foam that was used without further purification.
[1-(tert-Butoxycarbonyl)-4-(4-chloro-3-fluorophenyl)piperidin-4- yl](cyano)acetic Acid. tert-Butyl 4-(4-chloro-3-fluorophenyl)-4-(1 -cyano-2- ethoxy-2-oxoethyl)piperidine-1 -carboxylate was hydrolysed using the same procedure as in Example 16c to give [1-(tert-butoxycarbonyl)-4-(4-chloro-3- fluorophenyl) piperidin-4-yl](cyano)acetic acid as an amber solid that was used without further purification. tert-Butyl 4-(4-chloro-3-fluorophenyl)-4-(cyanomethyl)piperidine- 1 - carboxylate. [1-(tert-Butoxycarbonyl)-4-(4-chloro-3-fluorophenyl)piperidin-4- yl](cyano)acetic acid was subjected to the same decarboxylation conditions used in Example 16d and chromatographed on silica gel eluting with a gradient of ethyl acetate:hexane 1 :20 to 1 :1 to give tert-butyl 4-(4-chloro-3- fluorophenyl)-4-(cyanomethyl)piperidine-1 -carboxylate as a solid (2.3 g, 38% overall). 1H NMR (400 MHz, CDCI3) δ 7.44 (m, 1 H), 7.09-7.16 (m, 2H), 3.69- 3.75 (m, 2H), 3.09 (m, 2H), 2.54 (s, 2H), 2.20-2.25 (m, 2H), 1.85 (m, 2H), 1.43 (s, 9H). ES-LCMS m/z 253 (M-99). tert-Butyl 4-(4-chloro-3-fluorophenyl)-4-(2-oxoethyl)piperidine-1- carboxylate. Using the same procedure as in Example 16e tert-butyl 4-(4- chloro-3-fluorophenyl)-4-(cyanomethyl)piperidine-1 -carboxylate (2.3 g, 6.5 mmol) gave tert-butyl 4-(4-chloro-3-fluorophenyl)-4-(2-oxoethyl)piperidine-1- carboxylate as an amber foam (1.5 g, 65%). 1H NMR (400 MHz, CDCI3) δ 9.43 (t, 1H), 7.40 (m, 1H), 7.07-7.16 (m, 2H), 3.57-3.63 (m, 2H), 3.22-3.29 (m, 2H), 2.66 (s, 2H), 2.11-2.17 (m, 2H), 1.86 (m, 2H), 1.43 (s, 9H). ES- LCMS m/z 354 (M-1 ). tert-Butyl 4-(4-chloro-3-fluorophenyl)-4-{2-[3-(2-methyl-1H- benzimidazol-1-yl)-8-azabicyclo [3.2.1]oct-8-yl]ethyl}piperidine-1 -carboxylate. Using the same procedure as in Example 16f tert-butyl 4-(4-chloro-3- fluorophenyl)-4-(2-oxoethyl)piperidine-1 -carboxylate (1.5 g, 4.2 mmol) gave tert-butyl 4-(4-chloro-3-fluorophenyl)-4-{2-[3-(2-methyl-1 H-benzimidazol-1 -yl)- 8-azabicyclo[3.2.1]oct-8-yl]ethyl} piperidine-1 -carboxylate as a solid (1.4 g, 59%). 1H NMR (400 MHz, CDCI3) δ 7.66 (m, 1 H), 7.38 (m, 1 H), 7.28 (m, 1 H), 7.17 (m, 2H), 7.02-7.09 (m, 2H), 4.66 (m, 2H), 3.83 (m, 2H), 3.62 (m, 2H), 3.23 (m, 4H), 3.01 (m, 1H), 2.60 (s, 3H), 2.43 (m, 2H), 1.65-2.01 (m, 10H), 1.43 (s, 9H). ES-LCMS m/z 581 (M+1).
1-(8-{2-[4-(4-Chloro-3-fluorophenyl) piperidin-4-yl]ethyl}-8- azabicyclo[3.2.1]oct-3-yl)-2-methyl-1 H-benzimidazole dihydrochloride. Using the same procedure as in Example 16g tert-butyl 4-(4-chloro-3-fluorophenyl)- 4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl} piperidine-1 -carboxylate (1.4 g, 2.4 mmol) gave 1-(8-{2-[4-(4-chloro-3- fluorophenyl)piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1 ]oct-3-yl)-2-methyl-1 H- benzimidazole dihydrochloride as a solid (1.4 g, 93%). 1H NMR (400 MHz,
DMSO-d6) δ 11.22 (s, 1 H), 9.03 (s, 2H), 7.88 (m, 1 H), 7.80 (m, 1H), 7.46-7.62 (m, 4H), 7.26 (m, 1 H), 6.03 (m, 1H), 4.08 (m, 2H), 3.23 (m, 2H), 3.11 (m, 1 H), 2.87 (s, 3H), 2.75-2.90 (m, 4H), 2.30 (m, 2H), 2.10-2.25 (m, 8H), 2.08 (m, 2H). ES-LCMS m/z 481 (M+1). 1-((1R,5S)-8-{2-[4-(4-Chloro-3-fluorophenyl)-1-(2,2- dimethylpropanoyl)piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl- 1 H-benzimidazole (example 670). A mixture of 1 -(8-{2-[4-(4-chloro-3- fluorophenyl)piperidin-4-yl]ethyl}-8-azabicyclo [3.2.1]oct-3-yl)-2-methyl-1 H- benzimidazole dihydrochloride (0.20 g, 0.39 mmol), triethylamine (0.11 mL, 0.78 mmol) and trimethylacetyl chloride (0.053 mL, 0.43 mmol) in dichloromethane (4 mL) was stirred at rt for 1 h before the reaction mixture was quenched with saturated sodium bicarbonate solution. The organic layer was separated, dried, concentrated and purified by chromatography on silica gel eluting with a dichloromethane to 1 :9 methanohdichloromethane gradient to give 1-((1R,5S)-8-{2-[4-(4-chloro-3-fluorophenyl)-1-(2,2- dimethylpropanoyl)piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl- 1 H-benzimidazole as a white foam (0.11 g, 51%). 1H NMR (400 MHz, CDCI3) δ 7.67 (m, 1 H), 7.40 (m, 1H), 7.29 (m, 1 H), 7.03-7.19 (m, 4H), 4.72 (m, 1 H), 3.90 (m, 2H), 3.33 (m, 4H), 2.59 (s, 3H), 2.42 (m, 2H), 1.78-2.13 (m, 14H), 1.27 (s, 9H). HRMS C33H42CIFN4O m/z 565.3109 (M+H)Caι., 565.3134 (M+H)0bs..
Example 671 2-Chloro-5-r(4-(4-chloro-3-fluorophenylH-(2-fd R.5S)-3-(2-methyl-1H- benzimidazol-1 -vO-8-azabicvclo f3.2.11oct-8-yllethyl}piperidin-1 - vQcarbonv-lbenzene sulfonamide
Figure imgf000429_0001
A mixture of 1 -(8-{2-[4-(4-chloro-3-fluoro phenyl)piperidin-4-yl]ethyl}-8- azabicyclo[3.2.1]oct-3-yl)-2-methyl-1 H-benzimidazole dihydrochloride (0.40 g, 0.78 mmol), triethylamine (0.35 mL, 2.5 mmol) and 4-chloro-3- sulfamoylbenzoic acid (184 mg, 0.78 mmol) in dimethylformamide (2.5 mL) was treated with O-(7-azabenzotriazol-1-yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate (327 mg, 0.86 mmol) and the resulting mixture was stirred for 1 h at rt. The mixture was diluted with water and the resulting precipitate was collected, washed with saturated sodium bicarbonate solution, with water, dried and purified by chromatography on silica gel eluting with a 400:15:1 to 200:15:1 gradient of chloroform:methanol:ammonium hydroxide to give 2-chloro-5-[(4-(4-chloro-3-fluoro phenyl)-4-{2-[(1 R,5S)-3-(2-methyl-1 H- benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-1- yl)carbonyl]benzenesulfonamide as a solid (0.24 g, 43%). 1H NMR (400 MHz, CD3OD) δ 8.09 (s, 1H), 7.68 (m, 1H), 7.61 (m, 1 H), 7.34-7.54 (m, 4H), 7.17- 7.26 (m, 3H), 4.73 (m, 1H), 4.09 (m, 1 H), 3.59 (m, 1H), 3.43 (m, 1H), 3.30 (m, 3H), 2.53 (s, 3H), 2.40-2.48 (m, 4H), 2.28 (m, 1 H), 2.16 (m, 1 H), 1.83-2.04 (m, 10H), 1.70 (m, 2H). HRMS CssHssCfeFNgOaS m/z 698.2135 (M+H)Caι.. 698.2142 (M+H)0bs..
Example 672 2-Methyl-1 -(d R,5S)-8-(2-r4-phenyl-1 -(tetrahvdrofuran-2-ylcarbonyl)piperidin- 4-vnethyl)-8-azabicvclof3.2.noct-3-vπ-1 H-benzimidazole
Figure imgf000430_0001
A mixture of 2-methyl-1-{8-[2-(4-phenylpiperidin-4-yl)ethyl]-8- azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole dihydrochloride (75 mg, 0.16 mmol), tetrahydro-2-furoic acid (18 mg, 0.16 mmol) and triethylamine (48 mg, 0.48 mmol) in dimethylformamide (0.5 mL) was treated with O-(7- azabenzotriazol-1-yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate (68 mg, 0.18 mmol) and the resulting mixture was stirred at rt for 1 h. The reaction mixture was diluted with water and the resulting precipitate was collected, washed with water and dried. The precipitate was triturated with a mixture of dichloromethane, methanol and hexane to give 2-methyl-1-
((1 R,5S)-8-{2-[4-phenyl-1-(tetrahydrofuran-2-ylcarbonyl)piperidin-4-yl]ethyl}-8- azabicyclo[3.2.1]oct-3-yl)-1 H-benzimidazole as an off-white solid (0.017 g, 20%). 1H NMR (400 MHz, DMSO-d6) δ 7.61-7.66 (m, 2H), 7.41 (m, 5H), 7.27-7.35 (m, 2H), 4.94 (m, 1 H), 4.64 (m, 1 H), 4.03 (m, 2H), 3.68-3.77 (m, 5H), 2.98-3.25 (m, 2H), 2.62-2.70 (m, 7H), 2.09-2.24 (m, 7H), 1.88-2.06 (m, 4H), 1.68-1.84 (m, 4H). HRMS C33H42N4O2 m/z 527.3386 (M+H)Caι., 527.3380 (M+H)obs,
Example 673 2-Methyl-1 -(d R,5S)-8-(2-r4-phenyl-1 -(tetrahvdrofuran-3-ylcarbonyl)piperidin-
4-yl1ethyl)-8-azabicvclor3.2.11oct-3-yl)-1 H-benzimidazole
Figure imgf000431_0001
A mixture of 2-methyl-1-{8-[2-(4-phenyl piperidin-4-yl)ethyl]-8- azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole dihydrochloride (75 mg, 0.16 mmol), tetrahydro-3-furoic acid (18 mg, 0.16 mmol) and triethylamine (48 mg, 0.48 mmol) in dimethylformamide (0.5 mL) was treated with O-(7- azabenzotriazol-1-yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate (68 mg, 0.18 mmol) and the resulting mixture was stirred at rt for 1h. The reaction mixture was diluted with water and extracted with dichloromethane. The residue from the dichloromethane layer was purified by chromatography on silica gel eluting with 1 :20 methanohdichloromethane to give 2-methyl-1- ((1 R,5S)-8-{2-[4-phenyl-1-(tetrahydrofuran-3-ylcarbonyl)piperidin-4-yl]ethyl}-8- azabicyclo[3.2.1]oct-3-yl)-1 H-benzimidazole as a clear oil (0.019 g, 23%). 1H NMR (400 MHz, DMSO-d6) δ 7.46 (m, 1H), 7.36 (m, 5H), 7.21 (m, 1H), 7.09 (m, 2H), 4.49 (m, 1H), 3.58-3.87 (m, 7H), 3.12-3.35 (m, 6H), 2.28-2.39 (m, 2H), 1.89-2.12 (m, 5H), 1.58-1.86 (m, 10H), 1.53-1.60 (m, 2H). HRMS C-33H42N4O2 m/z 527.3386 (M+H)Caι., 527.3397 (M+H)0bs, Example 674 1 -((1 R,5S)-8-(2-[1 -d -Benzofuran-2-ylcarbonvn-4-ρhenylpiperidin-4-yllethyl -8- azabicvclo[3.2.noct-3-yl)-2-methyl-1 H-benzimidazole
Figure imgf000432_0001
A mixture of 2-methyl-1-{8-[2-(4-phenyl piperidin-4-yl)ethyl]-8- azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole dihydrochloride (100 mg, 0.22 mmol), 2-benzofurancarboxylic acid (36 mg, 0.22 mmol) and triethylamine (66 mg, 0.66 mmol) in dimethylformamide (0.75 mL) was treated with O-(7- azabenzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate (92 mg, 0.24 mmol) and the resulting mixture was stirred at rt for 1h. The reaction mixture was diluted with water and the resulting precipitate was collected, washed with water and dried. The precipitate was purified by chromatography on silica gel eluting with 1 :20 methano dichloromethane to give 1-((1R,5S)-8- {2-[1-(1-benzofuran-2-ylcarbonyl)-4-phenylpiperidin-4-yl]ethyl}-8- azabicyclo[3.2.1]oct-3-yl)-2-methyl-1 H-benzimidazole as a clear oil (0.075 g, 60%). 1H NMR (400 MHz, CDCI3) δ 7.66 (m, 2H), 7.52 (m, 1 H), 7.26-7.44 (m, 9H), 7.16 (m, 2H), 4.61 (m, 1 H), 4.16 (m, 2H), 3.40-3.57 (m, 2H), 3.26 (m, 1 H), 2.57 (m, 3H), 2.34 (m, 4H), 1.94 (m, 9H), 1.62 (m, 4H). HRMS C37H40N4O2 m/z 573.3229 (M+H)Caι., 573.3238 (M+H)0bs,
Example 675 (3R,3aS.6aR)-Hexahvdrofurol2.3-b1furan-3-yl 4-J2-IT1 R.5S 3-(2-methyl-1 H- benzimidazol-1-yl)-8-azabicvclo r3.2.1loct-8-vnethyl)-4-phenylpiperidine-1- carboxylate
Figure imgf000433_0001
A mixture of 2-methyl-1-{8-[2-(4-phenyl piperidin-4-yl)ethyl]-8- azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole dihydrochloride (100 mg, 0.22 mmol), (3R,3aS,6aR)-hexahydrofuro[2,3-ι ]furan-3-yl 4-nitrophenyl carbonate (78 mg, 0.26 mmol) and N,N-diisopropylethylamine (0.15 mL, 0.88 mmol) in acetonitrile (3 mL) was stirred at rt for 16 h. The reaction mixture was concentrated and the residue in dichloromethane was washed with saturated sodium carbonate solution, dried, concentrated and chromatographed on silica gel eluting with 1 :40 methanol:dichloromethane to give (3R,3aS,6aR)- hexahydrofuro[2,3-b]furan-3-yl 4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 - yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidine-1 -carboxylate as a clear glass (0.064 g, 50%). 1H NMR (400 MHz, CDCI3) δ 7.38 (m, 2H), 7.29 (m, 5H), 7.16 (m, 2H), 5.71 (m, 1H), 5.18 (m, 1 H), 4.59 (m, 1 H), 3.75-4.04 (m, 7H), 3.22 (m, 3H), 3.05 (m, 1 H), 2.58 (m, 3H), 2.19-2.36 (m, 4H), 1.80-1.92 (m, 9H), 1.61 (m, 5H). HRMS C35H44N4O4 m/z 585.3441 (M+H)Caι., 585.3440 (M+H)0bs.. Example 676 2-[(4-{2-r3-(2-Methyl-1 H-benzimidazol-1 -vn-8-azabicvclor3.2.noct-8-yl1ethyll- 4-phenylpiperidin-1-yl)carbonvnbenzenesulfonamide
Figure imgf000434_0001
Example 676 was prepared as outlined below.
1a 1b
Figure imgf000434_0002
example 676
Figure imgf000434_0003
Figure imgf000434_0004
Methyl 2-{[(tert-butoxycarbonyl)amino] sulfonyljbenzoate 1a. A mixture of methyl 2-(aminosulfonyl)benzoate (500 mg, 2.3 mmol, 1 eq.), triethylamine (320 μL, 2.3 mmol, 1 eq.), 4-(dimethylamino)pyridine (281 mg, 2.3 mmol, 1 eq.) and di(tert-butyl) dicarbonate (1.0 g, 4.6 mmol, 2 eq.) in dichloromethane (20 mL) was stirred at RT for 2 h. The reaction was concentrated and the residue partitioned between dichloromethane and saturated ammonia chloride. The organic layer was dried and concentrated, and the residue purified by column chromatography on silica gel eluting with 1 :1 hexane:ethyl acetate to afford methyl 2-{[(tert-butoxycarbonyl)amino]sulfonyl}benzoate (1a) as a white solid (326 mg, 45% yield). 1H NMR (300 MHz, DMSO) δ 11.71 (s, 1 H), 8.00 (m, 1 H), 7.75 (m, 2H), 7.67 (m, 1 H), 3.83 (s, 3H), 1.27 (s, 9H). ES- LCMS m/z 314.16 (M-H). 2-{[(tert-butoxycarbonyl)amino]sulfonyl} benzoic acid 1 b. A mixture of methyl 2-{[(tert-butoxycarbonyl)amino]sulfonyl}benzoate 1a (400 mg, 1.3 mmol, 1 equiv) and lithium hydroxide (1.6 g, 39 mmol, 30 equiv) in tetrahydrofuran (10 mL) and water (2.5 mL) was stirred at RT for 18 h. The reaction was partially concentrated, acidified with 1 N HCl and the product extracted into ethyl acetate. The organic layer was dried and concentrated to afford 2-{[(tert-butoxy carbonyl)amino]sulfonyl}benzoic acid (1b) as a white solid (200 mg, 51 % yield). 1H NMR (300 MHz, DMSO) δ 7.94 (m, 1 H), 7.71 (m, 3H), 1.26 (s, 9H). ES-LCMS m/z 300.08 (M-H). tert-Butyl {2-[(4-{2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]phenyl}sulfonyl carbamate, 1c. To a solution of endo 2-methyl-1-{8-[2-(4-phenylpiperidin-4- yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole dihydrochloride II (238 mg, 0.47 mmol, 1 eq.) in dimethylformamide (14 mL) was added 2-{[(tert- butoxycarbonyl)amino]sulfonyl}benzoic acid 1b (140 mg, 0.47 mmol, 1 eq.) and Λ/,Λ/-diisopropylethyl amine (0.3 mL, 1.41 mmol, 3 eq.). After stirring at RT for several minutes, O-(7-azabenzotriazol-1-yl)-Λ/ /V,Λ/, N- tetramethyluroniumhexafluorophosphate (179 mg, 1.41 mmol, 1 eq.) was added and the reaction was stirred for 2 h. The mixture was partitioned between dichloromethane and water. The organic layer was dried and concentrated to provide crude tert-butyl {2-[(4-{2-[3-(2-methyl-1 H- benzimidazol-1-yl)-8-azabicyclo[3.2.1] oct-8-yl]ethyl}-4-phenylpiperidin-1- yl)carbonyl]phenyl} sulfonylcarbamate 1c. The crude product was used without further purification. 2-[(4-{2-[3-(2-Methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1]oct-8- yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]benzenesulfonamide (example 676). A mixture of crude tert-butyl {2-[(4-{2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]phenyl}sulfonyl carbamate 1c and 4N HCl in dioxane (3 mL) was stirred at RT for 2 h. The reaction mixture was partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The organic layer was dried and concentrated and the residue was purified by prep. HPLC (Method Y) to provide 2-[(4-{2-[3- (2-methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1 ]oct-8-yl]ethyl}-4- phenylpiperidin-1-yl)carbonyl]benzenesulfonamide 1 as a white solid (45 mg, 16% yield). 1H NMR (300 MHz, DMSO) δ 8.05 (m, 1 H), 7.63 (m, 3H), 7.39- 7.15 (m, 9H), 5.61 (m, 2H), 4.60 (m, 1 H), 4.38 (m, 1 H), 3.43-3.04 (m, 5H), 2.54 (s, 3H), 2.35-2.17 (m, 4H), 2.13-1.40 (m, 12H). ES-LCMS m/z 612.25 (M+H). Analytical HPLC (Method W) Rt 7.59 (95.89%).
Example 677 4-Chloro-N-methyl-2-r(4-(2-r3-(2-methyl-1H-benzimidazol-1-yl)-8- azabicvclo[3.2.noct-8-vnethyl)-4-phenylpiperidin-1- vDcarbonvnbenzenesulfonamide
Figure imgf000436_0001
Example 677 was prepared as outlined below.
2a 2b - 2e
Figure imgf000436_0002
R=methyl, cyclopropyl, isopropyl, propyl
Figure imgf000436_0003
example 677: R = methyl; GW 854583X example 678: R = cyclopropyl; GW 854584X
HATU, DIEA example 679: R = isopropyl; GW 854585X DMF example 680: R = propyl; GW 854586X A mixture of 3-chloro-4-(chlorosulfonyl) benzoic acid and 5-chloro-2- (chlorosulfonyl)benzoic acid, 2a.
2a
Figure imgf000437_0001
3-Chlorobenzoic acid (7.0 g, 44.7 mmol, 1 equiv) was added at 0 °C to chlorosulfonic acid (40 mL). The reaction mixture was heated to 120 °C for 72 h, cooled to RT and poured slowly over ice. The product was extracted into diethyl ether, dried and concentrated to provide a 4:1 mixture of regioisomers, 5-chloro-4-(chlorosulfonyl)benzoic acid and 3-chloro-2-(chlorosulfonyl)benzoic acid 2a as a brown solid (5.26 g, 46% yield). 1H NMR (300 MHz, DMSO) δ 8.07 (m, 1 H), 7.96 (m, 1 H), 7.79 (m, 3 H), 7.59 (m, 1 H). ES-LCMS m/z 234.85 (M-2H) for C7H5CIO5S.
A mixture of 5-chloro-2-[(methylamino) sulfonyljbenzoic acid and 3- chloro-4-[(methylamino) sulfonyljbenzoic acid, 2b.
2b
Figure imgf000437_0002
To a solution of 3-chloro-4-(chlorosulfonyl)benzoic acid and 5-chloro-2- (chlorosulfonyl)benzoic acid 2a (0.5 g, 1.96 mmol, 1 eq.) in dichloromethane (10 mL) was added 4-(dimethylamino)pyridine (24 mg, 0.196 mmol, 0.1 eq.) and 2M methyl amine in THF (2.94 mL, 5.88 mmol, 3 eq.). The reaction mixture was stirred at RT for 18 h then concentrated to dryness. The residue was acidified with 1 N HCl and the product was extracted into dichloromethane. The organic layer was concentrated, the residue taken up in water and acidified with 1 N HCl. The product was extracted into dichloromethane, dried and concentrated to provide a crude mixture of 5- chloro-2-[(methylamino)sulfonyl] benzoic acid and 3-chloro-4- [(methylamino)sulfonyl] benzoic acid 2b. The residue was carried on without further purification. ES-LCMS m/z 248.01 (M-H).
4-Chloro-N-methyl-2-[(4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1 - yl)carbonyl]benzenesulfonamide (example 677). The title compound was prepared from a mixture of 5-chloro-2-[(methylamino)sulfonyl]benzoic acid and 3-chloro-4-[(methylamino)sulfonyl]benzoic acid 2b and endo 2-methyl-1- {8-[2-(4-phenylpiperidin-4-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1 H- benzimidazole dihydrochloride II following the general procedure for tert-butyl {2-[(4-{2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}- 4-phenyl piperidin-1-yl)carbonyl]phenyl}sulfonylcarbamate 1c. The desired regioisomer was purified by column chromatography on silica gel eluting with 10% methanol in ethyl acetate to afford 4-chloro-N-methyl-2-[(4-{2-[3-(2- methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1] oct-8-yl]ethyl}-4- phenylpiperidin-1-yl)carbonyl]benzene sulfonamide 2 as a white solid (15 mg, 8% yield). 1H NMR (400 MHz, CDCI3) δ 8.12 (d, 1 H, J=7.9 Hz), 7.65 (m, 1 H), 7.53 (m, 1 H), 7.39 (m, 3H), 7.27 (m, 4H), 7.19-7.12 (m, 2 H), 5.12 (q, 1 H, J=5.2 Hz), 4.60 (m, 1 H), 4.20 (m, 1 H), 3.48-3.20 (m, 5H), 2.64 (d, 3H, J=5.3 Hz), 2.56 (s, 3H), 2.40-2.33 (m, 3H), 2.18 (m, 1 H), 1.93-1.62 (m, 12H). ES- LCMS m/z 662.30 (M+2H). Analytical HPLC (Method Y) Rt 4.16 (90.0%).
Example 678 4-Chloro-N-cvclopropyl-2-r(4-(2-r3-(2-methyl-1H-benzimidazol-1-vn-8- azabicvclo 3.2.11oct-8-vnethyl)-4-phenylpiperidin-1 - yPcarbonvπbenzenesulfonamide
678
Figure imgf000438_0001
A mixture of 5-chloro-2-[(cyclopropylamino) sulfonyljbenzoic acid and 3-chloro-4-[(cyclopropyl amino)sulfonyl]benzoic acid, 2c.
2c
Figure imgf000439_0001
The mixture was prepared from a mixture of 3-chloro-4- (chlorosulfonyl)benzoic acid and 5-chloro-2-(chloro sulfonyl)benzoic acid 2a and cyclopropyl amine following the general procedure for 5-chloro-2-[(methyl amino)sulfonyl]benzoic acid and 3-chloro-4-[(methyl amino)sulfonyl]benzoic acid 2b. The crude reaction mixture was carried on without further purification. ES-LCMS m/z 274 (M-H).
4-Chloro-N-cyclopropyl-2-[(4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]benzene sulfonamide (example 678). The title compound was prepared from a mixture of 5-chloro-2-[(cyclopropyl amino)sulfonyl]benzoic acid and 3-chloro-4-[(cyclo propylamino)sulfonyl]benzoic acid 2c and endo 2-methyl-1-{8-[2-(4- phenylpiperidin-4-yl)ethyl]-8-azabicyclo [3.2.1]oct-3-yl}-1 H-benzimidazole dihydrochloride II following the general procedure for tert-butyl {2-[(4-{2-[3-(2- methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo [3.2.1]oct-8-yl]ethyl}-4-phenyl piperidin-1-yl)carbonyl]phenyl}sulfonylcarbamate 1c. The desired regioisomer was purified by column chromatography on silica gel eluting with 10% methanol in ethyl acetate to afford 4-chloro-N-cyclopropyl-2-[(4-{2-[3-(2- methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo [3.2.1]oct-8-yl]ethyl}-4- phenylpiperidin-1-yl)carbonyl] benzene sulfonamide 3 as a white solid (15 mg, 11% yield). 1H NMR (400 MHz, CDCI3) δ 8.18 (d, 1H, J=8.1 Hz), 7.65 (m, 1 H), 7.54 (m, 1 H), 7.41-7.12 (m, 9H), 5.48 (s, 1 H), 4.60 (m, 1H), 4.20 (m, 1 H), 3.45-3.23 (m, 6H), 2.56 (s, 3H), 2.40-2.33 (m, 3H), 2.20-2.17 (m, 1 H), 1.97-1.58 (m, 10H), 0.70-0.56 (m, 4H). ES-LCMS m/z 688.35 (M+2H). Analytical HPLC (Method Y) Rt 3.34 (89.34%). Example 679 4-Chloro-N-isopropyl-2-r(4-f2-r3-(2-methyl-1 H-benzimidazol-1-vn-8- azabicvclor3.2.1loct-8-yl1ethyl)-4-phenylpiperidin-1- vDcarbonyllbenzenesulfonamide
679
Figure imgf000440_0001
A mixture of 5-chloro-2-[(isopropylamino) sulfonyljbenzoic acid and 3- chloro-4-[(isopropyl amino)sulfonyl]benzoic acid, 2d.
Figure imgf000440_0002
The mixture was prepared from a mixture of 3-chloro-4- (chlorosulfonyl)benzoic acid and 5-chloro-2-(chloro sulfonyljbenzoic acid 2a and isopropyl amine following the general procedure for 5-chloro-2- [(methylamino) sulfonyljbenzoic acid and 3-chloro-4-[(methylamino) sulfonyljbenzoic acid 2b. The crude reaction mixture was carried on without further purification. ES-LCMS m/z 276 (M-H). 4-Chloro-N-isopropyl-2-[(4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]benzene sulfonamide (example 679). The title compound was prepared from a mixture of 5-chloro-2-[(isopropylamino) sulfonyljbenzoic acid and 3-chloro-4- [(isopropyl amino)sulfonyl]benzoic acid 2d and endo 2-methyl-1-{8-[2-(4- phenylpiperidin-4-yl)ethyl]-8-azabicyclo[3.2.1 ] oct-3-yl}-1 H-benzimidazole dihydrochloride II following the general procedure for tert-butyl {2-[(4-{2-[3-(2- methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1 ]oct-8-yl]ethyl}-4-phenyl piperidin-1-yl)carbonyl]phenyl} sulfonylcarbamate 1c. The desired regioisomer was purified by column chromatography on silica gel eluting with 10% methanol in ethyl acetate to afford 4-chloro-N-isopropyl-2-[(4-{2-[3-(2- O 2004/054974
440
methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo [3.2.1Joct-8-yl]ethyl}-4-phenyl piperidin-1-yl)carbonyl] benzenesulfonamide 4 as a white solid (30 mg, 22% yield). 1H NMR (400 MHz, CDCI3) δ 8.13 (d, 1H, J=8.0Hz), 7.65 (d, 1H, J=7.3Hz), 7.52 (m, 1H), 7.40-7.11 (m, 9H), 4.99 (d, 1H, J=7.32 Hz), 4.60 (m, 1 H), 4.20 (m, 1 H), 3.49-3.22 (m, 6H), 2.56 (s, 3H), 2.40-2.32 (m, 3H), 2.18 (m, 1H), 1.98-1.66 (m, 1H), 1.62 (m, 2H), 1.10 (d, 6 H, J=6.59Hz). ES-LCMS m/z 690.45 (M+2H). Analytical HPLC (Method Y) Rt 5.03 (88.43%).
Example 680 4-Chloro-2-r(4-(2-[3-(2-methyl-1 H-benzimidazol-1 -vn-8-azabicvclor3.2.1 Joct-8- vnethyl)-4-phenylpiperidin-1-yl)carbonvn-N-propylbenzenesulfonamide
680
Figure imgf000441_0001
A mixture of 5-chloro-2-[(propylamino) sulfonyljbenzoic acid and 3- chloro-4-[(propylamino) sulfonyljbenzoic acid, 2e.
Figure imgf000441_0002
The mixture was prepared from a mixture of 3-chloro-4- (chlorosulfonyl)benzoic acid and 5-chloro-2-(chloro sulfonyl)benzoic acid 2a and propyl amine following the general procedure for 5-chloro-2- [(methylamino) sulfonyljbenzoic acid and 3-chloro-4-[(methylamino) sulfonyljbenzoic acid 2b. The crude reaction mixture was carried on without further purification. ES-LCMS m/z 276 (M-H).
4-Chloro-2-[(4-{2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]-N- propylbenzene sulfonamide (example 680). The title compound was prepared from a mixture of 5-chloro-2-[(propylamino) sulfonyljbenzoic acid and 3- chloro-4-[(propylamino) sulfonyljbenzoic acid 2e and endo 2-methyl-1-{8-[2- (4-phenylpiperidin-4-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole dihydrochloride II following the general procedure for tert-butyl {2-[(4-{2-[3-(2- methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4- phenylpiperidin-1-yl)carbonyl]phenyl} sulfonylcarbamate 1c. The desired regioisomer was purified by column chromatography on silica gel eluting with 10% methanol in ethyl acetate to afford 4-chloro-2-[(4-{2-[3-(2-methyl-1 H- benzimidazol-1-yl)-8-aza bicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1- yl)carbonyl]-N-propylbenzenesulfonamide 5 as a white solid (15 mg, 11% yield). 1H NMR (400 MHz, CDCI3) δ (8.12, 1 H, J=8.0Hz), 7.65 (m, 1 H), 7.52 (m, 1 H), 7.41-7.12 (m, 9H), 5.10 (t, 1 H, J=6.0Hz), 4.59 (m, 1 H), 4.20 (m, 1 H), 3.48-3.19 (m, 6H), 2.89 (q, 1H, J=6.6Hz), 2.56 (s, 3H), 2.55-2.32 (m, 3H), 2.17 (m, 1 H), 1.93-1.64 (m, 10H), 1.61 (m, 1 H), 1.50 (m, 2H), 0.882 (t, 3H, J=7.3Hz). ES-LCMS m/z 690.33 (M+2H). Analytical HPLC (Method Y) Rt 5.39 (93.34%).
Example 681 4-Fluoro-2-r(4-f2-r3-.2-methyl-1 H-benzimidazol-1 -yl)-8-azabicvcloF3.2.1 loct-8- ylJethyl|-4-phenylpiperidin-1-yl)carbonyl1benzenesulfonamide
Figure imgf000442_0001
Example 681 was prepared as outlined below. 6a 6b - 6d
Figure imgf000443_0001
R = H, cyclopropyl, isopropyl,
Figure imgf000443_0002
example 681: R = H
HATU, DIEA example 682: R = cyclopropyl DMF example 683: R = isopropyl
A mixture of 2-(chlorosulfonyl)-5-fluorobenzoic acid and 4- (chlorosulfonyl)-3-fluorobenzoic acid, 6a.
6a
Figure imgf000443_0003
3-Fluorobenzoic acid (7.0 g, 50 mmol, 1 equiv) was added at 0 °C to chlorosulfonic acid (40 mL). The reaction mixture was heated to 130 °C for 6 h, cooled to RT and poured slowly over ice. The product was extracted into diethyl ether, dried and concentrated to provide a 4:1 mixture of regioisomers, 2-(chloro sulfonyl)-5-fluorobenzoic acid and 4-(chlorosulfonyl)-3-fluorobenzoic acid 6b, as a brown solid (5.26 g, 46% yield). 1H NMR (400 MHz, CDCI3) δ.8.14 (ddd, 1H, J=8.0Hz, 2.4Hz, 1.3Hz), 8.05-8.01 (m, 2H), 7.98 (ddd, 1 H, J=6.8Hz, 2.4Hz, 1.6Hz), 7.79 (dd, 1 H, J=6.8, 2.4Hz), 7.71 (td, 1 H, J=8.1 , 2.4Hz). ES-LCMS m/z 237.13 (M-H) for C7H5FO5S.
A mixture of 2-(aminosulfonyl)-5-fluoro benzoic acid and 4- (aminosulfonyl)-3-fluorobenzoic acid, 6b. 6b
Figure imgf000444_0001
Liquid ammonia was condensed at -78 °C into a reaction vessel containing a mixture of 2-(chlorosulfonyl)-5-fluorobenzoic acid and 4-(chlorosulfonyl)-3- fluoro benzoic acid 6a (100 mg, 0.419 mmol, 1 eq.). The reaction mixture was allowed to evaporate slowly upon warming to RT over 18 h. The crude residue contained a mixture of 2-(aminosulfonyl)-5-fluorobenzoic acid and 4- (aminosulfonyl)-3-fluorobenzoic acid and was used without further purification. ES-LCMS m/z 218 (M-H).
4-Fluoro-2-[(4-{2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin- 1 - yl)carbonyl]benzenesulfonamide (example 681). The title compound was prepared from a mixture of 2-(aminosulfonyl)-5-fluorobenzoic acid and 4- (aminosulfonyl)-3-fluorobenzoic acid 6b and endo 2-methyl-1-{8-[2-(4- phenylpiperidin-4-yl)ethyl]-8-aza bicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole dihydro-chloride II following the general procedure for tert-butyl {2-[(4-{2-[3-(2- methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1 ]oct-8-yl]ethyl}-4- phenylpiperidin-1-yl)carbonyl]phenyl}sulfonylcarbamate 1c. The desired regioisomer was purified by column chromatography on silica gel eluting with 20% methanol in ethyl acetate to afford 4-fluoro-2-[(4-{2-[3-(2-methyl-1 H- benzimidazol-1-yl)-8-azabicyclo[3.2.1Joct-8-yl]ethyl}-4-phenylpiperidin-1- yl)carbonylJbenzenesulfonamide 6 as a white solid (9.8 mg, 20% yield). 1H NMR (400 MHz, CDCI3) δ 7.90 (t, 1 H, J=7.7Hz), 7.64 (m, 1 H), 7.39 (m, 2H), 7.30-7.12 (m, 8H), 5.69 (broad s, 2H), 4.59 (m, 1 H), 4.20 (m, 1 H), 3.48-3.19 (m, 5H), 2.52 (s, 3H), 2.40-2.32 (m, 3H), 2.18 (m, 1 H), 2.04-1.70 (m, 10H), 1.62 (m, 2H). ES-LCMS m/z 630.19 (M+H). Analytical HPLC (Method Y) Rt 4.16 (90.0%). Example 682 N-Cyclopropyl-4-fluoro-2-[(4-{2-[3-(2-methyl-1 H-benzimidazol-1-yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]benzene sulfonamide was synthesized analogously to example 861.
Figure imgf000445_0001
A mixture of2-[(cyclopropylamino)sulfonyl]-5-fluorobenzoic acid and 4- [(cyclopropylamino) sulfonylJ-3-fluorobenzoic acid, 6c.
6c
Figure imgf000445_0002
The mixture was prepared from a mixture of 2-(chloro sulfonyl)-5- fluorobenzoic acid and 4-(chlorosulfonyl)-3-fluorobenzoic acid 6a and cyclopropyl amine following the general procedure for 5-chloro-2- [(methylamino) sulfonyljbenzoic acid and 3-chloro-4-[(methylamino) sulfonyljbenzoic acid 2b. The crude reaction mixture was carried on without further purification. ES-LCMS m/z 258 (M-H).
The title compound in example 682 was prepared from a mixture of 2- [(cyclopropylamino) sulfonyl]-5-fluorobenzoic acid and 4-[(cyclopropyl amino)sulfonyl]-3-fluorobenzoic acid 6c and endo 2-methyl-1-{8-[2-(4- phenylpiperidin-4-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole dihydrochloride II following the general procedure for tert-butyl {2-[(4-{2-[3-(2- methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1 ]oct-8-yl]ethyl}-4-phenyl piperidin-1-yl)carbonyl]phenyl}sulfonylcarbamate 1c. The desired regioisomer was purified by column chromatography on silica gel eluting with 10% methanol in ethyl acetate to afford N-cyclopropyl-4-fluoro-2-[(4-{2-[3-(2- methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1 ]oct-8-yl]ethyl}-4- phenylpiperidin-1-yl)carbonyl]benzenesulfonamide 7 as a white solid (40 mg, 20% yield). 1H NMR (400 MHz, CDCI3) δ 7.97 (t, 1H, J=7.4Hz), 7.65 (m, 1H), 7.38 (m, 2H, 7.29-7.12 (m, 8H), 5.87 (s, 1H), 4.59 (m, 1H), 4.19 (m, 2H), 3.50-3.10 (m, 5H), 2.55 (s, 3H), 2.39-2.16 (m, 5H), 1.92-1.73 (m, 10 H), 1.60 (m, 2H), 0.70-0.50 (m, 4H). ES-LCMS m/z 670.18 (M+H). Analytical HPLC (Method Y) Rt 4.35 (94.82%).
Example 683 4-Fluoro-N-isopropyl-2-r(4-(2-[3-(2-methyl-1H-benzimidazol-1-yl)-8- azabicvclo[3.2.1Joct-8-vnethyl)-4-phenylpiperidin-1- vDcarbonyllbenzenesulfonamide
Figure imgf000446_0001
Example 683 was prepared analogously to example 681. A mixture of 5-fluoro-2-[(isopropylamino)sulfonyl]benzoic acid and 4- fluoro-3-[(isopropylamino)sulfonyl]benzoic acid, 6d.
Figure imgf000446_0002
The mixture was prepared from a mixture of 2-(chloro sulfonyl)-5- fluorobenzoic acid and 4-(chlorosulfonyl)-3-fluorobenzoic acid 6a and isopropyl amine following the general procedure for 5-chloro-2-[(methylamino) sulfonyljbenzoic acid and 3-chloro-4-[(methylamino) sulfonyljbenzoic acid 2b. The crude reaction mixture was carried on without further purification. ES- LCMS m/z 260 (M-H).
Title compound in example 683 was prepared from a mixture of 5- fluoro-2-[(isopropylamino)sulfonyl] benzoic acid and 4-fluoro-3- [(isopropylamino)sulfonylj benzoic acid 6d and endo 2-methyl-1-{8-[2-(4- phenyl piperidin-4-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole dihydrochloride II following the general procedure for tert-butyl {2-[(4-{2-[3-(2- methyl-1 H-benzimidazol-1 -yl )-8-azabicyclo[3.2.1 ]oct-8-yl]ethyl}-4- phenylpiperidin-1-yl)carbonylJphenyl}sulfonyl carbamate 1c. The desired regioisomer was purified by column chromatography on silica gel eluting with 10% methanol in ethyl acetate to afford 4-fluoro-N-isopropyl-2-[(4-{2-[3-(2- methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1 ]oct-8-yl]ethyl}-4- phenylpiperidin-1-yl)carbonyl]benzenesulfonamide 8 as a white solid (45 mg, 25% yield). 1H NMR (400 MHz, CDCI3) δ 7.92 (t, 1 H, J=7.5Hz), 7.65 (m, 1 H), 7.38 (m, 2H), 7.29-7.11 (m, 8H), 5.14 (d, 1 H, J=7.5Hz), 4.59 (m, 1H), 4.18 (m, 1 H), 3.54-3.18 (m, 6H), 2.55 (s, 3H), 2.39-2.18 (m, 4H), 1.91-1.81 (m, 10H), 1.61 (m, 2H), 1.15 (m, 6 H). ES-LCMS m/z 672.22 (M+H). Analytical HPLC (Method Y) Rt 4.30 (100.0%).
Example 684 1-((1 R.5S)-8-(2-ri-(2,2-dimethylpropanoyl)-4-(3-methoχyphenvnpiperidin-4- vnethyl}-8-azabicvclor3.2.noct-3-yl)-2-methyl-1 H-benzimidazole
Figure imgf000447_0001
This compound was prepared from 3-methoxyphenylmagnesium bromide and 16a employing methods similar to those described in example 16. 1H NMR (400 MHz, DMSO-d6) δ 7.47 (d, 1 H, J=7 Hz), 7.34 (d, 1H, J=8 Hz), 7.27 (t, 1 H, J=8 Hz), 7.11 (t, 1 H, J=7 Hz), 7.08 (t, 1 H, J=7 Hz), 6.94 (d, 1 H, J=8 Hz), 6.88 (s, 1H), 6.79 (d, 1 H, J=8 Hz), 4.51 (m, 1 H), 3.75 (m, 2H), 3.74 (s, 3H), 3.23 (m, 4H), 2.50 (s, 3H, obscured by solvent peak), 2.34 (br dd, 2H, J=22, 9 Hz), 2.02 (m, 2H), 1.85 (m, 4H), 1.75 (m, 6H), 1.58 (d, 2H, J=8 Hz), 1.16 (s, 9H). HRMS C34H46N4O2 m/z 547.3186 (M+H)Caι.. 543.3699 (M+H)obs.543.3708. Example 685 1-((1 R,5S)-8-f2-π-(2,2-dimethylpropanovn-4-(4- trifluoromethylphenvπpiperidin-4-vnethyll-8-azabicvclo[3.2.noct-3-vπ-2- methyl-1 H-benzimidazole
Figure imgf000448_0001
This compound was prepared from 4-trifluoro methylphenylmagnesium bromide and 16a employing methods similar to those described in example 16. 1H NMR (400 MHz, DMSO-d6) δ 7.70 (d, 2H, J=8 Hz), 7.62 (d, 2H, J=8 Hz), 7.47 (d, 1H, J=7 Hz), 7.34 (d, 1H, J=7 Hz), 7.10 (t, 1H, J=7 Hz), 7.07 (t, 1 H, J=7 Hz), 4.49 (m, 1 H), 3.76 (m, 2H), 3.23 (m, 4H), 2.50 (s, 3H, obscured by solvent peak), 2.34 (br. dd, 2H, J=22, 9 Hz), 2.07 (m, 2H), 1.90-1.70 (m, 10H), 1.57 (d, 2H, J=7 Hz), 1.16 (s, 9H). HRMS C34H43F3N4O m/z 581.3467 (M+H)Cai., 581.3474 (M+H)obs.
Example 686 2-Chloro-5-«4-(2-IT1 R.5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicvclor3.2.11oct-8-vπethyll-4-r4-(trifluoromethyl)phenylJpiperidin-1 - yllcarbonvDbenzene sulfonamide
Figure imgf000448_0002
This compound was prepared from 4-trifluoro-methylphenylmagnesium bromide and 16a employing methods similar to those described in example 16. 1H NMR (400 MHz, CD3OD) δ 7.95-7.78 (m, 2H), 7.71 (d, 2H, J=8Hz), 7.67 (m, 1 H), 7.64 (d, 2H, J=8Hz), 7.52 (br.d, 1 H, J=7 Hz), 7.42 (br. d, 1 H, J=7 Hz), 7.20 (t, 1H, J=7 Hz), 7.17 (t, 1H, J=7 Hz), 4.74 (m, 1H), 4.19 (m, 1H), 3.40 (m, 4H), 3.18 (m, 1 H), 2.52 (s, 3H), 2.43 (m, 3H), 2.25 (m, 1 H), 1.99 (m, 10H), 1.71 (d, 2H, J=7 Hz). HRMS C36H39CIF3N5O3S m/z 714.2492 (M+H)Caι.. 714.2492 (M+H)0bs.
Example 687 2-Chloro-5-((4-f2-r(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicvclo[3.2.1Joct-8-yl1ethyl}-4-[4-(methyl sulfonyDphenvUpiperidin-l- vDcarbonvObenzene sulfonamide
Figure imgf000449_0001
This compound was prepared from 4-(methyl thio)phenylmagnesium bromide and 16a employing methods similar to those described in example 16. The 4-(methylthio)phenyl intermediate corresponding to 16d was oxidized to the methylsulfonyl derivative with MCPBA and converted to ompound 687 by methods similar to those outlined in example 16. 1H NMR (400 MHz,
CD3OD) δ 8.02 (d, 2H, J=6 Hz), 7.93 (m, 1 H), 7.92 (m, 1 H), 7.75 (d, 2H, J=6 Hz), 7.70 (m, 1 H), 7.58 (d, 1 H, J=7 Hz), 7.50 (d, 1 H, J=7 Hz), 7.28 (m, 2H), 4.24 (m, 1 H), 3.79 (m, 2H), 3.40 (m, 4H), 3.18 (m, 1 H), 3.15 (s, 3H), 2.59 (s, 3H), 2.47 (m, 2H), 2.35 (m, 1H), 2.25-2.00 (m, 12H). HRMS C36H42CIN5O5S2 m/z 724.2394 (M+H)Caι.. 724.2372 (M+H)obs,
Example 688 1 -[(1 R.5S)-8-(2-f 1 -(2.2-Dimethylpropanovn-4-r4- (methylsulfonyl)phenvnpiperidin-4-yllethyl)-8-azabicvclo[3.2.11oct-3-vπ-2- methyl-1 H-benzimidazole
Figure imgf000450_0001
This compound was prepared from 4-(methyl thio)phenylmagnesium bromide and 16a employing methods similar to those described in example 16. The 4-(methylthio)phenyl intermediate corresponding to 16d was oxidized to the methylsulfonyl derivative with MCPBA and converted by methods similar to those outlined in example 16. 1H NMR (400 MHz, DMSO-c/e) δ 7.90 (d, 2H, J=8 Hz), 7.68 (d, 2H, J=8 Hz), 7.48 (d, 1H, J=6 Hz), 7.35 (d, 1 H, J=7 Hz), 7.10 (m, 2H), 4.50 (m, 1 H), 3.75 (m, 2H), 3.27 (m, 4H), 3.20 (s, 3H), 2.50 (s, 3H, obscured by solvent peak), 2.35 (dd, 1 H, J=19, 10 Hz), 2.08 (m, 2H), 1.85 (m, 9H), 1.76 (m, 2H), 1.59 (m, 2H), 1.17 (s, 9H). HRMS C34H46N4O3S m/z 591.3369 (M+H)Caι., 591.3397 (M+H)0bs,
Example 689 2-Chloro-5-r(4-(3-isopropylphenyl)-4-f2-r(1R.5S)-3-(2-methyl-1H- benzimidazol-1-ylV8-azabicvclor3.2.noct-8-ylJethyl)piperidin-1- vDcarbonyllbenzenesulfonamide
Figure imgf000450_0002
This compound was prepared from 3-isopropyl phenylmagnesium bromide and 16a employing methods similar to those described in example 16. 1H NMR (400 MHz, DMSO-o* 6) δ 7.93 (s, 1H), 7.68 (d, 1H, J=8 Hz), 7.63 (br, 2H), 7.61 (d, 1 H, J=8Hz), 7.48 (d, 1 H, J=7 Hz), 7.34 (d, 1 H, J=7 Hz), 7.27 (t, 1 H, J=8 Hz), 7.23 (s, 1 H), 7.18 (d, 1 H, J=7 Hz), 7.09 (m, 3H), 4.49 (m, 1 H), 3.89 (m, 1H), 3.50-3.30 (m, 2H), 3.20 (m, 4H), 2.89 (m, 1H, J=7 Hz), 2.43 (s, 3H), 2.35 (br.dd, 2H, J=22, 10 Hz), 2.17 (m, 1 H), 2.07 (m, 1 H), 1.90-1.70 (m, 9H), 1.56 (br.d, 2H, J=8Hz), 1.20 (d, 6H, J=7 Hz). HRMS C∞hUβCINsOaS m/z 688.3088 (M+H)Caι., 688.3075 (M+H)0bs.-
Example 690 Methyl 3-[Y4-(3-isopropylphenvn-4-(2-IY1 R,5S)-3-(2-methyl-1 H-benzimidazol- 1-yl)-8-azabicvclor3.2.noct-8-yllethyl>piperidin-1-vπcarbonvnbenzoate
Figure imgf000451_0001
This compound was prepared from 3-isopropyl phenylmagnesium bromide and 16a employing methods similar to those described in example 16. 1H NMR (400 MHz, DMSO-de) δ 8.01 (d, 1 H, J=7 Hz), 7.91 (s, 1 H), 7.67 (d, 1 H, J=8 Hz), 7.58 (t, 1 H, J=8 Hz), 7.48 (d, 1 H, J=7 Hz), 7.34 (d, 1H, J=7 Hz), 7.27 (t, 1 H, J=8 Hz), 7.23 (s, 1 H), 7.23 (d, 1 H, J=8 Hz), 7.09 (m, 3H), 4.49 (m, 1 H), 3.89 (m, 1 H), 3.84 (s, 3H), 3.43 (m, 1 H), 3.37 (m, 1 H), 3.21 (m, 3H), 2.89 (m, 1 H, J=7 Hz), 2.41 (s, 3H), 2.35 (m,. 2H), 2.16 (m, 1 H), 2.07 (m, 1 H), 1.90-1.70 (m, 10H), 1.59 (br. d, 2H, J=8 Hz), 1.22 (d, 6H, J=8 Hz). HRMS C4oH48N4O3 m/z 633.3805 (M+H)Caι, 633.3787 (M+H)0 s..
Example 691 3-r(4-(3-lsopropylphenyl )-4-f2-r(1R,5S)-3-f2-methyl-1 H-benzimidazol-1 -vh-8- azabicvclor3.2.1Joct-8-yl1ethyl)piperidin-1-yl)carbonyl1benzoic acid
Figure imgf000452_0001
This compound was prepared by hydrolysis of the title compound in example 690 with lithium hydroxide employing methods familiar to those skilled in the art. 1H NMR (400 MHz, DMSO-d6) δ 13.1 (br, 1 H), 7.99 (d, 1 H, J=8 Hz), 7.89 (s, 1 H), 7.63 (d, 1 H, J=8Hz), 7.56 (t, 1 H, J=7 Hz), 7.49 (d, 1 H, J=7 Hz), 7.38 (br, 1 H), 7.25 (m, 2H), 7.19 (d, 1 H, J=8Hz), 7.11 (m, 3H), 4.51 (br, 1 H), 3.91 (br, 1 H), 3.45 (m, 1 H), 3.40-3.20 (m, 4H), 2.89 (m, 1 H, J=7 Hz), 2.45 (s, 3H), 2.40-1.60 (m, 16H), 1.20 (d, 6H, J=7 Hz). HRMS C39H46N4O3 m/z 619.3684 (M+H)Caι.. 619.3643 (M+H)0bs..
Example 692 (3S)-Tetrahvdrofuran-3-yl 4-J2-IΪ1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicvclor3.2.noct-8-vπethyl)-4-phenylpiperidine-1 -carboxylate
Figure imgf000452_0002
A solution of 1-({[(3S)-tetrahydrofuran-3-yloxy]carbonyl}oxy)pyrrolidine- 2,5-dione (US patent 6,344,465) (55 mg, 0.24 mmol), amine dihydrochloride II (100 mg, 0.199 mmol) and Λ/,Λ/-diisopropylethylamine (0.14 mL, 0.80 mmol) in acetonitrile (3 mL) was stirred overnight at rt. The solvent was removed at reduced pressure and the remaining material was dissolved in dichloromethane, washed with saturated sodium bicarbonate solution and dried over magnesium sulfate. Filtration and evaporation of the dichloromethane solution provided the crude product which was purified by chromatography on silica gel eluting with 5% methanol/dichloromethane. Title compound in example 692 was obtained as a white hygroscopic powder (70 mg, 65%). 1H NMR (400 MHz, CDCI3) δ 7.66 (d, 1 H, J=8 Hz), 7.37 (m, 2H), 7.30-7.20 (m, 4H), 7.16 (m, 2H), 5.25 (m, 1 H), 4.61 (m, 1 H), 3.85 (m, 4H), 3.73 (m, 2H), 3.22 (m, 4H), 2.58 (br s, 3H), 2.36 (m, 2H), 2.17 (m, 3H), 2.05- 1.70 (m, 13H). HRMS C33H42N4O3 m/z 543.3335 (M+H)Caι., 543.3331 (M+H)obs.-
Example 693 1 -f8-r2-(4-(3-fluorophenvn-1 -(β-ftrifluoromethyl) pyridin-2- yl1carbonyl)piperidin-4-yl)ethyl1-8-azabicvclo[3.2.11oct-3-yl)-2-methyl-1 H- benzimidazole
Figure imgf000453_0001
3-(Trifluoromethyl)-1H-pyrazole-4-carboxylic acid, 1a. A mixture of ethyl 3-(trifluoromethyl)-1H-pyrazole-4-carboxylate (100 mg, 0.48 mmol, 1 eq.), ethanol (5 mL) and 5N NaOH (5 mL) was heated to reflux for 72 h. The reaction was cooled to RT, acidified to pH 2 with 5 N HCl and the product extracted into ethyl acetate. The organic layers were dried over sodium sulfate, filtered and concentrated to provide 3-(trifluoromethyl)-1 H-pyrazole-4- carboxylic acid (1a) as a white solid (80 mg, 93% yield). 1H NMR (400 MHz, DMSO-d6) δ 13.95 (broad s, 1 H), 8.49 (s, 1 H), 3.50 (broad s, 1 H). ES-LCMS m/z 181.16 (M+H).
Figure imgf000454_0001
1-{8-[2-(4-(3-fluorophenyl)-1-{[3-(trifluoro methyl)pyridin-2- yl]carbonyl}piperidin-4-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-2-methyl- 1 H- benzimidazole (example 693). To a solution of 1 -(8-{2-[4-(3-fluoro phenyl)piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1 H- benzimidazole dihydrochloride II (130 mg, 0.25 mmol, 1 eq.) in dimethylformamide (4 mL) was added 3-(trifluoromethyl)-1 H-pyrazole-4- carboxylic acid, 1a, (50 mg, 0.27 mmol, 1 eq.) and Λ/,Λ/-diisopropylethyl amine (180 μL, 1.0 mmol, 4 eq.). After stirring at RT for several min, 0-(7- azabenzotriazol-1-yl)-Λ/ Λ/,/V, V-tetramethyl-uroniumhexafluorophosphate (95 mg, 0.25 mmol, 1 eq.) was added and the reaction was stirred for 2 h. The mixture was partitioned between dichloromethane and satd. aq. NaHCO3. The organic layer was dried and concentrated and the residue was purified by prep. HPLC (Method Y) to provide 1-{8-[2-(4-(3-fluorophenyl)-1-{[3- (trifluoromethyl)pyridin-2-yl]carbonyl}piperidin-4-yl)ethyl]-8- azabicyclo[3.2.1]oct-3-yl}-2-methyl-1 H-benzimidazole 1 as a white solid (30 mg, 20% yield).
1H NMR (300 MHz, DMSO-d6) δ 7.65 (m, 2H), 7.32 (m, 2H), 7.16 (m, 2H), 7.07 (m, 1 H), 6.97 (m, 2H), 4.62 (m, 1 H), 4.18 (m, 1 H), 3.50 (m, 1 H), 3.27 (m, 4H), 2.52 (m, 3H), 2.45 - 2.09 (m, 4H), 2.04-1.47 (m, 12H). ES-LCMS m/z 609.39 (M+H). Analytical HPLC (Method W) Rt 2.79 (95.89%). Example 694 1-((1 R.5S)-8 2-ri-(2.2-dimethylpropanoyl)-4-(4-fluorophenvnpiperidin-4- vnethyl}-8-azabicvclo[3.2.noct-3-ylV2-methyl-1 H-benzimidazole
Figure imgf000455_0001
example 6
5 The title compound was prepared according to procedures analogous to those described for example 16. 1H NMR (300 MHz, CDCI3) δ 7.68 (d, 1 H, J=2.3 Hz), 7.66 (d, 1 H, J=2.2 Hz), 7.32-7.25 (m, 2H), 7.18-7.15 (m, 2H), 7.09- 7.04 (m, 2H), 4.68-4.55 (m, 1 H), 3.95-3.90 (m, 2H), 3.41-3.20 (m, 4H), 2.57 (s, 3H), 2.43-2.33 (m, 2H), 2.19-2.14 (m, 2H), 1.95-1.62 (m, 12H), 1.26 (s, 0 9H). LRMS (ES, +ve ion) m/z 531.2 (M+H).
Example 695 1 -((1 R,5S)-8-(2-r4-(3,4-dichlorophenyl)-1 -(2.2-dimethylpropanovnpiperidin-4- yllethyl)-8-azabicvclof3.2.11oct-3-yl)-2-methyl-1 H-benzimidazole
Figure imgf000455_0002
c Example 695
The title compound was prepared according to procedures analogous to those described for example 16. 1H NMR (300 MHz, CDCI3) δ 7.66 (d, 1 H, J=6.9 Hz), 7.45 (d, 1H, J=8.3 Hz), 7.39 (br. s, 1H), 7.32-7.27 (m, 1 H), 7.20- 7.14 (br. m, 3H), 4.62 (app quint, 1 H, J=9.2 Hz), 3.97-3.87 (m, 2H), 3.41-3.25 0 (m, 4H), 2.58 (s, 3H), 2.44-2.34 (m, 2H), 2.16-2.10 (m, 2H), 1.97-1.65 (m, 12H), 1.27 (s, 9H). LRMS (ES, +ve ion) m/z 581.0 (M+), 583.3 (M+2, 37CI). Example 696 1-((1R.5S)-8-f2-f1-benzoyl-4-(3,4-dichlorophenvn iperidin-4-yllethyl)-8- azabicvclor3.2.noct-3-yl)-2-methyl-1 H-benzimidazole
example 696
Figure imgf000456_0001
The title compound was prepared according to procedures analogous to those described for example 16. 1H NMR (300 MHz, CDCI3) δ 7.66 (d, 1 H, J=7.2 Hz), 7.44 (app t) overlapping 7.39 (br s, 8H total), 7.32-7.25 (m) overlapping 7.26 (s, CHCI3, 2H total), 7.18-7.14 (m, 2H), 4.60 (app quint, 1 H, J=8.8 Hz), 4.13 (br s, 1 H), 3.57, 3.40, 3.27 (three overlapping br s, 6H total), 2.55 (s, 3H), 2.44-2.34 (m, 2H), 2.21-1.66 (m, 17H). FAB HRMS (calcd for MH+, C35H38CI2N4O) 601.2501 ; Found 601.2501.
Example 697 1-((1 R.5S)-8-f2-π-benzoyl-4-(3-chlorophenyl)piperidin-4-yl1ethyl)-8- azabicvclo[3.2.1 loct-3-v0-2-methyl-1 H-benzimidazole
Figure imgf000456_0002
The title compound was prepared according to procedures analogous to those described for example 16. 1H NMR (300 MHz, CDCI3) δ 7.66 (d, 1 H, J=6.9 Hz), 7.42-7.14 (m, 12H), 4.60 (app quint, 1H, J=9.1 Hz), 4.13 (br s, 1 H), 3.56, 3.42 and 3.27 (three overlapping br s, 6H total), 2.55 (s, 3H), 2.44-1.63 (m, 17H). FAB HRMS (calcd for MH+, C35H39CIN4O) 567.2891 ; Found 567.2885. Example 698
1 -((1 R.5SV-8-I2-M -(2.2-dimethylpropanoyl)-4-(3-fluorophenyl)piperidin-4- vnethyl)-8-azabicvclo[3.2.11oct-3-vπ-2-methyl-1 H-benzimidazole
Figure imgf000457_0001
The title compound was prepared according to procedures analogous to those described for example 16. 1H NMR (300 MHz, CDCI3) δ 7.66 (d, 1 H, J=7.2 Hz), 7.38-7.29 (m, 2H), 7.20-6.92 (m, 5H), 4.61 (app quint, 1 H, J=8.7 Hz), 3.96 and 3.91 (two overlapping br s, 2H total), 3.42-3.25 (m, 4H), 2.58 (s, 3H), 2.43-2.33 (m, 2H), 2.19-2.12 (m, 2H), 1.96-1.62 (m, 12H), 1.28 (s, 9H). LRMS (ES, +ve ion) m/z 531.3 (M+H).
Example 699 1 -((1 R,5S)-8-(2-ri -(2.2-dimethylpropanoyl)-4-thien-2-ylpiperidin-4-vnethyl)-8- azabicvclo[3.2.1]oct-3-vD-2-methyl-1 H-benzimidazole
Figure imgf000457_0002
The title compound was prepared according to procedures analogous to those described for example 16. 1H NMR (300 MHz, CDCI3) δ 7.66 (d, 1 H, J=6.6 Hz), 7.33-7.15 (m, 4H), 6.99 (app t, 1 H, J=4.3 Hz), 6.83 (d, 1 H, J=3.3 Hz), 4.64 (app quint, 1 H, J=9.0 Hz), 4.09 and 4.04 (two overlapping br s, 2H total), 3.33-3.20 (m, 4H), 2.58 (s, 3H), 2.45-2.34 (m, 2H), 2.20-1.64 (m, 14H), 1.28 (s, 9H). LRMS (ES, +ve ion) m/z 518.4 (M+). Example 700 2-chloro-5-r(4-(3-fluorophenvn-4-{2-IT1 R.5SV3-(2-methyl-1 H-benzimidazol-1 - v0-8-azabicvclof3.2.11oct-8-yllethyl)piperidin-1- vOcarbonv-lbenzenesulfonamide
Figure imgf000458_0001
The title compound was prepared according to procedures analogous to those described for example 16. 1H NMR (300 MHz, CD3OD) δ 7.93 (app d, 2H, J=9.6 Hz), 7.78-7.64 (m, 1H), 7.53-7.39 (m, 3H), 7.24-7.15 (m, 4H), 6.99 (app t, 1 H, J=8.0 Hz), 4.73 (app quint, 1 H, J=9.6 Hz), 4.20-4.15 (br m, 1 H), 3.48-3.29 (m) overlapping 3.30 (s, MeOH, 6H total), 3.22-3.14 (m, 1 H), 2.52 (s, 3H), 2.48-2.34 (m, 3H), 2.10-1.88 (m, 11 H), NH2 (not observed).
Example 701 1 -((1 R,5S)-8-f2-ri -(2,2-dimethylpropanoyl)-4-(3-ethylphenyl)piperidin-4- vnethyll-8-azabicvclor3.2.1loct-3-yl)-2-methyl-1 H-benzimidazole
Figure imgf000458_0002
The title compound was prepared according to procedures analogous to those described for example 16. 1H NMR (300 MHz, CDCI3) δ 7.69 (d, 1 H, J=7.2 Hz), 7.33-7.08 (m, 7H), 4.68 (app quint, 1 H, J=8.8 Hz), 3.98-3.93 (br m, 2H), 3.63 (br m, 2H), 3.36-3.29 (m, 4H), 2.68 (q, 2H, J=7.5 Hz), 2.59 (s, 3H), 2.47-2.37 (m, 2H), 2.26-2.20 (m, 2H), 2.01-1.66 (m, 10H), 1.29 (s) overlapping 1.26 (t, J=7.7 Hz, 12 H total). LRMS (ES, +ve ion) m/z 541.4 (M+H). Example 702 1-((1 R.5SV8-(2-[1-(2.2-dimethylpropanoyl)-4-(4-ethylphenyl)piperidin-4- vnethyli-8-azabicvclor3.2.1loct-3-yl)-2-methyl-1 H-benzimidazole
Figure imgf000459_0001
The title compound was prepared according to procedures analogous to those described for example 16. 1H NMR (300 MHz, CDCI3) δ 7.70-7.67 (m, 1 H), 7.33-7.28 (m, 1 H), 7.22-7.13 (m, 6H), 4.65 (app quint, 1 H, J=8.9 Hz), 4.00-3.93 (m, 2H), 3.34-3.26 (m, 4H), 2.66 (q, 2H, J=7.5 Hz), 2.59 (s, 3H), 2.45-2.34 (m, 2H), 2.25-2.19 (m, 2H), 1.96-1.62 (m, 12H), 1.28 (s) overlapping 1.26 (t, J=7.7 Hz, 12 H total). LRMS (ES, +ve ion) m/z 541.4 (M+H).
Example 703 Endo 1 -((1 R,5S)-8-{2-[4-(3-chloro-4-fluorophenyl)-1 -(2,2- dimethylpropanoyl)piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl- 1 H-benzimidazole was synthesized according to the procedures described in example 16 with a 3-chloro-4-fluoro instead of a 3-chloro substitution in the phenyl ring.
Figure imgf000459_0002
Tert-butyl 4-(3-chloro-4-fluorophenyl)-4-(1 -cyano-2-ethoxy-2- oxoethyl)piperidine-1 -carboxylate was prepared and used without further purification as described in example 16b from 1-fluoro-2-chloro-4- bromobenzene (10 g, 47.74 mmol) using tetrahydrofuran instead of diethyl ether as a solvent to afford an oil (6.76 g, 100%). ES-LCMS m/z 423 (M-H)4
Figure imgf000460_0001
[1-(Tert-butoxycarbonyl)-4-(3-chloro-4-fluorophenyl)piperidin-4- yl](cyano) acetic acid was prepared and used without further purification as described in example 16c (6.76 g, 15.9 mmol) to afford an oil (6.31 g, 100%).
Figure imgf000460_0002
Tert-butyl endo 4-(3-chloro-4-fluorophenyl)-4-(cyanomethyl)piperidine- 1 -carboxylate was prepared as described in example 16d (6.31 g, 15.9 mmol), purified by column chromatography on silica gel, eluting with a gradient of 5- 40% ethyl acetate in hexane to afford a beige solid (2.86 g, 51%). 1H NMR (300 MHz, CDCIs) δ 7.41 (dd, 1 H, J=2.3, 2.5 Hz) 7.30-7.21 (m, 2H), 3.76-3.72 (m, 2H), 3.13 (br t, 2H, J=10.4 Hz), 2.57 (s, 2H), 2.29-2.24 (br m, 2H), 1.93- 1.84 (m, 2H), 1.46 (s, 9H). ES-LCMS m/z 253 (M-BOC+H)+.
Figure imgf000460_0003
Tert-butyl 4-(3-chloro-4-fluorophenyl)-4-(2-oxoethyl)piperidine-1- carboxylate was prepared as described in example 16e from the product obtained in previous step (2.86 g, 8.106 mmol) to afford terf-butyl 4-(3-chloro- 4-fluorophenyl)-4-(2-oxoethyl)piperidine-1 -carboxylate as an oil (2.20 g, 76.2%). 1H-NMR (300 MHz, CDCI3) δ 9.45 (t, 1 H, J=2.6 Hz), 7.40(dd, 1 H, J=2.4 Hz), 7.28-7.20 (m, 2H), 3.66-3.60 (m, 2H), 3.33-3.25 (m, 2H), 2.68 (s, 2H), 2.24-2.17 (br m, 2H), 1.95-1.82 (m, 2H), 1.45 (s, 9H).
Figure imgf000461_0001
Tert-butyl 4-(3-chloro-4-fluorophenyl)-4-{2-[(1 R,5S)-3-(2-methyl-1 H- benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}piperidine-1 -carboxylate was prepared as described in example 16f from the product obtained in previous atep (2.20 g, 6.183 mmol) and purified by column chromatography on silica gel, eluting with a gradient of 2-7% methanol in dichloromethane to afford a rigid foam (1.35 g, 61.2%). 1H-NMR (300 MHz, CDCI3) δ 7.70 (dd, 1 H, J=2, 2.7 Hz), 7.35-7.31 (m, 2H), 7.23-7.11 (m, 4H), 4.72-4.63 (m, 1 H), 3.90- 3.81 (m, 2H), 3.68-3.63 (br m, 2H), 3.38-3.19 (m, 4H), 3.15-3.00 (m, 1 H), 2.61 (s, 3H), 2.55-2.40 (m, 2H), 2.10-1.65 (m, 11 H), 1.45 (s, 9H). ES-LCMS m/z 581 (M+H)+.
Endo 1-((1 R,5S)-8-{2-[4-(3-chloro-4-fluoro phenyl)piperidin-4-yl]ethyl}- 8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1 H-benzimidazole dihydrochloride was prepared and used without additional purification as described in example 16g from the product obtained in previous step (1.35 g, 2.26 mmol) to afford a rigid foam (1.28 g, 100%). ES-LCMS m/z 481 (M+H)+.
Figure imgf000461_0002
Endo 1-((1 R,5S)-8-{2-[4-(3-chloro-4-fluoro phenyl)-1-(2,2- dimethylpropanoyl)piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl- 1 H-benzimidazole (example 703). Title compound in example 703 was prepared as described in example 16 from endo 1-((1 R,5S)-8-{2-[4-(3-chloro- 4-fluorophenyl)piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1 H- benzimidazole dihydrochloride (100 mg, 0.18 mmol), using 3 equivalents of triethylamine abd then purified by column chromatography on silica gel, eluting with a gradient of 2-5% methanol in dichloromethane to afford endo 1- ((1 R,5S)-8-{2-[4-(3-chloro-4-fluorophenyl)-1-(2,2-dimethylpropanoyl)piperidin- 4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1 H-benzimidazole as a rigid foam (40 mg, 39.2 %). 1H-NMR (300 MHz, CDCI3) δ 7.69 (d, 1 H, J=6.9 Hz), 7.37-7.31 (m, 2H), 7.18-7.14 (m, 4H), 4.75-4.59 (m, 1 H), 3.96-3.90 (m, 2H), 3.40-3.32 (m, 4H), 2.60 (s, 3H), 2.47-2.37 (m, 2H), 2.19-2.16 (m, 2H), 2.12- 1.79 (m, 8H), 1.70-1.65 (m, 4H), 1.30 (s, 9H). HRMS m/z (M+H) 565.3109 Cal., 565.3104 Obs.
Example 704
Endo 2-chloro-5-[(4-(3-chloro-4-fluoro phenyl)-4-{2-[(1 R,5S)-3-(2- methyl-1 H-benzimidazoi-1 -yl)-8-azabicyclo[3.2.1 ]oct-8-yl]ethyl}piperidin-1 - yl)carbonyl]benzenesulfonamide was prepared from endo 1-((1 R,5S)-8-{2-[4- (3-chloro-4-fluorophenyl)piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2- methyl-1 H-benzimidazole dihydrochloride (200 mg, 0.36 mmol) as described in Example 719, purified by column chromatography on silica gel, eluting with a gradient of 0-5% methanol in dichloromethane to afford the title compound as an off white solid737 mg, 14.6%). 1H-NMR (300 MHz, CDCI3) δ 8.14 (s, 1 H), 7.69-7.54 (m, 3H), 7.35-7.29 (m, 2H), 7.20-7.15 (m, 4H), 5.41 (br s, 2H), 4.66-4.60 (m, 1 H), 4.18-4.10 (m , 1 H), 3.51-3.29 (m, 4H), 2.58 (s, 3H), 2.48- 2.37 (m, 2H), 2.03-1.67 (m, 15H). HRMS m/z (M+H)+ 698.2135 Cal., 698.2132 Obs.
Figure imgf000462_0001
Example 705
Endo 1-[(1 R,5S)-8-(2-{1-(2,2-dimethyl propanoyl)-4-[4- (methylthio)phenyl]piperidin-4-yl}ethyl)-8-azabicyclo[3.2.1]oct-3-yl]-2-methyl- 1 H-benzimidazole was synthesized according to the methods outlined in example 16 with a 4-methylthio instead of a 3-chloro substitution in the phenyl ring.
Figure imgf000463_0001
Tert-butyl endo 4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-[4-(methylthio)phenyl]piperidine-1- carboxylate was prepared as described in example 16f (1.15 g, 3.29 mmol scale) and purified by column chromatography on silica gel, eluting with a gradient of 2.5-5% methanol in dichloromethane to afford an oil (1.39 g, 73.5%). 1H NMR (300 MHz, CDCI3) δ 7.70 (d, 1 H, J=7 Hz), 7.33-7.15 (m, 7H), 4.78-4.65 (m, 1 H), 3.75-3.62 (br m, 2H), 3.38-3.31 (br m, 2H), 3.23-3.15 (m, 2H), 2.60 (s, 3H), 2.51 (s, 3H), 2.48-2.39 (m, 4H), 2.21-2.15 (m, 2H), 1.99- 1.66 (m, 10H), 1.46 (s, 9H). ES-LCMS m/z 575 (M+H)+.
Figure imgf000463_0002
Endo 2-methyl-1-[(1 R,5S)-8-(2-{4-[4-(methyl thio)phenyl]piperidin-4- yl}ethyl)-8-azabicyclo[3.2.1] oct-3-yl]-1 H-benzimidazole dihydrochloride was prepared and used without further purificatio as described in example 16g from product from previous step (1.39 g, 2.418 mmol) to afford off white solid (1.03 g, 78%). ES-LCMS m/z 475 (M+H)+.
Figure imgf000464_0001
Example 705 The title compound in example 705 endo 1-[(1 R,5S)-8-(2-{1-(2,2- dimethylpropanoyl)-4-[4-(methyl thio)phenyl]piperidin-4-yl}ethyl)-8- azabicyclo[3.2.1] oct-3-yl]-2-methyl-1 H-benzimidazole was prepared as described in example 16 from the product obtained in previous step (100 mg, 0.183 mmol), using 3 equivalents of triethylamine and purified by column chromatography on silica gel, eluting with a gradient of 1-10% methanol in dichloromethane to afford beige solid (100.8 mg, 98.8 %). 1H-NMR (300 MHz, CDCI3) δ 7.69 (d, 1 H, J=7.1 Hz), 7.34-7.18 (m, 7H), 4.71-4.57 (m, 1 H), 3.99- 3.94 (m, 2H), 3.32-3.25 (m, 4H), 2.59 (s, 3H), 2.52 (s, 3H), 2.45-2.35 (m, 2H), 2.28-2.12 (m, 2H), 1.97-1.89 (m, 5H), 1.83-1.75 (m, 4H), 1.68-1.60 (m, 2H), 1.35 (s, 9H). HRMS m/z (M+H) 559.3471 Cal., 559.3480 Obs.
Figure imgf000464_0002
Example 706
Figure imgf000465_0001
Endo 2-chloro-5-({4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-[4-(methylthio)phenyl]piperidin-1-yl}carbonyl) benzenesulfonamide was prepared from endo 2-methyl-1-[(1 R,5S)-8-(2-{4-[4- (methylthio)phenyl] piperidin-4-yl}ethyl)-8-azabicyclo[3.2.1]oct-3-yl]-1H- benzimidazole dihydrochloride (200 mg, 0.365 mmol) as described in Example 719 and purified by Plate Purification Method A to afford thick oil (61.4 mg, 24.3%). 1H-NMR (300 MHz, CDCI3) δ 8.41 (s, 1 H), 7.70 (d, 1 H, J=7.1 Hz,), 7.61-7.53 (m, 2H), 7.31-7.17 (m, 7H), 4.93-4.86 (m, 1 H), 4.19-4.15 (m, 1 H), 3.57-3.44 (m, 4H), 3.37-3.27 (m, 2H), 2.59 (s, 3H), 2.52 (s, 3H), 2.46- 2.00 (m, 8H), 1.96-1.78 (m, 7H). HRMS m/z (M+H)+ 692.2496 Cal., 692.2498 Obs.
Example 707
Figure imgf000465_0002
Endo 1 -[(1 R,5S)-8-(2-{1 -(2,2-dimethyl-propanoyl)-4-[3- (methylthio)phenyl]piperidin-4-yl}ethyl)-8-azabicyclo[3.2.1]oct-3-yl]-2-methyl- 1 H-benzimidazole was synthesized according to the methods described in example 16 with a 3-methylthio instead of a 3-chloro substitution in the phenyl ring.
Tert-butyl 4-[3-(methylthio)phenyl]-4-(2-oxoethyl)piperidine-1 - carboxylate was prepared and used without further purification as described in example 16e from respective intermediate described in example 720 (2.11 g, 6.09 mmol) to afford tert-butyl 4-[3-(methylthio)phenyl]-4-(2- oxoethyl)piperidine-1-carboxylate as an oil (1.14 g, 53.5%). 1H-NMR (300 MHz, CDCI3) δ 9.41 (t, 1H, J=3 Hz), 7.36-7.26 (m, 1 H), 7.17-7.04 (m, 3H), 3.66-3.61 (br m, 2H), 3.32-3.24 (m, 2H), 2.66 (s, 2H), 2.51 (s, 3H), 2.27-2.21 (br m, 2H), 1.91-1.82 (m, 2H), 1.46 (s, 9H).
Figure imgf000466_0001
Tert-butyl endo 4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-[3-(methylthio)phenyl]piperidine-1- carboxylate was prepared as described in example 16f from the product obtained in previous step (1.14 g, 3.26 mmol) and purified by column chromatography on silica gel, eluting with a gradient of 0-5% methanol in dichloromethane to afford a rigid foam (0.70 g, 37.3%). 1H-NMR (300 MHz, CDCI3) δ 7.70 (d, 1 H, J=7 Hz), 7.34-7.08 (m, 7H), 4.70-4.65 (m, 1H), 3.75-3.65 (br m, 2H), 3.35-3.21 (m, 4H), 2.61 (s, 3H), 2.52 (s, 3H), 2.49-2.41 (m, 2H), 2.24-2.18 (m, 2H), 1.99- 1.66 (m, 12H), 1.47 (s, 9H). ES-LCMS m/z 575 (M+H)+.
Figure imgf000466_0002
Endo 2-methyl-1 -[(1 R,5S)-8-(2-{4-[3-(methylthio)phenyl]piperidin-4- yl}ethyl)-8-azabicyclo[3.2.1]oct-3-yl]-1 H-benzimidazole dihydrochloride was prepared and used without purification as described in example 16g from the product obtained in previous step (0.70 g, 1.217 mmol) to afford off white solid (0.353 g, 100%).
Figure imgf000467_0001
Endo 1-[(1 R,5S)-8-(2-{1-(2,2-dimethyl propanoyl)-4-[3- (methylthio)phenyl]piperidin-4-yl}ethyl)-8-azabicyclo[3.2.1]oct-3-yl]-2-methyl- 1 H-benzimidazole was prepared as described in example 16 from the product obtained in previous step (100 mg, 0.1826 mmol), using 3 equivalents of triethylamine and purified by column chromatography on silica gel, eluting with a gradient of 0-5% methanol in dichloromethane to afford colorless oil (64 mg, 63 %). 1H NMR (300 MHz, CDCI3) δ 7.69 (d, 1H, J=6.9 Hz), 7.36-7.09 (m, 7H), 4.68-4.60 (m, 1 H), 3.98-3.93 (br m, 2H), 3.36-3.29 (m, 4H), 2.60 (s, 3H), 2.53 (s, 3H), 2.46-2.35 (m, 2H), 2.33-2.18 (m, 2H), 1.97-1.60 (m, 12H), 1.29 (s,
9H). HRMS m/z (M+H) 559.3471 Cal., 559.3464 Obs.
Figure imgf000467_0002
Example 708 endo 2-chloro-5-«4-f2-r(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicvclo[3.2.11oct-8-vnethyl)-4-[3-(methylthio)phenvnpiperidin-1- vDcarbonyDbenzene sulfonamide
Figure imgf000468_0001
The title compound was prepared as described in Example 719 from dihydrochloride intermediate descrived in example 707 (200 mg, 0.365 mmol) and purified by column chromatography on silica gel, eluting with a gradient of 3.75-7.50% methanol in dichloromethane with 0.25% ammonium hydroxide to afford white solid (110 mg, 44%). 1H-NMR (300 MHz, CDCI3) δ 8.13 (s, 1 H), 7.67 (d, 1 H, J=6.9Hz), 7.62-7.52 (m, 2H), 7.37-7.32 (m, 2H), 7.28-7.15 (m, 4H), 7.08 (d, 1 H, J=7.6 Hz), 5.44 (br s, 2H), 4.71-4.60 (m, 1 H), 4.25-4.18 (br m, 1 H), 3.58-3.50 (br m, 1 H), 3.40-3.27 (br m, 4H), 2.57 (s, 3H), 2.52 (s, 3H), 2.46-2.36 (m, 3H), 2.25-2.16 (br m, 1 H), 2.06-1.62 (m, 12H). HRMS m/z (M+H)+ 692.2496 Cal., 692.2520 Obs.
Example 709 endo 1 -((1 R,5S)-8-{2-[1 -(2,2-dimethylpropanoyl)-4-(4-methylphenyl)piperidin- 4-vnethyl)-8-azabicvclof3.2.noct-3-vπ-2-methyl-1 H-benzimidazole
Figure imgf000468_0002
The title compound was synthesized according to the methods described in example 16 with a 4-methyl instead of a 3-chloro substitution in the phenyl ring. Tert-butyl 4-(1 -cyano-2-ethoxy-2-oxoethyl)-4-(4- methylphenyl)piperidine-1 -carboxylate.
Figure imgf000469_0001
This intermediate was prepared as described in example 16b from 4- bromotoluene (11.97 g, 70 mmol) and using tetrahydrofuran instead of ether as a solvent zand purified by column chromatography on silica gel, eluting with 9:1-6:1 hexane-ethyl acetate to afford oily product (5.32 g, 81%). 1H- NMR (300 MHz, CDCI3) δ 7.28-7.20 (m, 4H), 4.03-3.92 (m, 4H), 3.57 (s,1 H), 2.93-2.84 (m, 2H), 2.63-2.51 (br m, 2H), 2.36 (s, 3H), 1.45 (s, 9H), 1.05 (t, 3H, J=7.1 Hz). ES-LCMS m/z 287 (M-BOC+H)+.
[1-(tert-butoxycarbonyl)-4-(4-methylphenyl)piperidin-4-yl](cyano)acetic acid.
Figure imgf000469_0002
This intermediate was prepared and used without purification as described in example 16c from the product obtained in previous step (5.32 g, 13.76 mmol) to afford rigid foam (4.93 g, 100%). ES-LCMS m/z 259 (M- BOC+H).
Tert-butyl 4-(cyanomethyl)-4-(4-methylphenyl)piperidine-1 -carboxylate.
Figure imgf000469_0003
This intermediate was prepared as described in example 16d from the product obtained in previous step (4.93 g, 13.76 mmol) to afford a thick oil (3.51 g, 81%). 1H-NMR (300 MHz, CDCI3) δ 7.28-7.21 (m, 4H), 3.80-3.72 (m, 2H), 3.10-3.03 (m, 2H), 2.54 (s, 2H), 2.37 (s, 3H) 2.35-2.31 (m, 2H), 1.89-1.80 (m, 2H), 1.46 (s, 9H). ES-LCMS m/z 215 (M-BOC+H)+.
Tert-butyl 4-(4-methylphenyl)-4-(2-oxoethyl)piperidine-1 -carboxylate.
Figure imgf000470_0001
This intermediate was prepared as described in example 16e from the product obtained in previous step (1.55 g, 4.93 mmol) to afford an oil (1.28g, 82%). 1H NMR (300 MHz, CDCI3) δ 9.40 (t, 1 H, J=2.9 Hz), 7.28-7.11 (m, 4H), 3.72-3.62 (m, 2H), 3.29-3.20 (m, 2H), 2.63 (s, 2H), 2.54 (s, 3H), 2.36-2.21 (m, 2H), 1.89-1.80 (m, 2H), 1.46 (s, 9H). ES-LCMS m/z 218 (M-BOC+Hf.
Tert-butyl endo 4-{2-[{1R, 5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-(4-methylphenyl)piperidine- 1 -carboxylate.
Figure imgf000470_0002
This intermediate was prepared as described in example 16f from the product obtained in previous step (0.60 g, 1.89 mmol) and purified by column chromatography on silica gel, eluting with a gradient of 2-5% methanol in dichloromethane to afford a rigid foam (0.61 g, 59%). 1H-NMR (300 MHz, CDCI3) δ 7.70 (d, 1 H, J=7.1 Hz), 7.33-7.12 (m, 7H), 4.71-4.65 (m, 1 H), 3.75- 3.62 (m, 2H), 3.40-3.19 (m, 4H), 2.60 (s, 3H), 2.48-2.25 (m, 2H), 2.36 (s, 3H), 2.22-2.09 (m, 2H), 2.05-1.60 (m, 12H), 1.45 (s, 9H). ES-LCMS m/z 543 (M+H)+. Endo 2-methyl-1-((1 R,5S)-8-{2-[4-(4-methyl phenyl)piperidin-4-yl]ethyl}- 8-azabicyclo[3.2.1]oct-3-yl)-1 H-benzimidazole dihydrochloride.
Figure imgf000471_0001
This intermeduate was prepared and used without purification, as described in example 16g from the product obtained in previous step (0.61 g, 1.124 mmol) to afford a white solid (0.579 g, 100%).
Figure imgf000471_0002
The 1 :1 formic acid salt of the title compound from example 709 endo 1 -((1 R,5S)-8-{2-[1 -(2,2-dimethylpropanoyl)-4-(4-methylphenyl)piperidin-4- yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1 H-benzimidazole was prepared as described in example 16 from the product obtained in previous step (100 mg, 0.194 mmol), using 3.2 equivalents of triethylamine and purified by Plate Purification Method A to afford a rigid foam (26.65 mg, 26 %). 1H-NMR (300 MHz, CDCI3) δ 8.44 (s, 1 H), 7.71 (d, J=7.2 Hz, 1 H), 7.30-7.16 (m, 7H), 6.20- 5.80 (br s, 1 H), 4.94-4.88 (m, 1 H), 3.98-3.93 (m, 2H), 3.51-3.43 (m, 2H), 3.33- 3.20 (m, 2H), 2.64-2.53 (m, 5H), 2.37 (s, 3H), 2.27-1.72 (m, 14H), 1.28 (s, 9H). HRMS m/z (M+H) 527.3750 Cal., 527.3745 Obs. Example 710 formic acid salt (1:1) of endo methyl 3-fl4-f2-IY1 R. 5S)-3-(2-methyl-1 H- benzimidazol-1 -yl)-8-azabicvclo r3.2.noct-8-vπethyl)-4-(4- methylphenyl)piperidin-1-vπcarbonyl)benzoate To a solution of the dihydrochloride intermediate obtained in Example
Figure imgf000472_0001
709 (250 mg, 0.485 mmol) in N,N-dimethylformamide (1 ml) was added methylhydrogen isophthalate (87.4 mg, 0.485 mmol), N,N- diisopropylethylamine (0.27 ml, 1.55 mmol) and O-(7-azabenzotriazol-1-yl)- 1 ,1 ,3,3-tetramethyluronium haxafluorophosphate (184.3 mg, 0.485 mmol). The reaction mixture was stirred at room temperature for 4h. Quenched by addition of a saturated solution of sodium bicarbonate and extracted with ethyl acetate (3x5 ml). The organic layer was washed with brine and concentrated. The product was purified by column chromatography on silica gel, eluting with a gradient of 2.5-5% methanol in dichloromethane. Further purification was accomplished by Plate Purification Method A to afford a solid product (72.2 mg, 23%).
1H NMR (300 MHz, CDCI3) δ 8.43 (br s, 1 H), 8.12-8.05 (m, 2H), 7.71 (d, 1 H, J=7.3 Hz), 7.61-7.59 (m, 1 H), 7.50 (t, 1 H, J=7.6 Hz), 7.30-7.23 ( m, 7H), 4.96- 4.83 (m, 1 H), 4.30-4.17 (m ,1 H), 3.94 (s, 3H), 3.89-3.80 (m, 4H), 3.43-3.27 (m, 3H), 2.64-2.52 (m, 2H), 2.59 (s, 3H), 2.38(s, 3H), 2.35-1.92 (m, 12H). HRMS m/z (M+H)+ 605.3492 Cal., 605.3479 Obs. Example 711 endo 3-([4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicvclor3.2.1 loct-8-vπethyl)-4-(4-methylphenvQpiperidin-1 ■ yllcarbonyDbenzoic acid
Figure imgf000473_0001
The title compound was prepared as described in example 718 from the product obtained in example 710 (43 mg, 0.0673 mmol) to afford a white solid (35.5 mg, 89.3%). 1H-NMR (300 MHz, MeOD) δ 8.15-8.11 (m, 1H), 8.05 (s, 1H), 7.60-7.50 (m, 4H), 7.38-7.19 ( m, 6H), 5.23-5.13 (m, 1H), 4.23-4.10 (br m, 2H), 3.61-3.57 (br m, 1 H), 3.40-3.28 (m, 4H), 2.80-2.60 (m, 4H), 2.59 (s, 3H), 2.42-2.15 (m, 9H), 2.38 (s, 3H), 2.05-1.75 (m, 2H). HRMS m/z (M+H)+ 591.3335 Cal., 591.3363 Obs.
Example 712 endo 1-((1 R,5S)-8-f2-ri-(2,2-dimethylpropanoyl)-4-(4- isopropylphenyl)piperidin-4-vnethyl)-8-azabicvclo r3.2.11oct-3-vO-2-methyl-1 H- benzimidazole
Figure imgf000473_0002
The title compound was synthesized according to the methods outlined in example 16 with a 4-isopropyl instead of a 3-chloro substitution in the phenyl ring. Tert-butyl 4-(1 -cyano-2-ethoxy-2-oxoethyl)-4-(4- isopropylphenyl)piperidine-1 -carboxylate.
Figure imgf000474_0001
This intermediate was prepared and used without further purification as described in example 16b from 1 -bromo-4-isopropylbenzene (10.25 g, 51.48 mmol) and purified by column chromatography on silica gel, eluting with a gradient of 9:1-6:1 hexane-ethyl acetate to afford 3.98g of oil product (56% yield). ES-LCMS m/z 413 (M+Na)+.
[1-(Tert-butoxycarbonyl)-4-(4-isopropylphenyl)piperidin-4- yl](cyano)acetic acid.
Figure imgf000474_0002
This intermediate was prepared and used without further purification as described in example 16c from the product obtained in previous step (3.98 g, 9.60 mmol) using isopropanol instead of ethanol to afford 3.71 g of oil (100%). ES-LCMS m/z 409 (M+Na)+.
Tert-butyl 4-(cyanomethyl)-4-(4-isopropyl phenyl)piperidine-1- carboxylate.
Figure imgf000474_0003
This intermediate was prepared as described in example 16d from the product from previous step (3.71 g, 9.60 mmol) and purified by column chromatography on silica gel, eluting with a gradient of 10-20% ethyl acetate in hexane to afford an oil which solidified upon standing (2.62 g, 78%). 1H- NMR (300 MHz, CDCI3) δ 7.26-7.29 (m, 4H), 3.80-3.72 (m, 2H), 3.17-3.05 (m, 2H), 2.94-2.90 (m, 1H), 2.54 (s, 2H), 2.46-2.32 (m, 2H), 1.91-1.81 (m, 2H), 1.46 (s, 9H), 1.28 (s, 3H), 1.26 (s, 3H).
Tert-butyl 4-(4-isopropylphenyl)-4-(2-oxoethyl)piperidine-1-carboxylate.
Figure imgf000475_0001
This intermediate was prepared as described in example 16e from the product obtained in previous step (2.62 g, 7.65 mmol) to afford 1.53 g of an oil (58%). 1H-NMR (300 MHz, CDCI3) δ 9.40 (t, 1H, J=2.9 Hz), 7.30-7.20 (m, 4H) 3.66-3.61 (br m, 2H), 3.35-3.22 (m, 2H), 2.96-2.87 (m, 1 H), 2.64 (d, 2H, J=2.9 Hz), 2.26-2.21 (br m, 2H), 1.90-1.81 (m, 2H), 1.46 (s, 9H) 1.27 (s, 3H), 1.25 (s, 3H). ES-LCMS m/z 368 (M+Na)+. tert-butyl endo 4-(4-isopropylphenyl)-4-{2-[(1 R,5S)-3-(2-methyl-1 H- benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}piperidine-1 -carboxylate. This intermediate was prepared as described in example 16f from the product obtained in previous step (0.30 g, 0.868 mmol) and purified by column chromatography on silica gel, eluting with a gradient of 2-4% methanol in dichloromethane to afford a rigid foam (0.23 g, 60%). 1H-NMR (300 MHz, CDCI3) δ 7.69 (d, 1 H, J=7 Hz), 7.33-7.19 (m, 7H), 4.75-4.65 (m, 1 H), 3.84- 3.65 (m, 2H), 3.39-3.22 (m, 4H), 2.96-2.85 (m, 1H), 2.60 (s, 3H), 2.47-2.37 (m, 2H), 2.16-2.09 (m, 2H), 2.05-1.87 (m, 10H), 1.85-1.80 (m, 2H), 1.45 (s, 9H), 1.29 (s, 3H), 1.27 (s, 3H). ES-LCMS m/z 571 (M+H)+.
Endo 1-((1R, 5S)-8-{2-[4-(4-isopropylphenyl) piperidin-4-yl]ethyl}-8- azabicyclo[3.2.1]oct-3-yl)-2-methyl-1 H-benzimidazole dihydrochloride.
Figure imgf000476_0001
This intermediate was prepared and used without further purification as described in example 16g from the product obtained in previous step (0.23 g, 0.403 mmol) to afford 0.219 g of a white solid (100%). ES-LCMS m/z 443 (M+H)+.
Endo 1-((1R,5S)-8-{2-[1-(2,2-dimethyl propanoyl)-4-(4- isopropylphenyl)piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H- benzimidazole (example 712). The title compound was prepared as described in example 16 from the dihydrochloride intermediate from example 711 (70 mg, 0.1287 mmol), using 3.2 equivalents of triethylamine and purified by column chromatography on silica gel, eluting with a gradient of 2-4% methanol in dichloromethane with 0.1% ammonium hydroxide to afford 49.7 mg of colorless oil. (70%). 1H-NMR (300 MHz, CDCI3) δ 7.68 (d, 1H, J=7.0 Hz), 7.33-7.16 (m, 7H), 4.78-4.60 (m, 1H), 3.98-3.93 (m, 2H), 3.36-3.20 (m, 4H), 2.97-2.88 (m, 1 H), 2.59 (s, 3H), 2.45-2.35 (m, 2H), 2.24-2.19 (m, 2H),
1.96-1.73 (m, 10H), 1.66-1.64 (m, 2H), 1.29 (s, 9H), 1.28 (s, 3H), 1.26 (s, 3H). HRMS m/z (M+H) 555.4063 Cal., 555.4072 Obs.
Example 713 endo methyl 3-[(4-(4-isopropylphenyl)-4-f2-r(1 R,5S)-3-(2-methyl-1 H- benzimidazol-1-yl)-8-azabicvclo[3.2.11oct-8-vnethyl)piperidin-1- vDcarbonvnbenzoate
Figure imgf000476_0002
The title compound was prepared as described in example 719 from the dihydrochloride described in example 711 (70 mg, 0.1287 mmol) and methyl hydrogen isophthalate (23.2 mg, 0.1287 mmol) and purified by column chromatography on silica gel, eluting with a gradient of 2.5-5% methanol in dichloromethane to afford a beige solid (46 mg, 56.4%). 1H-NMR (300 MHz, CDCI3) δ 8.11-8.03 (m, 2H), 7.70 (d, 1 H, J=7 Hz), 7.62-7.57 (m, 1 H), 7.53- 7.48 ( m, 1 H), 7.33-7.15 (m, 7H), 4.71-4.60 (m, 1 H), 4.30-4.20 (br s , 1 H), 3.94 (s, 3H), 3.45-3.20 (m, 4H), 2.98-2.89 (m, 1 H), 2.57 (s, 3H), 2.45-2.19 (m, 4H), 1.97-1.59 (m, 13H), 1.30 (s, 3H), 1.28 (s, 3H). HRMS m/z (M+H)+ 633.3804 Cal., 633.3801 Obs.
Example 714 endo 3-r(4-(4-isopropylphenyl)-4-f2-r(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1- yl)-8-azabicvclo[3.2.1loct-8-vnethyl}piperidin-1-yl)carbonvnbenzoic acid
Figure imgf000477_0001
The title compound was prepared as described in example 718 from title compound in example 713 (31 mg, 0.049 mmol) and purified by Plate Purification Method A to afford white solid (10.4 mg, 34.3%). 1H-NMR (300 MHz, MeOH-d4) δ 8.31 (s, 1H), 8.14 (t, 1H, J=3.3 Hz), 8.05 (s, 1H), 7.59-7.56 (m, 3H), 7.49 (d, 1H, J=6.7 Hz), 7.37-7.22 (m, 5H), 5.19-5.12 (m, 1H), 4.19- 4.15 (br m, 2H), 3.89-3.82 (br m, 2H), 3.59-3.54 (m, 1H), 3.39-3.27 (m, 4H), 2.99-2.88 (m, 1H), 2.77-2.67 (br m, 2H), 2.59-2.45 (m, 2H), 2.56 (s, 3H), 2.37- 1.80 (m, 10H), 1.27 (s, 3H), 1.25 (s, 3H). HRMS m/z (M+H)+ 619.3648 Cal., 619.3647 Obs. Example 715 endo 2-chloro-5-IY4-(4-isopropylphenvn-4-f2-IT1 R,5S)-3-(2-methyl-1 H- benzimidazol-1-yl)-8-azabicvclof3.2.n oct-8-vnethyl)piperidin-1- vPcarbonvπbenzene sulfonamide
Figure imgf000478_0001
The title compound was prepared as described in Example 719 from dihydrochloride intermediate described in example 711 (100 mg, 0.184 mmol) and purified by column chromatography on silica gel, eluting with a gradient of 2-4% methanol in dichloromethane with 1% ammonium hydroxide to afford an off white solid (43.2 mg, 34%). 1H-NMR (300 MHz, CDCI3) δ 8.13 (s, 1H), 7.67 (d, 1H, J=7Hz), 7.61-7.52 (m, 3H), 7.33-7.13 (m, 6H), 5.42 (br s, 2H), 4.67-4.61 (m, 1 H), 4.24-4.18 (br m ,1 H), 3.55-3.42 (br m, 1 H), 3.38-3.20 (br m, 4H), 3.00-2.91 (m, 1 H), 2.57 (s, 3H), 2.45-2.35 (m, 4H), 2.27-2.21 (br m, 1 H), 1.98-1.70 (m, 11 H), 1.28 (s, 3H), 1.26 (s, 3H). HRMS m/z (M+H)+ 688.3088 Cal., 688.3079 Obs.
Example 716 endo 1 -((1 R,5SV8-(2-ri -(2.2-dimethylpropanoylV4-(3-methylphenvnpiperidin- 4-yllethyl)-8-azabicvclor3.2.11oct-3-v0-2-methyl-1 H-benzimidazole
Figure imgf000479_0001
The title compound was synthesized according to the methods outlined in example 16 with a 3-methyl instead of a 3-chloro substitution in the phenyl ring.
Tert-butyl 4-(1 -cyano-2-ethoxy-2-oxoethyl)-4-(3- methylphenyl)piperidine-1 -carboxylate.
Figure imgf000479_0002
This intermediate was prepared and used without further purification as described in example 16b from 3-bromotoluene (11.97 g, 70 mmol) to afford 6.13g of an oil (93.4%). ES-LCMS m/z 287 (M-BOC+H)+.
[1-(Tert-butoxycarbonyl)-4-(3-methylphenyl)piperidin-4-yl](cyano)acetic acid.
Figure imgf000479_0003
This intermediate was prepared as described in example 16c from the product obtained in previous step (6.13 g, 15.86 mmol) and was used without further purification to afford 5.68 g of an oil (100%). ES-LCMS m/z 259 (M-BOC+H)+. Tert-butyl 4-(cyanomethyl)-4-(3-methylphenyl) piperidine-1 -carboxylate.
Figure imgf000480_0001
This intermediate was prepared as described in example 16d from the product obtained in previous step (5.68 g, 15.86 mmol) to afford 2.66 g of an oil (2.66 g, 53.3%). 1H NMR (300 MHz, CDCI3) δ 7.34-7.28 (m, 1 H), 7.18-7.12 (m, 3H) 3.82-3.72 (m, 2H), 3.13-3.04 (m, 2H), 2.55 (s, 2H), 2.39 (s, 3H) 2.37-2.31 (m, 2H), 1.91-1.82 (m, 2H), 1.46 (s, 9H). ES-LCMS m/z 215 (M-BOC+H)+.
Tert-butyl 4-(3-methylphenyl)-4-(2-oxoethyl)piperidine-1 -carboxylate.
Figure imgf000480_0002
This intermediate was prepared as described in example 16e from the product described in previous step (2.66 g, 8.46 mmol) to afford 2.24g of an oil (83%). 1H-NMR (300 MHz, CDCI3) δ 9.39 (t, 1 H, J=2.9 Hz), 7.31-7.28 (m, 1 H), 7.20- 7.07 (m, 3H), 3.68-3.60 (m, 2H), 3.31-3.22 (m, 2H), 2.64 (s, 2H), 2.38 (s, 3H), 2.27-2.21 (m, 2H), 1.90-1.81 (m, 2H), 1.46 (s, 9H).
Tert-butyl endo-4-{2-[(1R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-(3-methylphenyl)piperidine-1 -carboxylate.
Figure imgf000480_0003
This intermediate was prepared as described in example 16f from the product obtained in previous step (0.60 g, 1.89 mmol) and purified by column chromatography on silica gel, eluting with 5% methanol in dichloromethane to afford 0.58 g of a rigid foam (0.58 g, 57%). 1H-NMR (300 MHz, CDCI3) δ 7.70-7.68 (d, 1H, J=7 Hz), 7.34-7.04 (m, 7H), 4.73-4.63 (m, 1H), 3.70-3.66 (m, 2H), 3.30-3.21 (m, 4H), 2.60 (s, 3H), 2.46-2.32 (m, 2H), 2.39 (s, 3H), 2.18- 2.09 (m, 2H), 2.00-1.90 (m, 6H), 1.85-1.75 (m, 4H), 1.73-1.60 (m, 2H), 1.44 (s, 9H). ES-LCMS m/z 543 (M+H)+.
Endo 2-methyl-1-((1R,5S)-8-{2-[4-(3-methylphenyl)piperidin-4-yl]ethyl}- 8-azabicyclo[3.2.1]oct-3-yl)-1 H-benzimidazole dihydrochloride.
Figure imgf000481_0001
This intermediate was prepared and used without further purification as described in example 16g from the product obtained in previous step (0.58 g, 1.068 mmol) to afford 0.55g of a white solid (100%). ES-LCMS m/z 443 (M+H)+.
Example 716 endo 1 -((1 R,5S)-8-(2-H -(2,2-dimethylpropanovπ-4-(3-methylphenyl)piperidin- 4-vπethyll-8-azabicvclor3.2.π oct-3-vD-2-methyl-1 H-benzimidazole
Figure imgf000481_0002
The title compound was prepared as described in example 16 from the product obtained in previous step (100 mg, 0.194 mmol), using 3.2 equivalents of triethylamine to afford 33 mg of a colorless oil (32%). 1H NMR (300 MHz, CDCIs) δ 7.69 (d, 1 H, J=7.1 Hz), 7.33-7.06 (m, 7H), 4.70-4.50 (m, 1 H), 3.99-3.94 (m, 2H), 3.36-3.20 (m, 4H), 2.60 (s, 3H), 2.50-2.35 (m, 2H), 2.40 (s, 3H), 2.24-2.20 (m, 2H), 1.96-1.60 (m, 12H), 1.30 (s, 9H). HRMS m/z (M+H)+ 527.3750 Cal., 527.3769 Obs. Example 717 endo methyl 3-{[4-f2-IT1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicvclo[3.2.1loct-8-yllethyll-4-(3-methylphenyl)piperidin-1- yllcarbonyllbenzoate hydrochloride
Figure imgf000482_0001
To a solution of methyl hydrogen isophthalate (70 mg, 0.3879 mmol) in dichloromethane (4 ml) was added 1-[3-(dimethylamino)propyl]-3- ethylcarbodiimide hydrochloride (74.36 mg, 0.3879 mmol), 1-hydroxybenzo- triazole (52.42 mg, 0.3879 mmol), endo 2-methyl-1-{8-[2-(4-phenylpiperidin-4- yl)ethyl]-8-azabicyclo [3.2.1]oct-3-yl}-1 H-benzimidazole dihydrochloride II (200 mg, 0.3879 mmol) and N,N-diisopropylethylamine (0.225 ml, 1.29 mmol). After stirring at room temperature overnight, 10% citric acid (5 ml) was added to the mixture and extracted with dichloromethane (2 x 10 ml). The combined organic phase was washed with water (10 ml) and dried over anhydrous sodium sulfate.
After evaporation of the solvent the product was purified by column chromatography on silica gel, eluting with 2% methanol in dichloromethane and then treated with 4M HCI-dioxane solution (1.2 ml) to afford endo methyl 3-{[4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1]oct-8- yl]ethyl}-4-(3-methylphenyl)piperidin-1-yl]carbonyl}benzoate hydrochloride as a rigid white foam (94 mg, 38%). 1H NMR (300 MHz, CDCI3) δ 12.19 (br s, 1 H), 8.11-8.03 (m, 2H), 7.70-7.48 (m, 3H), 7.31-7.11 ( m, 7H), 4.69-4.60 (m, 1 H), 4.21-4.19 (m ,1H), 3.94 (s, 3H), 3.61-3.29 (m, 3H), 2.58 (s, 3H), 2.43- 2.25 (m, 4H), 2.39 (s, 3H), 2.18-2.15 (m, 2H), 1.96-1.76 (m, 10H), 1.67-1.60 (m, 2H). HRMS m/z (M+H)+ 605.3524 Cal., 605.3484 Obs. Example 718 endo 3-fl4-(2-IT1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicvclo[3.2.11oct-8-vπethyl)-4-(3-methylphenyl)piperidin-1 - vncarbonyllbenzoic acid
Figure imgf000483_0001
To a solution of the compound obtained in Example 717 (51 mg,
0.0795 mmol) in a 1 :1 mixture of diethyl ether- methanol (2ml), was added a 2M solution of sodium hydroxide (0.3 ml). The reaction mixture was heated at 50°C for 30 minutes and allowed to cool to room temperature. A solution of 1 N hydrochloric acid was added to adjust pH to 5 and the resulting mixture was extracted with dichloromethane (3x5 ml). After drying over sodium sulfate, the solution was concentrated to afford 42.5 mg of a rigid white foam (90.4%). 1H-NMR (300 MHz, MeOH-d4) δ 8.12-8.08 (m, 1 H), 8.01 (s, 1 H), 7.57-7.44 (m, 4H), 7.36-7.15 ( m, 5H), 7.10 (d, 1 H, J=7.1 Hz), 5.00-4.82 (m, 1 H), 4.19-4.15 (m , 1H), 3.58-3.49 (m, 3H), 3.43-3.33 (m, 3H), 2.61-2.40 (m, 2H), 2.55 (s, 3H), 2.38 (s, 3H), 2.27-2.17 (m, 2H), 2.15-1.95 (m, 10H), 1.90- 1.78 (m, 2H). HRMS m/z (M+H)+ 591.3313 Cal., 591.3345 Obs.
Example 719 endo 2-chloro-5-(r4-(2-[(1 R.5SV3-(2-methyl-1 H-benzimidazol-1 -ylV8- azabicvclor3.2.noct-8-yllethyl)-4-(3-methylphenvπpiperidin-1- vncarbonyllbenzene sulfonamide
Figure imgf000484_0001
To a solution of endo 2-methyl-1-{8-[2-(4-phenylpiperidin-4-yl)ethyl]-8- azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole dihydrochloride (200 mg, 0.3879 mmol) in N,N-dimethylformamide (1.5 ml) was added 4-chloro-3- sulfamoylbenzoic acid (91.4 mg, 0.3879 mmol), triethylamine (0.163 ml, 1.1637 mmol) and O-(7-azabenzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium haxafluorophosphate (162.2 mg, 0.4267). The reaction mixture was stirred at room temperature for 2h. Water was added until a precipitate formed, after filtration the resulting solid was washed with saturated sodium bicarbonate solution (10 ml) and water (10 ml). The product was purified by column chromatography on silica gel, eluting with 5% methanol in dichloromethane with 0.5% ammonium hydroxide to afford endo 2-chloro-5-{[4-{2-[(1R,5S)-3- (2-methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-(3- methylphenyl) piperidin-1-yl]carbonyl}benzenesulfonamide as a white solid (115 mg, 45%). 1H-NMR (300 MHz, CDCI3) δ 7.92-7.83 (m, 1 H), 7.74-7.66 (m, 1 H), 7.57-7.49 (m, 1 H), 7.33-7.07 (m, 8H), 5.44 (br s, 2H), 4.69-4.62 (m, 1 H), 4.35-4.23 (m ,1 H), 3.42-3.16 (m, 6H), 2.55 (s, 3H), 2.45-2.30 (m, 2H), 2.35 (s, 3H), 2.28-2.18 (m, 1H), 2.05-1.60 (m, 12H). HRMS m/z (M+H)+ 660.2775 Cal., 660.2772 Obs. Example 720 endo 1 -IΪ1 R.5S)-8-(2-f 1 -(2.2-di methyl propanovn-4-r3- (methylsulfonyl)phenvnpiperidin-4-yl)ethyl)-8-azabicvclor3.2.1loct-3-vn-2- methyl-1 H-benzimidazole
Figure imgf000485_0001
Title compound in example 720 was synthesized according to the methods outlined in example 16 with a 3-methylsulfonyl instead of a 3-chloro substitution in the phenyl ring.
Tert-butyl 4-(1-cyano-2-ethoxy-2-oxoethyl)-4-[3- (methylthio)phenyl]piperidine-1-carboxylate.
Figure imgf000485_0002
This intermediate was prepared as described in example 16b from 3- bromothioanisole (4.56 g, 22.45 mmol) and using tetrahydrofuran instead of diethyl ether as a solvent and purified by column chromatography on silica gel, eluting with a gradient of 9:1-6:1 hexane-ethyl acetate to afford tetf-butyl 4-(1-cyano-2-ethoxy-2-oxoethyl)-4-[3-(methylthio)phenyl]piperidine-1- carboxylate as an oil (1.61 g, 71%). 1H NMR (300 MHz, CDCI3) δ 7.37-7.14 (m, 4H), 4.01-3.82 (m, 4H), 3.59 (s, 1 H), 2.95-2.87 (m, 2H), 2.62-2.50 (m, 2H), 2.51 (s, 3H) 2.17-1.97 (m, 2H), 1.46 (m, 9H). ES-LCMS m/z 417 (M-H)".
{1-(tert-butoxycarbonyl)-4-[3-(methylthio) phenyl]piperidin-4- yl}(cyano)acetic acid.
Figure imgf000486_0001
This intermediate was prepared and used without further purification as described in example 16c from the product obtained in previous step (1.61 g, 3.846 mmol) to afford 1.50g of an oil (100%).
Tert-butyl 4-(cyanomethyl)-4-[3-(methylthio)phenyl]piperidine-1- carboxylate.
Figure imgf000486_0002
This intermediate was prepared as described in example 16d from the product from previous step (1.50 g, 3.846 mmol) and p urified by column chromatography on silica gel, eluting with a gradient of 10-20% ethyl acetate in hexane to afford 1.13 g of an oil (yield 85%). 1H-NMR (300 MHz, CDCI3) δ 7.39-7.15 (m, 4H), 3.80-3.70 (br m, 2H), 3.14-3.06 (m, 2H), 2.56 (s, 2H), 2.52 (s, 3H), 2.35-2.30 (m, 2H), 1.92-1.83 (m, 2H), 1.46 (s, 9H).
Tert-butyl 4-(cyanomethyl)-4-[3-(methylsulfonyl)phenyl]piperidine-1- carboxylate.
Figure imgf000486_0003
To a solution of product from previous step (1.13 g, 3.26 mmol) in dichloromethane (5 mml) cooled in an ice bath to 0°C, was added a solution of m-chloroperbenzoic acid (1.46 g, 8.48 mmol) in dichloromethane (15 ml) dropwise. The mixture was stirred at 0°C for 1 h and a 5% solution of sodium thiosulfate in saturated sodium bicarbonate (50 ml) was then added. The 486
resulting mixture was allowed to stir at room temperature for 30 minutes and extracted with dichloromethane (50 ml). The combined organic phase was washed with 1 N NaOH (2x30 ml), water (2x20 ml), dried over anhydrous sodium sulfate and concentrated the solvent to afford te/ -butyl 4- (cyanomethyl)-4-[3-(methylsulfonyl)phenyl] piperidine-1 -carboxylate as a rigid foam (1.05 g, 85%). AP-LCMS m/z 279 (M-BOC+H)+. This material was used without further purification.
Tert-butyl 4-[3-(methylsulfonyl)phenyl]-4-(2-oxoethyl)piperidine- 1 - carboxylate.
Figure imgf000487_0001
This intermediate was prepared as described in example 16e from the product obtained in previous step (1.05 g, 2.774 mmol) to afford 0.69g of a rigid foam (yield 65%), which was used further without additional purification. AP-LCMS m/z 282 (M-BOC+H)+.
Tert-butyl endo 4-{2-[(1R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-[3-(methylsulfonyl)phenyl]piperidine-1- carboxylate.
Figure imgf000487_0002
This intermediate was prepared as described in example 16f from the product obtained in previous step (0.69 g, 1.808 mmol) and purified by column chromatography on silica gel, eluting with 5% methanol in dichloromethane to afford 0.37 g of an oil (yield 34%). 1H-NMR (300 MHz, CDCI3) δ 7.94 (s, 1H), 7.90-7.83 (m, 1 H), 7.70-7.61 (m, 3H), 7.34-7.28 (m, 1H), 7.19-7.14 (m, 2H), 4.68-4.61 (m, 1H), 3.70-3.64 (m, 2H), 3.32-3.21 (m, 4H), 3.10 (s, 3H), 2.61 (s, 3H), 2.50-2.38 (m, 2H), 2.25-2.17 (m, 2H), 2.05-1.78 (m, 8H), 1.70-1.57 (m, 4H), 1.45 (s, 9H). ES-LCMS m/z 607 (M+H)+.
Tert-butyl endo 4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-[3-(methylsulfonyl)phenyl]piperidine- 1 - carboxylate dihydrochloride.
Figure imgf000488_0001
This intermediate was prepared as described in example 16g from the product from previous step (0.37 g, 0.6097 mmol) to afford the dihydrochloride as white solid (0.353 g, 100%). ES-LCMS m/z 507 (M+H)+. This material was used without further purification.
Endo 1-[(1R, 5S)-8-(2-{1-(2, 2-dimethyl propanoyl)-4-[3- (methylsulfonyl)phenyl]piperidin-4-yl}ethyl)-8-azabicyclo[3.2.1]oct-3-yl]-2- methyl-1 H-benzimidazole.
Figure imgf000488_0002
The title compound in example 720 was prepared as described in example 16 from the product obtained in previous step (100 mg, 0.1725 mmol), using 3.2 equivalents of triethylamine to afford 65.4 mg of a colorless oil (yield 64 %). 1H-NMR (300 MHz, CDCI3) δ 7.94 (s, 1 H), 7.88-7.83 (m, 1 H), 7.70-7.60 (m, 3H), 7.33-7.28 (m, 1 H), 7.20-7.14 (m, 2H), 4.71-4.58 (m, 1 H), 3.94-3.88 (m, 2H), 3.51-3.40 (m, 2H), 3.28-3.20 (m, 1H), 3.11 (s, 3H), 2.61 (s, 3H), 2.47- 2.37 (m, 2H), 2.30-2.18 (m, 2H), 2.05-1.90 (m, 10H), 1.75-1.58 (m, 3H), 1.41 (s, 9H). HRMS m/z (M+H) 591.3369 Cal., 591.3369 Obs.
Figure imgf000489_0001
Formic acid salt of endo1-((1 R,5S)-8-{2-[1-(2,2-dimethylpropanoyl)-4- (3-isopropoxyphenyl) piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2- methyl-1 H-benzimidazole (1 :1 ) was synthesized according to the methods outlined in example 16 with a 3-isopropoxy instead of a 3-chloro substitution in the phenyl ring.
Tert-butyl 4-(1 -cyano-2-ethoxy-2-oxoethyl)-4-(3- isopropoxyphenyl)piperidine-1 -carboxylate.
Figure imgf000489_0002
This intermediate was prepared as described in example 16b from 1-bromo-3- isopropoxybenzene (10 g, 46.5 mmol) using tetrahydrofuran instead of diethyl ether as a solvent and purified by column chromatography on silica gel, eluting with a gradient of 9:1-6:1 ethyl acetate in hexane to afford 4.68 g of an oil (yield 70%). ES-LCMS m/z 453 (M+Na)+. This material was used without further purification.
[1-(Tert-butoxycarbonyl)-4-(3-isopropoxyphenyl)piperidin-4- yl](cyano)acetic acid.
Figure imgf000489_0003
This intermediate was prepared and used without further purification as described in example 16c from the product obtained in previous step (4.68 g, 10.87 mmol) to afford 4.37g of an oil (yield 100%). ES-LCMS m/z 303 (M- BOC+H)+. Tert-butyl 4-(cyanomethyl)-4-(3-isopropoxyphenyl)piperidine- 1 - carboxylate.
Figure imgf000490_0001
This intermediate was prepared as described in example 16d from the product obtained in previous step (4.37 g, 10.87 mmol) and purified by column chromatography on silica gel, eluting with a gradient of 10-20% ethyl acetate in hexane to afford 2.45 g of an oil (yield 62.5%). 1H-NMR (300 MHz, CDCI3) δ 7.32 (t, 1 H, J=8 Hz), 6.93 (d, 1 H, J=7.9 Hz), 6.89 (s, 1 H), 6.83 (d, 1 H, J=5.9 Hz), 4.61-4.53 (m, 1 H), 3.81-3.72 (br m, 2H), 3.12-3.04 (m, 2H), 2.54 (s, 2H), 2.34-2.29 (m, 2H), 1.89-1.80 (m, 2H), 1.46 (s, 9H), 1.37 (s, 3H), 1.35 (s, 3H). ES-LCMS m/z 259 (M-BOC+H)+.
Tert-butyl 4-(3-isopropoxyphenyl)-4-(2-oxoethyl)piperidine-1 - carboxylate.
Figure imgf000490_0002
This intermediate was prepared and used without further purification as described in example 16e from the product obtained in previous step (2.45 g, 6.834 mmol) to afford 1.96 g of an oil (yield 79.3%).
Tert-butyl endo 4-(3-isopropoxyphenyl)-4-{2-[(1R, 5S)-3-(2-methyl-1 H- benzimidazol- 1 -yl) -8-azabicyclo [3.2.1]oct-8-yl]ethyl}piperidine- 1 -carboxylate .
Figure imgf000491_0001
This intermediate was prepared as described in example 16f from the product obtained in previous step (1.96 g, 5.422 mmol) and purified by column chromatography on silica gel, eluting with a gradient of 0-10% methanol in dichloromethane to afford 1.42g of a rigid foam (yield 46.4%). 1H-NMR (300 MHz, CDCI3) δ 7.70 (d, 1H, J=7.2 Hz), 7.30-7.15 (m, 3H), 6.93-6.70 (m, 4H), 4.74-4.61 (br m, 1 H), 4.59-4.53 (m, 1 H), 3.68-3.64 (br m, 2H), 3.35-3.00 (m, 4H), 2.61 (s, 3H), 2.57-2.41 (m, 2H), 2.20-2.15 (m, 2H), 2.05-1.60 (m, 12H), 1.46 (s, 9H), 1.37 (s, 3H), 1.35 (s, 9H).
Endo 1 -((1R, 5S)-8-{2-[4-(3-isopropoxyphenyl) piperidin-4-yl]ethyl}-8- azabicyclo[3.2.1]oct-3-yl)-2-methyl-1 H-benzimidazole dihydrochloride.
Figure imgf000491_0002
This intermediate was prepared and used without purification as described in example 16g from the product obtained in previous step (1.42 g, 2.42 mmol) to afford 1.32 g of a rigid foam (yield 97.5%). ES-LCMS m/z 487 (M +H)+.
Formic acid salt of endo 1-((1R,5S)-8-{2-[1-(2,2-dimethylpropanoyl)-4- (3-isopropoxyphenyl) piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2- methyl-1 H-benzimidazole. The title compound in example 721 was prepared as described in example 16 from the product obtained in previous step (100 mg, 0.179 mmol), using 3 equivalents of triethylamine and purified by Plate Purification Method A to afford 21.2 mg of a colorless oil (yield 21 %). 1H- NMR (300 MHz, CDCI3) δ 8.46 (s, 1H), 7.70 (d, 1 H, J=7.2 Hz), 7.32-7.15 (m, 4H), 6.93-6.78 (m, 3H), 4.85-4.76 (m, 1 H), 4.62-4.54 (m, 1 H), 3.98-3.93 (br m, 2H), 3.46-3.40 (br m, 2H), 3.36-3.28 (m, 2H), 2.60 (s, 3H), 2.57-2.46 (m, 2H), 2.21-1.73 (m, 14H), 1.39 (s, 3H), 1.37 (s, 3H), 1.30 (s, 9H). HRMS m/z (M+H) 571.4012 Cal., 571.4014 Obs.
Example 722 formic acid salt (1 :1 ) of endo 2-chloro-5-[(4-(3-isopropoxyphenyl)-4-{2- r(1 R.5S)-3-(2-methyl-1 H-benzimidazol-1 -vn-8-azabicvclo[3.2. noct-8- v-1ethyl)piperidin-1-yl)carbonyl1benzenesulfonamide
Figure imgf000492_0001
The title compound in example 722 was prepared as described in Example 719 from dihydrochloride described in example 721 (200 mg, 0.357 mmol) and purified by Plate Purification Method A to afford a 1 :1 salt of a formic acid and endo 2-chloro-5-[(4-(3-isopropoxyphenyl)-4-{2-[(1 R,5S)-3-(2- methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-1- yl)carbonyl]benzenesulfonamide as an off-white solid (34 mg, 13%). 1H-NMR (300 MHz, CDCI3) δ 8.41 (br s, 1H), 8.13 (s, 1H), 7.70 (d, 1H, J=7.2 Hz), 7.62- 7.53 (m, 1H), 7.59 (s, 1H), 7.34-7.24 (m, 2H), 7.20-7.15 (m, 2H ), 6.87-6.80 (m, 3H), 4.83-4.77 (m, 1 H), 4.65-4.52 (m ,1 H), 4.22-4.19 (br m ,1 H), 3.50-3.27 (m, 4H), 2.59 (s, 3H), 2.56-2.46 (m, 2H), 2.20-1.83 (m, 15H), 1.80-1.75 (m, 2H), 1.37 (s, 3H), 1.35 (s, 3H). HRMS m/z (M+H)+ 704.3037 Cal., 704.3055 Obs. Example 723 endo 3 (4-{2-r(1 R.5S 3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicvclof3.2.noct-8-yllethyl)-4-phenylpiperidin-1-yl)carbonyllbenzonitrile
Figure imgf000493_0001
To a solution of 1 ,1'-carbonyldiimidazole (68.1 mg, 0.42 mmol) and 3- cyanobenzoic acid (51.5 mg, 0.35 mmol) in dichloromethane (6 ml) was added endo 2-methyl-1-{8-[2-(4-phenylpiperidin-4-yl)ethyl]-8- azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole II and converted to the free base (0.15 g, 0.35 mmol). The mixture was stirred at room temperature for 4h and water (5 ml) was then added. The resultant mixture was extracted with dichloromethane (3x5 ml) and washed with saturated sodium bicarbonate (1x5 ml) and brine (1x5 ml). After drying over sodium sulfate, the solution was concentrated and purified by column chromatography on silica gel, eluting with 5% methanol in dichloro-methane to afford 70 mg of a colorless oil (yield 36%). 1H NMR (300 MHz, CDCI3) δ 7.74-7.22 (m, 11 H), 7.20-7.13 (m, 2H),
4.69-4.55 (m, 1 H), 4.30-4.20 (br m, 1 H), 3.40-3.19 (m, 4H), 2.58 (s, 3H), 2.44- 2.37 (m, 3H), 2.34-2.06 (br m, 1 H), 1.96-1.84 (m, 11 H), 1.65-1.60 (m, 2H). HRMS m/z (M+H) 558.3166 Cal., 558.3252 Obs.
Example 724 endo 2-methyl-1-IY1 R.5S)-8-(2-f4-phenyl-1-r3-(2H-tetraazol-5- yl)benzovnpiperidin-4-yl>ethvπ-8-azabicvclof3.2.1 loct-3-yll-l H-benzimidazole
Figure imgf000494_0001
To a solution of title compound from example 723 (40 mg, 0.0717 mmol) in toluene (4 ml)) was added trimethylsilylazide (24.77 mg, 0.215 mmol) and dibutyltin oxide (16.18 mg, 0.065 mmol), the mixture was heated to reflux for 15 h, diluted with dichloromethane (20 ml), dried over sodium sulfate and concentrated. The crude product was purified by column chromatography on silica gel, eluting with a gradient of 5-20% methanol in dichloromethane to afford endo 2-methyl-1-[(1 R,5S)-8-(2-{4-phenyl-1-[3-(2H- tetraazol-5-yl)benzoyl]piperidin-4-yl}ethyl)-8-azabicyclo[3.2.1] oct-3-yl]-1 H- benzimidazole as a solid (36 mg, 84%). 1H-NMR (300 MHz, MeOD) δ 8.18 (d, 1H, J=7.8 Hz), 8.11 (s, 1H), 7.61-7.55 (m, 2H), 7.50-7.42 (m, 6H), 7.33-7.22 (m, 3H), 5.01-4.82 (m, 1 H), 4.35-4.20 (br m, 1 H), 3.85-3.80 (br m, 2H), 3.70- 3.65 (br m, 1 H), 3.32-3.27 (m, 2H), 2.73-2.63 (m, 2H), 2.57 (s, 3H), 2.53-2.50 (m, 1 H), 2.48-2.37 (m, 1 H), 2.31-1.86 (m, 12H). HRMS m/z (M+H) 601.3211 Cal., 601.387 Obs.
Example 725 endo N'-hvdroxy-3-r(4-f2-lϊ1 R,5S 3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicvclo[3.2.1 loct-8-vπethylH~phenylpiperidin- vDcarbonvnbenzenecarboximidamide
Figure imgf000495_0001
To a suspension of hydroxylamine hydrochloride (1.706 g, 24.55 mmol) in a 9:1 mixture of methanol-water (8 ml) was added triethylamine (3.42 ml, 24.55 mmol), followed by the title compound from example 723 (2.74 g, 4.91 mmol). After heating to reflux for 1 h, a solid which precipitated was collected by filtration to afford endo N'-hydroxy-3-[(4-{2-[(1 R,5S)-3-(2-methyl-1 H- benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin- yl)carbonyl]benzenecarboximidamide (1.49 g, 51.3%). 1H NMR (300 MHz, DMSO-de) δ 9.71 (s, 1 H), 7.75 (d, 1 H, J= 7.6 Hz), 7.66 (s, 1 H), 7.51-7.35 (m, 8H), 7.26-7.21 (m, 1 H), 7.15-7.07 (m, 2H), 5.88 (s, 2H), 4.57-4.51 (br m, 1 H), 3.91-3.83 (br m, 1 H), 3.50-3.40 (m, 2H), 3.26-3.16 (br m, 3H), 2.44 (s, 3H), 2.38-2.32 (m, 2H), 2.13-2.09 (br m, 2H), 1.85-1.73 (m, 10H), 1.61-1.58 (br m, 2H). HRMS m/z (M+H) 591.3448 Cal., 591.3458 Obs.
Example 726 endo 2-methyl-1-rM R.5S)-8-(2-(1-r3-(2-oxido-3H-1 ,2,3, 5-oxathiadiazol-4- yl)benzoyll-4-phenylpiperidin-4-yl)ethvπ-8-azabicvclo[3.2.noct-3-vn-1 H- benzimidazole
Figure imgf000496_0001
The title compound was prepared (based on procedure from Yasuhisa Kohara, Keiji Kubo, Eiko Imamiya, Takeo Wada, Yoshiyuki Inada and Takehiko Naka, "Synthesis and Angiotensin II Receptor Antagonistic Activities of Benzimidazole Derivatives Bearing Acidic Heterocycles as Novel Tetrazole Bioisosteres." J. Med. Chem., 39, 5228-5235 (1996)) from the product obtained in example 725 (200 mg, 0.339 mmol) and purified by column chromatography on silica gel, eluting with a gradient of 2.5-15% methanol in dichloromethane to afford endo 2-methyl-1-[(1 R,5S)-8-(2-{1 -[3-(2-oxido-3H- 1 ,2,3,5-oxathiadiazol-4-yl)benzoyl]-4-phenylpiperidin-4-yl}ethyl)-8- azabicyclo[3.2.1]oct-3-yl]-1 H-benzimidazole as a white solid (41 mg, 19 %). 1H-NMR (300 MHz, MeOH-d4) δ 8.02 (d, 1 H, J=7.3 Hz), 7.96 (s, 1 H), 7.60- 7.43 (m, 8H), 7.34-7.23 (m, 3H), 4.98-4.89 (m, 1 H), 4.30-4.24 (br m, 1 H), 3.87-3.84 (br m, 2H), 3.71-3.63 (br m, 1 H), 3.36-3.25 (m, 3H), 2.73-2.40 (m, 5H), 2.61 (s, 3H), 2.31-1.92 (m, 9H). HRMS m/z (M+H) 637.2961 Cal., 637.2974 Obs. Example 727 endo 3-f3-IY4-f2-IY1 R.5SV3-(2-methyl-1 H-benzimidazol-1 -vh-8- azabicvclo[3.2.11oct-8-vnethyl)-4-phenylpiperi-din-1 -vDcarbonyllphenvD-l .2.4- thiadiazol-5(4H)-one
Figure imgf000497_0001
The title compound in example 727 was prepared (based on procedure from Yasuhisa Kohara, Keiji Kubo, Eiko Imamiya, Takeo Wada, Yoshiyuki Inada and Takehiko Naka, "Synthesis and Angiotensin II Receptor Antagonistic Activities of Benzimidazole Derivatives Bearing Acidic
Heterocycles as Novel Tetrazole Bioisosteres." J. Med. Chem., 39, 5228-5235 (1996)) from the product obtained in example 725 (300 mg, 0.5078 mmol) and purified by column chromatography on silica gel, eluting with a gradient of 5- 10% methanol in dichloromethane to afford endo 3-{3-[(4-{2-[(1 R,5S)-3-(2- methyl-1 H-benzimidazol-1 -yi)-8-azabicyclo[3.2.1 ]oct-8-yl]ethyl}-4- phenylpiperidin-1-yl)carbonyl]phenyl}-1 ,2,4-thiadiazol-5(4H)-one as a thick oil (57 mg, 17.7%). 1H-NMR (300 MHz, MeOH-d4) δ 8.06 (d, 1 H, J=7.6 Hz), 8.00 (s, 1 H), 7.82 (br s, 2H), 7.61-7.54 (m, 3H), 7.51-7.46 (m, 3H), 7.30-7.21 (m, 3H), 4.89-4.80 (m, 1 H), 4.30-4.18 (br m, 1 H), 3.75-3.52 (br m, 3H), 3.36-3.32 (m, 3H), 2.58-2.45 (m, 1H), 2.55 (s, 3H), 2.40-1.81 (m, 14H). HRMS m/z (M+H)+ 633.3011 Cal., 633.3013 Obs.
Example 728 endo 3-f3-IY4-{2-IY1 R.5S 3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicvclor3.2.1 "joct-8-vπethyl)-4-phenylpiperidin-1 -yl)carbonyllphenyll-1 ,2,4- oxadiazole-5(4HVthione
Figure imgf000498_0001
The title compound was prepared (based on procedure from Yasuhisa Kohara, Keiji Kubo, Eiko Imamiya, Takeo Wada, Yoshiyuki Inada and Takehiko Naka, "Synthesis and Angiotensin II Receptor Antagonistic Activities of Benzimidazole Derivatives Bearing Acidic Heterocycles as Novel Tetrazole Bioisosteres." J. Med. Chem., 39, 5228-5235 (1996)) from the product obtained in example 725 (300 mg, 0.5078 mmol) and purified by column chromatography on silica gel, eluting with a gradient of 5-10% methanol in dichloromethane to afford endo 3-{3-[(4-{2-[(1 R,5S)-3-(2-methyl-1 H- benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1- yl)carbonyl]phenyl}-1 ,2,4-oxadiazole-5(4H)-thione as a white solid (32 mg, 10%). 1H-NMR (300 MHz, MeOH-d4) δ 8.03 (d, 1 H, J=7.6 Hz), 7.96 (s, 1 H), 7.59-7.42 (m, 8H), 7.39-7.20 (m, 3H), 4.97-4.88 (m, 1 H), 4.25-4.18 (br m, 1 H), 3.73-3.25 (br m, 6H), 2.68-2.60 (m, 1H), 2.57 (s, 3H), 2.57-1.83 (m, 914H). HRMS m/z (M+H)+ 633.3011 Cal., 633.2999 Obs.
Example 729 exo 1 -f (1 R.5S)-8-[2-(1 -benzoyl-4-phenylpiperidin-4-vnethvn-8- azabicvclor3.2.11oct-3-yll-5-fluoro-2-methyl-1 H-benzimidazole
Figure imgf000498_0002
The title compound was prepared from exo 5-fluoro-2-methyl-1- {(1 R,5S)-8-[2-(4-phenylpiperidin-4-yl)ethyl]-8-azabicyclo[3.2.1 ]oct-3-yl}-1 H- benzimidazole (200 mg, 0.448 mmol), which was obtained using analogous chemistry to that described in the synthesis of exo1-(8-azabicyclo[3.2.1]oct-3- yl)-2-methyl-1 H-benzimidazole as described elsewhere in this application, and benzoyl chloride (75.6 mg, 0.54 mmol). Products were purified by Plate Purification Method A to afford exo 1-{(1 R,5S)-8-[2-(1-benzoyl-4- phenylpiperidin-4-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-5-fluoro-2-methyl-1 H- benzimidazole as an oil (1 mg, 0.4%). ES-LC/MS (CLND) m/z 551 (M+H)+.
Example 730 exo 1-((1 R,5S)-8-r2-(1-benzoyl-4-phenylpiperidin-4-yl)ethvn-8- azabicvclor3.2.1loct-3-yl)-5-fluoro-1 H-benzimidazole
Figure imgf000499_0001
The title compound was prepared as described in example 729 from exo 5-fluoro-1 -{(1 R,5S)-8-[2-(4-phenylpiperidin-4-yl)ethyl]-8- azabicyclo[3.2.1]oct-3-yl}-1H-benzimidazole (100 mg, 0.231 mmol), which was obtained using analogous chemistry to that described in the synthesis of exo1-(8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1 H-benzimidazole as described elsewhere in this application, and benzoyl chloride (35.7 mg, 0.254 mmmol) and purified by Plate Purification Method A to afford exo 1-{(1 R,5S)-8-[2-(1- benzoyl-4-phenylpiperidin-4-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-5-fluoro-1 H- benzimidazole as an oil (1 mg, 0.8%). ES-LCMS (CLND) m/z 537 (M+H)+. Example 731 exo 1-f(1 R.5SV8-[2-(1-benzoyl-4-phenylpiperidin-4-yl)ethvn-8- azabicvclor3.2.1 loct-3-yl)-2-methyl-5-(methylsulfonyl)-1 H-benzimidazole
Figure imgf000500_0001
The title compound was prepared from exo 2-methyl-5- (methylsulfonyl)-1-{(1 R,5S)-8-[2-(4-phenylpiperidin-4-yl)ethyl]-8- azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole (100 mg, 0.197 mmol), which was obtained using analogous chemistry to that described in the synthesis of exo-1-(8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1 H-benzimidazole as described elsewhere in this application, and benzoyl chloride (41.5 mg, 0.296 mmol), purified by Plate Purification Method A to afford exo 1-{(1 R,5S)-8-[2-(1- benzoyl-4-phenyl piperidin-4-yl)ethyl]-8-azabicyclo[3.2.1 ]oct-3-yl}-2-methyl-5- (methylsulfonyl)-l H-benzimidazole as an oil (1 mg, 0.8%). ES-LCMS (CLND) m/z 611 (M+H)+.
Example 732 exo 1-((1 R.5S)-8-f2-ri-(cvclopentylcarbonvπ-4-phenylpiperidin-4-vnethyl)-8- azabicvclor3.2.noct-3-vπ-2-methyl-5-(methylsulfonyl)-1 H-benzimidazole
Figure imgf000500_0002
The title compound was prepared from exo 2-methyl-5- (methylsulfonyl)-1-{(1 R,5S)-8-[2-(4-phenylpiperidin-4-yl)ethyl]-8- azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole (100 mg, 0.197 mmol), which was obtained using analogous chemistry to that described in the synthesis of exo-1-(8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1 H-benzimidazole as described elsewhere in this application, and cyclopentane carbonyl chloride (39.2 mg, 0.296 mmol) and purified by Plate Purification Method A to afford exo 1- ((1 R,5S)-8-{2-[1 -(cyclopentyl carbonyl)-4-phenylpiperidin-4-yl]ethyl}-8- azabicyclo [3.2.1]oct-3-yl)-2-methyl-5-(methylsulfonyl)-1 H-benzimidazole as an oil (0.9 mg, 0.75%). ES-LCMS (CLND) m/z 603 (M+H)+.
Example 733 exo 1 -f(1 R.5S)-8-l2-(1 -benzoyl-4-phenylpiperidin-4-vnethyl1-8- azabicvclo[3.2.1loct-3-yl)-5-(trifluoromethvn-1 H-benzimidazole
Figure imgf000501_0001
The title compound was prepared from exo 1-{(1 R,5S)-8-[2-(4- phenylpiperidin-4-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-5-(trifluoromethyl)-1H- benzimidazole (110 mg, 0.228 mmol), which was obtained using analogous chemistry to that described in the synthesis of exo 1-(8-azabicyclo[3.2.1]oct-3- yl)-2-methyl-1 H-benzimidazole as described elsewhere in this application, and benzoyl chloride (48.1 mg, 0.342 mmol). The crude was purified by Plate Purification Method A to afford exo 1 -{(1 R,5S)-8-[2-(1 -benzoyl-4- phenylpiperidin-4-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-5-(trifluoromethyl)-1 - - benzimidazole as an oil (3.4 mg, 2.5%). ES-LCMS (CLND) m/z 587 (M+H)+. Example 734 exo 1 -((1 R,5S)-8-f2-f1 -(cvclopentylcarbonv0-4-phenylpiperidin-4-yl1ethyl}-8- azabicvclor3.2.11oct-3-v0-5-(trifluoromethyl)-1 H-benzimidazole
Figure imgf000502_0001
The title compound was prepared from exo 1-{(1R,5S)-8-[2-(4- phenylpiperidin-4-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-5-(trifluoromethyl)-1 H- benzimidazole (110 mg, 0.228 mmol), which was obtained using analogous chemistry to that described in the synthesis of exo 1-(8-azabicyclo[3.2.1]oct-3- yl)-2-methyl-1 H-benzimidazole as described elsewhere in this application, and cyclopentane carbonyl chloride (48.1 mg, 0.342 mmol). The crude was purified by Plate Purification Method A to afford exo 1-((1R,5S)-8-{2-[1- (cyclopentylcarbonyl)-4-phenylpiperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3- yl)-5-(trifluoromethyl)-1 H-benzimidazole as an oil (4.8 mg, 3.6%). ES-LCMS (CLND) m/z 579 (M+H)+.
Examples 735-737 were synthesized by deprotecting the Boc-proteced intermediate depicted below and acylation via GDI method, described in example 723.
Figure imgf000502_0002
Example 735 endo 1 -((1 R.5SV8-(2-H -(cvclopropylcarbonv0-4-phenylpiperidin-4-yllethγl}-8- azabicvclor3.2.1loct-3-v0-2-methyl-1 H-benzimidazole
Figure imgf000503_0001
The title compound was prepared as described in example 723 from cyclopropane carboxylic acid (9.3 mg, 0.108 mmol) and purified by column chromatography on silica gel, eluting with a gradient of 2-10% methanol in dichloromethene to afford endo 1-((1 R,5S)-8-{2-[1-(cyclopropylcarbonyl)-4- phenylpiperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H- benzimidazole as a colorless oil (41 mg, 77%). 1H-NMR (300 MHz, DMSO- de) δ 7.50 (dd, 1 H, J=2.8, 2.1 Hz), 7.43-7.35 (m, 4H), 7.25-7.02 (m, 4H), 4.57- 4.49 (m, 1 H), 3.86-3.76 (m, 2H), 3.38-3.17 (m, 6H), 2.49 (s, 3H), 2.42-2.31 (m, 2H), 2.31-1.77 (m, 10H), 1.65-1.58 (m, 2H), 0.80-0.62 (m, 5H). HRMS m/z (M+H) 497.3280 Cal., 497.3274 Obs.
Example 736 endo 1 -((1 R,5S)-8-{2-[1 -(1 H-imidazol-1 -ylcarbonv0-4-phenylpiperidin-4- yllethyl)-8-azabicvclo[3.2.1loct-3-yl)-2-methyl-1 H-benzimidazole
Figure imgf000503_0002
The title compound was prepared as described in example 723 from 2- thiophene carboxylic acid (13.84 mg, 0.108 mmol). The reaction mixture was stirred at room temperature overnight. The crude product was purified by column chromatography on silica gel, eluting with a gradient of 2-10% methanol in dichloromethene to afford endo 1-((1 R,5S)-8-{2-[1-(1 H-imidazol- 1-ylcarbonyl)-4-phenylpiperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2- methyl-1 H-benzimidazole as a colorless oil (28.6 mg, 49.4%). 1H-NMR (300 MHz, CDCI3) δ 7.86 (s, 1 H), 7.71-7.67 (m, 1 H), 7.45-7.39 (m, 2H), 7.33-7.24 (m, 4H), 7.22-7.11 (m, 4H), 4.67-4.62 (m, 1 H), 3.91-3.80 (m, 2H), 3.40-3.22 (m, 4H), 2.60 (s, 3H), 2.50-2.34 (m, 4H), 2.10-1.96 (m, 10H), 1.69-1.63 (m, 2H). HRMS m/z (M+H) 523.3185 Cal., 523.3190 Obs.
Example 737 endo 4-r(4-f2-K1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicvclor3.2.1loct-8-vnethyll-4-phenylpiperidin-1-vπcarbonvnbenzonitrile
The title compound was prepared as described in example 723 from 4- cyanobenzoic acid acid (47.53 mg, 0.322 mmol). The reaction mixture was stirred at room temperature overnight. The crude was purified by column chromatography on silica gel, eluting with 3% methanol in dichloromethene to afford endo 4-[(4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]benzonitrile as a colorless oil (58 mg, 32%). 1H-NMR (300 MHz, CDCI3) δ 7.74-7.67 (m, 3H), 7.51-7.26 (m, 8H), 7.22-7.13 (m, 2H), 4.65-4.59 (m, 1 H), 4.25-4.20 (br m, 1 H), 3.55-3.25 (m, 4H), 2.58 (s, 3H), 2.45-2.33 (br m, 3H), 2.21-2.17 (br m, 1 H), 1.96-1.80 (m, 11 H), 1.76-1.62 (m, 2H). HRMS m/z (M+H) 558.3318 Cal., 558.3237 Obs. Example 738 endo 2-r(4-f2-IT1 R.5S.-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicvclor3.2.1 loct-8-yllethyll-4-phenylpiperidin-1 -vπcarbonyllbenzonitrile
Figure imgf000505_0001
The title compound was prepared as described in example 710 by coupling 2-carboxybenzonitrile (36.5 mg, 0.247 mmol) via HATU (method M) and purified by column chromatography on silica gel, eluting with 5% methanol in dichloromethane to afford endo 2-[(4-{2-[(1 R,5S)-3-(2-methyl-1 H- benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1- yl)carbonyl]benzonitrile as a rigid foam (66 mg, 48%). 1H NMR (300 MHz, CDCIs) δ 7.75-7.65 (m, 3H), 7.56-7.15 (m, 10H), 4.69-4.63 (m, 1 H), 4.32-4.27 (br m, 1 H), 3.45-3.35 (m, 4H), 2.58 (s, 3H), 2.46-2.38 (m, 3H), 2.20-2.19 (br m, 2H), 2.17-1.82 (m, 10H), 1.75-1.62 (m, 2H). HRMS m/z (M+H) 558.3233 Cal., 558.3226 Obs.
Example 739 endo 2-methyl-1 -((1 R.5S)-8-(2-[4-phenyl-1 -(thien-2-ylcarbonvQpiperidin-4- yllethyll-8-azabicvclo[3.2.11oct-3-yl)-1 H-benzimidazole
Figure imgf000505_0002
The title compound was prepared from 2-thiophene carboxylic acid (24 mg, 0.186 mmol) using EDCI-HOBT (method P) and purified by column chromatography on silica gel, eluting with 5% methanol in dichloromethane to afford endo 2-methyl-1-((1 R,5S)-8-{2-[4-phenyl-1-(thien-2- ylcarbonyl)piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-1 H-benzimidazole as a colorless oil (14 mg, 14%). 1 H-NMR (300 MHz, CDCI3) δ 7.68-7.67 (d, 1 H, J=6.9 Hz), 7.46-7.15 (m, 10H), 7.13-7.04 (m, 1 H), 4.66-4.60 (m, 1 H), 4.16-4.00 (br m, 2H), 3.50-3.40 (m, 2H), 3.30-3.25 (br m, 2H), 2.58 (s, 3H), 2.42-2.28 (m, 4H), 2.11-1.98 (m, 10H), 1.72-1.63 (m, 2H). HRMS m/z (M+H) 539.2845 Cal., 539.2859 Obs.
Example 740 endo 1-cvclopropyl-2-ri-(8-f2-ri-(cvclopropylcarbonyl)-4-phenylpiperidine-4- vnethyl)-8-azabicvclor3.2.1loct-3-yl)-1 H-benzimidazol-2-vnethanone
Figure imgf000506_0001
The title compound was prepared as described in Example 3, from cyclopropane carbonyl chloride (12.36 mg, 0.118 mmol), via acid chloride Method Q, to afford endo 1-cyclopropyl-2-[1-(8-{2-[1-(cyclopropylcarbonyl)-4- phenylpiperidine-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-1 H-benzimidazol-2- yl]ethanone as an off-white foam (26 mg, 43%). 1 H-NMR (300 MHz, CDCI3) δ 7.76-7.72 (m, 1 H), 7.40-7.34 (m, 5H), 7.33-7.18 (m, 3H), 4.56-4.54 (m, 1 H), 4.23-4.19 (m, 2H), 4.15-3.94 (m, 2H), 3.48-3.40 (m, 1 H), 3.38-3.26 (m, 3H), 2.42-2.13 (m, 5H), 1.94-1.74 (m, 11 H), 1.70-1.62 (m, 2H), 1.13-1.03 (m, 2H), 1.02-0.95 (m, 4H), 0.88-0.75 (m, 2H). HRMS m/z (M+H) 565.3543 Cal., 565.3541 Obs. Synthesis of carbamates. examples 741-743
Figure imgf000507_0001
TEA, DCM, rt
example 741 example 742
Figure imgf000507_0002
eχamp,e743
Synthesis of 3 of the above scheme: To a solution of 1 (0.3 g, 1 mmol) in dichloroethane (15 mL), amine 2
(0.032g, 0.148 mmol) was added NaBH(OAc)3 (0.424 g, 2 mmol). The mixture was stirred at r.t. overnight, and then quenched with saturated sodium bicarbonate solution, extracted with methylene chloride, dried over sodium sulfate, filtered and concentrated. Purification by chromatotron with 5% MeOH and 0.5% ammonium hydroxide in methylene chloride gave 0.267 g as white solid. 1H NMR (400 MHz, CDCI3, ppm) δ 7.62-7.59 (1 H, m), 7.36- 7.28 (5H, m), 7.20-7.18 (1 H, m), 7.14-7.10 (2H, m), 4.43-4.34 (1 H, m), 3.68- 3.60 (2H, broad), 3.24 (2H, broad s), 3.18 (2H, td, J=9.3 Hz, 2.5 Hz), 2.48 (3H, s), 2.39 (2H, broad t, J=11.9 Hz), 2.20-2.18 (4H, broad), 1.88-1.74 (6H, broad m), 2.10-1.97 (3H, m), 1.79-1.65 (6H, m), 1.55 (2H, d, J=8.1 Hz), 1.47 (2H, dd, J=5.2 Hz, 3.5 Hz), 1.40 (9H, s). 13C NMR (400 MHz, CDCI3, ppm) δ 155.20, 151.20, 144.83, 143.19, 133.75, 128.82, 126.82, 126.37, 121.96, 121.69, 119.42, 111.49, 79.53, 58.71 , 48.38, 46.41 , 41.38, 40.66, 39.43, 35.75, 34.42, 28.69, 26.88, 14.96. LRMS: calcd. for C34H45Cl2N4O2 (M+H)+ 611.3.
Synthesis of 4a-4c of the above scheme:
Deprotection of Boc with 25% TFA in dichloromethane at r.t. was followed by quenching with saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was dried, filtered and concentrated. 1 eq. of chloroformates or phenyl isocyanate and 3 eq. triethyl amine were used at r.t. until the reactions were complete by LC-MS. The final products were purified by PHPLC.
Example 741 : 1.7 mg. HRMS: calcd. for C31H4ιN402 (M+H)+ 501.3230, found: 501.3205.
Example 742: 1.3 mg. HRMS-calcd. for Cse^sN- a (M+H)+ 548.3389, found: 548.3405.
Example 743: 1.0 mg. HRMS: calcd. for C35H 2N5O (M+H)+563.3386, found: 563.3379.
The synthesis of analogues with C3-lin er dichloro analogues
Figure imgf000508_0001
Synthesis of 2 of the above scheme:
To a suspension of bis(2-chloroethyl)amine hydrochloride (22.48 g, 125.9 mmol) in dichloroethane (300 mL), benzaldehyde (14.1 mL, 138.5 mmol), triethyl amine (43.8 mL, 314.9 mmol) and NaBH(OAc)3 were added sequentially. The cloudy content was stirred at r.t. overnight. It was then quenched with saturated sodium bicarbonate solution, extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated to give 35.7 g product as oil. 1H NMR (400 MHz, CDCI3) δ[ppm]: 7.33-7.31 (5H, m), 3.73 (2H, s), 3.49 (4H, t, J=7.1 Hz), 2.92 (4H, t, J=7.2 Hz). 13CNMR (400 MHz, CDCI3) δ[ppm]: 139.06, 128.83, 128.69, 127.87, 127.62, 127.24, 59.43, 56.59, 42.43. Synthesis of 3 of the above scheme: To a solution of 1 (1.18 g, 6.32 mmol) in toluene (50 mL), NaNH2 (1.48 g, 50% in toluene, 18.96 mmol) was added at r.t. (the content turned red upon the addition of sodium amide). The mixture was then heated to reflux for 1 hour. The reaction was quenched with HCl (0.1 N, 50 mL). The content pH was adjusted to ~11 with NaOH (50% aqous solution). The organic layer was separated. The aquous layer was extracted twice with ethyl acetate. The combined organic layer was dried (Na2SO4), filtered and concentrated. The residue was purified by flash column chromatography with hexane/ethyl acetate (8/1 to 4/1) afforded 0.38 g product as red oil (17%). 1H NMR (400 MHz, CDCI3) δ[ppm]: 7.58 (1 H, d, J=2 Hz), 7.49 (1 H, d, J=14.1 Hz), 7.45-7.28 (6H, m), 3.59 (2H, s), 2.99 (2H, d, J=11.8 Hz), 2.51-2.48 (2H, broad m), 2.07- 2.05 (4H, broad). 13CNMR (400 MHz, CDCI3) δ[ppm]: 140.75, 138.18, 133.49, 131.16, 129.29, 128.62, 128.47, 128.15, 127.54, 125.40, 121.47, 63.07, 50.75, 42.62, 36.78. LRMS: calcd. for C19Hι8CI2N2 (M+) 344.1 , found 344.3. Synthesis of 4 of the above scheme: To a solution of 3 (3.28 g, 9.53 mmol) in dichloroethane (200 mL), 1 - chloroethyl chloroformate (1.54 mL, 14.30 mmol) was added at 0°C and stirred for 15 mins. It was then heated to reflux for 1 hr. After cooling to the r.t., the dichloroethane was removed under reduced pressure. The residue was dissolved in methanol and heated to reflux for 20 mins (reaction was complete by GC-MS). The methanol was removed under reduced pressure. After redissolving the residue in THF (150 mL), (Boc)2O (3.12 g, 14.3 mmol) and triethyl amine (4.0 mL, 28.60 mmol) were added. The content was stirred at r.t. overnight. Ethyl acetate was added. The organic layer was washed with saturated sodium bicarbonate solution, dried (Na2SO4), filtered and concentrated. Flash column chromatography with hexane/EtOAc (8/1 to 6/1) afforded 0.677 g product as yellow solid (20% yield) and another impure fraction (0.894 g, -85% purity). 1H NMR (400 MHz, CDCI3) δ[ppm]: 7.50 (1 H, d, J=2.2 Hz), 7.43 (1 H, d, J=8.7 Hz), 7.27 (1 H, dd, J=8.6 Hz, 2.2 Hz), 4.24 (2H, broad s), 3.12 (2H, broad s), 2.03-1.98 (2H, m), 1.88-1.80 (2H, m), 1.43 (9H, s). 13CNMR (400 MHz, CDCI3) δ[ppm]: 154.45, 140.09, 133.57, 132.87, 131.28, 128.01 , 125.31 , 120.68, 80.51 , 42.72, 41.31 , 36.30, 28.59. LRMS: calcd. for C17H20CI2N2O2 (M+) 354.1 found 354.2.
To a solution of the product from the last step (0.677 g, 1.91 mmol) in toluene (30 mL), DIBAL-H (5.7 mL, 1 M in toluene) was added at -78°C. The content was warmed to -35 °C over 3.5 hrs period. The reaction was completed (monitored by GC-MS) and then quenched with saturated ammonium chloride solution (30 mL). The content was extracted with ethyl acetate (GC-MS indicated that incomplete quenching might lead to the cleavage of Boc protecting group. MeOH might be a better choice of quenching reagent). So the content was retreated with (Boc)2O (2 eq.) and triethyl amine (2 eq.) for 2 hrs. The organic layer was washed with NaOH
(0.1 N), separated, dried (Na2SO4), filtered and concentrated. Flash column chromatography with hexane/ethyl acetate (8/1 ) afforded 0.14 g (21% yield). 1H NMR (400 MHz, CDCI3) δ[ppm]: 9.38 (1 H, s), 7.40 (1 H, d, J=17.4 Hz), 7.36 (1 H, d, J=2.2 Hz), 7.10 (1 H, J=2.1 Hz), 3.86 (2H, broad s), 3.08 (2H, broad), 2.34 (2H, d, J=13.7 Hz), 1.92 (2H, broad), 1.44 (9H, s). LRMS calcd. for C-12H13CI2NO (M-Boc+H)+ 257.0, found 257.1. Synthesis of 5 of the above scheme:
To a suspension of NaH (0.025 g, 60% in mineral oil, 0.627 mmol) in toluene, trimethyl phosphonoacetate (0.1 mL, 0.627 mmol) was added. The content was stirred at r.t. for 1 hr before 4 (0.14 g, 0.392 mmol) in toluene (2 mL) was added (in case of a large scale reaction, an ice bath is necessary to control the reaction). The content was stirred at r.t. overnight during which it turned cloudy. The reaction was quenched with water. The content was extracted with ethyl acetate. The combined organic layer was dried (Na2SO4), filtered and concentrated. 1H NMR (400 MHz, CDCI3) δ[ppm]: (crude) 7.40 (1 H, d, J=8.6 Hz), 7.33 (1 H, J=2 Hz), 7.10 (1 H, dd, J=8.4 Hz, 2.0 Hz), 6.90 (1 H, J=16.1 Hz), 5.67 (1 H, J=16.1 Hz), 3.71 (3H, s), 3.52-3.36 (4H, m), 2.08- 1.96 (4H, m), 1.44 (9H, s). Synthesis of 6 of the above scheme:
To a solution of the residue in EtOH (15 mL), PtO2 was added. The content was stirred under 1 atm H2 for 3 hrs (the reaction was complete by GC-MS). The content was filtered through celite and concentrated. Flash column chromatography with hexane/ethyl acetate (4/1 ) afforded 0.123 g (76% yield) product as oil. 1H NMR (400 MHz, CDCI3) δ[ppm]: 7.42 (1 H, d, J=8.4 Hz), 7.32 (1 H, J=2.1 Hz), 7.10 (1 H, dd, J=8.6 Hz, 2.2 Hz), 3.64 (2H, broad), 3.57 (3H, s), 3.11 (2H, t, J=10 Hz), 2.07-1.89 (6H, m), 1.72-1.67 (2H, m), 1.43 (9H, s). Synthesis of 7 of the above scheme:
DIBAL-H (0.593 mL, 1 M in toluene, 0.593 mmol) was cooled to -78°C and added into a solution of 6 (0.123 g, 0.296 mmol) in toluene (15 mL) (also cooled to -78°C with a dry ice-acetone bath, necessary to prevent overreduction) dropwise (to keep the internal temperature as low as possible). The content was stirred at -78°C for 2.5 hrs and the reaction was quenched with a cooled MeOH (-78°C) dropwise (the addition needs to be slow to keep the internal temperature low and prevent overreduction). After the addition completed, the content was warmed to r.t. and filtered through celite. The filtrate was washed with brine. The aquous layer was extracted with ethyl acetate. The combined organic layer was dried with Na2SO4, filtered and concentrated. 1H NMR (400 MHz, CDCI3) δ[ppm]: 9.59 (1 H, s), 7.41 (1 H, d, J=8.4 Hz), 7.37 (1 H, d, J=3.8 Hz), 7.31 (1 H, dd, J=8.3 Hz, 2.2 Hz), 3.66-3.63 (2H, m), 3.12-3.06 (2H, m), 2.13-2.02 (4H, m), 1.89-1.85 (2H, m), 1.77-1.64
(2H, m), 1.44 (9H, s). Synthesis of 10 of the above scheme:
To a solution of 7 (1/2 the residue from the last step, -0.148 mmol) in THF (15 mL), amine 8 (0.032g, 0.148 mmol) was added. The content was stirred at r.t. for 10 mins before NaBH(OAc)3 (0.094 g, 0.444 mmol) was added. It was stirred at r.t. overnight, and then quenched with saturated sodium bicarbonate solution, extracted with methylene chloride, dried over sodium sulfate, filtered and concentrated. Prep. TLC purification with 5% MeOH and 0.5% ammonium hydroxide in methylene chloride gave 9 mg product. 1H NMR (400 MHz, CDCI3) δ[ppm]: 9.13 (1 H, s), 7.40 (1 H, d, J=8.5 Hz), 7.34 (1 H, d, J=1.9 Hz), 7.07 (1H, dd, J=8.4 Hz, 1.9 Hz), 4.32 (1 H, broad s), 3.63 (2H, m), 3.12 (2H, broad t, J=10.2 Hz), 2.92 (2H, broad s), 2.42 (1 H, broad s), 2.22 (2H, broad s), 2.10-1.97 (3H, m), 1.79-1.65 (6H, m), 1.58 (2H, broad s), 1.43 (9H, s), 1.12-1.08 (2H, broad). HRMS: calcd. for C31H41CI2N4O3 (M+H)+ 587.2556, found 587.2565. Synthesis of 11 of the above scheme:
Following the route described towards 10, 43 mg of product 1_1 was synthesized. 1H NMR (400 MHz, CDCI3) δ[ppm]: 7.66-7.63 (1H, m), 7.56 (1 H, broad s), 7.40-7.36 (2H, m), 7.20-7.13 (3H, m), 4.52-4.43 (1 H, m), 3.63 (2H, m), 3.26 (2H, broad s), 3.18 (2H, td, J=9.2 Hz, 2.8 Hz), 2.58-2.48 (5H, broad), 2.33-2.28 (2H, m), 2.07-2.00 (4H, m), 1.76-1.60 (8H, m), 1.44 (9H, s), 1.19 (2H, broad s). LRMS: calcd. for C34H45CI2N4O2 (M+H)+ 611.3, found 611.0.
The synthesis of analogues with C3-linker- unsubstituted scaffold
Figure imgf000513_0001
C
Synthesis of 2 of the above scheme:
To a suspension of 1 (22 g, 98.8 mmol) in THF (300 mL), TEA (45 mL, 326 mmol) and (Boc)2θ (24 g, 110 mmol) were added and the content was stirred at r.t. overnight, followed by addition of HCl (250 mL, 0.1 N) and the mixture was extracted with ethyl acetate. The organic layer was combined, dried over Na2SO4, filtered and concentrated to give 26.2 g product as white crystalline solid (93% yield). 1H NMR (400 MHz, CDCI3) δ[ppm]: 7.46-7.25 (5H, m), 4.26 (2H, brs), 3.18 (2H, brs), 2.07 (2H, d, J=13.5Hz), 1.93 (3H, t, J=9.4Hz), 1.47 (9H, s). 13CNMR (400 MHz, CDCI3) δ[ppm]: 154.67, 139.88, 129.54, 129.38, 128.57, 125.77, 121.60, 80.39, 43.20, 41.52, 36.48, 28.65. LRMS: m/z calcd. for Cι7H22N2O2 (M+) 286.17, found 286.2. Synthesis of 3 of the above scheme: DIBAL-H (60 mL, 1 M in hexane, 60 mmol) was added to a solution of 2
(8.0 g, 28.0 mmol) in toluene (200 mL) at -78°C with a dry-ice acetone bath. The content was warmed to -35°C over about 2 hrs and stirred at -35°C for another hour. The reaction was quenched with saturated ammonium chloride (100 mL), filtered through celite. The organic layer was separated, dried (Na2SO4). filtered and concentrated to afford 6.95 g product as light yellow oil (86% yield). 1H NMR (400 MHz, CDCI3) δ[ppm]: 9.40 (1H, s), 7.45-7.25 (5H, m), 3.85 (2H, brs), 3.10 (2H, br), 2.36 (2H, d, J=13.6 Hz), 1.98 (2H, br), 1.44 (9H, s). 13CNMR (400 MHz, CDCI3) δ[ppm]: 201.18, 154.96, 138.34, 129.40, 128.02, 127.16, 79.93, 53.26, 40.88, 30.77, 28.64. LRMS: m/z calcd. for C17H23NO3289.2, found 289.2 (M+). Synthesis of 4 of the above scheme: To a suspension of NaH (1.15 g, 60% in mineral oil, 28.86 mmol) in toluene (100 mL) at 0°C, trimethyl phosphonoacetate (4.28 mL, 26.45 mmol) was added dropwise and the content was warmed up to r.t. and stirred for 50 mins. A solution of 3 (6.95 g, 24.05 mmol) in toluene (50 mL) was next added and the mixture stirred at r.t. overnight. Following addition of water, the organic layer was separated, dried (Na2SO4), filtered and concentrated to give 8.26 g product as colorless oil (>90% purity by GC-MS analysis). LRMS: m/z calcd. for C20H27NO4345.19, found 345.3 (M+). The oil from the last step was dissolved in MeOH (200 mL). Pd/C (1g, 5%) was added. The content was stirred under 1 atm H2 for 2.5 hrs and then filtered through celite. The solvent was removed under reduced pressure. The residue was purified by flash column chromatography with hexane/ethyl acetate (2/1) to give 6.5 g product as colorless oil (78% yield over two steps). 1H NMR (400 MHz, CDCI3) δ[ppm]: 7.47-7.18 (5H, m), 3.70-3.64 (2H, m), 3.54 (3H, s), 3.12 (2H, m), 2.16- 2.12 (2H, m), 1.98-1.87 (4H, m), 1.71-1.64 (2H, m), 1.43 (9H, s). LRMS: m/z calcd. for C-20H29NO4 347.2, found 347.3 (M+). Synthesis of 5 of the above scheme:
DIBAL-H (38 mL, 1 M in toluene, 38 mmol) was cooled to -78°C and added into a solution of 4 (6.5 g, 18.73 mmol) in toluene (80 mL) (also cooled to -78°C with a dry ice-acetone bath to prevent overreduction) dropwise (to keep the internal temperature as low as possible). The content was stirred at -78°C for 2.5 hrs and the reaction was quenched with a cooled MeOH (-78°C) dropwise (the addition needs to be slow to keep the internal temperature low and prevent overreduction). After the addition completed, the content was warmed to r.t. and filtered through celite. The filtrate was washed with brine. The aquous layer was extracted with ethyl acetate. The combined organic layer was dried with Na2SO , filtered and concentrated to give 5.72 g prodcut as light green oil (92% purity by GC-MS analysis). 1H NMR (400 MHz, CDCI ) δ[ppm]: 9.53 (1 H, s), 7.46-7.25 (5H, m), 3.73-3.67 (2H, m), 3.10-3.05 (2H, m), 2.17-2.09 (4H, m), 1.90-1.86 (2H, t, J=8.0 Hz), 1.71-1.64 (2H, m), 1.43 (9H, s). LRMS: m/z calcd. for C19H27NO3 317.2, found 317.3 (M+).
Figure imgf000515_0001
FlexChem Robins Block (24 glass tubes setting) was used for this parallel synthesis. To each glass tube, N2 was flushed to remove air. Then amines (0.92 eq.), NaBH(OAc)3 (2 eq.), DCE (1 mL), and aldehyde (1 eq) in THF (1 mL) were added sequentially. The block was sealed and rotated at r.t. overnight. The content was drained through a 24 wells filter plate overnight and the filtrate was collect in the same 24 tubes setting. TFA (1 mL) was added to each tube. The block was sealed and shaken for 80 min. The reaction was complete as evident by LC-MS. The gasket was removed and the solvent and TFA were removed under reduced pressure. Saturated sodium bicarbonate was added to each tube followed by DCM. The organic layer was pipeted out to another 24 tubes block. Acid chlorides or chloroformates (2.7 eq) and PS-DIEA (2.7 eq) were added. The block was sealed and rotated overnight. It was cooled in a freezer for 20 mins before the gasket was removed. PS-Trisamine (2.7 eq) was added and the block was sealed and rotated at r.t. for 4 hrs. The content was filtered, concentrated and the residue was purified with Preparative HPLC. All the compounds were obtained as formic acid salt.
Figure imgf000516_0001
Example 744: 2.7 mg product. 1H NMR (400 MHz, CDCI3) δ[ppm]: 11.00 (1 H, s), 7.82 (1 H, s), 7.41-7.34 (5H, m), 7.24-7.20 (2H, m), 6.98-6.93 (3H, m), 6.61-6.59 (1 H, m), 4.10-4.02 (1 H, m), 3.93-3.88 (2H, m), 2.79 (2H, broad d, J=15.4 Hz), 2.26-2.16 (9H, m), 1.92 (2H, broad t, J=11.5 Hz), 1.76 (2H, broad t, J=10.1 Hz), 10.64-10.55 (4H, m), 1.08-1.02 (2H, broad). HRMS: C29H37CIN4O3 calcd. for (M+H)+ 547.2476, found 547.2480.
Figure imgf000516_0002
Example 745: 6.7 mg product. 1H NMR (400 MHz, CDCI3) δ[ppm]:
10.67 (1 H, s), 7.79 (1 H, s), 7.39-7.33 (5H, m), 7.21-7.18 (1 H, t, J=6.7 Hz), 6.97-6.92 (2H, m), 6.78 (2H, dd, J=29.1 Hz, 7.9 Hz), 6.59-6.58 (1 H, m), 4.06- 4.00 (1H, m), 3.90-3.87 (2H, m), 2.79 (2H, broad d, J=10.5 Hz), 2.28 (3H, s), 2.25-2.15 (6H, m), 1.90 (2H, broad t, J=11 Hz), 1.68-1.63 (2H, m), 1.57-1.48 (4H, m), 1.02 (2H, broad s). HRMS: C32H38N4O3 calcd. for (M+H)+ 527.3022, found 527.3013.
Figure imgf000516_0003
Example 746: 9.6 mg product. 1H NMR (400 MHz, CDCI3) δ[ppm]: 10.67 (1 H, s), 7.34-7.32 (5H, m), 7.19-7.17 (1H, m), 6.96 (1 H, s), 6.77 (2H, dd, J=28.8 Hz, 7.7 Hz), 4.02-3.96 (3H, m), 3.06 (2H, m), 2.77 (2H, broad d, J=10.7 Hz), 2.28 (3H, s), 2.24-2.04 (6H, m), 1.88 (2H, broad d, J=11.2 Hz), 1.68-1.63 (2H, m), 1.57-1.51 (4H, m), 1.14 (3H, t, J=7.1 Hz), 1.04 (2H, m). HRMS: C30H40N4O3 calcd. for (M+H)+ 505.3179, found 505.3152.
Figure imgf000517_0001
Example 747: 5.3 mg product. 1H NMR (400 MHz, CDCI3) δ[ppm]:
10.68 (1H, s), 7.39-7.30 (10H, m), 7.23-7.19 (1 H, m), 6.98 (1 H, s), 6.79 (2H, dd, J=22.4 Hz, 8.9 Hz), 5.06 (2H, s), 4.09-4.01 (1H, m), 3.61 (2H, m), 3.12 (2H, broad s), 2.79 (2H, broad d, J=11.8 Hz), 2.31 (3H, s), 2.28-2.09 (6H, m), 1.91 (2H, t, J=11.3 Hz), 1.70 (2H, t, J=9.9 Hz), 1.60-1.50 (4H, m), 1.07-1.02 (2H, m). HRMS: C35H42N4O3 calcd. for (M+H)+ 567.3335, found 567.3334.
Figure imgf000517_0002
Example 748: 6.9 mg product. 1H NMR (400 MHz, CDCI3) δ[ppm]: 10.67 (1 H, s), 7.36-7.31 (5H, m), 6.97 (1 H, s), 6.78 (2H, dd, J=28.2 Hz, 7.7 Hz), 4.03-4.00 (1 H, broad s), 3.78-3.74 (1 H, broad), 3.57-3.53 (1 H, broad), 3.15-3.10 (1 H, m), 3.04-2.99 (1 H, m), 2.76 (1H, m), 2.29 (3H, s), 2.27-2.04 (9H, m), 1.85 (1 H, broad s), 1.72-1.54 (6H, m), 1.08 (2H, broad s), 0.94 (3H, t, J=7.5 Hz). HRMS: C30H40N4O3 calcd. for (M+H)+ 489.3229, found 489.3212. Synthesis of C2-scaffold, BBN method
Figure imgf000518_0001
Synthesis of 1 of the BBN method:
1H NMR (400 MHz, CDCI3) δ[ppm]: 7.37-7.34 (2H, m), 7.28-7.25 (3H, m), 3.77-3.73 (2H, m), 3.19-3.13 (2H, m), 2.37-2.33 (2H, m), 1.99-1.93 (2H, m), 1.90 (3H, s), 1.43 (9H, s). Synthesis of 2 of the BBN method:
To a solution of 1 (2.926 g, 9.66 mmol) in toluene (40 mL) at -78 °C, KHMDS (0.5 M in toluene, 21.2 mL) was added dropwise. The content was stirred at -78 °C for 10 mins and the dry ice-acetone bath was removed. The stirring was continued for another 15 mins and the content was cooled back to -78 °C. (CF3SO2)2NPh (4.14 g, 11.6 mmol) in toluene (30 mL) was added. The resulting light brown content was stirred overnight during which it was warmed to r.t. After work-up with water and ethyl acetate, the residue was purified by flash column chromatography with hexane/EtOAc (20/1 to 10/1 ) to give 3.20 g product (yield 76%). 1H NMR (400 MHz, CDCI3) δ[ppm]: 7.46- 7.44 (2H, m), 7.40-7.36 (2H, m), 7.30-7.26 (1 H, m), 5.41 (1 H, d, J=5.0 Hz), 5.32 (1 H, d, J=4.8 Hz), 3.62-3.56 (2H, m), 3.34 (2H, broad s), 2.30-2.24 (2H, m), 2.14-2.08 (2H, m), 1.43 (9H, s). 13C NMR (400 MHz, d6-acetone) δ[ppm]: 205.32, 160.71, 154.36, 140.30, 128.95, 127.60, 127.41, 103.26, 46.17, 40.65, 39.69, 33.04, 27.94. Synthesis of 3 of the BBN method:
A suspension of K2CO3 (0.105 g, 0.76 mmol) and (CH3) NH-BH3 (0.04 g, 0.76 mmol) in CH3CN (1 mL) in a pressure tube was stirred at r.t. for 10 min. A solution of 2 (0.33 g, 0.76 mmol) in CH3CN (4 mL) was added under nitrogen atomosphere, followed with Pd(PPfi3)4- The tube was sealed. The content was stirred at 65 °C overnight. After cooling to r.t., the content was filtered and concentrated. The residue was purified by fish column chromatography with hexane/EtOAc (20/1 ) to give 0.14 g product (64% yield). 1H NMR (400 MHz, d6-acetone) δ[ppm]: 7.36-7.29 (4H, m), 7.20-7.16 (1 H, m), 5.85 (1H, dd, J=10.8 Hz, 17.7 Hz), 5.11 (1 H, d, J=10.9 Hz), 4.95 (1 H, d, J=17.6 Hz), 3.50-3.44 (2H, m), 3.41-3.33 (2H, m), 2.07-2.01 (2H, m), 1.96- 1.91 (2H, m), 1.43 (9H, s). 13CNMR (400 MHz, d6-acetone) δ[ppm]: 205.39, 154.55, 145.93, 145.84, 128.67, 126.88, 114.46, 113.49, 78.67, 43.48, 40.70, 34.98, 28.05. Elemental Analysis: calcd. for Cι8Hι5NO2 C: 75.22%, H: 8.77%, N: 4.87%, found C 75.16%, H 8.81%, N 4.87%. IR is also available. Synthesis of 4 of of the BBN method:
To a solution of 3 (0.267 g, 0.93 mmol) in THF (20 mL) at r.t., 9-BBN (2.8 mL, 0.5 M in THF) was added. The content was heated to reflux overnight. The content was cooled to rt. Sodium hydroxide (0.5 mL, 6.0 M in H2O) was added, followed with hydrogen peroxide (30% in H20, 1 mL). The mixture was stirred at r.t. for 4 hrs, diluted with EtOAc, wsahed with brine. The organic layer was separated, dried over Na2SO4, filtered and concentrated. The residue was purified with chromatotron (1/1 hexane/EtOAc) to give 0.28 g (99% yield) alcohol. 1H NMR (400 MHz, de- acetone) δ[ppm]: 7.29-7.21 (4H, m), 7.16-7.13 (1H, m), 3.61-3.55 (2H, m), 3.26 (2H, t, J=7.3 Hz), 3.08-3.02 (2H, m), 2.10-2.07 (3H, m), 1.78 (2H, t, J=7.4 Hz), 1.71-1.64 (2H, m), 1.37 (9H, s). To a suspension of Dess-Matin periodinane in dichloromethane (15 mL) at r.t., t-BuOH was added and the content was stirred for 10 mins. A solution of the alcohol in dichloromethane was added dropwise at r.t. and stirred for 15 mins. The content was diluted with Et2O, washed with 1.3 N NaOH, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography with hexane/EtOAc (3/1 ) to give 0.2 g product as oil (72% yield).
Figure imgf000520_0001
Example 749: HRMS calc. for C38H41N4O2 (M+H)+ 585.3230, found 585.3201.
Figure imgf000520_0002
Example 750: HRMS calc. for C32H37N4O2 (M+H)+ 509.2917, found 509.2948. 1H NMR (400 MHz, CDCI3) δ[ppra]: 7.92 (1 H, s), 7.85 (1H, broad s), 7.71-7.23 (6 H, m), 4.57-4.42 (1 H, m), 3.71-3.63 (4H, m), 3.23-3.17 (2H, m), 2.85-2.76 (2H, m), 2.59 (3H, s), 2.46-2.45 (2H, m), 2.07-1.98 (4H, m), 1.90-1.87 (2H, m), 1.80-1.70 (6H, m), 1.42 (9H, s). MS calcd for C33H45N4O2 (M+H)+ 529, found 529.
Example 707
Figure imgf000520_0003
1H NMR (400 MHz, CDCI3) δ[ppm]: 7.90 (1 H, s), 7.51 (1 H, s), 7.46- 7.35 (7H, m), 6.99-6.94 (1 H, m), 6.46 (1 H, s), 4.49-4.43 (1 H, m), 4.14-4.11 (2H, m), 3.48 (2H, s), 3.28 (2H, s), 2.56 (3H, s), 2.40-2.34 (4H, m), 2.19 (2H, broad s), 1.93-1.85 (5H, m), 1.63-1.57 (5H, m). MS calcd. for C33H39N4O2 (M+H)+ 523, found 523.
O-linked piperidines were synthesized according to the scheme depicted below.
Figure imgf000521_0001
Synthesis of 3 in the scheme for O-linked piperidines: f-BuLi (31.2 mL, 1.7 M in pentane, 53.1 mmol) was added to Et2θ at - 78°C, followed by 1-bromo-3,4-dichlorobenzene (3.4 mL, 26.6 mmol) dropwise. The content was stirred at -78°C for another 5 mins before 2 (4.92 mL, 26.6 mmol) was added. It was stirred and gradually warmed up to r.t. overnight. Water was added. The mixture was extracted with ethyl acetate.
The combined organic layer was dried over sodium sulfate, filtered and concentrated to afford 9 g product as light brown oil (100% yield). 1H NMR (400 MHz, CDCIs) δ[ppm]: 7.62 (1 H, d, J=2.2 Hz), 7.39 (1H, d, J=8.4 Hz), 7.36-7.30 (5H, m), 7.28-7.24 (1H, m), 3.58 (2H, s), 2.79 (2H, d, J=11.4 Hz), 2.44 (2H, t, J=6.8 Hz), 2.11 (2H, td, J=13.4 Hz, 3.5 Hz), 1.76 (1 H, s), 1.68 (2H, dd, J=13.9 Hz, 2.2 Hz). Synthesis of 4 in the scheme for O-linked piperidines:
To a solution of 3 (9.0 g, 26.87 mmol) in DMF, NaH (2.15 g, 60% in mineral oil, 53.73 mmol) and allyl bromide (2.8 mL, 32.24 mmol) were added. The content was stirred at r.t. overnight. The reaction was quenched with water, extracted with ethyl acetate, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography with hexane/ethyl acetate (3/1 ) to give 7.47 g (74%) product as yellow oil. 1H NMR (400 MHz, CDCI3) δ[ppm]: 7.49 (1 H, d, J=2.0 Hz), 7.40 (1 H, d, J=8.4 Hz), 7.35-7.27 (5H, m), 7.27-7.23 (1 H, m), 5.91-5.82 (1 H, m), 5.28 (1 H, dd, J=17.2 Hz, 1.6 Hz), 3.58-3.55 (4H, m), 2.74 (2H, d, J=11.0 Hz), 2.50-2.43 (2H, m), 1.98 (4H, d, J=3.3). LRMS: calcd. for C21H24CI2NO (M+H)+ 376, found 376. Synthesis of 5 in the scheme for O-linked piperidines:
A solution of 4 (7.47 g, 199.92 mmol) in dichloroethane (120 mL) was cooled to 0 °C, 1-chloroethyl chloroformate (4.22 mL, 39.16 mmol) was added dropwise. The content was stirred at 0 °C for 15 mins and then heated to reflux for 1 hr. The solvent was removed under reduced pressure. The residue was redissolved in MeOH and the content was refluxed for 1 hr. After cooling to r.t., water and ethyl acetate were added (saw precipitate). The content was filtered to give crystalline pale-white solid. To a suspension of the solid in THF (150 mL), triethyl amine (8.35 mL, 60 mmol) and (Boc)2O were added. The content was stirred at r.t overnight. Water (100 mL) and brine (100 mL) were added. The mixture was extracted with ethyl acetate. The combined organic layer was washed with 0.1 N NaOH (2x), dried over sodium sulfate, filtered and concentrated. Flash column chromatography with hexane/ethyl acetate (9/1) gave 3.19 g product as colorless oil (42% yield). 1H NMR (400 MHz, CDCI3) δ[ppm]: 7.45 (1 H, d, J=2.0 Hz), 7.42 (1 H, d, J=8.4
Hz), 7.22 (1 H, dd, J=8.4 Hz, 2.2 Hz), 5.90-5.80 (1 H, m), 5.27 (1 H, dd, J=17.2 Hz, 1.6 Hz), 5.14 (1 H, dd, J=10.5 Hz, 1.3 Hz), 3.99 (2H, d, J=13.0 Hz), 3.58 (2H, d, J=5.1 Hz), 3.18 (2H, d, J=9.2 Hz), 1.98 (2H, d, J=12.7 Hz), 1.80 (2H, td, J=13.2 Hz, 5.6 Hz), 1.46 (9H, s). LRMS: calcd. for d^eC^NOs (M+H)+ 386, found 386. Synthesis of 6 in the scheme for O-linked piperidines:
To a solution of 5 (3.19 g, 8.29 mmol) in acetone (80 mL), f-BuOH (20 mL) and water (20 mL) were added, followed by OsO4 (2.5% in f-BuOH, 5.2 mL, 0.42 mmol). The content was stirred at r.t for 5 mins and then NMO (1.94 g, 16.6 mmol) was added. It was stirred for another 2 hrs at r.t. The reaction was quenched with saturated NaHSO3 (100 mL), extracted with ethyl acetate, dried over sodium sulfate, filtered and concentrated to give 3.5 g colorless oil. To a solution of the oil in THF (100 mL), water (25 mL) was added, followed by NalO (4.44 g, 20.73 mmol). The content was stirred at r.t for 4 hrs. Water (100 mL) was added. The mixture was extracted with ethyl acetate. The organic layer was washed with 1 :1 wateπbrine, dried over sodium sulfate, filtered and concentrated to give 2.66 g product (83% yield). 1H NMR (400 MHz, CDCIs) δ[ppm]: 9.66 (1 H, s), 7.46-7.43 (2H, m), 7.24-7.22 (2H, m), 4.00 (2H, broad d, J=10.6 Hz), 3.69 (2H, s), 3.22 (2H, broad d, J=11.7 Hz), 2.03- 2.00 (2H, m), 1.90-1.83 (2H, m), 1.46 (9H, s). Synthesis of 8a in the scheme for O-linked piperidines:
To a solution of 6 (0.885g, 2.29 mmol) in THF (10 mL), amine 7a (0.792 g, 3.44 mmol) was added. The content was stirred at r.t. for 5 mins and then NaBH(OAc)3 (1.214 g, 5.73 mmol) was added. The content was stirred at r.t. overnight. The reaction was quenched with saturated sodium bicarbonate solution, extracted with ethyl acetate, dried over sodium sulfate, filtered and concentrated. Chromatograph purification with 5%MeOH+0.5%ammonium hydroxide in methylene chloride gave 0.62 g product as white solid. 1H NMR (400 MHz, CDCI3) δ[ppm]: 7.89 (1 H, s), 7.45- 7.39 (2H, m), 7.26 (3H, broad s), 6.90-6.84 (3H, m), 4.72 (2H, s), 4.09-3.95 (2H, broad), 3.19 (4H, broad s), 2.87-2.63 (8H, m), 2.00-1.96 (2H, m), 1.77-
1.67 (4H, m), 1.45 (9H, s). LRMS: calcd. for C31H41CI2N4O4 603, found 603. Synthesis of 8b in the scheme for O-linked piperidines:
0.48 g product as white solid. 1H NMR (400 MHz, CDCI3) δ[ppm]: 7.45-7.41 (2H, m), 7.29 (1 H, d, J=7.5 Hz), 7.19-7.17 (1 H, broad), 6.59-6.57 (1 H, broad), 6.43-6.38 (2H, m), 6.25 (1 H, s), 4.70 (2H, s), 4.02-3.93 (2H, broad), 3.78 (3H, s), 3.18 (4H, broad s), 2.85-2.62 (8H, m), 2.04-1.97 (2H, broad), 1.78-1.66 (4H, m), 1.46 (9H, s).LRMS: calcd. for C32H43CI2N4O5 633, found 633. Synthesis of 8c in the scheme for O-linked piperidines:
0.56 g product as white solid. 1H NMR (400 MHz, CDCI3) δ[ppm]: 7.44 (1 H, d, J=1.6 Hz), 7.36 (1 H, d, J=8.5 Hz), 7.32-7.28 (4H, m), 7.22-7.17 (2H, m), 4.37 (2H, s), 3.96 (2H, broad s), 3.28 (2H, s), 3.10 (4H, broad), 2.76 (2H, d, J=11.2 Hz), 2.47 (2H, t, J=5.7 Hz), 2.04-1.91 (4H, m), 1.88-1.74 (4H, m), 1.45 (9H, s). LRMS: calcd. for C32H43CI2N4O4 617, found 617.
Parallel Synthesis using Robins Block
8a-8c were deprotected with TFA (1 mL) in dichloromethane (4 mL) at r.t for 20 min. Saturated sodium bicarbonate solution was added. The mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was dissolved in dichloromethane (4 mL) and added to Robins block (1 mL/each tube). To each tube were added PS-DIEA (3 eq) and acid chloride (1.5 eq.). The block was sealed and rotated overnight. It was cooled in a freezer for 15 mins and opened. PS-Trisamine (3 eq.) was added. The block was sealed and rotated for 4 hrs. The content in each tube was poured into a 24-wells filtering block and drained overnight. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC to give the desired product. Example 752
Figure imgf000525_0001
1H NMR (400 MHz, CD3OD) δ[ppm]: 8.47 (1H, s), 7.67 (2H, d, J=2.2 Hz), 7.45 (1 H, dd, J=8.4 Hz, 2.0 Hz), 7.26 (2H, t, J=8.2 Hz), 7.02-6.99 (3H, m), 6.89 (1 H, t, J=7.4 Hz), 6.57 (1 H, dd, J=3.5 Hz, 1.8 Hz), 4.72 (2H, s), 4.39 (2H, broad s), 3.75 (2H, td, J=12.6 Hz, 2.8 Hz), 3.44-3.29 (6H, m), 3.22 (2H, t, J=5.0 Hz), 2.79 (2H, td, J=14.5 Hz, 4.8 Hz), 2.24 (2H, d, J=13.5 Hz), 2.01- 1.94 (4H, m). HRMS calcd. for C31H35CI2N4O4 (M+H)+ 597.2035, found 597.2045.
Example 753
Figure imgf000525_0002
1H NMR (400 MHz, CD3OD) δ[ppm]: 8.55 (1H, s), 7.69 (1 H, d, J=1.8 Hz), 7.58 (1H, dd, J=5.7 Hz, 1.8 Hz), 7.47 (1H, d, J=8.4 Hz), 7.30 (2H, t, J=8.0 Hz), 7.04 (2H, d, J=8.2 Hz), 6.92 (1 H, t, J=8.2 Hz), 4.74 (2H, s), 4.45 (1 H, broad d, J=12.2), 3.98 (1 H, t, J=13.5 Hz), 3.72 (2H, t, J=12.1 Hz), 3.58 (1 H, t, J=8.2 Hz), 3.43-3.32 (6H, m), 3.21 (2H, broad s), 3.16-3.08 (1 H, m), 2.81 (2H, broad t, J=10.6 Hz), 2.32-2.15 (3H, m), 2.03-1.30 (10H, m). HRMS calcd. for C32H41CI2N4O3 (M+H)+ 599.2555, found 599.2520. Example 754
Figure imgf000526_0001
HRMS calcd. for C-28H35CI2N4O3 (M+H)+ 545.2084, found 545.2062. Elemental Analysis: calcd. for C-29H37CI2N4O5 (formic acid salt) C 58.88%, H 6.13%, N 9.47%; found C 58.19%, H 6.13%, N 9.27%.
Example 755
Figure imgf000526_0002
broad s), 7.86-7.79 (2H, m), 7.62-7.51 (5H, m), 7.41-7.32 (3H, m), 7.06-6.95 (3H, m), 4.76 (2H, s),
3.76 (2H, d, J=19.6 Hz), 3.51-2.99 (8H, m), 2.71 (2H, t, J=11.2 Hz), 2.58 (2H, td, J=14.5 Hz, 0.6 Hz), 2.20 (2H, t, J=13.5 Hz), 2.02 (2H, td, J=12.6 Hz, 4.1 Hz), 1.75 (2H, d, J=14.6 Hz). HRMS cacld for C32H37CI2N4O4S (M+H)+ 643.1912, found 643.1926. Elemental Analysis for C33H38CI2N4O4S (formic acid salt) calcd. C 57.47%, H 5.55%, N 8.12%; found C 56.94%, H 5.68%, N 8.04%. Example 756
Figure imgf000527_0001
1HNMR (400 MHz, CD3OD) δ[ppm]: 8.51 (1 H, broad s), 7.70 (1 H, s), 7.59 (1 H, d, J=8.5 Hz), 7.84 (1 H, dd, J=6.5 Hz, 1.8 Hz), 7.21 (1 H, t, J=8.1 Hz), 1.05 (1 H, d, J=3.5 Hz), 6.68 (2H, dd, 8.3 Hz, 1.4 Hz), 6.61 (1 H, dd, J=3.3 Hz, 1.7 Hz), 6.54-6.49 (3H, m), 4.72 (2H, s), 4.43 (2H, broad d, J=11.8 Hz), 3.85- 3.75 (5H, m), 3.46-3.27 (8H, m), 2.85 (2H, td, J=14.5 Hz, 3.5 Hz), 2.28 (2h, d, J=13.5 Hz), 2.06-1.95 (4H, m). HRMS calcd. for C32H37CI2N4O5 (M+H)+, 627.2141 found 627.2128. Elemental Analysis for C33H38Cl2N4O7 (formic acid salt) calcd. C 58.84%, H 5.69%, N 8.32%; found C 58.21% H 5.76%, N 8.26%.
Example 757
Figure imgf000527_0002
1HNMR (400 MHz, CD3OD) δ[ppm]: 8.51 (1 H, broad s), 7.69 (1 H, d,
J=1.8 Hz), 7.58 (1 H, d, J=8.4 Hz), 7.47 (1 H, dd, J=8.4 Hz, 1.8 Hz), 7.22 (1 H, t, J=8.1 Hz), 6.67 (1 H, broad d, J=8.1 Hz), 6.55-6.50 (4H, m), 4.73 (2H, s), 4.45 (1 H, d, J=12.8 Hz), 4.00 (1 H, d, J=14.4 Hz), 3.79-3.62 (5H, m), 3.55 (1 H, t, J=7.1 Hz), 3.45-3.32 (6H, m), 3.22-3.11 (4H, m), 2.80 (2H, td, J=14.3Hz, 3.5 Hz), 2.22 (2H, broad d, J=11.6 Hz), 1.99-1.62 (10H, m). HRMS calcd. for C33H43CI2N4O4 (M+H)+ 629.2661 , found 629.2664. Example 758
Figure imgf000528_0001
1HNMR (400 MHz, CD3OD) δ[ppm]: 8.50 (1H, broad s), 7.69 (1 H, d, J=1.8 Hz), 7.58 (1 H, d, J=8.5 Hz), 7.47 (1 H, dd, J=8.4 Hz, 1.8 Hz), 7.22 (1 H, t, J=8.1 Hz), 6.68 (1 H, dd, J=8.3 Hz, 1.6 Hz), 6.55-6.50 (4H, m), 4.73 (2H, s), 4.43 (1 H, d, J=13.1 Hz), 3.86-3.74 (6H, m), 3.59 (1 H, t, J=10.9 Hz), 3.44-3.32 (4H, m), 3.23 (2H, s), 3.12 (1 H, t, J=9.4 Hz), 2.85-2.77 (2H, m), 2.25-2.25- 2.17 (5H, m), 2.04-1.75 (4H, m). HRMS calcd. for C29H37CI2N4θ4 (M+H)+ 575.2192, found 575.2190. Elemental Analysis calcd. for C30H39CI2N4O6 (formic acid salt) C 57.97%, H 6.16%, N 9.01 %; found C 57.83%, H 6.31%, N 8.94%.
Example 759
Figure imgf000528_0002
1HNMR (400 MHz, CD3OD) δ[ppm]: 8.47 (1 H, broad s), 7.82-7.78 (2H, m), 7.61 (1 H, d, J=1.8 Hz), 7.57-7.52 (4H, m), 7.40 (1 H, dd, J=8.4 Hz, 1.8 Hz), 7.26 (1 H, t, J=8.3 Hz), 6.64 (1 H, dd, J=8.3 Hz, 1.8 Hz), 6.58 (1 H, broad d, J=8.2 Hz), 6.50 (1 H, s), 4.74 (2H, s), 3.82 (3H, s), 3.72 (2H, d, J=11.8 Hz), 3.41-3.35 (2H, m), 3.25 (2H, t, J=4.7 Hz), 3.04 (2H, broad d, J=11.0 Hz), 2.91 (2H, broad s), 2.71 (2H, t, J=10.7 Hz), 2.54 (2H, td, J=14.3 Hz, 4.8 Hz), 2.22 (2H, d, J=13.4 Hz), 2.00 (2H, td, J=12.7 Hz, 3.1 Hz), 1.73 (2H, d, J=14.3 Hz). HRMS: calcd. for C33H39CI2N4O4S (M+H)+ 673.2018, found 673.2002. Example 760
Figure imgf000529_0001
1HNMR (400 MHz, CD3OD) δ[ppm]: 8.43 (1 H, broad s), 7.70 (1 H, s), 7.65 (1 H, d, J=1.6 Hz), 7.55 (1 H, d, J=14.7 Hz), 7.41 (1 H, dd, J=8.4 Hz, 1.8 Hz), 7.36-7.29 (4H, m), 7.26-7.22 (1 H, m), 7.05 (1 H, d, J=3.3 Hz), 6.62-6.59 (1 H, m), 4.45-4.41 (4H, m), 3.40 (2H, s), 3.33-3.27 (4H, m), 3.05 (2H, d, J=12.1 Hz), 2.80 (2H, t, J=4.8 Hz), 2.40 (2H, t, J=12.5 Hz), 2.22 (2H, d, J=13.5 Hz), 2.05-1.94 (4H, m), 1.60 (2H, d, J=13.1 Hz). HRMS: calcd. for C32H37CI2N4O4 (M+H)+ 611.2192, found 611.2205. Elemental Analysis: calcd. for C33H39CI2N4O6 (formic acid salt) C 60.27%, H 5.82%, N 8.52%; found C 61.08%, H 5.91 %, N 8.44%.
Example 761
Figure imgf000529_0002
1HNMR (400 MHz, CD3OD) δ[ppm]: 7.59 (1 H, d, J=2.0 Hz), 7.46 (1 H, d, J=8.4 Hz), 7.37-7.27 (5H, m), 7.23-7.20 (1 H, m), 4.44-4.37 (3H, m), 3.97 (1H, d, J=12.8 Hz), 3.54-3.45 (2H, m), 3.34 (2H, s), 3.23-3.18 (2H, m), 3.11- 3.00 (1 H, m), 2.86 (2H, broad d, J=11.4 Hz), 2.60 (2H, t, J=15.5 Hz), 2.17- 2.11 (4H, m), 1.95-1.49 (14H, m). HRMS: calcd. for C-ssH-^C^Os (M+H)+ 613.2712, found 613.2723.
Figure imgf000530_0001
1HNMR (400 MHz, CD3OD) δ[ppm]: 8.38 (1H, broad), 7.63 (1 H, d, J=1.7 Hz), 7.51 (1 H, d, J=8.4 Hz), 7.41-7.25 (6H, m), 4.52 -4.41 (3H, m), 3.80 (2H, t, J=11.8 Hz), 3.53 (1 H, t, J=13.2 hz), 3.38 (2H, d, J=10.1 Hz), 3.26 (2H, broad s), 3.09-2.95 (4H, m), 2.83-2.67 (2H, m), 2.45-2.30 (2H, m), 2.17-1.81 (8H, m), 1.58-1.51 (2H, m). HRMS cacld for C29H37CI2N4O3 (M+H)+ 559.2243, found 559.2240.
Examples 763-774 were synthesized analogously to example 16 and
703.
ESI-MS Example R1 R2 m/z (M+H)
Figure imgf000530_0002
Example # ""°<T-%
Figure imgf000531_0001
Figure imgf000531_0002
The following compounds were synthesized using chemistry described elsewhere in this application.
Example 775 tert-butyl 4-f3-[4-(2-oxo-2,3-dihvdro-1 H-benzimidazol-1 -yl)piperidin-1- yllpropyl -phenylpiperidine-1 -carboxylate
Figure imgf000531_0003
1H NMR (400MHz, CDCI3) δ 10.43 (m, 1 H), 7.32-6.98 (m, 10H), 4.28
(m, 1H), 3.65 (m, 2H), 3.09 (m, 2H), 2.87-2.84 (m, 2H), 2.37 (m, 2H), 2.18 (m, 4H), 1.95 (m, 1 H), 1.70 (m, 4H), 1.54 (m, 2H), 1.41 (s, 9H), 1.14-1.00 (m, 2H). MS (electrospray +) 519.27 (M+1). Example 776 tert-butyl 4-(2-IT1 R.5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicvclo[3.2.1 loct-8-vπethyll-4-phenylpiperidine-1 -carboxylate
Figure imgf000532_0001
1H NMR (300MHz, methanol-d4) δ 7.76 (m, 1H), 7.59-7.38 (m, 5H), 7.39-7.13 (m, 3H), 4.80-4.63 (m, 1 H), 3.95 (m, 2H), 3.81-3.63 (m, 2H), 3.20- 3.09 (m, 2H), 2.80-2.55 (m, 7H), 2.28-2.20 (m, 2H), 2.13-1.92 (m, 8H), 1.90- 1.75 (m, 2H), 1.47 (s, 9H). MS (electrospray +) 529.60 (M+1).
Example 777 1 -((1 R.5SV8-f2-π -(cvclopentylcarbonvπ-4-phenylpiperidin-4-vnethyll-8- azabicvclo[3.2.noct-3-yl)-2-methyl-1 H-benzimidazole
Figure imgf000532_0002
1H NMR (300 MHz, methanol-d4) δ 7.65 (m, 1 H), 7.48-7.32 (m, 5H), 7.26-7.06 (m, 3H), 4.65 (m, 1 H), 4.04-3.71 (m, 4H), 3.20 (m, 1 H), 3.09-2.94 (m, 2H), 2.71-2.46 (m, 7H), 2.32-2.16 (m, 2H), 2.10-1.86 (m, 8H), 1.83-1.47 (m, 10H). HR MS (M+H) calc: 525.3593, found 525.3595, delta 0.2mmu. Example 778 1 -((1 R.5S V8-I2-M -benzoyl-4-phenylpiperidin-4-yl)ethvπ-8- azabicvclor3.2.noct-3-yll-2-methyl-1 H-benzimidazole
Figure imgf000533_0001
1H NMR (300 MHz, methanol-d4) δ 7.80 (m, 1 H), 7.62-7.17 (m, 13H), 4.74 (m, 1 H), 4.30-4.13 (m, 1 H), 4.02 (m, 2H), 3.71-3.55 (m, 1 H), 3.32 (s, 2H), 2.84-2.71 (m, 4H), 2.65 (s, 3H), 2.45 (m, 1 H), 2.29-1.81 (m, 11 H). HRMS (M+H) calc: 533.3280, found 533.3267, delta 1.3 mmu.
Example 779 1-benzoyl-4-phenyl-4-f2-r4-(3-phenylpropyl)piperidin-1-vnethyl)piperidine
Figure imgf000533_0002
1H NMR (300 MHz, methanol-d4) δ 7.45-7.33 (m, 9H), 7.29-7.17 (m, 3H), 7.14-7.05 (m, 3H), 4.15 (m, 1 H), 3.55 (m, 1 H), 3.30-3.15 (m, 4H), 2.58- 2.33 (m, 7H), 2.26-2.18 (m, 1 H), 2.00-1.73 (m, 6H), 1.59 (m, 2H), 1.41 (m, 1 H), 1.29-1.15 (m, 4H). HRMS (M+H) calc: 495.3375, found 495.3376, delta 0.1 mmu. Example 780 1 -benzoyl-4-(2-[4-(3-benzyl-1.2.4-oxadiazol-5-yl)piperidin-1 -yl1ethyl)-4- phenylpjperidine
Figure imgf000534_0001
1H NMR (300 MHz, methanol-d4) δ 7.45-7.39 (m, 9H), 7.29-7.18 (m, 6H), 4.14 (m, 1 H), 4.01 (s, 2H), 3.58 (m, 1H), 3.30-3.16 (m, 3H), 3.02-2.86 (m, 3H), 2.38 (m, 1 H), 2.20 (m, 4H), 2.06-1.98 (m, 2H), 1.91-1.74 (m, 6H). HRMS (M+H) calc: 535.3073, found 535.3098, delta 2.5 mmu.
Example 781 1 -(1 -{2-H -(cvclopentylcarbonyl)-4-phenylpiperidin-4-yllethyl piperidin-4-yl)-2- methyl-1 H-benzimidazole
Figure imgf000534_0002
1H NMR (400 MHz, methanol-d4) δ 7.65 (m, 1H), 7.52-7.44 (m, 2H), 7.39-7.30 (m, 5H), 7.24-7.14 (m, 1 H), 4.89 (m, 1 H), 4.02-3.91 (m, 1H), 3.81- 3.75 (m, 1 H), 3.62-3.53 (m, 2H), 3.13-3.02 (m, 3H), 3.00-2.73 (m, 8H), 2.26- 2.09 (m, 6H), 1.84-1.49 (m, 10H), 1.24-1.13 (m, 1 H). HRMS (M+H) calc: 499.3435, found 499.3434, delta 0.1 mmu. Example 782 1-f1-[2-(1-benzoyl-4-phenylpiperidin-4-vhethyllpiperidin-4-yll-2-methyl-1 H- benzimidazole
Figure imgf000535_0001
1H NMR (400 MHz, methanol-d4) δ 7.63 (m, 1H), 7.51-7.45 (m, 3H), 7.40-7.32 (m, 6H), 7.24-7.16 (m, 2H), 6.91 (s, 1 H), 6.70 (s, 1 H), 4.89 (m, 1 H), 4.89 (m, 1 H), 4.10 (m, 1 H), 3.80 (m, 1 H), 3.60 (m, 2H), 3.37-3.24 (m, 3H), 3.10 (m, 3H), 2.95-2.86 (m, 2H), 2.77 (m, 2H), 2.31 (m, 2H), 2.22-2.13 (m, 4H), 1.92-1.87 (m, 2H), 1.23-1.18 (m, 1H). HRMS (M+H) calc: 507.3126, found 507.3115, delta 1.1 mmu.
Example 783 1-(1-f2-ri-(2-furoyl)-4-phenylpiperidin-4-yllethyl)piperidin-4-yl)-2-methyl-1 H- benzimidazole
Figure imgf000535_0002
1H NMR (400 MHz, methanol-d4) δ 8.22 (m, 1H), 7.67 (m, 1H), 7.58 (s, 1 H), 7.60-7.48 (m, 2H), 7.42-7.31 (m, 4H), 7.22 (m, 1 H), 6.91 (m, 1 H), 6.49 (s, 1 H), 4.89 (m, 1 H), 4.06 (m, 2H), 3.68-3.56 (m, 2H), 3.08 (m, 2H), 3.00-2.75 (m, 7H), 2.56 (s, 3H), 2.32-2.18 (m, 5H), 1.88 (m, 2H). MS (electrospray +) 523.42 (M+1). Example 784 1-(1-{2-ri-(isoxazol-5-ylcarbonvπ-4-phenylpiperidin-4-vnethyl)piperidin-4-vh-2- methyl-1 H-benzimidazole
Figure imgf000536_0001
1H NMR (400 MHz, methanol-d4) δ 7.64 (m, 1 H), 7.46 (m, 2H), 7.41- 7.27 (m, 7H), 7.24-7.10 (m, 1H), 4.88 (m, 1 H), 4.07 (m, 2H), 3.61-3.49 (m, 1 H), 3.20 (s, 2H), 3.11-3.00 (m, 2H), 2.93-2.84 (m, 2H), 2.79-2.71 (m, 4H), 2.30 (m, 1 H), 2.21-2.09 (m, 4H), 1.92-1.75 (m, 2H), 1.21 (m, 1 H). HRMS (M+H) calc: 498.2869, found 498.2845, delta 2.4 mmu.
Example 785 tert-butyl 4-{2-IY1 R.5SV3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclol3.2.1 loct-8-yllethyl)-4-phenylpiperidine-1 -carboxylate
Figure imgf000536_0002
1H NMR (400 MHz, CDCI3) δ 7.22 (m, 1 H), 6.91-6.68 (m, 8H), 4.15 (m, 1 H), 3.23-3.18 (m, 2H), 2.82-2.67 (m, 4H), 2.12 (s, 3H), 1.97-1.87 (m, 2H), 1.76-1.64 (m, 2H), 1.51-1.29 (m, 10H), 1.17-1.13 (m, 2H), 1.00 (s, 9H). MS (electrospray +) 529.61 (M+1). Example 786 1 -rd R.5S .-8-(2~T 1 -r(3-chlorothien-2-vncarbonyll-4-phenylpiperidin-4-yl)ethvh- 8-azabicvclor3.2.1 loct-3-yll-2-methyl-1 H-benzimidazole
Figure imgf000537_0001
1H NMR (400 MHz, methanol-d4) δ 7.66 (m, 1 H), 7.56-7.43 (m, 5H), 7.34-7.23 (m, 3H), 7.01 (m, 2H), 4.72 (m, 1 H), 4.10 (m, 2H), 3.41-3.28 (m, 4H), 2.90 (m, 2H), 2.79 (m, 2H), 2.68 (s, 3H), 2.41-1.94 (m, 12H). HRMS (M+H) calc: 573.2455, found 573.2452, delta 0.3 mmu.
Example 787 (1R.5S)-8-f2-H-(2-furovn-4-phenylpiperidin-4-yllethyl)-3-phenyl-8- azabicvclol"3.2.1 loctane
Figure imgf000537_0002
1H NMR (400 MHz, CDCI3) δ 7.38 (s, 1 H), 7.31-7.00 (m, 10H), 6.86 (m, 1 H), 6.38 (m, 1 H), 3.98 (m, 1 H), 3.48-3.27 (m, 2H), 3.12 (m, 2H), 2.96-2.86 (m, 1 H), 2.38-2.15 (m, 4H), 1.98 (m, 3H), 1.86-1.76 (m, 4H), 1.60-1.50 (m, 4H), 1.29 (m, 2H). HRMS (M+H) calc: 469.2855, found 469.2858, delta 0.3 mmu. Example 788 (1R.5SV8-r2-(1-benzoyl-4-phenylpiperidin-4-vπethyll-3-phenyl-8- azabicvclor3.2.1loctane
Figure imgf000538_0001
1H NMR (400 MHz, CDCI3) δ 7.44-7.26 (m, 13H), 7.15 (m, 2H), 4.16- 4.12 (m, 1H), 3.58 (m, 1H), 3.45 (m, 1H), 3.32-3.16 (m, 3H), 3.01 (m, 1H), 2.41-2.26 (m, 3H), 2.16-1.86 (m, 5H), 1.78-1.63 (m, 5H), 1.38-1.24 (m, 3H). HRMS (M+H) calc: 479.3062, found 479.3057, delta 0.6 mmu.
Example 789 1-r(1 R.5S)-8-(2-f1-r(2.4-dimethyl-1-oxidopyridin-3-vπcarbonvn-4- phenylpiperidin-4-yl)ethvπ-8-azabicvclor3.2.noct-3-yl1-2-methyl-1 H- benzimidazole
Figure imgf000538_0002
1H NMR (500 MHz, DMSO-d6) δ 8.18 (m, 1 H), 7.49 (m, 1 H), 7.37 (m, 5H), 7.26-7.08 (m, 4H), 4.51 (m, 1 H), 4.02-3.89 (m, 2H), 3.60-3.44 (m, 2H), 3.35-3.21 (m, 4H), 3.02 (m, 1 H), 2.54-2.38 (m, 4H), 2.38-2.28 (m, 3H), 2.25- 2.09 (m, 3H), 2.03 (m, 2H), 1.87-1.70 (m, 8H), 1.58 (m, 2H). HRMS (M+H) calc: 578.3495, found 578.3519, delta 2.4 mmu. Example 790 (1 R,5S)-3-(1.3-benzodioxol-5-vD-8-r2-(1 -benzoyl-4-phenylpiperidin-4-vnethvn-
8-azabicvclor3.2.1loctane
Figure imgf000539_0001
1H NMR (400 MHz, CDCI3) δ 73.7-7.12 (m, 9H), 6.67-6.63 (m, 2H), 5.83 (s, 2H), 4.04 (m, 1 H), 3.61-3.10 (m, 5H), 2.89 (m, 1 H), 2.41-2.17 (m, 3H), 2.10-1.82 (m, 6H), 1.71 (m, 1 H), 1.64-1.46 (m, 4H), 1.36-1.28 (m, 2H), 1.19 (m, 2H). HRMS (M+H) calc: 523.2961 , found 523.2957, delta 0.4 mmu.
Example 791 6-r(4-(2-r(1 R.5SV3-(2-methyl-1 H-benzimidazol-1 -vn-8-azabicvclor3.2.noct-8- vnethyl)-4-phenylpiperidin-1-yl)carbonyl1-2H-1 ,2,4-benzothiadiazin-3(4H)-one 1 ,1-dioxide
Figure imgf000539_0002
1H NMR (500 MHz, DMSO-d6) δ 11.17 (s, 1H), 7.84-7.69 (m, 3H), 7.65- 7.56 (m, 1 H), 7.51-7.36 (m, 6H), 7.3-7.17 (m, 2H), 5.15 (m, 1 H), 4.34-3.84 (m, 5H), 3.27 (m, 2H), 2.81-2.71 (m, 5H), 2.62 (m, 2H), 2.54-2.50 (m, 2H), 2.25- 2.11 (m, 8H), 1.86 (m, 2H). MS (electrospray +) 653.18 (M+1). Example 792 24(1 R.5S 8-r2-(1 -benzoyl-4-phenylpiperidin-4-vnethyll-8- azabicvclor3.2.1loct-3-yl)-1 H-isoindole-1 ,3(2H)-dione
Figure imgf000540_0001
Λ
1H NMR (500 MHz, DMSO-d6) δ 7.80 (s, 4H), 7.43-7.33 (m, 9H), 7.21 (m, 1 H), 4.31 (m, 1 H), 4.07 (m, 1H), 3.88 (m, 1 H), 3.13 (m, 3H), 2.50 (s, 2H), 2.18-1.98 (m, 4H), 1.80-1.66 (m, 9H), 1.42-1.36 (m, 2H). HRMS (M+H) calc: 548.2913, found 548.2900, delta 1.3 mmu.
Example 793 methyl 3.3-dimethyl-4-(4-f2-IT1 R.5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicvclor3.2.noct-8-vnethyl)-4-phenylpiperidin-1-vπ-4-oxobutanoate
Figure imgf000540_0002
1H NMR (400 MHz, CDCI3) δ 7.61 (m, 1 H), 7.32-7.05 (m, 8H), 4.62- 4.52 (m, 1 H), 4.10-3.99 (m, 1 H), 3.89-3.82 (m, 2H), 3.59 (m, 4H), 2.51 (m, 5H), 2.31 (m, 2H), 2.17 (m, 1 H), 1.91-1.70 (m, 9H), 1.54 (m, 2H), 1.18 (m, 6H). HRMS (M+H) calc: 571.3646, found 571.3666, delta 1.8 mmu. Example 794 tert-butyl 4 2-IΪ1 R.5SV3-M H-1.2.3-benzotriazol-1-vn-8-azabicvclor3.2.11oct- 8-yllethyl)-4-phenylpiperidine-1-carboxylate
Figure imgf000541_0001
1H NMR (300 MHz, CDCI3) δ 7.95 (m, 1 H), 7.43-7.08 (m, 8H), 4.78 (m, 1 H), 3.62-3.57 (m, 2H), 3.17-3.08 (m, 4H), 2.46-2.34 (m, 2H), 2.27-2.18 (m, 2H), 2.12-1.92 (m, 4H), 1.81-1.54 (m, 8H), 1.38 (s, 9H). HRMS (M+H) calc: 516.3339, found 516.3336, delta 0.2 mmu.
Example 795 1 -((1 R.5SV8-(2-H -(cvclopropylcarbonv0-4-phenylpiperidin-4-yllethyl)-8- azabicvclor3.2.1loct-3-yl)-2-methyl-1 H-benzimidazole
Figure imgf000541_0002
1H NMR (400 MHz, methanol-d4) δ 7.92 (m, 1 H), 7.55-7.39 (m, 5H), 7.31-7.16 (m, 3H), 4.71 (m, 1 H), 4.09-3.95 (m, 4H), 3.52-3.39 (m, 1 H), 3.29- 3.07 (m, 2H), 2.88-2.74 (m, 4H), 2.65 (s, 3H), 2.39-1.73 (m, 12H), 0.83-0.74 (m, 4H). HRMS (M+H) calc: 497.3280, found 497.3286, delta 0.6 mmu. Example 796 1 -((1 R.5SV8-f2-F1 -(cvclobutylcarbonvn-4-phenylpiperidin-4-vπethyl 8- azabicvclor3.2.11oct-3-vπ-2-methyl-1 H-benzimidazole
Figure imgf000542_0001
1H NMR (400 MHz, methanol-d4) δ 8.28 (s, 1 H), 7.50-7.38 (m, 5H), 7.29-7.13 (m, 3H), 4.69 (m, 1 H), 4.10-3.93 (m, 3H), 3.62-3.57 (m, 1 H), 3.37- 3.04 (m, 4H), 2.86-2.66 (m, 4H), 2.60 (s, 3H), 2.26-1.89 (m, 14H), 1.77-1.70 (m, 3H). HRMS (M+H) calc: 511.3437, found 511.3434, delta 0.6 mmu.
Example 797 2-methyl-1 -((1 R,5S)-8-f2-r4-phenyl-1 -(thien-2-ylcarbonvQpiperidin-4-yllethyll- 8-azabicvclor3.2.11oct-3-yl)-1 H-benzimidazole
Figure imgf000542_0002
1H NMR (300 MHz, methanol-d4) δ 7.96 (m, 1 H), 7.62-7.59 (m, 1 H), 7.52-7.17 (m, 9H), 7.10 (m, 1 H), 4.73 (m, 1H), 4.06 (m, 4H), 3.49-3.36 (m, 2H), 2.90-2.73 (m, 4H), 2.64 (s, 3H), 2.38-1.91 (m, 12H). HRMS (M+H) calc: 539.2845, found 539.2854, delta 0.9 mmu. Example 798 1-((1 R,5SV8-(2-π-(2.2-dimethylpropanovn-4-phenylpiperidin-4-yllethyl>-8- azabicvclor3.2.11oct-3-vπ-2-methyl-1 H-benzimidazole
Figure imgf000543_0001
1H NMR (400 MHz, methanol-d4) δ 7.84 (m, 1 H), 7.56-7.40 (m, 5H), 7.32-7.26 (m, 1 H), 7.20 (m, 2H), 4.73 (m, 1 H), 4.03 (m, 3H), 3.30-3.20 (m, 3H), 2.85-2.74 (m, 4H), 2.64 (s, 3H), 2.32-2.29 (m, 2H), 2.20-2.11 (m, 4H), 2.03 (m, 4H), 1.87-1.82 (m, 3H), 1.27 (s, 9H). HRMS (M+H) calc: 513.3593, found 513.3607, delta 1.3 mmu.
Example 799 2-methyl-1-r(1 R,5S)-8-(2-l1-r(3-methylthien-2-vncarbonyl1-4-phenylpiperidin-4- ylfethv0-8-azabicvclor3.2.1 loct-3-yll-1 H-benzimidazole
Figure imgf000543_0002
MS (electrospray +) 553 (M+1).
Example 800 2-methyl-1 -IT 1 R.5SV8-(2 1 --Y4-methyl-1.2.3-thiadiazol-5-vncarbonvn-4- phenylpiperidin-4-yl)ethyl)-8-azabicvclor3.2.noct-3-yll-1 H-benzimidazole
Figure imgf000544_0001
MS (electrospray +) 555 (M+1).
Example 802
Preparation of 2-chloro-4-fluoro-5-r(methylamino)sulfonyllbenzoic acid
Figure imgf000545_0001
20.02g (73.4 mmol) of 2-chloro-3-chlorosulfonyl-4-fluorobenzoic acid was added as a solid to a cooled solution of 10.5 mL of methylamine (40% aqueous solution, 293.6mmol) in 400 mL of water. Reaction was monitored by LC/MS and complete after one hour. The reaction was acidified to pH=1 with concentrated HCl, and solid precpitated out. Product was obtained by filtration. 17.54 g obtained as a pale tan solid (89% yield). 1H NMR (300 MHz, DMSO-de) 613.83-14.01 (br, 1 H), 8.21-8.26 (d, 1 H, J=9.11 Hz), 7.98- 8.03 (q, 1 H, J=4.82), 7.88-7.92 (d, 1 H, J=9.11 Hz), 2.55-2.56 (d, 3 H, J= 4.82 Hz).
Preparation of 4-chloro-2-fluoro-5-r(4-(3-fluorophenyl)-4-f2-r(1 f?,5S)-3-(2- methyl-1 H-benzimidazol-1 -vπ-8-azabicvclof3.2.1loct-8-yl"|ethyl>piperidin-1- yl)carbonyll-A/-methylbenzenesulfonamide
Figure imgf000545_0002
5.36g (12.0 mmol) 1-((1R,5S)-8-{2-[4-(3-fluorophenyl)piperidin-4-yl]ethyl}-8- azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole, 3.20 g (12.0 mmol) 2- chloro-4-fluoro-5-[(methylamino)sulfonyl]benzoic acid were combined following the general procedure in Example 5. 3.97 g recovered (47.6% yield). 1H NMR (300 MHz, DMSO-d6) δ 7.96-8.05 (br, 1 H), 7.75-7.94 (m, 2 H), 7.38-7.56 (m, 3 H), 7.24-7.30 (m, 2 H), 7.07-7.18 (m, 3 H), 4.48-4.60 (m, 1 H), 3.91-4.03 (m, 1 H), 3.23-3.49 (m, 6 H), 3.04-3.13 (m, 1 H), 2.52-2.60 (m, 4 H), 2.33-2.44 (m, 2 H), 2.12-2.32 (br, 2 H), 2.01-2.09 (m, 2H), 1.76-1.95 (m, 8 H), 1.60-1.66 (m, 2 H). LC/MS m/z (M+H): 696
Preparation of (1f?,5S)-8-{2-[1-{2-chloro-4-fluoro-5- [(methylamino)sulfonyl]benzoyl}-4-(3-fluorophenyl)piperidin-4-yl]ethyl}-3-(2- methyl-1 H-benzimidazol-1 -yl)-8-azoniabicyclo[3.2.1]octane, toluenesulfonic acid salt
Figure imgf000546_0001
The reaction vessel was charged with (1 ,5S)-8-{2-[1-{2-chloro-4-fluoro-5- [(methylamino)sulfonyl3benzoyl}-4-(3-fluorophenyl)piperidin-4-yl]ethyl}-3-(2- methyl-1 H-benzimidazol-1 -yl)-8-azoniabicyclo[3.2.1]octane (5.0 g) and tetrahydrofuran (65 ml, 13 volumes). The mixture was stirred and heated to 50°C. A solution of toluenesulfonic acid monohydrate (1.4 g, 1 M in tetrahydrofuran, 1 equivalent) was added to the hot mixture. After cooling, the solid was collected by filtration, washed with tetrahydrofuran (2 x 2.5 volumes) and dried in vacuo. Yield 93%.
Example 803
Preparation of 2-chloro-5-r(ethylajτιJng suifonyi -4-fluorobenzoic acid
Figure imgf000547_0001
1.023 g (3.6 mmol) 3-chlorosulfonyl-4-fluorobenzoic acid was added to 5.49 mL (10.98 mmol) ethylamine in THF. THF was evaporated off at the completion of the reaction. Diluted with dichloromethane and extracted with 6N NaOH. Combined aqueous layers were then acidified to pH=1 with 6N HCl. Product creashes out and is collected by filtration and rinsed with water. Crude product was used in subsequent step without further purification. 1H NMR (300 MHz, DMSO-d6) δ 8.13-8.16 (d, 1 H, J=7.96 Hz), 8.07-8.11 (t, 1 H, J=9.79 Hz), 7.79-7.82 (d, 1 H, J=9.79 Hz), 2.86-2.95 (m, 2H), 0.96-1.01 (t, 3 H, J=7.34 Hz).
Preparation of 4-chloro-Λ/-ethyl-2-fluoro-5-r(4-(3-fluorophenvn-4-f2-r(1 R.5SV3- (2-methyl-1 H-benzimidazol-1 -yl)-8-azabicvclor3.2.noct-8-yl1ethyl)piperidin-1 - vDcarbonvπbenzenesulfonamide
Figure imgf000547_0002
0.103 g (.23 mmol) 1-((1R,5S)-8-{2-[4-(3-fluorophenyl)piperidin-4-yl]ethyl}-8- azabicyclo[3.2.1]oct-3-yl)-2-methyl-1 H-benzimidazole and .129 g ( .46 mmol) 2-chloro-5-[(ethylamino)sulfonyl]-4-fluorobenzoic acid were combined following the HATU general procedure in Example 5. This compound was purified by flash chromatography on a 0-100% gradient of 1 N methanolic ammonia in ethyl acetate in ethyl acetate. 0.76 g obtained (44% yield). 1H NMR (300 MHz, DMSO-d6) δ 8.04-8.14 (m, 1 H), 7.86-7.89 (d, 1 H J=9.83 Hz), 7.72-7.79 (m, 3 H), 7.41-7.51 (m, 3 H), 7.21-7.26 (m, 2 H), 7.09-7.15 (m,
1 H), 5.00-5.11 (m, 1 H), 4.03-4.14 (m, 2 H), 3.87-3.99 (m, 1 H), 3.19-3.38 (m,
2 H), 2.96-3.05 (m, 1 H), 2.85-2.94 (m, 3 H), 2.69-2.80 (m, 4 H), 2.51-2.64 (m, 2 H), 1.93-2.26 (m, 11 H), 1.73-1.88 (m, 2H), 0.94-1.12 (m, 3H). LC/MS m/z (M+H): 710.
Example 804
Preparation of 2-chloro-4-fluoro-5-(r(2.2,2-trifluoroethyl)aminolsulfonyl>benzoic acid
° ° ρ r X, Cl
4.997 g (18.3 mmol) 3-chlorosulfonyl-4-fluorobenzoic acid, 2.90 g (27.5 mmol) NaHCO3 were dissolved in 50 mL water. 1.45 mL (18.3 mmol) trifluoroethylamine was added dropwise to solution. Solution was acidified to pH=1 with concentrated HCl and product was extracted into ethyl acetate. Dried over MgSO4 and concentrated. 5.27 g recovered (83% yield). Crude product was used in subsequent step without further purification. 1H NMR (300 MHz, DMSO-de) δ 9.22-9.37 (dt, 1 H, J=6.44, 30.24 Hz), 7.80-7.92 (dd, 1 H, J=9.91 , 25.78 Hz), 4.04-4.16 (m, 1 H), 3.77-3.90 (m, 1 H).
Preparation of 4-chloro-2-fluoro-5-r(4-(3-fluorophenyl)-4-f2-r(1 f?,5S)-3-(2- methyl-1 H-benzimidazol-1 -yl)-8-azabicyclor3.2.11oct-8-vnethyl)piperidin-1- yl)carbonyl1-/V-(2,2,2-trifluoroethyl)benzenesulfonamide
Figure imgf000548_0001
8.792 g (19.7mmol) 1-((1R,5S)-8-{2-[4-(3-fluorophenyl)piperidin-4-yl]ethyl}-8- azabicyclo[3.2.1]oct-3-yl)-2-methyl-1 H-benzimidazole and 6.59 g ( 19.7 mmol) 2-chloro-5-[(2,2,2-trifluoroethylamino)sulfonyl]-4-fluorobenzoic acid were combined following the HATU general procedure in Example 5. This compound was purified by flash chromatography on a 0-100% gradient of 1 N methanolic ammonia in ethyl acetate in ethyl acetate. 6.31 g obtained (42% yield). 1H NMR (300 MHz, DMSO-d6) δ 9.18-9.25 (br, 1 H), 7.75-7.94 (m, 2 H), 7.35-7.52 (m, 3 H), 7.22-7.28 (m, 2 H), 7.04-7.15 (m, 3 H), 4.45-4.56 (m, 1 H), 3.80-4.00 (m, 3 H), 3.20-3.43 (m, 6 H), 2.99-3.07 (m, 1 H), 2.48-2.52 (m, 3 H), 2.32-2.41 (m, 2 H), 1.97-2.29 (br, 2 H), 1.74-1.91 (m, 8 H), 1.59-1.64 (m, 2 H).
Example 805
Preparation of 2-chloro-4-fluoro-5-f(propylamino)sulfonyllbenzoic acid
Figure imgf000549_0001
2.512 g (9.2 mmol) 3-chlorosulfonyl-4-fluorobenzoic acid was added to 2.27 mL (27.6 mmol) propylamine following the general procedure in for 2-chloro-5- [(ethylamino)sulfonyl]-4-fluorobenzoic acid. Crude product was used in subsequent step without further purification. 1H NMR (300 MHz, DMSO-d6) δδ.19-8.22 (d, 1 H, J= 7.84 Hz), 8.12-8.16 (t, 1 H, J=11.59 Hz), 7.85-7.88 (d, 1 H, J=9.90 Hz), 2. 80-2.87 (q, 2 H, J=6.82), 1.33-1.45 (m, 2 H), 0.77-0.82 (t, 3 H, J=7.51 Hz).
Preparation of 4-chloro-2-fluoro-5-r(4-(3-fluorophenvn-4-(2-r(1 R.5SV3-(2- methyl-1 H-benzimidazol-1 -yl)-8-azabicvclo[3.2.11oct-8-vπethyl)piperidin-1 - vDcarbonv-V-V-propylbenzenesulfonamide
Figure imgf000549_0002
0.366 g (0.82 mmol) 1-((1R,5S)-8-{2-[4-(3-fluorophenyl)piperidin-4-yl]ethyl}-8- azabicyclo[3.2.1]oct-3-yl)-2-methyl-1 H-benzimidazole and 0.363 g ( 1.23 mmol) 2-chloro-4-fluoro-5-[(propylamino)sulfonyl]benzoic acid were combined following the HATU general procedure in Example 5. This compound was purified by flash chromatography on a 0-100% gradient of 90:5:5 acetonitrile: ammonium hydroxide: water in acetonitrile. 0.24 g obtained (40% yield). 1H NMR (300 MHz, DMSO-de) δ 8.04-8.15 (br, 1 H), 7.69-7.90 (m, 2 H), 7.32- 7.52 (m, 3 H), 7.19-7.26 (m, 2 H), 7.01-7.15 (m, 3 H), 4.41-4.56 (m, 1 H), 3.86-3.98 (m, 1 H), 3.19-3.43 (m, 6 H), 2.97-3.08 (m, 1 H), 2.77-2.88 (m, 2 H), 2.44 (s, 3H), 2.28-2.41 (m, 2 H), 1.96-2.17 (m, 2H), 1.71-1.92 (m, 9 H), 1.56- 1.64 (m, 2 H), 1.31-1.42 (m, 2 H), 0.73-0.81 (m, 3 H).
Example 806
Preparation of 2-chloro-4-fluoro-5-r(isopropylamino)sulfonvnbenzoic acid
Figure imgf000550_0001
1.002 g (3.6 mmol) 3-chlorosulfonyl-4-fluorobenzoic acid was added to 0.94 mL (10.9 mmol) isopropylamine following the general procedure in for 2- chloro-5-[(ethylamino)sulfonyl]-4-fluorobenzoic acid. Crude product was used in subsequent step without further purification
1H NMR (300 MHz, DMSO-d6) δ 8.20-8.23 (d, 1 H, J=8.28 Hz), 8.12-8.17 (t, 1 H, J=7.30 Hz), 7.83-7.87 (d, 1 H, J=10.23 Hz), 3.30-3.43 (m, 1 H), 0.98-1.01 (d, 6 H, J=6.34 Hz).
Preparation of 4-chloro-2-fluoro-5-r(4-(3-fluorophenyl)-4-(2-r(1 R,5S)-3-(2- methyl-1 H-benzimidazol-1 -yl)-8-azabicvclor3.2.1loct-8-vnethyl}piperidin-1- yl)carbonyll-Λ/-isopropylbenzenesu-fonamide
Figure imgf000551_0001
0.290 g (0.65 mmol) 1-((1R,5S)-8-{2-[4-(3-fluorophenyl)piperidin-4-yl]ethyl}-8- azabicyclo[3.2.1]oct-3-yl)-2-methyl-1 H-benzimidazole and 0.288 g ( 0.975 mmol) 2-chloro-4-fluoro-5-[(isopropylamino)sulfonyl]benzoic acid were combined following the HATU general procedure in Example 5. This compound was purified by reverse phase chromatography on a 0-100% gradient of 0.1% TFA in water in acetonitrile. 0.196 g obtained (42% yield). 1H NMR (300 MHz, DMSO-d6) δ 8.09-8.19 (m, 1 H), 7.76-7.99 (m, 2 H), 7.38- 7.55 (m, 4 H), 7.25-7.31 (m, 1 H), 7.07-7.20 (m, 3 H), 4.52-4.62 (m, 1 H), 3.92-4.01 (m, 1 H), 3.29-3.43 (m, 6 H), 3.01-3.11 (m, 1 H), 2.76 (s, 1 H), 2.47- 2.51 (m, 2 H), 2.36-2.45 (m, 1 H), 1.78-2.04 (m, 12 H), 1.25-1.32 (m, 3H), 0.99-1.07 (m, 6H).
Example 807 Preparation of 2-chloro-5-[(cvclopropylamino)sulfonyl1-4-fluorobenzoic acid
Figure imgf000551_0002
1.005 g (3.6 mmol) 3-chlorosulfonyl-4-fluorobenzoic acid was added to 0.76 mL (10.9 mmol) cyclopropylamine following the general procedure in for 2- chloro-5-[(ethylamino)sulfonyl]-4-fluorobenzoic acid. Crude product was used in subsequent step without further purification
1H NMR (300 MHz, DMSO-d6) 68.46-8.48 (d, 1 H, J= 2.83 Hz), 8.22-8.26 (d, 1 H, J=7.69 Hz), 7.86-7.90 (d, 1 H, J=9.70), 2.23-2.32 (m, 1 H), 0.46-0.56 (m, 2 H), 0.36-0.44 (m, 2 H). Preparation of 4-chloro-A/-cvclopropyl-2-fluoro-5-r(4-(3-fluorophenvh-4-{2- r(1 5SV3-f2-methyl-1H-benzimidazol-1-vn-8-azabicvclor3.2.noct-8- yljethyltoiperidin-1-yltoarbonvπbenzenesulfonamide
Figure imgf000552_0001
0.335 g (0.75 mmol) 1-((1R,5S)-8-{2-[4-(3-fluorophenyl)piperidin-4-yl]ethyl}-8- azabicyclo[3.2.1]oct-3-yl)-2-methyl-1 H-benzimidazole and 0.242 g ( 0.83 mmol) 2-chloro-4-fluoro-5-[(cyclopropylamino)sulfonyl]benzoic acid were combined following the HATU general procedure in Example 5. This compound was purified by reverse phase chromatography on a 0-100% gradient of 0.1% TFA in water in acetonitrile. 0.231 g obtained (43% yield). 1H NMR (300 MHz, DMSO-de) δ 8.38-8.47 (br, 1 H), 7.72-7.92 (m, 2 H), 7.33- 7.51 (m, 3 H), 7.20-7.28 (m, 2 H), 7.01-7.16 (m, 3 H), 4.45-4.57 (m, 1 H), 4.06-4.12 (m, 1 H), 3.87-3.98 (m, 1 H), 3.21-3.42 (m, 6 H), 2.97-3.10 (m, 1 H), 2.44 (s, 3 H), 2.23-2.42 (m, 2 H), 1.95-2.17 (m, 2 H), 1.72-1.92 (m, 8 H), 1.55- 1.65 (m, 2 H), 0.34-0.53 (m, 4 H).
Example 808 Preparation of 2-chloro-5-r(cvclopentylamino)sulfonvπ-4-fluorobenzoic acid
Figure imgf000552_0002
1.01 g (3.7 mmol) 3-chlorosulfonyl-4-fluorobenzoic acid was added to 1.08 mL (10.9 mmol) cyclopentylamine following the general procedure in for 2-chloro- 5-[(ethylamino)sulfonyl]-4-fluorobenzoic acid. Crude product was used in subsequent step without further purification 1H NMR (300 MHz, DMSO-de) δδ.21-8.24 (m, 2 H), 7.84-7.88 (d, 1 H, J=10.14 Hz), ..48-3.59 (m, 1 H), 1.48-1.70 (m, 4 H), 1.28-1.46 (m, 4 H).
Preparation of 4-chloro-Λ/-cvclopentyl-2-fluoro-5-[(4-(3-fluorophenv -4-(2- r(1 5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8-azabicvclor3.2.noct-8- yllethyl}piperidin-1-yl)carbonyllbenzenesulfonamide
Figure imgf000553_0001
0.103 g (0.23 mmol) 1-((1 R,5S)-8-{2-[4-(3-fluorophenyl)piperidin-4-yl]ethyl}-8- azabicyclo[3.2.1]oct-3-yl)-2-methyl-1 H-benzimidazole and 0.148 g ( 0.46 mmol) 2-chloro-4-fluoro-5-[(cyclopentylamino)sulfonyl]benzoic acid were combined following the HATU general procedure in Example 5. This compound was purified by reverse phase chromatography on a 0-100% gradient of 0.1 % TFA in water in acetonitrile. 0.068 g obtained (40% yield). 1H NMR (300 MHz, DMSO-d6) δ 9.32-9.49 (br, 1 H), 8.13-8.25 (m, 2 H), 7.73- 7.91 (m, 3 H), 7.39-7.56 (m, 2 H), 7.08-7.30 (m, 3 H), 5.00-5.15 (m, 1 H), 4.03-4.16 (m, 2 H), 3.83-4.02 (m, 1 H), 3.35-3.58 (m, 2 H), 3.19-3.33 (m, 2 H), 3.16 (s, 1 H), 2.94-3.08 (m, 2 H), 2.67-2.80 (m, 6 H), 2.54-2.65 (m, 1 H), 2.02- 2.26 (m, 8H), 1.72-2.01 (m, 2 H), 1.47-1.67 (m, 4H), 1.26-1.44 (m, 4 H)
(Alkyl- or alkoxy-amino)benzoic Acids listed below were prepared using the following scheme
Figure imgf000554_0001
R= methyl, ethyl, propyl, isopropyl, cyclopropyl cyclopentyl, methoxy, ethoxy, etc.
X, Y = Cl, F,
Preparation of 2-Chloro-4-Fluoro-5-r(Methylamino)sulfonyl1benzoic Acid
xX At 0 °C, to a stirred ice-water suspension (~200 mL) of 2-chloro-5- (chlorosulfonyl)-4-fluorobenzoic acid was slowly added a precooled 40% methylamine (13 mL). The reaction mixture was then stirred for 2 hours before being acidified to pH~2. The desired product was precipitated and filtered out. After being dried overnight, the pure 2-chloro-4-fluoro-5- [(methylamino)sulfonyl]benzoic acid was obtained as white solid (9.8g, 100%).
The corresponding substituted aminosulfonyl benzoic acids used in this patent were prepared in the similar methods as described above.
Example 809
Preparation of 2.4-Difluoro-3-f(4-(3-fluorophenyl)-4-f2-r(1 R,5S)-3-(2- methyl-1 H-benzimidazol-1 -yl)-8-azabicvclor3.2.11oct-8-yllethyl)piperidin-1 - yDcarbonyll-N-methoxybenzenesulfonamide
Figure imgf000555_0001
2,4-Difluoro-3-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H- benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-1-yl)carbonyl]-Λ/- methoxybenzenesulfonamide (11 mg, 17%) was obtained as solid from 3- (chlorosulfonyl)-2,6-difluorobenzoic acid (105 mg, 0.4 mmol), 1-((1R,5S)-8-{2- [4-(3-fluorophenyl)piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl- 1 H-benzimidazole (52 mg, 0.1 mmol) and methoxyamine hydrochloride (33mg, 0.4 mmol) following the coupling procedure in example 473. 1H NMR (400 MHz, CD3OD), δ 8.04 (q, J=3.3 Hz, 1 H), 7.97 (s, 2 H), 7.53 (d, J=9.6 Hz, 1 H), 7.45-7.40 (m, 2 H), 7.36-7.16 (m, 4, H), 7.01 (t, J=6.8 Hz, 1 H), 4.80- 4.71 (m, 1 H), 4.20-4.19 (br, 1 H), 3.74 (d, J=10.1 Hz, 3 H), 3.57-3.42 (m, 4 H), 3.30-3.27 (m, 1 H), 2.54 (s, 3 H), 2.51-2.25 (m, 4 H), 2.09-1.93 (m, 10 H), 1.75 (d, J=7.6 Hz, 2 H). HRMS m/z (M+H)+ calcd: 696.2831 , obsd: 696.2831.
Example 810
Preparation of 2-(4-fluorophenvn-2-(4-(3-fluorophenyl)-4-{2-lϊ1 R,5S)-3-(2- methyl-1 H-benzimidazol-1 -yl)-8-azabicvclo[3.2.1loct-8-yllethyl)piperidin-1-yl)- Λ/-methylacetamide
Figure imgf000555_0002
(4-Fluorophenyl)(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H- benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-1-yl)acetic acid (prepared from 1 -((1 R,5S)-8-{2-[4-(3-fluorophenyl)piperidin-4-yl]ethyl}-8- azabicyclo[3.2.1]oct-3-yl)-2-methyl-1 H-benzimidazole and 4- fluorophenylboronic acid following the procedure outlined in example 412. (19 mg, 0.032 mmol) was coupled with methylamine (16 μL, 2M in THF) under promotion of HATU (12 mg, 0.032mmol) The title compound was obtained as solid (12mg, 60%) after purification by flash chromatography, eluting with a gradient of 0-10%methanol in ethyl acetate. 1H NMR (400 MHz, CDCI3) δ 7.66 (d, J=7.1 Hz, 1 H), 7.32-7.24 (m, 4 H), 7.19-7.12 (m, 2 H), 7.03-6.89 (m, 6H), 4.59 (br, 1 H), 3.75 (s, 1 H), 3.22 (br, 2 H), 2.84 (d, J=4.9 Hz, 3 H), 2.55 (s, 3 H), 2.52-2.47 (m, 1 H), 2.40-2.09 (m, 6 H), 1.93-1.87 (m, 7 H), 1.78-1.61 (m, 6 H). HRMS m/z (M+H)+ calcd 612.3514, obsd 612.3530.
Example 811
Preparation of 2,4-difluoro-5-IT4-(3-fluorophenvn-4-(2-r(1 R.5S)-3-(2-methyl- 1 H-benzimidazol-1 -ylV8-azabicvclof3.2.1loct-8-yllethyl piperidin-1- vOcarbonvπ-N-methoxybenzenesulfonamide
Figure imgf000556_0001
2,4-Difluoro-5-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H- benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-1-yl)carbonyl]-/V- methoxybenzene sulfonamide (119 mg, 43%) was obtained as solid from 1-((1R,5S)-8-{2-[4-(3- fluorophenyl)piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1 ]oct-3-yl)-2-methyl-1 H- benzimidazole dihydrochloride (244mg. 0.4 mmol) and 2,4-difluoro-5- [(methoxyamino)sulfonyl]benzoic acid (266mg, 1 mmol) and HATU (152 mg, 0.4 mmol), following the coupling procedure in example 5. 1H NMR (400 MHz, CDCI3) δ 7.66 (d, J=7.3 Hz, 1 H), 7.40-7.34 (m. 1 H), 7.0 (d, J=7.3 Hz, 1 H), 7.21-7.14 (m, 2 H), 7.04-6.96 (m, 5H), 4.65-4.60 (m, 1 H), 4.23-4.20 (m, 1 H), 3.80 (s, 3 H), 3.34-3.24 (m, 6 H), 2.58 (s, 3 H), 2.45-2.37 (m, 2 H), 2.34- 2.14 (m, 2 H), 2.07-1.77 (m, 12 H). HRMS m/z (M+H)+ calcd 696.2831 , obsd 696.2812.
Example 812
Preparation of 4-chloro-2-fluoro-5-K4-(3-fluorophenyl)-4-f2-r(1 R,5S)-3-(2- methyl-1 H-benzimidazol-1 -yl)-8-azabicvclor3.2.11oct-8-yllethyl)piperidin-1 - vDcarbonvπ-Λ/-methoxybenzenesulfonamide
Figure imgf000557_0001
4-Chloro-2-fluoro-5-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H- benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-1-yl)carbonyl]-Λ/- methoxybenzenesulfonamide (170 mg, 60%) was obtained as solid from 1- ((1R,5S)-8-{2-[4-(3-fluorophenyl)piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3- yl)-2-methyl-1 H-benzimidazole dihydrochloride (244 mg. 0.4 mmol) and 2- chloro-4-fluoro-5-[(methoxyamino)sulfonyl]benzoic acid (283mg, 1 mmol) and HATU (152 mg, 0.4 mmol), following the procedures outlined in example 5. 1H NMR (400 MHz, CDCI3) δ 7.91 (d, J=7.2 Hz, Vz H, rotamer), 7.76 (d, J=7.1 Hz, Vz H, rotamer), 7.63 (d, J=7.5 Hz, 1 H), 7.38-7.28 (m, 3 H), 7.18-7.12 (m, 2 H), 7.08-7.04 (m, 1 H), 6.98-6.94 (m, 2 H), 4.62-4.57 (m, 1 H), 4.26-4.17 (m, 1 H), 3.78 (d, J=9.9 Hz, 3 H), 3.42-3.10 (m, 6 H), 2.55 (s, 3/2 H, rotamer), 2.54 (s, 3/2 H, rotamer), 2.42-2.32 (m, 3 H), 2.14-2.07 (m, 1 H), 1.94-1.70 (m, 10 H), 1.64-1.63 (m, 2 H). HRMS m/z (M+H)+ calcd 712.2536, obsd 712.2546. Example 813
Preparation of 2,4-dichloro-3-r(4-(3-fluorophenyl)-4-f2-r(1 R.5S)-3-(2-methyl- 1 H-benzimidazol-1 -ylV8-azabicvclof3.2.11oct-8-yllethyl>piperidin-1 - vπcarbonvn-/V-propylbenzenesulfonamide
Figure imgf000558_0001
2,4-Dichloro-3-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H- benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-1-yl)carbonyl]-/V- propylbenzenesulfonamide (11 mg, 15%) was obtained as solid from 2,6- dichloro-3-(chlorosulfonyl)benzoic acid (58 mg, 0.2 mmol), propyl amine (20 μL, 0.2mmol) and 1-((1R,5S)-8-{2-[4-(3-fluorophenyl)piperidin-4-yl]ethyl}-8- azabicyclo[3.2.1]oct-3-yl)-2-methyl-1 H-benzimidazole dihydrochloride (61 mg, 0.1 mmol) following the procedure outlined in example 473. 1H NMR (400 MHz, CD2CI2), δ 8.06=8.01 (m, 1 H), 7.59-7.48 (m, 2 H), 7.42-7.34 (m, 2 H), 7.20-7.16 (m, 3 H), 7.14-6.96 (m, 2 H), 4.68 (br, 1 H), 4.23-4.20 (m, 1 H), 3.47-3.13 (m, 6 H), 2.96-2,82 (m, 4 ), 2.53 (s, 3/2 H), 2.41 (s, 3/2 H), 2.36- 2.16 (m, 5 H), 1.98-1.84 (m, 7 h), 1.68-1.61 (m, 2 H), 1.52-1.44 (m, 2 H), 0.90- 0.86 (m, 3 H). HRMS m/z (M+H)+ calcd: 740.2604, obsd: 740.2589.
Example 814
Preparation of 2.4-dichloro-3-r(4-(3-fluorophenylV4-(2-f(1 R,5S)-3-(2-methyl-
1 H-benzimidazol-1 -vπ-8-azabicvclo[3.2.11oct-8-vπethyl)piperidin-1 - vOcarbonvπ-Λ/-isopropylbenzenesulfonamide
Figure imgf000559_0001
2,4-Dichloro-3-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H- benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-1-yl)carbonyl]-A/- isopropyl benzene sulfonamide (13.5 mg, 18%) was obtained as solid from 2,6-dichloro-3- (chlorosulfonyl)benzoic acid (58 mg, 0.2 mmol), isopropyl amine (20 μL, 0.2 mmol) and 1-((1 R,5S)-8-{2-[4-(3-fluorophenyl)piperidin-4-yl]ethyl}-8- azabicyclo[3.2.1]oct-3-yl)-2-methyl-1 H-benzimidazole dihydrochloride (61 mg, 0.1 mmol) following the procedure outlined in example 473. 1H NMR (400 MHz, CD2CI2), δ 8.07 (d, J=8.6 Hz, 1 H), 7.58-7.50 (m, 2 H), 7.42-7.35 (m, 2 H), 7.21-7.12 (m, 2 H), 7.06-6.95 (m, 3 H), 4.70-4.65 (m, 1 H), 4.23-4.19 (m, 1 H), 3.47-3.27 (m, 5 H), 3.22-3.14 (m, 2 H), 2.53 (s, 3 H), 2.46-2.32 (m, 3 H), 2.16 (br, 1 H), 1.98-1.83 (m, 11 H), 1.68 (d, J=7.7 Hz, 2 H), 1.25-1.03 (m, 6 H). HRMS m/z (M+H)+ calcd: 740.2604, obsd: 740.2590.
Example 815
Preparation of 2,4-dichloro-Λ/-cvclopropyl-3-r(4-(3-fluorophenyl)-4-f2-[(1 R.5S)- 3-(2-methyl-1 H-benzimidazol-1 -vπ-8-azabicvclor3.2.11oct-8-vnethyl)piperidin- 1 -vDcarbonvnbenzenesulfonam.de
Figure imgf000559_0002
2,4-Dichloro-/V-cyclopropyl-3-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2- methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-1- yl)carbonyl]benzene sulfonamide (12 mg, 15%) was obtained as solid from 2,6-dichloro-3- (chlorosulfonyl)benzoic acid (58 mg, 0.2 mmol), cyclopropyl amine (17 μL, 0.2 mmol) and 1-((1R,5S)-8-{2-[4-(3-fluorophenyl)piperidin-4-yl]ethyl}-8- azabicyclo[3.2.1]oct-3-yl)-2-methyl-1 H-benzimidazole dihydrochloride (61 mg, 0.1 mmol) following the procedure outlined in example 473. 1H NMR (400 MHz, CD2CI2), δ 8.10 (d, J=7.6 Hz, 1 H), 7.59-7.52 (m, 2 H), 7.42-7.36 (m, 2 H), 7.19-7.12 (m, 3 H), 7.07-6.97 (m, 2 H), 4.67-4.63 (m, 1 H), 4.24-4.20 (m, 1 H), 3.49-3.14 (m, 6 H), 2.53 (s, 3 H), 2.44-2.33 (m, 3 H), 2.12 (br, 1 H), 1.96- 1.85 (m, 11 H), 1.67-1.65 (m, 2 H), 0.74-0.67 (m, 1 H), 0.61-0.51 (m, 3 H). HRMS m/z (M+H)+ calcd: 738.2448, obsd: 738.2433.
Example 816
Preparation of 2,4-dichloro-3-IT4-(3-fluorophenvn-4-f2-IY1 R,5S)-3-(2-methyl- 1 H-benzimidazol-1 -yl)-8-azabicvclor3.2.1 loct-8-yl1ethyl)piperidin-1 - yl)carbonvπ-Λ/-(2,2,2-trifluoroethyl)benzenesulfonamide
Figure imgf000560_0001
2,4-Dichloro-3-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H- benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-1-yl)carbonyl]-/V- (2,2,2-trifluoroethyl) benzenesulfonamide (220 mg, 56%) was obtained as solid from 2,6-dichloro- 3-(chlorosulfonyl)benzoic acid (290 mg, 1 mmol), 2,2,2-trifluroethylamine (160 μL, 2 mmol) and 1-((1R,5S)-8-{2-[4-(3-fluorophenyl)piperidin-4-yl]ethyl}-8- azabicyclo[3.2.1]oct-3-yl)-2-methyl-1 H-benzimidazole dihydrochloride (305 mg, 0.5 mmol) following the procedure outlined in example 473. 1H NMR (400 MHz, CD2CI2), δ 8.03 (d, J=8.4 Hz, 1 H), 7.59-7.54 (m, 1 H), 7.562-7.47 (m, 1 H), 7.42-7.34 (m, 2 H), 7.19-7.12 (m, 3 H), 7.06-6.96 (m, 2 H), 4.65-4.60 (m, 1 H), 4.22-4.18 (m, 1 H), 3.79-3.69 (m, 2 H), 3.48-3.45 (m, 1 H), 3.27-3.12 (m, 3 H), 3.11-3.05 (m, 1 H), 2.52 (s, 3 H), 2.43-2.30 (m, 3 H), 2.19-2.16 (m, 2 H), 1.97-1.81 (m, 10 H), 1.66-1.62 (m, 2 H). HRMS m/z (M+H)+ calcd: 780.2165, obsd: 780.2164.
Example 817
Preparation of 2,4-difluoro-3-IT4-(3-fluorophenvn-4-f2-.T1 R.5S)-3-(2-methyl- 1 H-benzimidazol-1 -yl)-8-azabicvclof3.2.11oct-8-vπethyl)piperidin-1 - yl)carbonvπ-Λ/-(2,2,2-trifluoroethyl)benzenesulfonamide
Figure imgf000561_0001
2,4-Difluoro-3-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H- benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-1-yl)carbonyl]-yV- (2,2,2-trifluoroethyl) benzenesulfonamide (260 mg, 70 %) was obtained as solid from 2,6-difluro-3- (chlorosulfonyl)benzoic acid (260 mg, 1 mmol), 2,2,2-trifluroethylamine (160 μL, 2 mmol) and 1-((1R,5S)-8-{2-[4-(3-fluorophenyl)piperidin-4-yl]ethyl}-8- azabicyclo[3.2.1]oct-3-yl)-2-methyl-1 H-benzimidazole dihydrochloride (305 mg, 0.5 mmol) following the procedure outlined in example 473. 1H NMR (400 MHz, CD2CI2), δ 7.98-7.92 (m, 1 H), 7.60-7.58 (m, 1 H), 7.41-7.32 (m, 2 H), 7.22-7.20 (m, 2 H), 7.16-6.98 (m, 4 H), 4.69-4.67 (m, 1 H), 4.18 (br, 1 H), 3.80-3.62 (m, 1 HO, 3.45-3.39 (m, 3 H), 3.25-3.20 (m, 1 H), 2.55 (s, 3 H), 2.402.42 (m, 2 H), 2.42-2.40 (m, 1 H), 2.32-1.83 (m, 212 H), 1.73-1.38 (m, 2 H). HRMS m/z (M+H)+ calcd: 748.2756, obsd: 748.2759. Example 818
Preparation of 2-chloro-Λ/-ethoxy-4-fluoro-5-r(4-(3-fluorophenyl)-4-f2-IY1 R.5S)-
3-(2-methyl-1 H-benzimidazol-1 -yl)-8-azabicvclor3.2.11oct-8-vπethyl}piperidin-
1-yl)carbonvnbenzenesulfonamide
O
Figure imgf000562_0001
2-Chloro-Λ/-ethoxy-4-fluoro-5-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2- methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-1- yl)carbonyl] benzenesulfonamide (60 mg, 16%) was obtained as solid from 1-((1R,5S)-8- {2-[4-(3-fluorophenyl)piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2- methyl-1 H-benzimidazole dihydrochloride (305 mg. O.δmmol) and 2- fluoro -4- chloro -5-[(ethoxyamino)sulfonyl]benzoic acid (297mg, 1 mmol) and HATU (190 mg, 0.5 mmol), following the procedures outlined in example 5. 1H NMR (400 MHz, CD2CI2) δ 8.15 (br, 1 H), 7.59-7.57 (m, 1 H), 7.42-7.35 (m, 3 H), 7.16-7.12 (m, 3 H), 7.07-6.97 (m, 2 H), 4.64-4.60 (m, 1 H), 4.15-4.01 (m, 4 H), 3.42-3.19 (m, 5 H), 2.53 (s, 3 H), 2.43-2.32 (m, 3 H), 2.18-2.11 (m, 1 H), 1.96- 1.83 (m, 10 H), 1.66-1.64 (m, 2 H), 1.17 (t, J=6.9 Hz, 3 H). HRMS m/z (M+H)+ calcd 726.2692, obsd 726.2704.
Example 819
Preparation of 2,4-dichloro-Λ/-ethoxy-3-r(4-(3-fluorophenvn-4-{2-IT1 R,5S)-3-(2- methyl-1 H-benzimidazol-1 -yl)-8-azabicvclor3.2.11oct-8-vπethyl)piperidin-1 - vDcarbonvπbenzenesulfonamide O 2004/054974
562
Figure imgf000563_0001
2,4-Dichloro-/V-ethoxy-3-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl- 1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-1-yl)carbonyl] benzenesulfonamide (22.5 mg, 6%) was obtained as solid from 2,6-dichloro- 3-(chlorosulfonyl)benzoic acid (290 mg, 1 mmol), ethoxyamine hydrichloride (195 mg, 2 mmol) and 1-((1R,5S)-8-{2-[4-(3-fluorophenyl)piperidin-4-yl]ethyl}- 8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1 H-benzimidazole dihydrochloride (305 mg, 0.5 mmol) following the procedure outlined in example 473. 1H NMR (400 MHz, CD2CI2), δ 8.10-8.08 (m, 1 H), 7.60-7.55 (m, 2 H), 7.40-7.35 (m, 2 H), 7.18-7.12 (m, 3 H), 7.07-6.96 (m, 2 H), 4.65-4.60 (m, 2 H), 4.23-4.20 (m, 1 H), 4.06-4.00 (m, 2 H), 3.3403.12 (m, 6 H), 2.54-2.53 (m, 2 H), 2.44-2.44 (m, 4 H), 2.20-2.03 (m, 2 H), 1.97-1.84 (m, 12 H), 1.65 (d, J=7.9 Hz, 2 H), 1.18-1.14 (m, 3 H). HRMS m/z (M+H)+ calcd: 742.2397, obsd: 742.2424.
Example 820
Preparation of Λ/-ethoxy-2,4-difluoro-3-r(4-(3-fluorophenyl)-4-f2-r(1 R,5S)-3-(2- methyl-1 H-benzimidazol-1 -v0-8-azabicvclor3.2.11oct-8-vπethyl)piperidin-1 - yDcarbonvnbenzenesulfonamide
Figure imgf000563_0002
Λ/-ethoxy-2,4-difluoro-3-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl- 1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-1- yl)carbonyl]benzene sulfonamide (27.9mg, 8%) was obtained as solid from 2,6-difluoro-3- (chlorosulfonyl)benzoic acid (260 mg, 1 mmol), ethoxyamine hydrichloride (195 mg, 2 mmol) and 1-((1R,5S)-8-{2-[4-(3-fluorophenyl)piperidin-4-yl]ethyl}- 8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1 H-benzimidazole dihydrochloride (305 mg, 0.5 mmol) following the procedure outlined in example 473. 1H NMR (400 MHz, CD2CI2), δ 8.00-7.95 (m, 1 H), 7.58-7.56 (m, 1 H), 7.42-7.35 (m, 2 H), 7.17-7.10 (m, 4 H), 7.06-6.97 (m, 2 H), 4.65-4.60 (m, 1 H), 4.21-4.00 (m, 3 H), 3.43-3.19 (m, 5 H), 2.53 (s, 3 H), 2.44-2.32 (m, 4 H), 2.17-2.15 (m, 1 H), 1.97- 1.80 (m, 10 H), 1.65 (d, J=7.8 Hz, 2 H), 1.18-1.11 (m, 3 H). HRMS m/z (M+H)+ calcd: 710.2988, obsd: 710.2975.
Example 821
Preparation of /V-ethoxy-2.4-difluoro-5-r(4-(3-fluorophenyl)-4-l2-lϊ1 R.5S)-3-(2- methyl-1 H-benzimidazol-1 -yl)-8-azabicvclor3.2.noct-8-vnethyl>piperidin-1 - vDcarbonyllbenzenesulfonamide
Figure imgf000564_0001
Λ/-ethoxy-2,4-difluoro-5-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl- 1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-1- yl)carbonyl]benzene sulfonamide (25mg, 7%) was obtained as solid from 2,4-difluoro-3- (chlorosulfonyl)benzoic acid (260 mg, 1 mmol), ethoxyamine hydrichloride (195 mg, 2 mmol) and 1-((1R,5S)-8-{2-[4-(3-fluorophenyl)piperidin-4-yl]ethyl}- 8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1 H-benzimidazole dihydrochloride (305 mg, 0.5 mmol) following the procedure outlined in example 473. 1H NMR (400 MHz, CD2CI2), δ 7.96 (br, 1 H), 7.57-7.55 (m, 1 H), 7.42-7.35 (m, 2 H), 7.16- 7.11 (m, 3 H), 7.08-6.96 (m, 3 H), 4.65-4.60 (m, 1 H), 4.14-4.03 (m, 3 H), 3.42-3.17 (m, 5 H), 2.52 (s, 3 H), 2.43-2.31 (m, 4 ), 2.13-2.09 (m, 1 H), 1.98- 1.80 (m, 10 H), 1.65 (d, J=7.8 Hz, 2 H), 1.18 (t, J=7.0 Hz, 3 H). HRMS m/z (M+H)+ calcd: 710.2988, obsd: 710.2975.
Example 822
Preparation of 1 -((1 R.5S)-8-(2-π -(2,4-difluoro-5-IT4-methylpiperazin-1 • yl)sulfonyllbenzoylV4-(3-fluorophenyl)piperidin-4-vnethyl)-8- azabicvclor3.2.1 loct-3-yl)-2-methyl-1 H-benzimidazole
Figure imgf000565_0001
1 -((1 R,5S)-8-{2-[1 -{2,4-difluoro-5-[(4-methylpiperaz - yl)sulfonyl]benzoyl}-4-(3-fluorophenyl)piperidin-4-yl]ethyl}-8- azabicyclo[3.2.1]oct-3-yl)-2-methyl-1 H-benzimidazole (170mg, 44%) was obtained as solid from 2-chloro-4-fluoro-5-[(4-methylpiperazin-1- yl)sulfonyl]benzoic acid (170 mg, 0.5 mmol) , HATU (190 mg, 0.5 mmol) and 1-((1R,5S)-8-{2-[4-(3-fluorophenyl)piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct- 3-yl)-2-methyl-1 H-benzimidazole dihydrochloride (305 mg, 0.5 mmol) following the procedure outlined in example 5. 1H NMR (400 MHz, DMSO-de), δ 7.93-7.88 (m, 1 H), 7.79-7.75 (m, 1 H), 7.47 (d, J=8.4 Hz, 1 H), 7.43-7.33 (m, 2 H), 7.23-7.21 (m, 3 H), 7.12-7.04 (m, 3 H), 4.50-4.46 (m, 1 H), 3.93-3.90 (m, 1 H), 3.30 (br, 4 H), 3.16-3.04 (m, 5 H), 2.43(s, 3 H), 2.32(br, 6 H), 2.13- 2.12 (m, 4 H), 1.98-1.57 (m, 13 H). HRMS m/z (M+H)+ calcd: 765.3149, obsd: 765.3165.
Figure imgf000566_0001
Figure imgf000567_0001
Example 827
Preparation of
2-r(4 2-r(1R.5S)-3-(2-methyl-1 H-benzimidazol-1 -vn-8-azabicvclor3.2. noct-8- yl1ethyll-4-phenyl-1-piperidinyl)carbonyl1-5,6,7,8-tetrahydro-4(1H)-quinolinone
Figure imgf000568_0001
2-[(4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1 ]oct-8- yl]ethyl}-4-phenyl-1-piperidinyl)carbonyl]-5,6,7,8-tetrahydro-4(1H)-quinolinone (5.2 mg; 17% yield) was obtained as a solid from 4-oxo-1 ,4,5,6,7,8- hexahydro-2-quinolinecarboxylic acid (9.66 mg, 0.05 mmol), 2-methyl-1-{8-[2- (4-phenyl-4-piperidinyl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole hydrochloride (25 mg, 0.05 mmol) and HATU (19 mg, 0.05 mmol) following the procedure outlined in example 5. ES-LCMS m/z (M-H): 602.36.
Example 828
3-hvdroxy-5-r(4-f2-r3-(2-methyl-1 H-benzimidazol-1 -yl)-8-azabicvclor3.2. Hoct- 8-vnethyl)-4-phenyl-1-piperidinyl)carbonyll-2-pyrrolidinone
3-hydroxy-5-[(4-{2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1 ]oct- 8-yl]ethyl}-4-phenyl-1-piperidinyl)carbonyl]-2-pyrrolid inone (12.05 mg; 43% yield) was obtained as a solid from 4-hydroxy-5-oxoproline (7.25 mg, 0.05 mmol), 2-methyl-1-{8-[2-(4-phenyl-4-piperidinyl)ethyl]-8-azabicyclo[3.2.1]oct- 3-yl}-1 H-benzimidazole hydrochloride (25 mg, 0.05 mmol) and HATU (19 mg, 0.05 mmol) following the procedure outlined in example 5. ES-LCMS m/z (M+H): 556.22.
Example 829
Λ/.Λ/-dimethyl-4-r(4-f2-r3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicvclo[3.2.noct-8-vnethyl)-4-phenyl-1-piperidinyl)carbonvn-1 ,3-thiazol-2- amine
Figure imgf000569_0001
A/,Λ/-dimethyl-4-[(4-{2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenyl-1-piperidinyl)carbonyl]-1 ,3-thiazol-2- amine (14.49 mg; 50% yield) was obtained as a solid from 2-(dimethylamino)- 1 ,3-thiazole-4-carboxylic acid hydrobromide (12.65 mg, 0.05 mmol), 2-methyl- 1 -{8-[2-(4-phenyl-4-piperidinyl)ethyl]-8-azabicyclo[3.2.1 ]oct-3-yl}-1 H- benzimidazole hydrochloride (25 mg, 0.05 mmol) and HATU (19 mg, 0.05 mmol) following the procedure outlined in example 5. ES-LCMS m/z (M+H): 583.23.
Example 830
2-methyl-1 -I8-I2-M -ff 1 -methyl-4-(methyloxy)-1 H-1.2.3-triazol-5-vncarbonyl)-4- phenyl-4-piperidinyl.ethvn-8-azabicvclor3.2.1loct-3-yll-1 H-benzimidazole
Figure imgf000570_0001
2-methyl-1 -{8-[2-(1 -{[1 -methyl-4-(methyloxy)-1 H-1 ,2,3-triazol-5-yl]carbonyl}-4- phenyl-4-piperidinyl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole (2.99 mg; 11% yield) was obtained as a solid from 1-methyl-4-(methyloxy)-1H-1 ,2,3- triazole-5-carboxylic acid (8.95 mg, 0.05 mmol), 2-methyl-1-{8-[2-(4-phenyl-4- piperidinyl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole hydrochloride (25 mg, 0.05 mmol) and HATU (19 mg, 0.05 mmol) following the procedure outlined in example 5. ES-LCMS m/z (M+H): 568.20.
Example 831
5-methyl-3-[(4-(2-r3-(2-methyl-1 H-benzimidazol-1 -vn-8-azabicvclof3.2.noct-8- yllethyl)-4-phenyl-1-piperidinyl)carbonyl1dihvdro-2(3H)-furanone
Figure imgf000570_0002
5-methyl-3-[(4-{2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1]oct-8- yl]ethyl}-4-phenyl-1 -piperidinyl)carbonyl]dihydro-2(3H)-furanone (10.39 mg; 36% yield) was obtained as a solid from 5-methyl-2-oxotetrahydro-3- furancarboxylic acid (7.90 mg, 0.05 mmol), 2-methyl-1-{8-[2-(4-phenyl-4- piperidinyl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole hydrochloride (25 mg, 0.05 mmol) and HATU (19 mg, 0.05 mmol) following the procedure outlined in example 5. ES-LCMS m/z (M+H): 569.25
Example 832
Λ/-r2-methyl-3-(4-(2-r3-(2-methyl-1H-benzimidazol-1-vn-8-azabicvclor3.2.1loct-
8-yl1ethyl}-4-phenyl-1-piperidinyl)-3-oxopropyll-1H-pyrrole-2-carboxamide
Figure imgf000571_0001
Λ/-[2-methyl-3-(4-{2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1 ]oct- 8-yl]ethyl}-4-phenyl-1-piperidinyl)-3-oxopropyl]-1H-pyrrole-2-carboxamide (13.35 mg; 44% yield) was obtained as a solid from 2-methyl-3-[(1H-pyrrol-2- ylcarbonyl)amino]propanoic acid (7.90 mg, 0.05 mmol), 2-methyl-1-{8-[2-(4- phenyl-4-piperidinyl)ethyl]-8-azabicyclo[3.2.1 ]oct-3-yl}-1 H-benzimidazole hydrochloride (25 mg, 0.05 mmol) and HATU (19 mg, 0.05 mmol) following the procedure outlined in example 5. ES-LCMS m/z (M+H): 607.26
Example 833
2-methyl-1 -(8-f2-l4-phenyl-1 -(1 H-pyrrolor2.3-olpyridin-3-ylcarbonyl)-4- piperidinvnethyl)-8-azabicyclor3.2.noct-3-yl)-1 H-benzimidazole
Figure imgf000572_0001
2-methyl-1 -(8-{2-[4-phenyl-1 -(1 H-pyrrolo[2,3-D]pyridin-3-ylcarbonyl)-4- piperidinyl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-1 H-benzimidazole (9.29 mg; 32% yield) was obtained as a solid from 1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid (8.10 mg, 0.05 mmol), 2-methyl-1-{8-[2-(4-phenyl-4-piperidinyl)ethyl]-8- azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole hydrochloride (25 mg, 0.05 mmol) and HATU (19 mg, 0.05 mmol) following the procedure outlined in example 5. ES-LCMS m/z (M+H): 573.21
Example 834
1 8-r2-(1 -f I2-(1 H-imidazol-4-vπcvclopropyncarbonyl}-4-phenyl-4- piperidinvπethvn-8-azabicvclor3.2.11oct-3-yl>-2-methyl-1 H-benzimidazole
Figure imgf000572_0002
2-methyl-1 -(8-{2-[4-phenyl-1 -(1 H-pyrrolo[2,3-b]pyridin-3-ylcarbonyl)-4- piperidinyl]ethyl}-8-azabicyclo[3.2.1 ]oct-3-yl)-1 H-benzimidazole (12.60 mg; 45% yield) was obtained as a solid from 2-(1H-imidazol-4- yl)cyclopropanecarboxylic acid hydrochloride (9.43 mg, 0.05 mmol), 2-methyl- 1-{8-[2-(4-phenyl-4-piperidinyl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1H- benzimidazole hydrochloride (25 mg, 0.05 mmol) and HATU (19 mg, 0.05 mmol) following the procedure outlined in example 5. ES-LCMS m/z (M+H): 563.24
Example 835
4.5-diethyl-2-r(4-f2-r3-(2-methyl-1H-benzimidazol-1-vn-8-azabicvclor3.2.11oct-
8-yllethyl>-4-phenyl-1-piperidinyl)carbonvnphenol
Figure imgf000573_0001
4,5-diethyl-2-[(4-{2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1 ]oct- 8-yl]ethyl}-4-phenyl-1-piperidinyl)carbonyl]phenol (6.39 mg; 21 % yield) was obtained as a solid from 4,5-diethyl-2-hydroxybenzoic acid (9.71 mg, 0.05 mmol), 2-methyl-1-{8-[2-(4-phenyl-4-piperidinyl)ethyl]-8-azabicyclo[3.2.1]oct- 3-yl}-1 H-benzimidazole hydrochloride (25 mg, 0.05 mmol) and HATU (19 mg, 0.05 mmol) following the procedure outlined in example 5. ES-LCMS m/z (M+H): 605.27.
Example 836
1-r8-(2-(1-r(3.4-dichloro-2-furanyl)carbonyll-4-phenyl-4-piperidinyl>ethyl)-8- azabicvclor3.2.11oct-3-yll-2-methyl-1 H-benzimidazole
Figure imgf000574_0001
1-[8-(2-{1-[(3,4-dichloro-2-furanyl)carbonyl]-4-phenyl-4-piperidinyl}ethyl)-8- azabicyclo[3.2.1]oct-3-yl]-2-methyl-1 H-benzimidazole (12.19 mg; 41% yield) was obtained as a solid from 3,4-dichloro-2-furancarboxylic acid (9.04 mg, 0.05 mmol), 2-methyl-1-{8-[2-(4-phenyl-4-piperidinyl)ethyl]-8- azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole hydrochloride (25 mg, 0.05 mmol) and HATU (19 mg, 0.05 mmol) following the procedure outlined in example 5. ES-LCMS m/z (M+H): 591.12.
Example 837
(2S.3S)-Λ/,Λ/,3-trimethyl-1 -(4-{2-r3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicvclof3.2.11oct-8-vnethyll-4-phenyl-1 -piperidinyl)-1 -oxo-2-pentanamine
Figure imgf000574_0002
(2S,3S)-/V,Λ/,3-trimethyl-1 -(4-{2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenyl-1-piperidinyl)-1-oxo-2-pentanamine (10.05 mg; 35% yield) was obtained as a solid from Λ/,Λ/-dimethyl-L-isoleucine (7.96 mg, 0.05 mmol), 2-methyl-1-{8-[2-(4-phenyl-4-piperidinyl)ethyl]-8- azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole hydrochloride # (25 mg, 0.05 mmol) and HATU (19 mg, 0.05 mmol) following the procedure outlined in example 5. ES-LCMS m/z (M+H): 570.15.
Example 838
1-r8-(2-(1-r(2,6-difluoro-3-pyridinvπcarbonvn-4-phenyl-4-piperidinv ethylV8- azabicvclo[3.2.1loct-3-yll-2-methyl-1 H-benzimidazole
Figure imgf000575_0001
1-[8-(2-{1-[(2,6-difluoro-3-pyridinyl)carbonyl]-4-phenyl-4-piperidinyl}ethyl)-8- azabicyclo[3.2.1]oct-3-yl]-2-methyl-1 H-benzimidazole (8.35 mg; 29% yield) was obtained as a solid from 2,6-difluoro-3-pyridinecarboxylic acid (7.95 mg, 0.05 mmol), 2-methyl-1-{8-[2-(4-phenyl-4-piperidinyl)ethyl]-8- azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole hydrochloride (25 mg, 0.05 mmol) and HATU (19 mg, 0.05 mmol) following the procedure outlined in example 5. ES-LCMS m/z (M+H): 570.19.
Example 839
1 -(4-f2-r3-(2-methyl-1 H-benzimidazol-1 -yl)-8-azabicvclof3.2.noct-8-yllethyl)-
4-phenyl-1 -piperidinvD- 1 -oxo-2-(2-thienv0-2-propanol
Figure imgf000576_0001
1-(4-{2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1 ]oct-8-yl]ethyl}- 4-phenyl-1-piperidinyl)-1-oxo-2-(2-thienyl)-2-propanol (4.95 mg; 17% yield) was obtained as a solid from 2-hydroxy-2-(2-thienyl)propanoic acid (8.60mg, 0.05 mmol), 2-methyl-1-{8-[2-(4-phenyl-4-piperidinyl)ethyl]-8- azabicyclo[3.2.1]oct-3-yl}-1H-benzimidazole hydrochloride (25 mg, 0.05 mmol) and HATU (19 mg, 0.05 mmol) following the procedure outlined in example 5. ES-LCMS m/z (M+H): 583.17.
Example 840
2-methyl-1-(8-r2-(1-fr3-(1-methylethyl)-5-isoxazolvncarbonyl)-4-phenyl-4- piperidinyl)ethyll-8-azabicvclor3.2.noct-3-yl)-1 H-benzimidazole
Figure imgf000576_0002
2-methyl-1 -{8-[2-(1 -{[3-(1 -methylethyl)-5-isoxazolyl]carbonyl}-4-phenyl-4- piperidinyl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole (11.29 mg; 40% yield) was obtained as a solid from 3-(1-methylethyl)-5- isoxazolecarboxylic acid hydrochloride (8.86mg, 0.05 mmol), 2-methyl-1-{8-[2- (4-phenyl-4-piperidinyl)ethyl]-8-azabicyclo[3.2.1 ]oct-3-yl}-1 H-benzimidazole hydrochloride (25 mg, 0.05 mmol) and HATU (19 mg, 0.05 mmol) following the procedure outlined in example 5. ES-LCMS m/z (M+H): 566.27.
Example 841
2-methyl-1 -f8-(2-(4-phenyl-1 -IT4-phenyl-1 H-1 ,2.3-triazol-5-vncarbonvn-4- piperidinyltethviy-8-azabicvclor3.2.11oct-3-yll-1 H-benzimidazole
Figure imgf000577_0001
2-methyl-1 -[8-(2-{4-phenyl-1 -[(4-phenyl-1 H-1 ,2,3-triazol-5-yl)carbonyl]-4- piperidinyl}ethyl)-8-azabicyclo[3.2.1]oct-3-yl]-1 H-benzimidazole (10.29 mg; 34% yield) was obtained as a solid from 4-phenyl-1H-1 ,2,3-triazole-5- carboxylic acid hydrochloride (9.45 mg, 0.05 mmol), 2-methyl-1-{8-[2-(4- phenyl-4-piperidinyl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole hydrochloride (25 mg, 0.05 mmol) and HATU (19 mg, 0.05 mmol) following the procedure outlined in example 5. ES-LCMS m/z (M+H): 600.20.
Example 842
2-methyl-1 -l"8-(2-{1 -IT4-methyl-1 H-imidazol-5-vπcarbonvn-4-phenyl-4- piperidinyl)ethyl)-8-azabicvclor3.2.noct-3-yl1-1 H-benzimidazole
Figure imgf000578_0001
2-methyl-1 -[8-(2-{1 -[(4-methyl-1 H-imidazol-5-yl)carbonyl]-4-phenyl-4- piperidinyl}ethyl)-8-azabicyclo[3.2.1]oct-3-yl]-1 H-benzimidazole (9.10 mg; 34% yield) was obtained as a solid from 4-methyl-1H-imidazole-5-carboxylic acid (6.30 mg, 0.05 mmol), 2-methyl-1-{8-[2-(4-phenyl-4-piperidinyl)ethyl]-8- azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole hydrochloride (25 mg, 0.05 mmol) and HATU (19 mg, 0.05 mmol) following the procedure outlined in example 5. ES-LCMS m/z (M-H): 535.52.
Example 843
1-f2-r(4-{2-r3-(2-methyl-1 H-benzimidazol-1 -vn-8-azabicvclor3.2.noct-8- vnethyl}-4-phenyl-1-piperidinyl)carbonyl1-3-pyridinyllethanone
Figure imgf000578_0002
1-{2-[(4-{2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1]oct-8- yl]ethyl}-4-phenyl-1-piperidinyl)carbonyl]-3-pyridinyl}ethanone (12.60 mg; 44% yield) was obtained as a solid from 3-acetyl-2-pyridinecarboxylic acid (9.35 mg, 0.05 mmol), 2-methyl-1-{8-[2-(4-phenyl-4-piperidinyl)ethyl]-8- azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole hydrochloride (25 mg, 0.05 mmol) and HATU (19 mg, 0.05 mmol) following the procedure outlined in example 5. ES-LCMS m/z (M+H): 576.24. Example 844
5-r(4-f2-r3-(2-methyl-1 H-benzimidazol-1 -vn-8-azabicvclor3.2.1loct-8-vnethyl)-
4-phenyl-1-piperidinvDcarbonvπ-4-pyridazinol
Figure imgf000579_0001
5-[(4-{2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1 ]oct-8-yl]ethyl}- 4-phenyl-1-piperidinyl)carbonyl]-4-pyridazinol (9.75mg; 35% yield) was obtained as a solid from 5-hydroxy-4-pyridazinecarboxylic acid (7.00 mg, 0.05 mmol), 2-methyl-1-{8-[2-(4-phenyl-4-piperidinyl)ethyl]-8-azabicyclo[3.2.1]oct- 3-yl}-1 H-benzimidazole hydrochloride (25 mg, 0.05 mmol) and HATU (19 mg, 0.05 mmol) following the procedure outlined in example 5. ES-LCMS m/z (M+H): 551.24.
Example 845
2-methyl-1-{8-[2-(4-phenyl-1-fr3-(4-pyridinyl)-5-isoxazolvncarbonyl)-4- piperidinyl)ethvn-8-azabicvclof3.2.1loct-3-yl)-1 H-benzimidazole
Figure imgf000579_0002
2-methyl-1-{8-[2-(4-phenyl-1-{[3-(4-pyridinyl)-5-isoxazolyl]carbonyl}-4- piperidinyl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole (15.39mg; 51% yield) was obtained as a solid from 3-(4-pyridinyl)-5-isoxazolecarboxylic acid (9.51 mg, 0.05 mmol), 2-methyl-1-{8-[2-(4-phenyl-4-piperidinyl)ethyl]-8- azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole hydrochloride (25 mg, 0.05 mmol) and HATU (19 mg, 0.05 mmol) following the procedure outlined in example 5. ES-LCMS m/z (M+H): 601.16.
Example 846
1 -(8-f2-ri -(2,3-dihvdro-1 -benzofuran-3-ylcarbonyl)-4-phenyl-4- piperidinyl1ethyll-8-azabicvclor3.2.1loct-3-yl)-2-methyl-1 H-benzimidazole
Figure imgf000580_0001
1 -(8-{2-[1 -(2,3-dihydro-1 -benzofuran-3-ylcarbonyl)-4-phenyl-4- piperidinyl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1 H-benzimidazole (17.9 mg; 62% yield) was obtained as a solid from 2,3-dihydro-1-benzofuran-3- carboxylic acid (8.20 mg, 0.05 mmol), 2-methyl-1-{8-[2-(4-phenyl-4- piperidinyl)ethyl]-8-azabicyclo[3.2.1 ]oct-3-yl}-1 H-benzimidazole hydrochloride (25 mg, 0.05 mmol) and HATU (19 mg, 0.05 mmol) following the procedure outlined in example 5. ES-LCMS m/z (M+H): 575.2.
Example 847
3-r(4-f2-r3-(2-methyl-1 H-benzimidazol-1 -vn-8-azabicvclor3.2.noct-8-vnethyll-
4-phenyl-1 -piperidinvπcarbonvn-2.3-dihvdro-1 H-pyrroloH ,2-a1pyrrol-1 -one
Figure imgf000581_0001
3-[(4-{2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}- 4-phenyl-1 -piperidinyl)carbonyl]-2,3-dihydro-1 H-pyrrolo[1 ,2-a]pyrrol-1 -one (11.5 mg; 40% yield) was obtained as a solid from 1-oxo-2,3-dihydro-1H- pyrrolo[1 ,2-a]pyrrole-3-carboxylic acid (9.35 mg, 0.05 mmol), 2-methyl-1-{8-[2- (4-phenyl-4-piperidinyl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole hydrochloride (25 mg, 0.05 mmol) and HATU (19 mg, 0.05 mmol) following the procedure outlined in example 5. ES-LCMS m/z (M+H): 576.22.
Example 848
3-(4-(2-r3-(2-methyl-1 H-benzimidazol-1 -yl)-8-azabicvclor3.2.noct-8-yllethyl)-
4-phenyl-1 -piperidinyl)-3-oxo-1 -(4-pyridinyl)-1 -propanol
Figure imgf000581_0002
3-(4-{2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1 ]oct-8-yl]ethyl}- 4-phenyl-1-piperidinyl)-3-oxo-1-(4-pyridinyl)-1 -propanol (18.59mg; 64% yield) was obtained as a solid from 3-hydroxy-3-(4-pyridinyl)propanoic acid (8.35 mg, 0.05 mmol), 2-methyl-1-{8-[2-(4-phenyl-4-piperidinyl)ethyl]-8- azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole hydrochloride (25 mg, 0.05 mmol) and HATU (19 mg, 0.05 mmol) following the procedure outlined in example 5. ES-LCMS m/z (M+H): 578.22.
Example 849
2-methyl-1 -(8-l2-(1 -IIY2S)-1 -methyl-2-phenylcvclopropyllcarbonyl)-4-phenyl-4- piperidinyl)ethvπ-8-azabicvcloF3.2.πoct-3-yll-1 H-benzimidazole
Figure imgf000582_0001
2-methyl-1 -{8-[2-(1 -{[(2S)-1 -methyl-2-phenylcyclopropyl]carbonyl}-4-phenyl-4- piperidinyl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole (18.91 mg; 64% yield) was obtained as a solid from (2S)-1-methyl-2- phenylcyclopropanecarboxylic acid (8.81 mg, 0.05 mmol), 2-methyl-1-{8-[2-(4- phenyl-4-piperidinyl)ethyl]-8-azabicyclo[3.2.1 ]oct-3-yl}-1 H-benzimidazole hydrochloride (25 mg, 0.05 mmol) and HATU (19 mg, 0.05 mmol) following the procedure outlined in example 5. ES-LCMS m/z (M+H): 587.26.
Example 850
4.6-dimethyl-3-IT4-f2-r3-(2-methyl-1 H-benzimidazol-1 -vh-8- azabicvclor3.2.11oct-8-yllethyl)-4-phenyl-1 -piperidinyl .arbonv-l-2(1 H)- pyridinone
Figure imgf000583_0001
4,6-dimethyl-3-[(4-{2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenyl-1-piperidinyl)carbonyl]-2(1H)- pyridinone (17.84 mg; 62% yield) was obtained as a solid from 4,6-dimethyl-2- oxo-1 ,2-dihydro-3-pyridinecarboxylic acid (8.35 mg, 0.05 mmol), 2-methyl-1- {8-[2-(4-phenyl-4-piperidinyl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1H- benzimidazole hydrochloride (25 mg, 0.05 mmol) and HATU (19 mg, 0.05 mmol) following the procedure outlined in example 5. ES-LCMS m/z (M+H): 578.23.
Example 851
Λ/-(hvdroxymethyl)-5-r(4-f2-f3-(2-methyl-1H-benzimidazol-1-vn-8- azabicvclo[3.2.noct-8-yllethyl)-4-phenyl-1-piperidinyl)carbonyl1-3- pyridinecarboxamide
Figure imgf000583_0002
Λ/-(hydroxymethyl)-5-[(4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenyl-1-piperidinyl)carbonyl]-3- pyridinecarboxamide (5.55 mg; 18% yield) was obtained as a solid from 5- {[(hydroxymethyl)amino]carbonyl}-3-pyridinecarboxylic acid (10.90 mg, 0.05 mmol), 2-methyl-1-{8-[2-(4-phenyl-4-piperidinyl)ethyl]-8-azabicyclo[3.2.1]oct- 3-yl}-1 H-benzimidazole hydrochloride (25 mg, 0.05 mmol) and HATU (19 mg, 0.05 mmol) following the procedure outlined in example 5. ES-LCMS m/z (M+H): 601.2.
Example 852
1 -(8-12-11 -(1 H-benzimidazol-5-ylacetvπ-4-phenyl-4-piperidinvnethyl -8- azabicvclof3.2.1loct-3-yl)-2-methyl-1 H-benzimidazole
Figure imgf000584_0001
1-(8-{2-[1-(1H-benzimidazol-5-ylacetyl)-4-phenyl-4-piperidinyl]ethyl}-8- azabicyclo[3.2.1]oct-3-yl)-2-methyl-1 H-benzimidazole (15.20 mg; 52% yield) was obtained as a solid from 1 H-benzimidazol-5-ylacetic acid (10.63 mg, 0.05 mmol), 2-methyl-1-{8-[2-(4-phenyl-4-piperidinyl)ethyl]-8-azabicyclo[3.2.1]oct- 3-yl}-1 H-benzimidazole hydrochloride (25 mg, 0.05 mmol) and HATU (19 mg, 0.05 mmol) following the procedure outlined in example 5. ES-LCMS m/z (M+H): 587.18. Example 853
6-chloro-4-r(4-(2-r3-(2-methyl-1 H-benzimidazol-1 -vn-8-azabicvclor3.2.1loct-8- yllethyl)-4-phenyl-1 -piperidinyl .arbonvπ-2(1 H oyrid inone
Figure imgf000585_0001
6-chloro-4-[(4-{2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1]oct-8- yl]ethyl}-4-phenyl-1-piperidinyl)carbonyl]-2(1H)-pyridinone (7.69 mg; 26% yield) was obtained as a solid from 6-chloro-2-oxo-1 ,2-dihydro-4- pyridinecarboxylic acid (8.67 mg, 0.05 mmol), 2-methyl-1-{8-[2-(4-phenyl-4- piperidinyI)ethyl]-8-azabicyclo[3.2.1 ]oct-3-yl}-1 H-benzimidazole hydrochloride (25 mg, 0.05 mmol) and HATU (19 mg, 0.05 mmol) following the procedure outlined in example 5. ES-LCMS m/z (M+H): 584.16.
Example 854
5-r(4-f2-r3-(2-methyl-1 H-benzimidazol-1 -vn-8-azabicvclor3.2. noct-8-yllethyl)- 4-phenyl-1-piperidinyl)carbonvn-5,6,7,8-tetrahvdro-2-naphthalenol
Figure imgf000585_0002
5-[(4-{2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1 ]oct-8-yl]ethyl}- 4-phenyl-1-piperidinyl)carbonyl]-5,6,7,8-tetrahydro-2-naphthalenol (18.15 mg; 60% yield) was obtained as a solid from 6-hydroxy-1 ,2,3,4-tetrahydro-1- naphthalenecarboxylic acid (9.61 mg, 0.05 mmol), 2-methyl-1-{8-[2-(4-phenyl- 4-piperidinyl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole hydrochloride (25 mg, 0.05 mmol) and HATU (19 mg, 0.05 mmol) following the procedure outlined in example 5. ES-LCMS m/z (M+H): 603.24.
Example 855
2-r2-(4-f2-r3-(2-methyl-1 H-benzimidazol-1 -yl)-8-azabicvclor3.2.11oct-8- yl]ethyl|-4-phenyl-1 -piperidinyl)-2-oxoethyl][1 ,2,41triazolof1 ,5-alpyrimidine
Figure imgf000586_0001
2-[2-(4-{2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1 ]oct-8- yl]ethyl}-4-phenyl-1 -piperidinyl)-2-oxoethyl][1 ,2,4]triazolo[1 ,5-a]pyrimidine (10.54 mg; 36% yield) was obtained as a solid from [1 ,2,4]triazolo[1 ,5- a]pyrimidin-2-ylacetic acid (8.90 mg, 0.05 mmol), 2-methyl-1-{8-[2-(4-phenyl- 4-piperidinyl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole hydrochloride (25 mg, 0.05 mmol) and HATU (19 mg, 0.05 mmol) following the procedure outlined in example 5. ES-LCMS m/z (M+H): 589.22. Example 856
3-f1-r(4-f2-r3-(2-methyl-1H-benzimidazol-1-vn-8-azabicvclor3.2.1loct-8- yllethyl)-4-phenyl-1-piperidinvπcarbonyllpropyl)dihvdro-2(3H)-furanone
Figure imgf000587_0001
3-{1-[(4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8- yl]ethyl}-4-phenyl-1 -piperidinyl)carbonyl]propyl}dihydro-2(3H)-furanone (15.24 mg; 52% yield) was obtained as a solid from 2-(2-oxotetrahydro-3- furanyl)butanoic acid (8.60 mg, 0.05 mmol), 2-methyl-1-{8-[2-(4-phenyl-4- piperidinyl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole hydrochloride (25 mg, 0.05 mmol) and HATU (19 mg, 0.05 mmol) following the procedure outlined in example 5. ES-LCMS m/z (M+H): 583.26.
Example 857
1-r8-(2-f1-r(3-ethenyl-2-pyridinyl)carbonvn-4-phenyl-4-piperidinyl)ethvπ-8- azabicvclor3.2.1loct-3-vn-2-methyl-1 H-benzimidazole
Figure imgf000587_0002
1-[8-(2-{1-[(3-ethenyl-2-pyridinyl)carbonyl]-4-phenyl-4-piperidinyl}ethyl)-8- azabicyclo[3.2.1]oct-3-yl]-2-methyl-1 H-benzimidazole (5.05 mg; 18% yield) was obtained as a solid from 3-ethenyl-2-pyridinecarboxylic acid (7.54 mg, 0.05 mmol), 2-methyl-1-{8-[2-(4-phenyl-4-piperidinyl)ethyl]-8- azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole hydrochloride (25 mg, 0.05 mmol) and HATU (19 mg, 0.05 mmol) following the procedure outlined in example 5. ES-LCMS m/z (M+H): 560.22.
Example 858
5-r(4-f2-r3-(2-methyl-1 H-benzimidazol-1 -vn-8-azabicvclor3.2.11oct-8-vnethyl)- 4-phenyl-1 -piperidinyl)carbonyl"|-1 ,3-benzothiazole
Figure imgf000588_0001
5-[(4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}- 4-phenyl-1-piperidinyl)carbonyl]-1 ,3-benzothiazole (7.95 mg; 27% yield) was obtained as a solid from 1 ,3-benzothiazole-5-carboxylic acid (8.95 mg, 0.05 mmol), 2-methyl-1-{8-[2-(4-phenyl-4-piperidinyl)ethyl]-8-azabicyclo[3.2.1]oct- 3-yl}-1 H-benzimidazole hydrochloride (25 mg, 0.05 mmol) and HATU (19 mg, 0.05 mmol) following the procedure outlined in example 5. ES-LCMS m/z (M+H): 590.17. Example 859
1-r8-(2-f1-r(1.1-dioxidotetrahvdro-2-thienyl)carbonvn-4-phenyl-4- piperidinyl)ethyl)-8-azabicvclor3.2.1loct-3-yll-2-methyl-1 H-benzimidazole
Figure imgf000589_0001
1 -[8-(2-{1 -[(1 ,1 -dioxidotetrahydro-2-thienyl)carbonyl]-4-phenyl-4- piperidinyl}ethyl)-8-azabicyclo[3.2.1 ]oct-3-yl]-2-methyl-1 H-benzimidazole (8.89 mg; 31% yield) was obtained as a solid from tetrahydro-2-thiophenecarboxylic acid 1 ,1-dioxide (8.20 mg, 0.05 mmol), 2-methyl-1-{8-[2-(4-phenyl-4- piperidinyl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole hydrochloride (25 mg, 0.05 mmol) and HATU (19 mg, 0.05 mmol) following the procedure outlined in example 5. ES-LCMS m/z (M+H): 575.16.
Example 860
2-methyl-7-f(4-f2-r3-(2-methyl-1 H-benzimidazol-1 -vn-8-azabicvclor3.2.11oct-8- vnethyl)-4-phenyl-1-piperidinyl)carbonvnfuror2.3-c1pyridine
Figure imgf000589_0002
2-methyl-7-[(4-{2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1 ]oct-8- yl]ethyl}-4-phenyl-1-piperidinyl)carbonyl]furo[2,3-c]pyridine (10.35 mg; 35% yield) was obtained as a solid from 2-methylfuro[2,3-c]pyridine-7-carboxylic acid (8.85 mg, 0.05 mmol), 2-methyl-1-{8-[2-(4-phenyl-4-piperidinyl)ethyl]-8- azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole hydrochloride (25 mg, 0.05 mmol) and HATU (19 mg, 0.05 mmol) following the procedure outlined in example 5. ES-LCMS m/z (M+H): 588.22.
Example 861
2-methyl-1 -f8-(2-{1 -IT1 -oxidotetrahvdro-2H-thiopyran-4-vπcarbonyl]-4-phenyl- 4-piperidinyllethvπ-8-azabicvclor3.2.1loct-3-vn-1 H-benzimidazole
Figure imgf000590_0001
2-methyl-1 -[8-(2-{1 -[(1 -oxidotetrahydro-2H-thiopyran-4-yl)carbonyl]-4-phenyl- 4-piperidinyl}ethyl)-8-azabicyclo[3.2.1]oct-3-yl]-1 H-benzimidazole (15.85 mg; 55% yield) was obtained as a solid from tetrahydro-2H-thiopyran-4-carboxylic acid 1-oxide (8.11 mg, 0.05 mmol), 2-methyl-1-{8-[2-(4-phenyl-4- piperidinyl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole hydrochloride (25 mg, 0.05 mmol) and HATU (19 mg, 0.05 mmol) following the procedure outlined in example 5. ES-LCMS m/z (M+H): 573.24. Example 862
2-methyl-1 -{8-l2-(1 -f r2-(methyloxy)-1 ,3-thiazol-5-yllcarbonyll-4-phenyl-4- piperidinyl)ethyl1-8-azabicvclor3.2.1loct-3-yll-1 H-benzimidazole
Figure imgf000591_0001
2-methyl-1 -{8-[2-(1 -{[2-(methyloxy)-1 ,3-thiazol-5-yl]carbonyl}-4-phenyl-4- piperidinyl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole (10.75 mg; 38% yield) was obtained as a solid from 2-(methyloxy)-1 ,3-thiazole-5- carboxylic acid (7.95 mg, 0.05 mmol), 2-methyl-1-{8-[2-(4-phenyl-4- piperidinyl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole hydrochloride (25 mg, 0.05 mmol) and HATU (19 mg, 0.05 mmol) following the procedure outlined in example 5. ES-LCMS m/z (M+H): 570.21.
Example 863
4-methyl-1 -IT4-f2-r3-(2-methyl-1 H-benzimidazol-1 -vn-8-azabicvclor3.2.11oct-8- yl1ethyl)-4-phenyl-1-piperidinyl)carbonyllcvclohexanol
Figure imgf000592_0001
4-methyl-1 -[(4-{2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1 ]oct-8- yl]ethyl}-4-phenyl-1-piperidinyl)carbonyl]cyclohexanol (11.20 mg; 40% yield) was obtained as a solid from 1-hydroxy-4-methylcyclohexanecarboxylic acid (7.90 mg, 0.05 mmol), 2-methyl-1-{8-[2-(4-phenyl-4-piperidinyl)ethyl]-8- azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole hydrochloride (25 mg, 0.05 mmol) and HATU (19 mg, 0.05 mmol) following the procedure outlined in example 5. ES-LCMS m/z (M+H): 569.27.
Example 864
4-r(4-f2-r3-(2-methyl-1H-benzimidazol-1-vn-8-azabicvclor3.2.noct-8-vnethyl>- 4-phenyl-1-piperidinyl)carbonyll-2.1.3-benzoxadiazole
Figure imgf000592_0002
4-[(4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}- 4-phenyl-1-piperidinyl)carbonyl]-2,1 ,3-benzoxadiazole (19.39 mg; 67% yield) was obtained as a solid from 2,1 ,3-benzoxadiazole-4-carboxylic acid (8.20 mg, 0.05 mmol), 2-methyl-1-{8-[2-(4-phenyl-4-piperidinyl)ethyl]-8- azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole hydrochloride (25 mg, 0.05 mmol) and HATU (19 mg, 0.05 mmol) following the procedure outlined in example 5. ES-LCMS m/z (M+H): 575.22.
Example 865
2-(4-f2-f3-(2-methyl-1 H-benzimidazol-1 -yl)-8-azabicvclor3.2.1loct-8-yllethyll- 4-phenyl-1 -piperidinyl)-2-oxo-1 -(3-pyridinvPethanol
Figure imgf000593_0001
2-(4-{2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1 ]oct-8-yl]ethyl}- 4-phenyl-1-piperidinyl)-2-oxo-1-(3-pyridinyl)ethanol (15.04 mg; 54% yield) was obtained as a solid from hydroxy(3-pyridinyl)acetic acid (7.65 mg, 0.05 mmol), 2-methyl-1-{8-[2-(4-phenyl-4-piperidinyl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1H- benzimidazole hydrochloride (25 mg, 0.05 mmol) and HATU (19 mg, 0.05 mmol) following the procedure outlined in example 5. ES-LCMS m/z (M+H): 564.16.
Example 866
Λ/-f2,2-dimethyl-3-[2-(4-f2-r3-(2-methyl-1H-benzimidazol-1-yl)-8- azabicvclor3.2.1loct-8-yllethyll-4-phenyl-1-piperidinyl)-2- oxoethvHcvclobutyllacetamide
Figure imgf000594_0001
Λ/-{2,2-dimethyl-3-[2-(4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenyl-1-piperidinyl)-2- oxoethyl]cyclobutyl}acetamide (15.85 mg; 52% yield) was obtained as a solid from [3-(acetylamino)-2,2-dimethylcyclobutyl]acetic acid (9.96 mg, 0.05 mmol), 2-methyl-1-{8-[2-(4-phenyl-4-piperidinyl)ethyl]-8-azabicyclo[3.2.1]oct- 3-yl}-1 H-benzimidazole hydrochloride (25 mg, 0.05 mmol) and HATU (19 mg, 0.05 mmol) following the procedure outlined in example 5. ES-LCMS m/z (M+H): 610.30.
Example 867
2-methyl-1-r8-(2-f4-phenyl-1-|"(4-phenyl-2-pyridinvπcarbonvn-4- piperidinyl)ethyl)-8-azabicvclo[3.2.noct-3-yll-1 H-benzimidazole
Figure imgf000594_0002
2-methyl-1-[8-(2-{4-phenyl-1-[(4-phenyl-2-pyridinyl)carbonyl]-4- piperidinyl}ethyl)-8-azabicyclo[3.2.1]oct-3-yl]-1 H-benzimidazole (14.94 mg; 49% yield) was obtained as a solid from 4-phenyl-2-pyridinecarboxylic acid (9.96 mg, 0.05 mmol), 2-methyl-1-{8-[2-(4-phenyl-4-piperidinyl)ethyl]-8- azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole hydrochloride (25 mg, 0.05 mmol) and HATU (19 mg, 0.05 mmol) following the procedure outlined in example 5. ES-LCMS m/z (M+H): 610.20.
Example 868
1-{8-[2-(1-fr6-chloro-4-(methyloxy)-3-pyridinyllcarbonyl)-4-phenyl-4- piperidinyl)ethyll-8-azabicvclor3.2.11oct-3-yl)-2-methyl-1 H-benzimidazole
Figure imgf000595_0001
1-{8-[2-(1-{[6-chloro-4-(methyloxy)-3-pyridinyl]carbonyl}-4-phenyl-4- piperidinyl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-2-methyl-1 H-benzimidazole (17.05 mg; 57% yield) was obtained as a solid from 6-chloro-4-(methyloxy)-3- pyridinecarboxylic acid (9.37 mg, 0.05 mmol), 2-methyl-1 -{8-[2-(4-phenyl-4- piperidinyl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole hydrochloride (25 mg, 0.05 mmol) and HATU (19 mg, 0.05 mmol) following the procedure outlined in example 5. ES-LCMS m/z (M+H): 598.19.
Example 869
8-r(4-f2-r3-(2-methyl-1 H-benzimidazol-1 -vn-8-azabicvclor3.2. noct-8-yllethviμ 4-phenyl-1 -pjperidinyl :arbonv-l-2H-chromen-2-one
Figure imgf000596_0001
8-[(4-{2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1 ]oct-8-yl]ethyl}- 4-phenyl-1-piperidinyl)carbonyl]-2H-chromen-2-one (20.64 mg; 68% yield) was obtained as a solid from 2-oxo-2H-chromene-8-carboxylic acid (9.50 mg, 0.05 mmol), 2-methyl-1-{8-[2-(4-phenyl-4-piperidinyl)ethyl]-8- azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole hydrochloride (25 mg, 0.05 mmol) and HATU (19 mg, 0.05 mmol) following the procedure outlined in example 5. ES-LCMS m/z (M+H): 601.19.
Example 870
2-methyl-1-f8-r2-(4-phenyl-1-fr3-(2-pyridinvπ-5-isoxazolyl1carbonyl)-4- piperidinv0ethvπ-8-azabicvclor3.2.πoct-3-yll-1 H-benzimidazole
Figure imgf000596_0002
2-methyl-1-{8-[2-(4-phenyl-1-{[3-(2-pyridinyl)-5-isoxazolyl]carbonyl}-4- piperidinyl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1H-benzimidazole (13.15 mg; 44% yield) was obtained as a solid from 3-(2-pyridinyl)-5-isoxazolecarboxylic acid (9.50 mg, 0.05 mmol), 2-methyl-1-{8-[2-(4-phenyl-4-piperidinyl)ethyl]-8- azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole hydrochloride (25 mg, 0.05 mmol) and HATU (19 mg, 0.05 mmol) following the procedure outlined in example 5. ES-LCMS m/z (M+H): 601.22.
Example 871
methyl 2-r(4-(2-r3-(2-methyl-1 H-benzimidazol-1 -vn-8-azabicvclor3.2.noct-8- vnethyl)-4-phenyl-1-piperidinyl)carbonyll-3-pyridinecarboxylate
Figure imgf000597_0001
Methyl 2-[(4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8- yl]ethyl}-4-phenyl-1-piperidinyl)carbonyl]-3-pyridinecarboxylate (8.45 mg; 28% yield) was obtained as a solid from 3-[(methyloxy)carbonyl]-2- pyridinecarboxylic acid (9. 05 mg, 0.05 mmol), 2-methyl-1-{8-[2-(4-phenyl-4- piperidinyl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole hydrochloride (25 mg, 0.05 mmol) and HATU (19 mg, 0.05 mmol) following the procedure outlined in example 5. ES-LCMS m/z (M+H): 592.21.
Example 872
(1R)-2-(4-(2-f3-(2-methyl-1 H-benzimidazol-1 -vn-8-azabicvclor3.2.1loct-8- vnethyl)-4-phenyl-1-piperidinyl)-1-(3-methylphenvπ-2-oxoethanol
Figure imgf000598_0001
(1 R)-2-(4-{2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1 ]oct-8- yl]ethyl}-4-phenyl-1-piperidinyl)-1-(3-methylphenyl)-2-oxoethanol (11.85 mg; 41 % yield) was obtained as a solid from (2R)-hydroxy(3- methylphenyl)ethanoic acid (8.30 mg, 0.05 mmol), 2-methyl-1-{8-[2-(4-phenyl- 4-piperidinyl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole hydrochloride (25 mg, 0.05 mmol) and HATU (19 mg, 0.05 mmol) following the procedure outlined in example 5. ES-LCMS A7?/z (M+H): 577.24.
Example 873
2-methyl-1 -[8-(2-f 1 -IY2-methyl-1 -benzofuran-7-yl)carbonvπ-4-phenyl-4- piperidinyl)ethyl)-8-azabicvclo[3.2.1loct-3-yll-1 H-benzimidazole
Figure imgf000598_0002
2-methyl-1 -[8-(2-{1 -[(2-methyl-1 -benzofuran-7-yl)carbonyl]-4-phenyl-4- piperidinyl}ethyl)-8-azabicyclo[3.2.1]oct-3-yl]-1 H-benzimidazole (12.30 mg; 42% yield) was obtained as a solid from 2-methyl-1-benzofuran-7-carboxylic acid (8.80 mg, 0.05 mmol), 2-methyl-1-{8-[2-(4-phenyl-4-piperidinyl)ethyl]-8- azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole hydrochloride (25 mg, 0.05 mmol) and HATU (19 mg, 0.05 mmol) following the procedure outlined in example 5. ES-LCMS m/z (M+H):587.22.
Example 874
2-methyl-1-f8-r2-(1-fr6-(methyloxy)-3-pyridinvncarbonyll-4-phenyl-4- piperidinv0ethvπ-8-azabicvclor3.2.1foct-3-yl)-1 H-benzimidazole
Figure imgf000599_0001
2-methyl-1-{8-[2-(1-{[6-(methyloxy)-3-pyridinyl]carbonyl}-4-phenyl-4- piperidinyl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole (13.0 mg; 43% yield) was obtained as a solid from 6-(methyloxy)-3-pyridinecarboxylic acid (9.37 mg, 0.05 mmol), 2-methyl-1-{8-[2-(4-phenyl-4-piperidinyl)ethyl]-8- azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole hydrochloride (25 mg, 0.05 mmol) and HATU (19 mg, 0.05 mmol) following the procedure outlined in example 5. ES-LCMS m/z (M+H):598.18.
Example 875
2-methyl-1-f8-r2-(4-phenyl-1-(r3-(trifluoromethyl)-2-pyridinvncarbonyll-4- piperidinyl)ethyl1-8-azabicvclor3.2.noct-3-yl)-1 H-benzimidazole
Figure imgf000600_0001
2-methyl-1-{8-[2-(4-phenyl-1-{[3-(trifluoromethyl)-2-pyridinyl]carbonyl}-4- piperidinyl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole (11.89 mg; 39% yield) was obtained as a solid from 3-(trifluoromethyl)-2- pyridinecarboxylic acid (9.56 mg, 0.05 mmol), 2-methyl-1-{8-[2-(4-phenyl-4- piperidinyl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole hydrochloride (25 mg, 0.05 mmol) and HATU (19 mg, 0.05 mmol) following the procedure outlined in example 5. ES-LCMS m/z (M+H):602.19.
Example 876
2-methyl-1 8-r2-(4-phenyl-1 -ir4-(trifluoromethvπ-1 H-pyrazol-3-yllcarbonyl)-4- piperidinyl)ethyl1-8-azabicvclo[3.2.11oct-3-yl}-1 H-benzimidazole
Figure imgf000600_0002
2-methyl-1 -{8-[2-(4-phenyl-1 -{[4-(trifluoromethyl)-1 H-pyrazol-3-yl]carbonyl}-4- piperidinyl)ethyl]-8-azabicyclo[3.2.1 ]oct-3-yl}-1 H-benzimidazole_(3.94 mg; 13% yield) was obtained as a solid from 4-(trifluoromethyl)-1H-pyrazole-3- carboxylic acid (9.00 mg, 0.05 mmol), 2-methyl-1-{8-[2-(4-phenyl-4- piperidinyl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole hydrochloride (25 mg, 0.05 mmol) and HATU (19 mg, 0.05 mmol) following the procedure outlined in example 5. ES-LCMS m/z (M+H):591.19.
Example 877
5-r(4-(3-fluorophenyl)-4-f2-r3-(2-methyl-1H-benzimidazol-1-vn-8- azabicvclor3.2.noct-8-vnethyl)-1-piperidinyl)carbonvn-3H-1.2.3- benzoxathiazole 2,2-dioxide
Figure imgf000601_0001
5-[(4-(3-fluorophenyl)-4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8- azabicyclo[3.2.1 ]oct-8-yl]ethyl}-1 -piperidinyl)carbonyl]-3H-1 ,2,3- benzoxathiazole 2,2-dioxide
(18 mg; 27% yield) was obtained as a solid from 3H-1 ,2,3-benzoxathiazole-5- carboxylic acid 2,2-dioxide (22 mg, 0.1 mmol), 1-(8-{2-[4-(3-fluorophenyl)-4- piperidinyl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1 H-benzimidazole hydrochloride (50 mg, 0.1 mmol) and HATU (38 mg, 0.1 mmol) following the procedure outlined in example 5. ES-LCMS m/z (M+H): 644.29.
Example 878
1 -(8-(2-r4-(3-fluorophenyl)-1 -(1 H-pyrazol-4-ylcarbonv0-4-piperidinvπethyl)-8- azabicvclor3.2.1 loct-3-yl)-2-methyl-1 H-benzimidazole
Figure imgf000602_0001
1 -(8-{2-[4-(3-fluorophenyl)-1 -(1 H-pyrazol-4-ylcarbonyl)-4-piperidinyl]ethyl}-8- azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole (38 mg; 37% yield) was obtained as a solid from 1 H-pyrazole-4-carboxylic acid (21 mg, 0.2 mmol), 1- (8-{2-[4-(3-fluorophenyl)-4-piperidinyl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2- methyl-1 H-benzimidazole hydrochloride (100 mg, 0.2 mmol) and HATU (73 mg, 0.2 mmol) following the procedure outlined in example 5. ES-LCMS m/z (M+H): 541.20.
Example 879
1 -f8-l"2-(4-(3-fluorophenvP-1 -■!T3-(methyloxy)-1 H-pyrazol-4-vncarbonyl)-4- piperidinyl)ethyll-8-azabicvclo 3.2.noct-3-yl)-2-methyl-1 H-benzimidazole
Figure imgf000602_0002
1 -{8-[2-(4-(3-fluorophenyl)-1 -{[3-(methyloxy)-1 -(phenylmethyl)-l H-pyrazol-4- yl]carbonyl}-4-piperidinyl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-2-methyl-1H- benzimidazole was obtained as a crude mixture from 3-(methyloxy)-1- (phenylmethyl)-1H-pyrazole-4-carboxylic acid (23 mg, 0.1 mmol), 1-(8-{2-[4- (3-fluorophenyl)-4-piperidinyl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H- benzimidazole hydrochloride (50 mg, 0.1 mmol) and HATU (38 mg, 0.1 mmol) following the procedure outlined in example 5. ES-LCMS m/z (M+H): 661.46. The crude mixture was then treated with PdCI2 (25 mg) under 50 psi H2 to provide 1 -{8-[2-(4-(3-fluorophenyl)-1 -{[3-(methyloxy)-1 H-pyrazol-4- yl]carbonyl}-4-piperidinyl)ethyl]-8-azabicyclo[3.2.1 ]oct-3-yl}-2-methyl-1 H- benzimidazole as solid (30, 52%). ES-LCMS m/z (M+H): 571.24
Example 880
2,4-dichloro-3-r(4-(3-fluorophenvn-4-f2-r3-(2-methyl-1 H-benzimidazol-1-vn-8- azabicvclof3.2.noct-8-yllethyl)-1-piperidinvπcarbonvn-N- methylbenzenesulfonamide
Figure imgf000603_0001
Example 880 was prepared according to figure below.
example 880-1 a example 880-1 b
Figure imgf000604_0001
example 880
Figure imgf000604_0002
Synthesis of 880-1 a
2, 6-dichloro-3-(chlorosulfonyl)benzoic acid
Chlorosulfonic acid was slowly added to 2,6-dichlorobenzoic acid at RT under N2. The reaction was heated to 150 °C for 3 h, then slowly poured over ice and the product extracted into Et2O. The organic layer was dried over MgSO4, filtered and concentrated to give 2,6-dichloro-3- (chlorosulfonyl)benzoic acid 880-1 a as a brown solid (12.9 g, 85% yield).
1H NMR (400 MHz, DMSO) δ 13.42 (broad s, 1 H), 7.88 (d, J = 8. Hz, 1 H), 7.46 (d, J = 8.4 Hz, 1 H).
Synthesis of 880-1 b
2, 6-dichloro-3-[(methylamino)sulfonyl]benzoic acid A mixture of 2,6-dichloro-3-(chlorosulfonyl)benzoic acid 880-1 a (200 mg, 0.69 mmol, 1 equiv) and 4 mL CH2CI2 was treated with diisopropylamine (248 μL, 1.38 mmol, 2 equiv) and 2M methyl amine (415 μL, 0.83 mmol, 1.2 equiv). The reaction was stirred at RT overnight, wherein the crude mixture contained 2,6-dichloro-3-[(methylamino)sulfonyl]benzoic acid 880-1 b. The mixture was carried directly into the following reaction. ES-LCMS m/z 284.0 (M-H)
Synthesis of 880 2.4-dichloro-3-r(4-(3-fluorophenyl)-4-f2-r3-(2-methyl-1 H-benzimidazol-1-vn-8- azabicvclo[3.2.noct-8-vnethyl)-1-piperidinyl)carbonyll-N- methylbenzenesulfonamide
Figure imgf000605_0001
To a solution of 1-(8-{2-[4-(3-fluorophenyl)piperidin-4-yl]ethyl}-8- azabicyclo[3.2.1]oct-3-yl)-2-methyl-1 H-benzimidazole dihydrochloride (100 mg, 0.16 mmol, 1 equiv) and Λ/,V-diisopropylethyl amine (117 μL, 0.66 mmol, 4 equiv) in dimethylformamide (2 mL) was added the mixture of 2,6-dichloro- 3-[(methylamino)sulfonyl]benzoic acid 880-1 b. After stirring at RT for several min, O-(7-azabenzotriazol-1-yl)-Λ/ /V,Λ/', N- tetramethyluroniumhexafluorophosphate (62 mg, 0.16 mmol, 1 equiv) was added and the reaction was stirred for 18 h. The mixture was partitioned between dichloromethane and satd. aq. NaHCO3. The organic layer was dried and concentrated and the residue was purified by SiO2 flash column chromatography (100% EtOAc -> 10% 2M NH3 in MeOH in EtOAC) to provide
2,4-dichloro-3-[(4-(3-fluorophenyl)-4-{2-[3-(2-methyl-1 H-benzimidazol-1-yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]-N- methylbenzenesulfonamide (example 880) as a white solid (25 mg, 22% yield).
1H NMR (300 MHz, CDCI3) δ 8.05 (m, 1 H), 7.65 (m, 1 H), 7.49 (m, 1H), 7.39- 7.29 (m, 3H), 7.19-6.95 (m, 5H), 5.34 (m, 1 H), 4.60 (m, 1 H), 4.27 (m, 1 H), 3.48-3.12 (m, 6H), 2.66 (m, 3H), 2.56 (m, 3H), 2.42-2.27 (m, 3H), 2.22-1.76 (m, 7H), 1.64 (m, 2H), 1.42 (m, 2H). ES-LCMS m/z 712.2 (M+H).
Example 881
4-chloro-N-(1 ,1 -dimethylethvn-3-r(4-(3-fluorophenyl)-4-f2-r3-(2-methyl-1 H- benzimidazol-1 -vπ-8-azabicvclor3.2.1 loct-8-yllethylH - piperidinvDcarbonvnbenzenesulfonamide
Figure imgf000606_0001
Example 881 was prepared according to figure below
881 -2a
Figure imgf000607_0001
Figure imgf000607_0002
Synthesis of 881 -2a
2-chloro-5-{[(1 , 1-dimethylethyl)amino]sulfonyl}benzoic acid
Figure imgf000607_0003
Prepared from a mixture of 2-chloro-5-(chlorosulfonyl)benzoic acid (200 mg, 0.78 mmol, 1 euiqv) tert-butyl amine (98 μL, 0.94 mmol, 1.2 equiv) and DIEA (248 μL, 1.38 mmol, 2 equiv) following the general procedure for 2,6-dichloro- 3-[(methylamino)sulfonyl]benzoic acid 881 -1b. The crude reaction mixture was carried on without further purification.
ES-LCMS m/z 315.2 (M+Na)
Synthesis of 881
4-chloro-N-(1 ,1 -dimethylethvn-3-r(4-(3-fluorophenvn-4-(2-f3-(2-methyl-1 H- benzimidazol-1 -yl)-8-azabicvclor3.2.1 loct-8-vnethyll-1 - piperidinvDcarbonyllbenzenesulfonamide
Figure imgf000608_0001
Prepared from a mixture of 2-chloro-5-{[(1 ,1- dimethylethyl)amino]sulfonyl}benzoic acid
2b, 1-(8-{2-[4-(3-fluorophenyl)-4-piperidinyl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-
2-methyl-1 H-benzimidazole (100 mg, 0.16 mmol, 1 equiv), DIEA (117 μL,
0.66 mmol, 4 equiv) and HATU (62 mg, 0.16 mmol, 1 equiv) following the general procedure for 2,4-dichloro-3-[(4-(3-fluorophenyl)-4-{2-[3-(2-methyl-1 H- benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]-N- methylbenzenesulfonamide example 880. The crude product was purified by column chromatography on silica gel eluting with 10% 2M NH3 in methanol in ethyl acetate to afford 4- chloro-N-(1 ,1 -dimethylethyl)-3-[(4-(3-fluorophenyl)-4-{2-[3-(2-methyl-1 H- benzimidazol-1 -yl)-8-azabicyclo[3.2.1 ]oct-8-yl]ethyl}-1 - piperidinyl)carbonyl]benzenesulfonamide as a white solid (40.3 mg, 35% yield).
1H NMR (300 MHz, CDCI3) δ 7.89-7.80 (m, 1 H), 7.71-7.64 (m, 1 H), 7.55-7.48 (m, 1H), 7.38-7.26 (m, 3H), 7.19-6.94 (m, 6H), 4.92-4.54 (m, 2H), 4.23 (m, 1 H), 3.47-3.04 (m, 6H), 2.56 (m, 3H), 2.54-1.34 (m, 14H), 1.24 (m, 9H). ES- LCMS m/z 720.2 (M+H).
Example 882
N-(1 ,1-dimethylethvn-2.4-difluoro-5-r(4-(3-fluorophenvn-4-f2-r3-(2-methyl-1 H- benzimidazol-1-ylV8-azabicvclor3.2.noct-8-vnethyl)-1- piperidinvπcarbonvnbenzenesulfonamide
Figure imgf000609_0001
Prepared according to figure below.
882-3a
Figure imgf000609_0002
Figure imgf000609_0003
Synthesis of 882-3a 5-{[(1,1-dimethylethyl)amino]sulfonyl}-2,4-difluorobenzoic acid
Figure imgf000609_0004
Prepared from a mixture of 5-(chlorosulfonyl)-2,4-difluorobenzoic acid (200 mg, 0.78 mmol, 1 equiv), tetf-butyl amine (98 μL, 0.94 mmol, 1.2 equiv) and DIEA (280 μL, 1.56 mmol, 2 equiv) following the general procedure for 2,6- dichloro-3-[(methylamino)sulfonyl]benzoic acid 880-1 b. The crude reaction mixture was carried on without further purification.
ES-LCMS m/z 292.3 (M-H)
Synthesis of 882 N-(1.1-dimethylethyl)-2.4-difluoro-5-r(4-(3-fluorophenvn-4-f2-r3-(2-methyl-1 H- benzimidazol-1 -yl)-8-azabicvclor3.2.1 loct-8-yllethyl)-1 - piperidinvDcarbonyllbenzenesulfonamide
Figure imgf000610_0001
Prepared from a mixture of 5-{[(1 ,1-dimethylethyl)amino]sulfonyl}-2,4- difluorobenzoic acid 882-3b 1-(8-{2-[4-(3-fluorophenyl)-4-piperidinyl]ethyl}-8- azabicyclo[3.2.1]oct-3-yl)-2-methyl-1 H-benzimidazole (100mg, 0.16 mmol, 1 equiv), DIEA (117 μL, 0.66 mmol, 4 equiv) and HATU (62 mg, 0.16 mmol, 1 equiv) following the general procedure for 2,4-dichloro-3-[(4-(3-fluorophenyl)- 4-{2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1- piperidinyl)carbonyl]-N-methylbenzenesulfonamide 1. The crude product was purified by column chromatography on silica gel eluting with 10% 2M NH3 in methanol in ethyl acetate to afford N-(1 ,1-dimethylethyl)-2,4-difluoro-5-[(4-(3- fluorophenyl)-4-{2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1]oct- 8-yl]ethyl}-1-piperidinyl)carbonyl]benzenesulfonamide (example 882) as a white solid (46 mg, 40% yield).
1HNMR (400 MHz, CDCI3) δ 8.00 (m, 1 H), 7.66 (m, 1 H), 7.93-6.95 (m, 9H), 4.86 (m, 1H), 4.62 (m, 1H), 4.15 (m, 2H), 3.44-3.14 (m, 5H), 2.92 (m, 3H), 2.58-1.60 (m, 14H), 1.25 (m, 9H). HRMS m/z (M+H): Calcd for C39H46F3N5O3S, 722.34; found 722.3352.
Example 883
4-chloro-N-(1.1-dimethylethvn-2-fluoro-5-r(4-(3-fluorophenvn-4-f2-r3-(2- methyl-1 H-benzimidazol-1 -yl)-8-azabicvclor3.2.1 loct-8-vπethylH - piperidinvDcarbonvπbenzenesulfonamide
Figure imgf000611_0001
Prepared according to figure below
883-4a
Figure imgf000611_0002
Figure imgf000611_0003
Synthesis of 883-4a 2-chloro-5-{[(1,1-dimethylethyl)amino]sulfonyl}-4-fluorobenzoic acid
Figure imgf000612_0001
te/f-Butyl amine (77 mL, 0.7 mol, 10 equiv) was added to 300 mL dioxane at 0 °C. Ice chips were added to the flask for several minutes before the addition of 2-chloro-5-(chlorosulfonyl)-4-fluorobenzoic acid (20 g, 73.24 mmol, 1 equiv). Both the internal and external temperature of the reaction was maintained at or below 0 °C for 2 h. The reaction was then concentrated halfway and acidified to pH 2 with 1 N HCl. The product was extracted into EtOAc. The organics were dried over Na2SO , filtered and concentrated down to give 2-chloro-5-{[(1 ,1-dimethylethyl)amino]sulfonyl}-4-fluorobenzoic acid 883-4a as a brown solid (21 g; 92% yield).
1H NMR (400 MHz, DMSO) δ 8.23 (d, J = 7.8 Hz, 1 H), 8.06 (broad s, 1 H), 7.82 (d, J = 9.8 Hz, 1 H). ES-LCMS m/z 308.2 (M-H)
Synthesis of 883 4-chloro-N-(1 ,1-dimethylethvn-2-fluoro-5-[(4-(3-fluorophenyl)-4-f2-r3-(2- methyl-1 H-benzimidazol-1 -yl)-8-azabicyclor3.2.1loct-8-yllethyl)-1- piperidinvOcarbonyllbenzenesulfonamide
Figure imgf000612_0002
To a solution of 1-(8-{2-[4-(3-fluorophenyl)-4-piperidinyl]ethyl}-8- azabicyclo[3.2.1]oct-3-yl)-2-methyl-1 H-benzimidazole (32.0 g, 61.6 mmol, 1 equiv) in dimethylformamide (300 mL) was added 2-chloro-5-{[(1 ,1- dimethylethyl)amino]sulfonyl}-4-fluorobenzoic acid 883-4b (21 g, 67.8 mmol, 1.1 equiv) and /V,/V-diisopropylethyl amine (44 mL, 0.25 mol, 4 equiv). After stirring at RT for several min, O-(7-azabenzotriazol-1-yl)-Λ/ N,N, N- tetramethyluroniumhexafluorophosphate (23.4 g, 61.6 mmol, 1 equiv) was added and the reaction was stirred for 2 h. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with satd. aq. NaHCO3, H2O and satd. aq. NaCI, then dried over Na2SO , filtered and concentrated. The residue was taken up in 200 mL MeOH and stirred with Amberjet 4400 OH Basic Ion Exchanger (60 g) for 1 h. The mixture was filtered and concentrated and the residue was purified by silica gel flash column chromatography in 20% 2M NH3 in MeOH in EtOAc to afford 4-chloro- N-(1 , 1 -dimethylethyl)-2-fluoro-5-[(4-(3-fluorophenyl)-4-{2-[3-(2-methyl-1 H- benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1- piperidinyl)carbonyl]benzenesulfonamide (example 883) as a white solid (21 g; 46% yield).
1H NMR (400 MHz, CDCI3) δ 8.00 (m, 1 H), 7.86-7.76 (m, 2H), 7.49 (m, 1 H), 7.44-7.35 (m, 2H), 7.23 (m, 2H), 7.15-7.04 (m, 3H), 4.55^1.45 (m, 1 H), 3.98- 3.86 (m, 1H), 3.42-3.35 (m, 1 H), 3.25 (m, 2H), 3.05-2.96 (m, 1 H), 2.45 (m, 3H), 2.39-2.32 (m, 2H), 2.23-1.99 (m, 2H), 1.92-1.72 (m, 11 H), 1.60 (m, 2H), 1.12 (m, 9H). HRMS m/z (M+H) Calcd for
Figure imgf000613_0001
738.30; Found, 738.30.
Example 884
2.4-dichloro-N-(1.1-dimethylethvn-3-r(4-(3-fluorophenyl)-4-f2-f3-(2-methyl-1 H- benzimidazol-1 -yl)-8-azabicvclor3.2.1 ]oct-8-yllethyl -1 - piperidinvDcarbonvnbenzenesulfonamide
Figure imgf000613_0002
Example 884 was prepared according to figure below.
880-1 a 884-5a
Figure imgf000614_0001
Synthesis of 884-5a
2, 6-dichloro-3-{[(1 , 1-dimethylethyl)amino]sulfonyl}benzoic acid
Figure imgf000614_0002
Prepared from a mixture of 2,6-dichloro-3-{[(1 ,1- dimethylethyl)amino]sulfonyl}benzoic acid 884-5a (200mg, 0.69 mmol, 1 equiv), te/f-butyl amine and DIEA (248 μL, 1.38 mmol, equiv) following the general procedure for 2,6-dichloro-3-[(methylamino)sulfonyl]benzoic acid 880- 1 b. The crude reaction mixture was carried on without further purification.
ES-LCMS m/z 327.4 (M+H) Synthesis of 884
2,4-dichloro-N-(1 ,1 -dimethylethyl)-3-[(4-(3-fluorophenyl)-4-{2-[3-(2-methyl-1 H- benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1- piperidinyl)carbonyl]benzenesulfonamide
Figure imgf000615_0001
Prepared from a mixture of 2,6-dichloro-3-{[(1 ,1- dimethylethyl)amino]sulfonyl}benzoic acid 884-5a, 1-(8-{2-[4-(3-fluorophenyl)- 4-piperidinyl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1 H-benzimidazole (100 mg, 0.16 mmol, lequiv), DIEA (117 μL, 0.66 mmol, 4 equiv) and HATU (62 mg, 0.16 mmol, 1 equiv) following the general procedure for 2,4-dichloro- 3-[(4-(3-fluorophenyl)-4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]-N- methylbenzenesulfonamide (example 880). The crude product was purified by column chromatography on silica gel eluting with 10% 2M NH3 in methanol in ethyl acetate to afford 2,4-dichloro-N-(1 ,1-dimethylethyl)-3-[(4-(3- fluorophenyl)-4-{2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1]oct- 8-yl]ethyl}-1-piperidinyl)carbonyl]benzenesulfonamide 5 as a white solid (21 mg, 17% yield).
1H NMR (400 MHz, CDCI3) δ 8.08 (m, 1 H), 7.66 (m, 1 H), 7.47 (m, 1 H), 7.39- 7.26 (m, 3H), 7.20-6.95 (m, 5H), 4.98 (m, 1 H), 4.61 (m, 1 H), 4.27 (m, 1 H), 3.71 (m, 1 H), 3.51 - 3.07 (m, 7H), 2.57 (m, 3H), 2.47-1.37 (m, 11 H), 1.23 (m, 9H). HRMS m/z (M+H) Calcd for CagH^CIzFNsOaS, 754.2761: Found, 754.2761. Example 885
2,4-difluoro-5-r(4-(3-fluorophenvn-4-(2-r3-f2-methyl-1H-benzimidazol-1-vn-8- azabicvcloF3.2.11oct-8-vπethyl)-1 -piperidinvπcarbonyllbenzenesulf inic acid
Figure imgf000616_0001
Example was prepared according the figure below.
Figure imgf000616_0002
885-6a
885-6b
Figure imgf000616_0003
Synthesis of 885-6a 5-(chlorosulfonyl)-2,4-difluorobenzoic acid
Figure imgf000616_0004
A mixture of chlorosulfonic acid (200 mL) and 2,4-difluorobenzoic acid (40 g, 253 mmol, 1 equiv) was heated to 155 °C for 3 h. The reaction was cooled to RT and poured slowly over ice. The product was extracted into ether and the organics dried over MgSO4, filtered and concentrated to give 5- (chlorosulfonyl)-2,4-difluorobenzoic acid 6a as brown solid (61 g, 94% yield).
1H NMR (400 MHz, CDCI3) δ 8.98 ( broad s, 1 H), 8.72 (t, J = 7.6 Hz, 1 H), 7.21 (t, J = 9.5 Hz, 1 H). ES-LCMS m/z 255.3 (M-H)
Synthesis of 885-6b
2, 4-difluoro-5-sulfobenzoic acid
Figure imgf000617_0001
Sodium borohydride (0.59 g, 15.6 mmol, 8 equiv) was added portionwise to a solution of 5-(chlorosulfonyl)-2,4-difluorobenzoic acid 885-6a (0.5 g, 1.9 mmol, 1 equiv) in 10 mL THF at 0 °C. The reaction was stirred at this temperature for 1 h and then concentrated down and the residue acidified to pH 2 with 5N HCl. The precipitate was removed by filtration and the liquid concentrated down to provide 2,4-difluoro-5-sulfobenzoic acid 885-6b as a white solid (433 mg, 100% yield)
1H NMR (400 MHz, DMSO) δ 8.18 (t, J = 8.0 Hz, 1 H), 7.52 (t, J = 10.2 Hz, 1 H).
Synthesis of example 885 2,4-difluoro-5-[(4-(3-fluorophenyl)-4-{2-[3-(2-methyl-1 H-benzimidazol-1-yl)-8- azabicyclo[3.2.1 ]oct-8-yl]ethyl}-1 -piperidinyl)carbonyl]benzenesulfonic acid
Figure imgf000618_0001
Prepared from a mixture of 2,4-difluoro-5-sulfobenzoic acid 885-6b(580 mg, 0.58 mmol, 2 equiv), 1-(8-{2-[4-(3-fluorophenyl)-4-piperidinyl]ethyl}-8- azabicyclo[3.2.1]oct-3-yl)-2-methyl-1 H-benzimidazole (150 mg, 0.29 mmol, 1 equiv), DIEA (260 μL, 1.45 mmol, 5 equiv) and HATU (110 mg, 0.29 mmol, 1 equiv) following the general procedure for 2,4-dichloro-3-[(4-(3-fluorophenyl)- 4-{2-[3-(2-methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1- piperidinyl)carbonyl]-N-methylbenzenesulfonamid, example 880. The crude product was purified by prep HPLC (HPLC Method C) to afford 2,4-difluoro-5- [(4-(3-fluorophenyl)-4-{2-[3-(2-methyl-1 H-benzimidazol-1-yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]benzenesulfonic acid (example 885) as a white solid (40 mg, 22% yield).
1H NMR (400 MHz, CDCI3) δ 7.64 (m, 1 H), 7.53 (m, 1 H), 7.47-7.40 (m, 2H), 7.27-7.03 (m, 6H), 4.88 (m, 1 H), 3.88-3.05 (m, 4H), 2.64-2.34 (m, 14H, 2.22- 1.80 (m, 8H). ES-LCMS m/z 651.3 (M+H).
HPLC Method C
Preparative High Pressure Liquid Chromatography data was acquired using a Waters LC-UV system. The system operates using a Waters Symmetry Shield RP18 3.9x150mm, 5μm column at 35mL/minute. The mobile phase consists of Water (0.1 %NH4OH) and MeOH. The gradient used starts a 0% MeOH: 90% Water (0.1 %NH4OH) and moves to 90% MeOh : 10% Water (0.1%NH4OH) over 7 minutes. There is a one minute wash of the column using 100% MeOH for one minute, until eight minutes and then original conditions return at 8.1 minutes to 8.5 Example 886
4-fluoro-7-r(4-(2-r3-(2-methyl-1 H-benzimidazol-1 -ylV8-azabicvclor3.2.1 loct-8- yllethyll-4-phenyl-1-piperidinvπcarbonvn-1.3-benzoxazol-2(3H)-one
Figure imgf000619_0001
Prepared from a mixture of 4-fluoro-2-oxo-2,3-dihydro-1 ,3-benzoxazole-7- carboxylic acid (9.8 mg, 0.05 mmol, 1 equiv), endo 2-methyl-1-{8-[2-(4- phenylpiperidin-4-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole dihydrochloride (25 mg, 0.05 mmol, 1 equiv), DIEA (36 μL, 0.2 mmol, 4 equiv) and HATU (19 mg, 0.05 mmol, 1 equiv) following the general procedure for 2,4-dichloro-3-[(4-(3-fluorophenyl)-4-{2-[3-(2-methyl-1 H-benzimidazol-1-yl)-8- azabicyclo[3.2.1 ]oct-8-yl]ethyl}-1 -piperidinyl)carbonyl]-N- methylbenzenesulfonamide (example 880). The crude product was purified by prep HPLC (HPLC Method C) to provide 4-fluoro-7-[(4-{2-[3-(2-methyl-1 H- benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenyl-1- piperidinyl)carbonyl]-1 ,3-benzoxazol-2(3H)-one as a white solid (5 mg, 17% yield).
NMR (400 MHz, CDCI3) δ 7.51-7.34 (m, 1 H), 7.26-7.22 (m, 1 H), 7.16-7.07 (m, 4H), 4.53 (m, 1 H), 3.94 (m, 1 H), 3.5-3.1 (m, 6H), 2.54-2.05 (m, 12H), 1.96- 1.59 (m, 6H). ES-LCMS m/z 608.17 (M+H). Example 887
1-(1-(2.2-dimethylpropanovn-4-phenylpiperdin-4-vn-2-r3-(2-methyl-1 H- benzimidaol-1-vh-8-azabicvclof3.2.noct-8-yl1ethanol
Figure imgf000620_0001
Synthesis of 2-bromo-1-[1-(2,2-dimethylpropanoyl)-4-phenylpiperdin-4- yl]ethanone
Figure imgf000620_0002
To a suspension of 4-acetyl-4-phenyl piperdine hydrochloride (20.8mmol) in DCM (200ml) was added TEA (541.1 mmol) and the mixture was stirred under an inert atmosphere for 10 minutes. Pivaloyl chloride (22.8mmol) was added and the mixture was stirred until HPLC analysis indicated that the reaction was complete. Water and EtOAc were added. The ethyl acetate layer was separated and washed with satd. NaHCO3) water, brine and dried (Na2SO4). Removal of solvent under vacuum gave the intermediate ketone, which was used directly in the next step. 1H NMR (400 MHz, DMSO d-6) 7.21-7.40 (m, 5 H), 3.77-3.82 (dt, 2 H), 3.14-3.21 (t, 2 H), 2.45-2.51 (m, 2H), 2.31-2.41 (d, 2H), 1.20 (s, 2H), 1.14 (s, 9H). LCMS m/z (M+H) calcd: 287.48 obsd: 288.44. To a solution of 1-[1-(2,2-dimethylpropanoyl)-4-phenylpiperdin-4-yl]ethanone in MeOH (125ml) at 0° C. Br2 was added (24.5mmol) dropwise over 10 minutes. The mixture was stirred 12 hrs. at room temperature under an inert atmosphere. H2O (20ml) was added and the resulting mixture was stirred for an additional 0.5 hr. Et2O and water (250ml 1 :1) were added, the organic layer was washed with water, satd. K2CO3 solution, dried (Na2SO4) and the solvent was removed in-vacuo to give 2 as a lightly colored powder (7g, 92%). HPLC: rt=5.26 min. This compound was used directly in the following step.
The synthesis of 1-{1-(2,2-dimethylpropanoyl)-4-phenylpiperdin-4-yl]-2-[3-(2- methyl-1 H-benzimidaol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethanone
Figure imgf000621_0001
To the amine IV in scheme III (3mmol) in Et2O was added TEA (17.9mmol) and the reaction mixture was stirred under inert atmosphere for 1hr. Next, 2- bromo-1-[1-(2,2-dimethylpropanoyl)-4-phenylpiperdin-4-yl]ethanone (2.7mmol) in Et2O (20ml) was added and the resulting mixture was stirred overnight. Benzene (50ml) and TEA (14.3mmol) were added to the reaction and the whole was heated to 90° C overnight. The reaction was cooled to room temperature and concentrated in-vacuo. The crude material in DCM was washed with brine, and water and then dried (Na2SO4). Concentration under vacuum gave 1-{1-(2,2-dimethylpropanoyl)-4-phenylpiperdin-4-yl]-2-[3-(2- methyl-1 H-benzimidaol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethanone, which was purified by silica gel chromatoghraphy (DCM: MeOH; 9.5: 0.5) to give (400mg, 30%) as a white powder. 1H NMR (400 MHz, CDCI3), 7.67 (d,1 H), 7.29-7.42 (m, 6H), 7.08-7.22 (m, 2H), 4.63-4.78 (m, 1H), 4.08-4.18 (m, 3H), 3.28-3.39 (m, 2H), 3.12-3.23 (m, 2H), 3.08-3.10 (s, 2H), 2.61 (s, 3H), 2.50(m, 2H), 2.39- 2.40 (m, 2H), 2.10 (s, 2H), 1.84-1.90 (m, 2H), 1.61 (s, 3H), 1.28 (s, 9H). LCMS m/z (M+H) calcd: 526.72, obsd: 527.45 The syntheis of 1-{1-(2,2-dimethylpropanoyl)-4-phenylpiperdin-4-yl]-2-[3-(2- methyl-1 H-benzimidaol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethanol
Figure imgf000622_0001
To a solution of 1-{1-(2,2-dimethylpropanoyl)-4-phenyipiperdin-4-yl]-2- [3-(2-methyl-1 H-benzimidaol-1 -yl)-8-azabicyclo[3.2.1 ]oct-8-yl]ethanone
(30mg) in MeOH (5ml) was added NaBH4 (0.9mmol) and the reaction mixture was stirred overnight. Satd. NaHCO3 was added and the product was extracted with DCM (3x). The organics were dried (Na2SO ). Removal of solvent under of vacuum gave the desired product 4 as a white solid. 1H NMR (CDCIs) 7.64-7.70 (m, 1 H), 7.35-7.41 (m, 4H), 7.29-7.30 (m, 1 H), 7.11 (m, 2H), 4.49-4.62 (m, 1 H), 4.22-4.30 (s, 2H), 3.50-3.60 (dd, 1 H), 3.34 (t, 1 H), 3.15 (t, 1 H), 2.90-2.77 (q, 2H), 2.51 (s, 3H), 2.34-2.44 (m, 3H), 2.22 (d, 1 H), 2.1 (dd, 1 H), 1.94 (m, 4H), 1.90 (m,1 H), 1.71-1.80 (m, 3H), 1.25 (s, 9H). HPLC (3.483 min, 100%)
HPLC : ZORBAX (2.1x50mm; 3.5micron), T=40°C; ACN/water+0.05%TFA; 0- to-95% over 8min.
Example 888
3-(4-(3-isopropy|phenvn-4-f2-r3-(2-methyl-1H-benzimidazole-1-yl)-8- azabicvclof3.2.noct-8-yllethyl)piperdin-1-v 2.2-dimethyl-3-oxopropan-1-ol
Figure imgf000623_0001
This compound was prepared from 3-isopropyl phenylmagnesium bromide and 16a according to the procedure described in example 16. To a solution of 3-hydroxy-2,2-dimethylpropanoic acid (0.14mmol), DIEA (1.7mmol) and HATU (0. Mmmol) in DMF was added 1-(8-{2-[4(-3- isopropylphenyl)piperdin-4-yl]ethyl}-8-azabicyclo[3.2.1 ]oct-3-yl)-2-methyl-1 H- benzimidazole hydrochloride (0.13mmol) in the same solvent and stirring was continued overnight. The reaction mixture was diluted with EtOAc, and washed with NaHCO3, water, and satd. brine and dried (Na2SO4). The solvent was removed in-vacuo and the crude material was purified by HPLC to 1 as a clear film. H NMR (400MHz, CDCI3) 9.72 (s, 2H), 8.48 (s, 1 H), 7.64 (d, 1 H), 7.04-7.36 (m, 8H), 4.74 (t, 1 H), 3.19-3.32 (m, 4H), 2.88-2.97 (m, 3H), 2.60 (s, 3H), 2.43-2.47 (d, 4H), 2.37 (s,2H), 1.86-2.33 (m, 10H), 1.77 (d, 2H), 1.26- 1.28 (d, 6H). LCMS m/z (M+H) calc: 556.79, obsd: 557.79.
Example 889 Preparation of
1-(4-(3-Fluoro-phenvπ-4-f2-f3-(2-methyl-benzoimidazol-1-vπ-8-aza- bicvclor3.2.noct-8-vn-ethyl)-piperidine-1-carbonyl)-cvclobutanecarboxylic acid
Figure imgf000624_0001
1-(4-(3-Fluoro-phenyl)-4-{2-[3-(2-methyl-benzoimidazol-1-yl)-8-aza- bicyclo[3.2.1]oct-8-yl]-ethyl}-piperidine-1-carbonyl)-cyclobutanecarboxylic acid was obtained from a solution of 1-(ethoxycarbonyl)cyclobutane carboxylic acid (0.031 g, 0.18 mmol), 1-(8-{2-[4-(3-Fluoro-phenyl)-piperidin-4-yl]-ethyl}-8-aza- bicyclo[3.2.1]oct-3-yl)-2-methyl-1 H-benzoimidazole dihydrochloride (0.075 g, 0.18 mmol), and HATU (0.067 g, 0.18 mmol) following the procedure outlined in example 5 to produce 1-(4-(3-Fluoro-phenyl)-4-{2-[3-(2-methyl- benzoimidazol-1-yl)-8-aza-bicyclo[3.2.1]oct-8-yl]-ethyl}-piperidine-1-carbonyl)- cyclobutanecarboxylic acid ethyl ester. The ester (0.100 g, 0.167 mmol), 5 N NaOH (10 ml) and ethanol (4 ml) was stirred at 90°C for 3 hrs. The reaction was evaporated to dryness and residue was suspend in water (10 ml) and neutralized with 1 N HCl. The aqueous layer was extracted with ethyl acetate (3 x 10 ml). The organic layer was dried using magnesium sulfate and concentrated down to form the title compound as a white solid (0.078 g, 81 %). 1 H NMR (400 MHz, CDCI3), 7.70 (m,1 H), 7.32-7.16 (m, 4H), 7.04 (m, 1 H), 6.97-6.92 (m, 2H), 4.74 (m, 1 H), 4.24-3.99 (m, 4H), 3.44-3.40 (m, 1 H), 3.30 (br, 2H), 3.19 (m, 1 H), 3.10 (m, 1 H), 2.77 (m, 1 H), 2.59 (s, 3H), 2.44-2.28 (br, 4H) 2.10-2.00 (m, 4H), 1.91-1.78 (m, 8H), 1.66 (m, 2H). ES-LCMS m/z 573 (M+1 ). Example 890
Preparation of
N-[1 -Ethyl-1 -(4-(3-fluoro-phenyl)-4-{2-[3-(2-methyl-benzoimidazol-1 -yl)-8-aza- bicyclo[3.2.1 ]oct-8-yl]-ethyl}-piperidine-1 -carbonyl )-propyl]-2,2-dimethyl- propionamide
Figure imgf000625_0001
Prepared as outlined below.
Figure imgf000625_0002
DMF
Figure imgf000625_0003
Example 890: R = t-butyl Example 891: = methyl Preparation of [1 -Ethyl-1 -(4-(3-fluoro-phenyl)-4-{2-[3-(2-methyl-benzoimidazol- 1-yl)-8-aza-bicyclo[3.2.1]oct-8-yl]-ethyl}-piperidine-1-carbonyl)-propyl]- carbamic acid tert-butyl ester
Figure imgf000626_0001
A mixture of 2-tert-Butoxycarbonylamino-2-ethyl-butyric acid (0.291 g, 1.35 mmol), 1-(8-{2-[4-(3-Fluoro-phenyl)-piperidin-4-yl]-ethyl}-8-aza- bicyclo[3.2.1]oct-3-yl)-2-methyl-1 H-enzoimidazole dihydrochloride (0.700 g,
1.35 mmol), and HATU (0.514 g, 1.35 mmol) following the procedure outlined in example 5. Obtained 0.712 g (80%) of an oil. ES-LCMS m/z 660(M+1 ).
Preparation of 2-Amino-2-ethyl-1 -(4-(3-fluoro-phenyl)-4-{2-[3-(2-methyl- benzoimidazol-1-yl)-8-aza-bicyclo[3.2.1] oct-8-yl]-ethyl}-piperidin-1-yl)-butan- 1-one
Figure imgf000626_0002
bicyclo[3.2.1 ]oct-8-yl]-ethyl}-piperidine-1 -carbonyl)-propyl]-carbamic acid tert- butyl ester was treated with 4N HCl (20ml) in dioxane and then solvent was removed in vacuo. Residue was dissloved in water nuetralized and extracted with EtOAcX3 to yield 0.600 g (99%) of the deprotected amine product as an oil. ES-LCMS m/z 560(M+1 ).
Preparation of title example 890:
A solution of 2-Amino-2-ethyl-1-(4-(3-fluoro-phenyl)-4-{2-[3-(2-methyl- benzoimidazol-1-yl)-8-aza-bicyclo[3.2.1] oct-8-yl]-ethyl}-piperidin-1-yl)-butan- 1-one (0.100 g, 0.178 mmol), 2,2-Dimethyl-propionyl chloride (0.021 g, 0.178 mmol)and DIEA (0.069 g, 0.534 mmol) were stirred at room temperature in DCE (3 ml) for 2 hours. Solvent was removed and compound was purified by RP-HPLC to yield 0.065 g (57%). 1 H NMR (400 MHz, CDCI3) 7.82 (s, 1 H), 7.67 (m, 1 H), 7.36 (m, 1 H), 7.29 (m, 1 H), 7.16 (m, 2H), 7.09 (m, 1 H), 6.99 (m, 1 H), 4.60 (m, 1 H), 4.07 (br, 2H), 3.32-3.23 (m, 4H), 2.79 (m, 2H), 2.57 (s, 3H), 2.36 (m, 2H), 2.21 (m, 2H), 1.92 (m, 6H), 1.80 (m, 4H), 1.65 (m, 6H), 1.23 (s, 9H) 0.76 (br, 5H). ES-LCMS m/z 644(M+1).
Example 891
Preparation of N-M -Ethyl-1 -(4-(3-fluoro-phenvn-4-{2-r3-(2-methyl- benzoimidazol-1-yl)-8-aza-bicvclo[3.2.noct-8-yll-ethyl>-piperidine-1-carbonyl)- propyll-acetamide
Figure imgf000627_0001
A solution of 2-Amino-2-ethyl-1-(4-(3-fluoro-phenyl)-4-{2-[3-(2-methyl- benzoimidazol-1-yl)-8-aza-bicyclo[3.2.1] oct-8-yl]-ethyl}-piperidin-1-yl)-butan- 1-one (0.100 g, 0.178 mmol), acetyl chloride (0.014 g, 0.178 mmol)and DIEA (0.069 g, 0.534 mmol) were stirred at room temperature in DCM (3 ml) for 2 hours. Solvent was removed and compound was purified by RP-HPLC to yield 0.072 g (67%). 1H NMR (400 MHz, CDCI3) 7.67 (m, 1 H), 7.40-7.29 (m, 2H), 7.18 (m, 2H), 7.09 (m, 1 H), 6.99 (m, 2H), 4.60 (m, 1 H) 4.04 (br, 2H), 3.32-3.23 (m, 4H), 2.74 (m, 2H), 2.57(s, 3H), 2.36 (m, 2H), 2.20 (m, 2H), 2.01 (s, 3H), 1.92 (m, 6H), 1.82-1.63 9 (m, 10H), 0.78 (br, 5H). ES-LCMS m/z 602(M+1). Example 892
Preparation of 2.4-Difluoro-5-(4-(3-fluoro-phenvh-4-f2-r3-(2-methyl- benzoimidazol-1-vπ-8-aza-bicvclor3.2.noct-8-yll-ethyl>-piperidine-1-carbonylV
N-propyl-benzenesulfonamide
Figure imgf000628_0001
2,4-Difluoro-5-(4-(3-fluoro-phenyl)-4-{2-[3-(2-methyl-benzoimidazol-1-yl)-8- aza-bicyclo[3.2.1]oct-8-yl]-ethyl}-piperidine-1-carbonyl)-N-propyl- benzenesulfonamide (0.068 g, 53%) was obtained from a solution of 2,4- Difluoro-5-propylsulfamoyl-benzoic acid (ACID 34) (0.050 g, 0.18 mmol), 1-(8- {2-[4-(3-Fluoro-phenyl)-piperidin-4-yl]-ethyl}-8-aza-bicyclo[3.2.1]oct-3-yl)-2- methyl-1 H-benzoimidazole dihydrochloride (0.075 g, 0.18 mmol), and HATU (0.067 g, 0.18 mmol) following the procedure outlined in example 5. 1 H NMR (400MHz, CDCI3)7.63 (m, 1 H), 7.36-7.28 (m, 3H), 7.15 (m, 2H), 7.08 (m, 1 H), 6.96 (m, 3H), 4.60 (m, 1 H), 4.22 (m, 1 H), 3.37 (m, 2H), 3.23 (m, 3H), 2.98 (m, 2H) 2.56 (s, 3H), 2.38 (m, 3H), 2.12 (m, 1H), 1.93- 1.82 (m, 11H), 1.62 (m, 2H), 1.51 (m, 2H), 0.89 (m, 3H). ES-LCMS m/z 708(M+1 ).
Example 893
Preparation of 2.4-Difluoro-5-(4-(3-fluoro-phenvn-4-f2-r3-(2-methyl- benzoimidazol-1-vπ-8-aza-bicvclor3.2.noct-8-vn-ethyl)-piperidine-1-carbonvπ-
N-isopropyl-benzenesulfonamide
Figure imgf000629_0001
2,4-Difluoro-5-(4-(3-fluoro-phenyl)-4-{2-[3-(2-methyl-benzoimidazol-1-yl)-8- aza-bicyclo[3.2.1]oct-8-yl]-ethyl}-piperidine-1-carbonyl)-N-isopropyl- benzenesulfonamide (0.071 g, 55%) was obtained from a solution of 2,4- Difluoro-5-isopropylsulfamoyl-benzoic acid (ACID 35) (0.050 g, 0.18 mmol), 1- (8-{2-[4-(3-Fluoro-phenyl)-piperidin-4-yl]-ethyl}-8-aza-bicyclo[3.2.1]oct-3-yl)-2- methyl-1 H-enzoimidazole dihydrochloride (0.075 g, 0.18 mmol), and HATU (0.067 g, 0.18 mmol) following the procedure outlined in example 5. 1 H NMR (400MHz, CDCI3)7.96 (m, 1 H), 7.66 (m, 1 H), 7.36-7.29 (m, 2H), 7.17 (m, 2H), 7.08 (m, 1 H), 6.98 (m, 3H), 4.91 (m, 1 H), 4.61 (m, 1 H), 4.23 (m, 1 H), 3.54 (m, 1 H), 3.37 (m, 1 H), 3.25 (m, 3H), 2.56 (s, 3H), 2.41-2.28 (m, 3H), 2.14 (m, 1 H), 1.96-1.74 (m, 10H), 1.63 (m, 2H), 1.12 (m, 6H). ES-LCMS m/z 708(M+1).
Example 894
Preparation of N-Cvclopropyl-2,4-difluoro-5-(4-(3-fluoro-phenyl)-4-{2-r3-(2- methyl-benzoimidazol-1 -yl)-8-aza-bicyclor3.2.1 loct-8-yll-ethyl)-piperidine-1 - carbonvO-benzenesulfonamide
Figure imgf000630_0001
N-Cyclopropyl-2,4-difluoro-5-(4-(3-fluoro-phenyl)-4-{2-[3-(2-methyl- benzoimidazol-1-yl)-8-aza-bicyclo[3.2.1]oct-8-yl]-ethyl}-piperidine-1-carbonyl)- benzenesulfonamide (0.081 g, 64%) was obtained from a solution of 5- Cyclopropylsulfamoyl-2,4-difluoro-benzoic acid (ACID 36) (0.050 g, 0.18 mmol), 1-(8-{2-[4-(3-Fluoro-phenyl)-piperidin-4-yl]-ethyl}-8-aza- bicyclo[3.2.1]oct-3-yl)-2-methyl-1 H-enzoimidazole dihydrochloride (0.075 g, 0.18 mmol), and HATU (0.067 g, 0.18 mmol) following the procedure outlined in example 5. 1 H NMR (400MHz, CDCI3)8.01 (m, 1 H), 7.66 (m, 1H), 7.37- 7.29 (m, 2H), 7.16 (m, 2H), 7.08-6.90 (m, 4H), 5.47 (m, 1 H), 4.64 (m, 1 H), 4.24 (m, 1 H), 3.37 (m, 2H), 3.27-3.17 (m, 3H), 2.57 (s, 3H), 2.42-2.29 (m, 4H), 2.13 (m, 1 H), 1.94-1.78 (m, 10 H), 1.65 (m, 2H), 0.65 (m, 4H). ES-LCMS m/z 706(M+1 ).
Example 895
Preparation of 2.4-Difluoro-5-(4-(3-fluoro-phenyl)-4-(2-r3-(2-methyl- benzoimidazol-1-yl)-8-aza-bicvclof3.2.noct-8-vn-ethyll-piperidine-1-carbonvπ- benzenesulfonamide
Figure imgf000631_0001
2,4-Difluoro-5-(4-(3-fluoro-phenyl)-4-{2-[3-(2-methyl-benzoimidazol-1-yl)-8- aza-bicyclo[3.2.1]oct-8-yl]-ethyl}-piperidine-1-carbonyl)-benzenesulfonamide (0.059 g, 49%) was obtained from a solution of 2,4-Difluoro-5-sulfamoyl- benzoic acid (ACID 31) (0.043 g, 0.18 mmol), 1-(8-{2-[4-(3-Fluoro-phenyl)- piperidin-4-yl]-ethyl}-8-aza-bicyclo [3.2.1]oct-3-yl)-2-methyl-1 H-enzoimidazole dihydrochloride (0.075 g, 0.18 mmol), and HATU (0.067 g, 0.18 mmol) following the procedure outlined in example 5. 1 H NMR (400MHz, CDCI3) 7.98 (m, 1 H), 7.66 (m, 1 H), 7.37-7.29 (m, 2H), 7.18-6.97 (m, 6H), 5.35 (m, 1 H), 4.61 (m, 1 H), 4.20 (m, 1 H), 3.38 (m, 2H), 3.25 (m, 3H), 2.56 (s, 3H), 2.44-2.27 (m, 3H), 2.14 (m, 1 H), 1.96-1.79 (m, 10 H), 1.66 (m, 2H). ES-LCMS m/z 666(M+1 ).
Example 896
Preparation of 2.4-Difluoro-5-(4-(3-fluoro-phenyl)-4-(2-r3-(2-methyl- benzoimidazol-1-yl)-8-aza-bicvclor3.2.noct-8-yll-ethyl}-piperidine-1-carbonyl)-
N-methyl-benzenesulfonamide
Figure imgf000632_0001
2,4-Difluoro-5-(4-(3-fluoro-phenyl)-4-{2-[3-(2-methyl-benzoimidazol-1-yl)-8- aza-bicyclo[3.2.1]oct-8-yl]-ethyl}-piperidine-1-carbonyl)-N-methyl- benzenesulfonamide (0.063 g, 51 %) was obtained from a solution of 2,4- Difluoro-5-methylsulfamoyl-benzoic acid (ACID 32) (0.045 g, 0.18 mmol), 1- (8-{2-[4-(3-Fluoro-phenyl)-piperidin-4-yl]-ethyl}-8-aza-bicyclo [3.2.1]oct-3-yl)-2- methyl-1 H-benzoimidazole dihydrochloride (0.075 g, 0.18 mmol), and HATU (0.067 g, 0.18 mmol) following the procedure outlined in example 5. 1 H NMR (400MHz, CDCI3) 7.98 (m, 1 H), 7.68 (m, 1 H), 7.36 (m, 1 H), 7.29 (m, 1 H), 7.19 (m, 2H), 7.09 (m, 1 H), 6.99 (m, 3H), 4.82 (m, 1 H), 4.63 (m, 1 H), 4.23 (m, 1 H), 3.39 (m, 2 H), 3.30 (m, 2H), 3.22 (m, 1H), 2.74 (s, 3H), 2.59 (s, 3H), 2.42 (m, 2H), 2.29 (m, 2H), 2.17 (m, 2H), 1.98-1.71 (m, 10H), 1.67 (m, 2H). ES-LCMS m/z 680(M+1).
Example 897
Preparation of N-Ethyl-2,4-difluoro-5-(4-(3-fluoro-phenyl)-4-f2-r3-(2-methyl- benzoimidazol-1-vπ-8-aza-bicvclor3.2.noct-8-yll-ethyl}-piperidine-1-carbonyl)- benzenesulfonamide
Figure imgf000633_0001
Preparation of N-Ethyl-2,4-difluoro-5-(4-(3-fluoro-phenyl)-4-{2-[3-(2-methyl- benzoimidazol-1-yl)-8-aza-bicyclo[3.2.1]oct-8-yl]-ethyl}-piperidine-1-carbonyl)- benzenesulfonamide (0.067 g, 54%) was obtained from a solution of 5- Ethylsulfamoyl-2,4-difluoro-benzoic acid (ACID 33) (0.047 g, 0.18 mmol), 1-(8- {2-[4-(3-Fluoro-phenyl)-piperidin-4-yl]-ethyl}-8-aza-bicyclo [3.2.1]oct-3-yl)-2- methyl-1 H-benzoimidazole dihydrochloride (0.075 g, 0.18 mmol), and HATU (0.067 g, 0.18 mmol) following the procedure outlined in example 5. 1 H NMR (400MHz, CDCI3) 7.98 (m, 1 H), 7.68 (m, 1 H), 7.39 (m, 1 H), 7.31 (m, 1 H), 7.18 (m, 2H), 7.09 (m, 1 H), 6.98 (m, 3H), 4.81 (br, 2H), 4.20 (m, 1 H), 3.38 (m, 4H), 3.21 (m, 1 H), 3.16 (m, 2H), 2.61 (s, 3H), 2.44 (m, 2H), 2.31 (m, 1 H), 2.19 (m, 1 H), 2.02-1.61 (m, 12H), 1.16 (m, 3H). ES-LCMS /??/z 694(M+1).
Example 898
Preparation of H -(4-(3-Fluoro-phenv0-4-f2-r3-(2-methyl-benzoimidazol-1 -yl)-
8-aza-bicvclor3.2.1 loct-8-yll-ethyl)-piperidine-1 -carbonvD-propy-1-carbamic acid tert-butyl ester
Figure imgf000633_0002
[1-(4-(3-Fluoro-phenyl)-4-{2-[3-(2-methyl-benzoimidazol-1-yl)-8-aza- bicyclo[3.2.1]oct-8-yl]-ethyl}-piperidine-1-carbonyl)-propyl]-carbamic acid tert- butyl ester(0.580 g, 66%) was obtained as an oil from 2-tert- Butoxycarbonylamino-butyric acid (0.298 g, 1.40 mmol), 1-(8-{2-[4-(3-Fluoro- phenyl)-piperidin-4-yl]-ethyl}-8-aza-bicyclo[3.2.1 ]oct-3-yl)-2-methyl-1 H- benzoimidazole dihydrochloride (0.725 g, 1.40 mmol) and HATU(0.590 g, 1.50 mmol) following the procedure outlined in example 5. ES-LCMS m/z 632(M+1).
Example 899
Preparation of 2,2.2-Trifluoro-N-H -(4-(3-fluoro-phenvn-4-f2-[3-(2-methyl- benzoimidazol-1-yl)-8-aza-bicyclor3.2.1"| oct-8-yll-ethyl)-piperidine-1- carbonvD-propyn-acetamide
Figure imgf000634_0001
2,2,2-Trifluoro-N-[1-(4-(3-fluoro-phenyl)-4-{2-[3-(2-methyl-benzoimidazol-1-yl)- 8-aza-bicyclo[3.2.1] oct-8-yl]-ethyl}-piperidine-1-carbonyl)-propyl]-acetamide was obtained from treating [1-(4-(3-Fluoro-phenyl)-4-{2-[3-(2-methyl- benzoimidazol-1-yl)-8-aza-bicyclo[3.2.1]oct-8-yl]-ethyl}-piperidine-1-carbonyl)- propylj-carbamic acid tert-butyl ester(0.580 g, 0.92 mmol) with HCl as outlined in the procedure for example 890 to form 2-Amino-1-(4-(3-fluoro-phenyl)-4-{2- [3-(2-methyl-benzoimidazol-1 -yl)-8-aza-bicyclo[3.2.1 ]oct-8-yl]-ethyl}-piperidin- 1-yl)-butan-1-one(0.488 g, 99%). 2-Amino-1-(4-(3-fluoro-phenyl)-4-{2-[3-(2- methyl-benzoimidazol-1-yl)-8-aza-bicyclo [3.2.1]oct-8-yl]-ethyl}-piperidin-1-yl)- butan-1-one(0.049 g, 0.09 mmol, trifluoroaceticanhydirde (0.019 g, 0.09 mmol) and DIEA (0.034 g, 0.534 mmol) were reacted following the procedure outlined in example 890 to give the title compound, 2,2,2-Trifluoro-N-[1-(4-(3- fluoro-phenyl)-4-{2-[3-(2-methyl-benzoimidazol-1-yl)-8-aza-bicyclo[3.2.1] oct- 8-yl]-ethyl}-piperidine-1-carbonyl)-propyl]-acetamide(0.034 g, 60%) as an oil. ES-LCMS m/z 628(M+1).
Example 900
Preparation of 2-Chloro-N-M -(4-(3-fluoro-phenvn-4-f2-r3-(2-methyl- benzoimidazol-1-yl)-8-aza-bicvclor3.2.11oct-8-vn-ethyl}-piperidine-1-carbonyl)- propyll-acetamide
Figure imgf000635_0001
2-Chloro-N-[1-(4-(3-fluoro-phenyl)-4-{2-[3-(2-methyl-benzoimidazol-1-yl)-8- aza-bicyclo[3.2.1]oct-8-yl]-ethyl}-piperidine-1-carbonyl)-propyl]-acetamide was obtained from treating [1-(4-(3-Fluoro-phenyl)-4-{2-[3-(2-methyl- benzoimidazol-1-yl)-8-aza-bicyclo[3.2.1]oct-8-yl]-ethyl}-piperidine-1-carbonyl)- propylj-carbamic acid tert-butyl ester(0.580 g, 0.92 mmol) with HCl as outlined in the procedure for example 890 to form 2-Amino-1-(4-(3-fluoro-phenyl)-4-{2- [3-(2-methyl-benzoimidazol-1-yl)-8-aza-bicyclo[3.2.1]oct-8-yl]-ethyl}-piperidin- 1-yl)-butan-1-one(0.488 g, 99%). 2-Amino-1-(4-(3-fluoro-phenyl)-4-{2-[3-(2- methyl-benzoimidazol-1 -yl)-8-aza-bicyclo [3.2.1 ]oct-8-yl]-ethyl}-piperidin-1 -yl)- butan-1-one(0.049 g, 0.09 mmol, Chloro-acetyl chloride (0.010 g, 0.09 mmol) and DIEA (0.034 g, 0.534 mmol) were reacted following the procedure outlined in example 890 to give the title compound, 2-Chloro-N-[1-(4-(3-fluoro- phenyl)-4-{2-[3-(2-methyl-benzoimidazol-1-yl)-8-aza-bicyclo[3.2.1]oct-8-yl]- ethyl}-piperidine-1-carbonyl)-propyl]-acetamide (0.024 g, 44%) as an oil. ES- LCMS m/z 608(M+1). Example 901
Preparation of N-H -(4-(3-Fluoro-phenylV4-{2-r3-(2-methyl-benzoimidazol-1 - yl)-8-aza-bicvclor3.2.noct-8-yll-ethyll-piperidine-1-carbonyl)-propyl1-2.2- dimethyl-propionamide
Figure imgf000636_0001
N-[1-(4-(3-Fluoro-phenyl)-4-{2-[3-(2-methyl-benzoimidazol-1-yl)-8-aza- bicyclo[3.2.1 ]oct-8-yl]-ethyl}-piperidine-1 -carbonyl)-propyl]-2,2-dimethyl- propionamide was obtained from treating [1-(4-(3-Fluoro-phenyl)-4-{2-[3-(2- methyl-benzoimidazol-1 -yl)-8-aza-bicyclo[3.2.1 ]oct-8-yl]-ethyl}-piperidine-1 - carbonyl)-propyl]-carbamic acid tert-butyl ester(0.580 g, 0.92 mmol) with HCl as outlined in the procedure for example 890 to form 2-Amino-1-(4-(3-fluoro- phenyl)-4-{2-[3-(2-methyl-benzoimidazol-1-yl)-8-aza-bicyclo[3.2.1]oct-8-yl]- ethyl}-piperidin-1-yl)-butan-1-one(0.488 g, 99%). 2-Amino-1 -^-^-fluorophenyl )-4-{2-[3-(2-methyl-benzoimidazol-1 -yl)-8-aza-bicyclo [3.2.1 ]oct-8-yl]- ethyl}-piperidin-1-yl)-butan-1-one(0.049 g, 0.09 mmol, 2,2-Dimethyl-propionyl chloride(0.011 g, 0.09 mmol) and DIEA (0.034 g, 0.534 mmol) were reacted following the procedure outlined in example 890 to give the title compound, N- [1-(4-(3-Fluoro-phenyl)-4-{2-[3-(2-methyl-benzoimidazol-1-yl)-8-aza- bicyclo[3.2.1 ]oct-8-yl]-ethyl}-piperidine-1 -carbonyl)-propyl]-2,2-dimethyl- propionamide (0.030 g, 54%) as an oil. ES-LCMS m/z 616(M+1 ).
Example 892
Preparation of 2.2-Dichloro-N-π -(4-(3-fluoro-phenyl)-4-f2-r3-(2-methyl- benzoimidazol-1-vπ-8-aza-bicvclo[3.2.noct-8-vn-ethyl)-piperidine-1-carbonvπ- propyll-acetamide
Figure imgf000637_0001
2,2-Dichloro-N-[1-(4-(3-fluoro-phenyl)-4-{2-[3-(2-methyl-benzoimidazol-1-yl)-8- aza-bicyclo[3.2.1]oct-8-yl]-ethyl}-piperidine-1 -carbonyl )-propyl]-acetamide was obtained from treating [1-(4-(3-Fluoro-phenyl)-4-{2-[3-(2-methyl- benzoimidazol-1-yl)-8-aza-bicyclo[3.2.1]oct-8-yl]-ethyl}-piperidine-1-carbonyl)- propylj-carbamic acid tert-butyl ester(0.580 g, 0.92 mmol) with HCl as outlined in the procedure for example 890 to form 2-Amino-1-(4-(3-fluoro-phenyl)-4-{2- [3-(2-methyl-benzoimidazol-1 -yl)-8-aza-bicyclo[3.2.1 ]oct-8-yl]-ethyl}-piperidin- 1-yl)-butan-1-one(0.488 g, 99%). 2-Amino-1-(4-(3-fluoro-phenyl)-4-{2-[3-(2- methyl-benzoimidazol-1-yl)-8-aza-bicyclo [3.2.1]oct-8-yl]-ethyl}-piperidin-1-yl)- butan-1-one(0.049 g, 0.09 mmol, Dichloro-acetyl chloride(0.013 g, 0.09 mmol) and DIEA (0.034 g, 0.534 mmol) were reacted following the procedure outlined in example 890 to give the title compound, 2,2-Dichloro-N-[1-(4-(3- fluoro-phenyl)-4-{2-[3-(2-methyl-benzoimidazol-1 -yl)-8-aza-bicyclo[3.2.1 ]oct-8- yl]-ethyl}-piperidine-1-carbonyl)-propyl]-acetamide (0.039 g, 67%) as an oil. ES-LCMS m/z 642(M+1).
Example 893
Preparation of r2-(4-(3-Fluoro-phenvD-4-f2-r3-(2-methyl-benzoimidazol-1 -yl)-
8-aza-bicvclor3.2.noct-8-yll-ethyl)-piperidin-1-yl)-1 ,1-dimethyl-2-oxo-ethyl1- carbamic acid tert-butyl ester
Figure imgf000638_0001
2-(4-(3-Fluoro-phenyl)-4-{2-[3-(2-methyl-benzoimidazol-1-yl)-8-aza- bicyclo[3.2.1]oct-8-yl]-ethyl}-piperidin-1-yl)-1 ,1-dimethyl-2-oxo-ethyl]-carbamic acid tert-butyl ester
(0.610 g, 69%) was obtained as a oil from 2-tert-Butoxycarbonylamino-2- methyl-propionic acid (0.284 g, 1.40 mmol), 1-(8-{2-[4-(3-Fluoro-phenyl)- piperidin-4-yl]-ethyl}-8-aza-bicyclo[3.2.1]oct-3-yl)-2-methyl-1 H-enzoimidazole dihydrochloride(0.725 g, 1.40 mmol) and HATU(0.590 g, 1.50 mmol) following the procedure outlined in example 5. ES-LCMS m/z 632(M+1).
Example 904
Preparation of 2.2.2-Trifluoro-N-[2-(4-(3-fluoro-phenvn-4-(2-[3-(2-methyl- benzoimidazol-1-yl)-8-aza-bicvclof3.2.n oct-8-yll-ethyll-piperidin-1-v0-1 , dimethyl-2-oxo-ethvπ-acetamide
Figure imgf000638_0002
2,2,2-Trifluoro-N-[2-(4-(3-fluoro-phenyl)-4-{2-[3-(2-methyl-benzoimidazol-1-yl)-
8-aza-bicyclo[3.2.1] oct-8-yl]-ethyl}-piperidin-1-yl)-1 ,1-dimethyl-2-oxo-ethyl]- acetamide was obtained from treating 2-(4-(3-Fluoro-phenyl)-4-{2-[3-(2-methyl- benzoimidazol-1-yl)-8-aza-bicyclo[3.2.1]oct-8-yl]-ethyl}-piperidin-1-yl)-1 ,1- dimethyl-2-oxo-ethyl]-carbamic acid tert-butyl ester (0.610 g, 0.97 mmol) with HCl as outlined in the procedure in example 890 to form 2-Amino-1-(4-(3- fluoro-phenyl)-4-{2[3-(2-methyl-benzoimidazol-1 -yl)-8-aza-bicyclo[3.2.1 ]oct-8- yl]-ethyl}-piperidin-1-yl)-2-methyl-propan-1-one(0.510 g, 99%). 2-Amino-1 -(4- (3-fluoro-phenyl)-4-{2[3-(2-methyl-benzoimidazol-1 -yl)-8-aza-bicyclo[3.2.1 ]oct- 8-yl]-ethyl}-piperidin-1-yl)-2-methyl-propan-1-one (0.050 g, 0.09 mmol, trifluoroaceticanhydirde (0.019 g, 0.09 mmol) and DIEA (0.034 g, 0.534 mmol) were reacted following the procedure outlined in example 890 to give the title compound, 2,2,2-Trifluoro-N-[2-(4-(3-fluoro-phenyl)-4-{2-[3-(2-methyl- benzoimidazol-1-yl)-8-aza-bicyclo[3.2.1] oct-8-yl]-ethyl}-piperidin-1-yl)-1 ,1- dimethyl-2-oxo-ethyl]-acetamide(0.024 g, 42%) as an oil. ES-LCMS m/z 628(M+1).
Example 905
Preparation of 2,2-Dichloro-N-r2-(4-(3-fluoro-phenylV4-f2-r3-(2-methyl- benzoimidazol-1 -yl)-8-aza-bicvclo[3.2.11oct-8-vn-ethyl)-piperidin-1 -v0-1 , 1 • d i meth yl-2-oxo-ethyll-acetam ide
Figure imgf000639_0001
2,2-Dichloro-N-[2-(4-(3-fluoro-phenyl)-4-{2-[3-(2-methyl-benzoimidazol-1-yl)-8- aza-bicyclo[3.2.1 ]oct-8-yl]-ethyl}-pi perid in- 1 -yl )-1 , 1 -d i methyl-2-oxo-ethyl]- acetamide was obtained from treating 2-(4-(3-Fluoro-phenyl)-4-{2-[3-(2-methyl- benzoimidazol-1-yl)-8-aza-bicyclo[3.2.1]oct-8-yl]-ethyl}-piperidin-1-yl)-1 ,1- dimethyl-2-oxo-ethyl]-carbamic acid tert-butyl ester (0.610 g, 0.97 mmol) with
HCl as outlined in the procedure for example 890 to form 2-Amino~1-(4-(3- fluoro-phenyl)-4-{2[3-(2-methyl-benzoimidazol-1-yl)-8-aza-bicyclo[3.2.1]oct-8- yl]-ethyl}-piperidin-1-yl)-2-methyl-propan-1-one (0.510 g, 99%). 2-Amino-1-(4- (3-fluoro-phenyl)-4-{2[3-(2-methyl-benzoimidazol-1-yl)-8-aza-bicyclo[3.2.1]oct- 8-yl]-ethyl}-piperidin-1-yl)-2-methyl-propan-1-one (0.050 g, 0.09 mmol), Dichloro-acetyl chloride(0.013 g, 0.09 mmol) and DIEA (0.034 g, 0.534 mmol) were reacted following the procedure outlined in example 890 to give the title compound, 2,2-Dichloro-N-[2-(4-(3-fluoro-phenyl)-4-{2-[3-(2-methyl- benzoimidazol-1-yl)-8-aza-bicyclo[3.2.1]oct-8-yl]-ethyl}-piperidin-1-yl)-1 ,1- dimethyl-2-oxo-ethyl]-acetamide(0.028 g, 48%) as an oil. ES-LCMS m/z 642(M+1 ).
Example 906
Preparation of 2-Chloro-N-r2-(4-(3-fluoro-phenyl)-4-f2-r3-(2-methyl- benzoimidazol-1-yl)-8-aza-bicvclo[3.2.noct-8-vn-ethyl)-piperidin-1-yl)-1.1- d i meth yl-2-oxo-eth yll-acetam ide
Figure imgf000640_0001
2-Chloro-N-[2-(4-(3-fluoro-phenyl)-4-{2-[3-(2-methyl-benzoimidazol-1-yl)-8- aza-bicyclo[3.2.1]oct-8-yl]-ethyl}-piperidin-1-yl)-1 ,1-dimethyl-2-oxo-ethyl]- acetamide was obtained from treating 2-(4-(3-Fluoro-phenyl)-4-{2-[3-(2- methyl-benzoimidazol-1-yl)-8-aza-bicyclo[3.2.1]oct-8-yl]-ethyl}-piperidin-1-yl)- 1 ,1-dimethyl-2-oxo-ethyl]-carbamic acid tert-butyl ester (0.610 g, 0.97 mmol) with HCl as outlined in the procedure for Example 890 to form 2-Amino-1-(4- (3-fluoro-phenyl)-4-{2[3-(2-methyl-benzoimidazol-1-yl)-8-aza-bicyclo[3.2.1]oct- 8-yl]-ethyl}-piperidin-1-yl)-2-methyl-propan-1-one(0.510 g, 99%). 2-Amino-1- (4-(3-fluoro-phenyl)-4-{2[3-(2-methyl-benzoimidazol-1-yl)-8-aza- bicyclo[3.2.1]oct-8-yl]-ethyl}-piperidin-1-yl)-2-methyl-propan-1-one (0.050 g, 0.09 mmol, Chloro-acetyl chloride(0.010 g, 0.09 mmol) and DIEA (0.034 g, 0.534 mmol) were reacted following the procedure outlined in Example 890 to give the title compound, 2-Chloro-N-[2-(4-(3-fluoro-phenyl)-4-{2-[3-(2-methyl- benzoimidazol-1-yl)-8-aza-bicyclo[3.2.1]oct-8-yl]-ethyl}-piperidin-1-yl)-1 ,1- dimethyl-2-oxo-ethyl]-acetamide (0.027 g, 49%) as an oil. ES-LCMS m/z 608 (M+1).
Example 907
Preparation of 1.1-dimethylethyl ((1S)-1-f(4-(3-fluorophenvn-4-f2-r(1 5S)-3-
(2-methyl-1 H-benzimidazol-1 -vn-8-azabicvclor3.2.11oct-8-vnethyl)-1 - pjperidinyl) carbonyll-2-methylpropyl)carbamate
Figure imgf000641_0001
1 ,1-dimethylethyl {(1 S)-1 -[(4-(3-fluorophenyl)-4-{2-[(1 R,5S)-3-(2-methyl-1 H- benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl) carbonyl]-2- methylpropyljcarbamate (0.614 g, 68%) was obtained as a oil from Λ/-{[(1 ,1- dimethylethyl)oxy]carbonyl}-L-valine (0.303 g, 1.40 mmol), 1 -(8-{2-[4-(3- Fluoro-phenyl)-piperidin-4-yl]-ethyl}-8-aza-bicyclo[3.2.1]oct-3-yl)-2-methyl-1 H- enzoimidazole dihydrochloride(0.725 g, 1.40 mmol) and HATU(0.590 g, 1.50 mmol) following the procedure outlined in example 5. ES-LCMS m/z 648(M+1).
Example 908A
Preparation of 2.2-dichloro-Λ/-f(1 S)-1 -r(4-(3-fluorophenvn-4-f2-lϊ1 R.5S)-3-(2- methyl-1 H-benzimidazol-1 -yl)-8-azabicvclor3.2.noct-8-yllethyl)-1- piperidinyl)carbonvn-2-methylpropyl}acetamide
Figure imgf000642_0001
2,2-dichloro-/V-{(1 S)-1 -[(4-(3-fluorophenyl)-4-{2-[(1 fi,5S)-3-(2-methyl-1 H- benzimidazol-1-yl)-8-azabicyclo[3.2,1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]-2- methylpropyl}acetamide was obtained from treating 1 ,1-dimethylethyl {(1 S)-1- [(4-(3-fluorophenyl)-4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-1 -piperidinyl) carbonyl]-2- methylpropyl}carbamate(0.614 g,0.95 mmol) with HCl as outlined in the procedure for Example 890 to form {(1 S)-1-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)- 3-(2-methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1- piperidinyl) carbonyl]-2-methylpropyl}amine (0.512 g, 99%). {(1 S)-1-[(4-(3- fluorophenyl)-4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yi)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-1 -piperidinyl) carbonyl]-2-methylpropyl} amine(0.050 g, 0.09 mmol), Dichloro-acetyl chloride(0.013 g, 0.09 mmol) and DIEA (0.034 g, 0.534 mmol) were reacted following the procedure outlined in Example 890 to give the title compound, 2,2-dichloro-Λ/-{(1 S)-1-[(4-(3- fluorophenyl)-4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]-2- methylpropyl}acetamide(0.031 g, 53%) as an oil. ES-LCMS m/z 656 (M+1 ).
Example 908B
Preparation of 2-chloro-Λ/-f(1 S)-1 -r(4-(3-fluorophenyl)-4-f2-F(1 f?,5SV3-(2- methyl-1 H-benzimidazol-1 -vπ-8-azabicvclor3.2.1loct-8-vnethyl)-1- piperidinyl)carbonvn-2-methylpropyl}acetamide
Figure imgf000643_0001
2-chloro-N-{(1 S)-1 -[(4-(3-fluorophenyl)-4-{2-[(1 R,5S)-3-(2-methyl-1 H- benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]-2- methylpropyljacetamide was obtained from treating 1 ,1-dimethylethyl {(1S)-1- [(4-(3-fluorophenyl)-4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-1 -piperidinyl) carbonyl]-2- methylpropyl}carbamate(0.614 g,0.95 mmol) with HCl as outlined in the procedure for Example 890 to form {(1S)-1-[(4-(3-fluorophenyl)-4-{2-[(1 R,5S)- 3-(2-methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1 - piperidinyl) carbonyl]-2-methylpropyl}amine (0.512 g, 99%). {(1S)-1-[(4-(3- fluorophenyl)-4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1 ]oct-8-yl]ethyl}-1 -piperidinyl) carbonyl]-2-methylpropyl} amine(0.050 g, 0.09 mmol), Chloro-acetyl chloride(0.011 g, 0.09 mmol) and DIEA (0.034 g, 0.534 mmol) were reacted following the procedure outlined in Example 890 to give the title compound, 2-chloro-N-{(1S)-1-[(4-(3- fluorophenyl)-4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]-2- methylpropyl}acetamide(0.037 g, 66%) as an oil. ES-LCMS m/z 622 (M+1 ).
Example 909
Preparation of 1 ,1-dimethylethyl (2S)-2-r(4-(3-fluorophenyl)-4-f2-r(1 5S)-3-
(2-methyl-1 H-benzimidazol-1 -vn-8-azabicvclof3.2.noct-8-yl1ethyl}-1 - piperidinyl)carbonvn-1-pyrrolidinecarboxylate
Figure imgf000644_0001
1 ,1-dimethylethyl (2S)-2-[(4-(3-fluorophenyl)-4-{2-[(1 R,5S)-3-(2-methyl-1 H- benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]-1- pyrrolidinecarboxylate(0.645 g, 72%) was obtained as a oil from 1-{[(1 ,1- dimethylethyl)oxy]carbonyl}-L-proline(0.301 g, 1.4 mmol), 1 -(8-{2-[4-(3-Fluoro- phenyl)-piperidin-4-yl]-ethyl}-8-aza-bicyclo[3.2.1]oct-3-yl)-2-methyl-1 H- enzoimidazole dihydrochloride(0.725 g, 1.40 mmol) and HATU(0.590 g, 1.50 mmol) following the procedure outlined in example 5. ES-LCMS m/z 644(M+1).
Example 910
Preparation of 1-r(1 R.5S)-8-(2-f4-(3-fluorophenyl)-1-π-(trifluoroacetvn-L- prolyll-4-pi perid i n vDethyl )-8-azabicvclof 3.2.11oct-3-yll-2-meth yl- 1 H- benzimidazole
Figure imgf000644_0002
1 -[(1 R,5S)-8-(2-{4-(3-fluorophenyl)-1 -[1 -(trifluoroacetyl)-L-prolyl]-4- piperidinyl}ethyl)-8-azabicyclo[3.2.1 ]oct-3-yl]-2-methyl-1 H-benzimidazole was obtained from treating 1 ,1-dimethylethyl (2S)-2-[(4-(3-fluorophenyl)-4-{2- [(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1 ]oct-8-yl]ethyl}- 1-piperidinyl)carbonyl]-1-pyrrolidinecarboxylate (0.645 g, 1.01 mmol) with HCl as outlined in the procedure for Example 890 to form 1-((1R,5S)-8-{2-[4-(3- fluorophenyl)-1-L-prolyl-4-piperidinyl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2- methyl-1H-benzimidazole(0.545 g, 99%).1-((1 ,5S)-8-{2-[4-(3-fluorophenyl)- 1 -L-prolyl-4-piperidinyl]ethyl}-8-azabicyclo[3.2.1 ]oct-3-yl)-2-methyl-1 H- benzimidazole(0.050 g, 0.09 mmol), trifluoroaceticanhydirde (0.019 g, 0.09 mmol) and DIEA (0.034 g, 0.534 mmol) were reacted following the procedure outlined in Example 890 to give the title compound, 1-[(1R,5S)-8-(2-{4-(3- fluorophenyl)-1-[1-(trifluoroacetyl)-L-prolyl]-4-piperidinyl}ethyl)-8- azabicyclo[3.2.1]oct-3-yl]-2-methyl-1H-benzimidazole(0.021 g, 36%) as an oil. ES-LCMS m/z 640 (M+1).
Example 911
Preparation of 1 -((1 R.5S)-8-i2-M -f1 -(dichloroacetvn-L-prolyll-4-(3- fluorophenyl)-4-piperidinyllethyl)-8-azabicyclor3.2.1loct-3-yl)-2-methyl-1H- benzimidazole
Figure imgf000645_0001
1 -((1 R,5S)-8-{2-[1 -[1 -(dichloroacetyl)-L-prolyl]-4-(3-fluorophenyl)-4- piperidinyl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1 H-benzimidazole was obtained from treating 1 ,1-dimethylethyl (2S)-2-[(4-(3-fluorophenyl)-4-{2- [(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}- 1-piperidinyl)carbonyl]-1-pyrrolidinecarboxylate (0.645 g, 1.01 mmol) with HCl as outlined in the procedure for Example 890 to form 1-((1R,5S)-8-{2-[4-(3- fluorophenyl)-1 -L-prolyl-4-piperidinyl]ethyl}-8-azabicyclo[3.2.1 ]oct-3-yl)-2- methyl-1 H-benzimidazole(0.545 g, 99%).1 -((1 R,5S)-8-{2-[4-(3-fluorophenyl)- 1 -L-prolyl-4-piperidinyl]ethyl}-8-azabicyclo[3.2.1 ]oct-3-yl)-2-methyl-1 H- benzimidazole(0.050 g, 0.09 mmol), Dichloro-acetyl chloride(0.013 g, 0.09 mmol)and DIEA (0.034 g, 0.534 mmol) were reacted following the procedure outlined in Example 890 to give the title compound, 1-((1R,5S)-8-{2-[1-[1- (dichloroacetyl)-L-prolyl]-4-(3-fluorophenyl)-4-piperidinyl]ethyl}-8- azabicyclo[3.2.1]oct-3-yl)-2-methyl-1 H-benzimidazole (0.029 g, 49%) as an oil. ES-LCMS m/z 654 (M+1).
Example 912
Preparation of 1.1-dimethylethyl f 1 -r(4-(3-fluorophenvn-4-(2-r(1 R,5S)-3-(2- methyl-1 H-benzimidazol-1 -vπ-8-azabicvclo[3.2.1loct-8-vnethyll-1- piperidinyl)carbonyllcvclopentyl|carbamate
Figure imgf000646_0001
1 ,1-dimethylethyl {1 -[(4-(3-fluorophenyl)-4-{2-[(1 R,5S)-3-(2-methyl-1 H- benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1- piperidinyl)carbonyl]cyclopentyl}carbamate (0.627 g, 68%) was obtained as a oil from 1-({[(1 ,1 dimethylethyl)oxy]carbonyl}amino)cyclopentanecarboxylic acid (0.320 g, 1.4 mmol), 1-(8-{2-[4-(3-Fluoro-phenyl)-piperidin-4-yl]-ethyl}-8- aza-bicyclo[3.2.1]oct-3-yl)-2-methyl-1 H-enzoimidazole dihydrochloride(0.725 g, 1.40 mmol) and HATU(0.590 g, 1.50 mmol) following the procedure outlined in example 5. ES-LCMS m/z 658(M+1). Example 913
Preparation of 2.2.2-trifluoro-/V 1 -lϊ4-(3-fluorophenvn-4-(2-[(1 R,5S)-3-(2- methyl-1 H-benzimidazol-1 -yl)-8-azabicvclor3.2. noct-8-yllethyll-1- piperidinvOcarbonvπcvclopentvDacetamide
Figure imgf000647_0001
2,2,2-trifluoro-N-{1 -[(4-(3-fluorophenyl)-4-{2-[(1 R,5S)-3-(2-methyl-1 H- benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1- piperidinyl)carbonyl]cyclopentyl}acetamide was obtained from treating 1 ,1- dimethylethyl {1-[(4-(3-fluorophenyl)-4-{2-[(1 R,5S)-3-(2-methyl-1 H- benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1- piperidinyl)carbonyl]cyclopentyl}carbamate(0.627 g, 0.95 mmol) with HCl as outlined in the procedure for Example 890 to form 1-[(4-(3-fluorophenyl)-4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1 ]oct-8-yl]ethyl}-1 -piperidinyl)carbonyl]cyclopentanamine(0.528 g, 99%). 1-[(4-(3-fluorophenyl)-4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 - yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1- piperidinyl)carbonyl]cyclopentanamine(0.050 g, 0.09 mmol), trifluoroacetic anhydride (0.019 g, 0.09 mmol) and DIEA (0.034 g, 0.534 mmol) were reacted following the procedure outlined in Example 890 to give the title compound, 2,2,2-trifluoro-N-{1 -[(4-(3-fluorophenyl)-4-{2-[(1 R,5S)-3-(2-methyl-1 H- benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1- piperidinyl)carbonyl]cyclopentyl}acetamide (0.027 g, 46%) as an oil. ES- LCMS m/z 654 (M+1). Example 914
Preparation of Λ -J1 -IT4-(3-f luorophenvn-4-(2-IT1 R.5S)-3-(2-methyl-1 H- benzimidazol-1-yl)-8-azabicvclor3.2.noct-8-yllethyl)-1- piperidinv0carbonyllcvclopentyl)-2,2-dimethylpropanamide
Figure imgf000648_0001
Λ/-{1 -[(4-(3-fluorophenyl)-4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]cyclopentyl}-2,2- dimethylpropanamide was obtained from treating 1 ,1-dimethylethyl {1-[(4-(3- fluorophenyl)-4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]cyclopentyl}carbamate
(0.627 g, 0.95 mmol) with HCl as outlined in the procedure for Example 890 to form 1 -[(4-(3-fluorophenyl)-4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]cyclopentanamine(0.528 g, 99%). 1 -[(4-(3-fluorophenyl)-4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 - yl)-8-azabicyclo[3.2.1 ]oct-8-yl]ethyl}-1 - piperidinyl)carbonyl]cyclopentanamine(0.050 g, 0.09 mmol), 2,2-Dimethyl- propionyl chloride(0.011 g, 0.09 mmol) and DIEA (0.034 g, 0.534 mmol) were reacted following the procedure outlined in Example 890 to give the title compound, Λ/-{1 -[(4-(3-fluorophenyl)-4-{2-[(1 R,5S)-3-(2-methyl-1 H- benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1- piperidinyl)carbonyl]cyclopentyl}-2,2-dimethylpropanamide (0.031 g, 54%) as an oil. ES-LCMS m/z 642 (M+1). Example 915
Preparation of 1.1-dimethylethyl f(1 SV1-r(4-(3-fluorophenyl)-4 2-r(1R.5S.-3-
(2-methyl-1 H-benzimidazol-1 -vn-8-azabicvclor3.2.11oct-8-yllethyl)-1- piperidinvπcarbonyll-2,2-dimethylpropyllcarbamate
Figure imgf000649_0001
1 ,1-dimethylethyl {(1 S)-1 -[(4-(3-fluorophenyl)-4-{2-[(1 R,5S)-3-(2-methyl-1 H- benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]- 2,2-dimethylpropyl}carbamate(0.591 g, 64%) was obtained as a oil from N- {[(1 ,1-dimethylethyl)oxy]carbonyl}-3-methyl-L-valine (0.320 g, 1.4 mmol), 1-(8- {2-[4-(3-Fluoro-phenyl)-piperidin-4-yl]-ethyl}-8-aza-bicyclo[3.2.1]oct-3-yl)-2- methyl-1 H-enzoimidazole dihydrochloride(0.725 g, 1.40 mmol) and HATU(0.590 g, 1.50 mmol) following the procedure outlined in example 5. ES- LCMS m/z 660(M+1).
Example 916
Preparation of 2.2,2-trifluoro-Λ/-f(1 S)-1-r(4-(3-fluorophenvn-4-f2-r(1R.5S)-3-(2- methyl-1 H-benzimidazol-1 -yl)-8-azabicvclor3.2.11oct-8-vNethyl)-1 -piperidinyl) carbonvn-2,2-dimethylpropyl)acetamide
Figure imgf000649_0002
2,2,2-trifluoro-Λ/-{(1 S)-1 -[(4-(3-fluorophenyl)-4-{2-[(1 R,5S)-3-(2-methyl-1 H- benzimidazol-1-yl)-8-azabicyclo [3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]- 2,2-dimethylpropyl}acetamide was obtained from treating 1 ,1-dimethylethyl {(1 S)-1-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)- 8-azabicyclo[3.2.1 ]oct-8-yl]ethyl}-1 -piperidinyl)carbonyl]-2,2-dimethylpropyl} carbamate (0.591 g, 0.90 mmol) with HCl as outlined in the procedure for Example 890 to form (2S)-1-(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H- benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)-3,3- dimethyl-1-oxo-2-butanamine(0.500 g, 99%). 2S)-1-(4-(3-fluorophenyl)-4-{2- [(1R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1 ]oct-8-yl]ethyl}- 1-piperidinyl)-3,3-dimethyl-1-oxo-2-butanamine (0.050 g, 0.09 mmol), trifluoroaceticanhydirde (0.019 g, 0.09 mmol) and DIEA (0.034 g, 0.534 mmol) were reacted following the procedure outlined in Example 890 to give the title compound, 2,2,2-trifluoro-Λ/-{(1 S)-1 -[(4-(3-fluorophenyl)-4-{2-[(1 R,5S)-3-(2- methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo [3.2.1]oct-8-yl]ethyl}-1- piperidinyl)carbonyl]-2,2-dimethylpropyl} acetamide(0.033 g, 56%) as an oil. ES-LCMS m/z 656 (M+1).
Example 917
Preparation of 2-chloro-ΛH(1 S)-1 -[(4-(3-fluorophenvn-4-f2-r(1 R,5S)-3-(2- methyl-1H-benzimidazol-1-yl)-8-azabicvclo[3.2.11oct-8-vnethyl|-1- piperidinyl)carbonyl1-2,2-dimethylpropyl)acetamide
Figure imgf000650_0001
2-chloro-/V-{(1 S)-1 -[(4-(3-fluorophenyl)-4-{2-[(1 R,5S)-3-(2-methyl-1 H- benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]- 2, 2-dimethyl propyl} acetamide was obtained from treating 1 ,1-dimethylethyl {(1 S)-1 -[(4-(3-fluorophenyl)-4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)- 8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]-2,2-dimethylpropyl} carbamate (0.591 g, 0.90 mmol) with HCl as outlined in the procedure for Example 890 to form (2S)-1-(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H- benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)-3,3- dimethyl-1-oxo-2-butanamine(0.500 g, 99%). 2S)-1-(4-(3-fluorophenyl)-4-{2- [(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}- 1-piperidinyl)-3,3-dimethyl-1-oxo-2-butanamine (0.050 g, 0.09 mmol), Chloro- acetyl chloride(0.011 g, 0.09 mmol) and DIEA (0.034 g, 0.534 mmol) were reacted following the procedure outlined in Example 890 to give the title compound, 2-chloro-Λ/-{(1 S)-1 -[(4-(3-fluorophenyl)-4-{2-[(1 R,5S)-3-(2-methyl- 1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1 ]oct-8-yl]ethyl}-1 - piperidinyl)carbonyl]-2,2-dimethylpropyl} acetamide (0.038 g, 66%) as an oil. ES-LCMS m/z 636 (M+1).
Example 918
Preparation of 2,2-dichloro-A/-f(1 S)-1-r(4-(3-fluorophenyl)-4-{2-r(1 R.5S)-3-(2- methyl-1H-benzimidazol-1-yl)-8-azabicvclo[3.2.noct-8-yllethyl)-1- piperidinyl)carbonvn-2,2-dimethylpropyl}acetamide
Figure imgf000651_0001
2,2-dichloro-Λ/-{(1 S)-1 -[(4-(3-fluorophenyl)-4-{2-[(1 R,5S)-3-(2-methyl-1 H- benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]- 2,2-dimethylpropyl} acetamide was obtained from treating 1 ,1-dimethylethyl {(1 S)-1 -[(4-(3-fluorophenyl)-4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)- 8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]-2,2-dimethylpropyl} carbamate, example 915, (0.591 g, 0.90 mmol) with HCl as outlined in the procedure for Example 890 to form (2S)-1-(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3- (2-methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1 - piperidinyl)-3,3-dimethyl-1-oxo-2-butanamine(0.500 g, 99%). 2S)-1-(4-(3- fluorophenyl)-4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)-3,3-dimethyl-1-oxo-2-butanamine (0.050 g, 0.09 mmol), Dichloro-acetyl chloride(0.013 g, 0.09 mmol)and DIEA (0.034 g, 0.534 mmol) were reacted following the procedure outlined in Example 890 to give the title compound, 2,2-dichloro-Λ/-{(1 S)-1-[(4-(3- fluorophenyl)-4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-1 -piperidinyl) carbonyl]-2,2- dimethylpropyl}acetamide(0.036 g, 60%) as an oil. ES-LCMS m/z 670 (M+1 ).
Example 919
Preparation of Λ- 1 S)-1 -r(4-(3-fluorophenvn-4-f2-r(1 R,5S)-3-(2-methyl-1 H- benzimidazol-1-yl)-8-azabicvclo[3.2.noct-8-vnethyl|-1-piperidinyl)carbonvn-
2.2-dimethylpropyl)-2,2-dimethylpropanamide
Figure imgf000652_0001
Λ/-{(1 S)-1 -[(4-(3-fluorophenyl)-4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 - yl)-8-azabicyclo[3.2.1 ]oct-8-yl]ethyl}-1 -piperidinyl)carbonyl]-2,2- dimethylpropyl}-2,2-dimethylpropanamide was obtained from treating 1 ,1- dimethylethyl {(1S)-1 -[(4-(3-fluorophenyl)-4-{2-[(1 R,5S)-3-(2-methyl-1 H- benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]- 2,2-dimethylpropyl} carbamate, example 915, (0.591 g, 0.90 mmol) with HCl as outlined in the procedure for Example 890 to form (2S)-1-(4-(3- fluorophenyl)-4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1 ]oct-8-yl]ethyl}-1 -piperidinyl)-3,3-dimethyl-1 -oxo-2- butanamine(0.500 g, 99%). 2S)-1-(4-(3-fluorophenyl)-4-{2-[(1 ,5S)-3-(2- methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)- 3,3-dimethyl-1-oxo-2-butanamine (0.050 g, 0.09 mmol), 2,2-Dimethyl- propionyl chloride(0.011 g, 0.09 mmol) and DIEA (0.034 g, 0.534 mmol) were reacted following the procedure outlined in Example 890 to give the title compound, Λ/-{(1 S)-1 -[(4-(3-fluorophenyl)-4-{2-[(1 R,5S)-3-(2-methyl-1 H- benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]- 2,2-dimethylpropyl}-2,2-dimethylpropanamide(0.032 g, 55%) as an oil. ES- LCMS m/z 644 (M+1).
Example 920
Preparation of 1.1-dimethylethyl f1-[(4-(3-fluorophenyl)-4-f2-r(1R,5S)-3-(2- methyl-1 H-benzimidazol-1 -yl)-8-azabicvclof3.2.noct-8-vnethyl)-1 -piperidinyl) carbonyl]cvclohexyl)carbamate
Figure imgf000653_0001
1 ,1-dimethylethyl {1 -[(4-(3-fluorophenyl)-4-{2-[(1 R,5S)-3-(2-methyl-1 H- benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1 -piperidinyl) carbonyl]cyclohexyl}carbamate (0.598 g, 64%) was obtained as a oil from 1- ({[(1 ,1-dimethylethyl)oxy]carbonyl}amino)cyclohexanecarboxylic acid (0.320 g, 1.4 mmol), 1-(8-{2-[4-(3-Fluoro-phenyl)-piperidin-4-yl]-ethyl}-8-aza- bicyclo[3.2.1]oct-3-yl)-2-methyl-1 H-enzoimidazole dihydrochloride(0.725 g, 1.40 mmol) and HATU(0.590 g, 1.50 mmol) following the procedure outlined in example 5. ES-LCMS m/z 672(M+1 ).
Example 921
Preparation of 1 ,1-dimethylethyl f1-r(4-(3-fluorophenyl)-4 2-f(1R.5S)-3-(2- methyl-1 H-benzimidazol-1 -yl)-8-azabicvclo[3.2.11oct-8-vnethyl)-1 - piperidinyl)carbonyll-1 ,2-dimethylpropyl)carbamate
Figure imgf000654_0001
1 ,1-dimethylethyl {1 -[(4-(3-fluorophenyl)-4-{2-[(1 R,5S)-3-(2-methyl-1 H- benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]- 1 ,2-dimethylpropyl} carbamate (0.623 g, 67%)was obtained as a oil from N- {[(1 ,1-dimethylethyl)oxy]carbonyl}-3-methylisovaline (0.320 g, 1.4 mmol), 1-(8- {2-[4-(3-Fluoro-phenyl)-piperidin-4-yl]-ethyl}-8-aza-bicyclo[3.2.1]oct-3-yl)-2- methyl-1 H-enzoimidazole dihydrochloride(0.725 g, 1.40 mmol) and HATU(0.590 g, 1.50 mmol) following the procedure outlined in example 5. ES- LCMS m/z 660(M+1 ). Example 922
Preparation of 2.2.2-trifluoro-Λ/-(1 -f(4-f3-fluorophenvn-4-(2-[(1 R.5SV3-(2- methyl-1 H-benzimidazol-1 -ylV8-azabicvclor3.2.1 loct-8-vnethyl)-1 - piperidinyl)carbonyll-1.2-dimethylpropy| acetamide
Figure imgf000655_0001
2,2,2-trifluoro-Λ/-{1 -[(4-(3-fluorophenyl)-4-{2-[(1 R,5S)-3-(2-methyl-1 H- benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]- 1 ,2-dimethylpropyl} acetamide was obtained from treating 1 ,1-dimethylethyl {1 -[(4-(3-fluorophenyl)-4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]-1 ,2- dimethylpropyljcarbamate, example 915, (0.623 g, 0.94 mmol) with HCl as outlined in the procedure for Example 890 to form 1-(4-(3-fluorophenyl)-4-{2- [(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1 ]oct-8-yl]ethyl}- 1-piperidinyl)-2,3-dimethyl-1-oxo-2-butanamine(0.524 g, 99%). 1-(4-(3- fluorophenyl)-4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)-2,3-dimethyl-1 -oxo-2- butanamine(0.050 g, 0.09 mmol), trifluoroaceticanhydirde (0.019 g, 0.09 mmol) and DIEA (0.034 g, 0.534 mmol) were reacted following the procedure outlined in Example 890 to give the title compound, 2,2,2-trifluoro-Λ/-{1-[(4-(3- fluorophenyl)-4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1 ]oct-8-yl]ethyl}-1 -piperidinyl)carbonyl]-1 ,2-dimethylpropyl} acetamide(0.036 g, 61 %) as an oil. ES-LCMS m/z 656 (M+1 ).
Example 923A Preparation of 2-chloro-Λ/-f 1 -r(4-(3-fluorophenyl)-4-f2-r(1 R,5S)-3-(2-methyl- 1 H-benzimidazol-1 -yl )-8-azabicvclo[3.2.1 loct-8-yl.ethylH - piperidinvhcarbonvn-1.2-dimethylpropyl)acetamide
Figure imgf000656_0001
2-chloro-Λ/-{1 -[(4-(3-fluorophenyl)-4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol- 1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]-1 ,2- dimethylpropyljacetamide was obtained from treating 1 ,1-dimethylethyl {1-[(4- (3-fluorophenyl)-4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]-1 ,2- dimethylpropyljcarbamate, example 915, (0.623 g, 0.94 mmol) with HCl as outlined in the procedure for Example 890 to form 1-(4-(3-fluorophenyl)-4-{2- [(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}- 1-piperidinyl)-2,3-dimethyl-1-oxo-2-butanamine(0.524 g, 99%). 1-(4-(3- fluorophenyl)-4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)-2,3-dimethyl-1 -oxo-2- butanamine(0.050 g, 0.09 mmol), Chloro-acetyl chloride(0.011 g, 0.09 mmol) and DIEA (0.034 g, 0.534 mmol) were reacted following the procedure outlined in Example 890 to give the title compound, 2-chloro-Λ/-{1 -[(4-(3- fluorophenyl)-4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]-1 ,2- dimethylpropyl}acetamide(0.030 g, 52%) as an oil. ES-LCMS m/z 636 (M+1).
Example 923B
Preparation of N 1 -IY4-(3-fluorophenviy-4-f2-r(1 R.5S)-3-(2-methyl-1 H- benzimidazol-1-vh-8-azabicvclo[3.2.1loct-8-vnethyl>-1-piperidinvncarbonyl]-
1.2-dimethylpropyl)-2,2-dimethylpropanamide
Figure imgf000657_0001
Λ/-{1 -[(4-(3-fluorophenyl)-4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]-1 ,2-dimethylpropyl}-2,2- dimethylpropanamide was obtained from treating 1 ,1-dimethylethyl {1-[(4-(3- fluorophenyl)-4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]-1 ,2- dimethylpropyljcarbamate, example 915, (0.623 g, 0.94 mmol) with HCl as outlined in the procedure for Example 890 to form 1-(4-(3-fluorophenyl)-4-{2- [(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}- 1 -piperidinyl)-2,3-dimethyl-1 -oxo-2-butanamine(0.524 g, 99%). 1 -(4-(3- fluorophenyl)-4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1 ]oct-8-yl]ethyl}-1 -piperidinyl)-2,3-dimethyl-1 -oxo-2- butanamine(0.050 g, 0.09 mmol), 2,2-Dimethyl-propionyl chloride(0.011 g, 0.09 mmol) and DIEA (0.034 g, 0.534 mmol) were reacted following the procedure outlined in Example 890 to give the title compound, Λ/-{1-[(4-(3- fluorophenyl)-4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-1 -piperidinyl) carbonyl]-1 ,2-dimethylpropyl}- 2,2-dimethylpropanamide(0.039 g, 67%) as an oil. ES-LCMS m/z 643 (M+1).
Example 924
Preparation of 2.2-dichloro-Λ/-f 1 -lϊ4-(3-fluorophenyl)-4-f2-lϊ1 R.5S)-3-(2- methyl-1 H-benzimidazol-1 -yl)-8-azabicvclor3.2.11oct-8-yllethyl)-1 - piperidinyl)carbonvn-1 ,2-dimethylpropyl)acetamide
Figure imgf000658_0001
2,2-dichloro-/V-{1 -[(4-(3-fluorophenyl)-4-{2-[(1 R,5S)-3-(2-methyl-1 H- benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]- 1 ,2-dimethylpropyl} acetamide was obtained from treating 1 ,1-dimethylethyl {1 -[(4-(3-fluorophenyl)-4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]-1 ,2- dimethylpropyljcarbamate, example 915, (0.623 g, 0.94 mmol) with HCl as outlined in the procedure for Example 890 to form 1-(4-(3-fluorophenyl)-4-{2- [(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}- 1-piperidinyl)-2,3-dimethyl-1-oxo-2-butanamine(0.524 g, 99%). 1-(4-(3- fluorophenyl)-4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)-2,3-dimethyl-1 -oxo-2- butanamine(0.050 g, 0.09 mmol), Dichloro-acetyl chloride(0.013 g, 0.09 mmol)and DIEA (0.034 g, 0.534 mmol) were reacted following the procedure outlined in Example 890 to give the title compound, 2,2-dichloro-Λ/-{1-[(4-(3- fluorophenyl)-4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl) carbonyl]-1 ,2- dimethylpropyl}acetamide(0.042 g, 69%) as an oil. ES-LCMS m/z 643 (M+1).
Example 925
Preparation of 3-(4-(3-fluorophenyl)-4-f2-f(1 R.5S)-3-(2-methyl-1 H- benzimidazol-1-vπ-8-azabicvclor3.2.noct-8-vnethyl>-1-piperidinylV2.2- dimethyl-3-oxopropanoic acid
Figure imgf000659_0001
3-(4-(3-fluorophenyl)-4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)-2,2-dimethyl-3-oxopropanoic acid was obtained from 3-Ethoxy-2,2-dimethyl-3-oxopropanoic acid, Example 628, (0.029 g, 0.18 mmol), 1-(8-{2-[4-(3-Fluoro-phenyl)-piperidin-4-yl]-ethyl}-8- aza-bicyclo[3.2.1]oct-3-yl)-2-methyl-1 H-enzoimidazole dihydrochloride (0.075 g, 0.18 mmol), and HATU (0.067 g, 0.18 mmol) following the procedure outlined in example 5 to produce ethyl 3-(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3- (2-methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1 - piperidinyl)-2,2-dimethyl-3-oxopropanoate. Ethyl 3-(4-(3-fluorophenyl)-4-{2- [(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}- 1-piperidinyl)-2,2-dimethyl-3-oxopropanoate (0.100 g, 0.170 mmol), 5 N NaOH (10 ml) and ethanol (4 ml) was stirred at 90°C for 3 hrs. The reaction was evaporated to dryness and residue was suspend in water (10 ml) and neutralized with 1 N HCl. The aqueous layer was extracted with ethyl acetate (3 x 10 ml). The organic layer was dried using magnesium sulfate and concentrated down to form the title compound as a white solid (0.081 g, 85%). ES-LCMS m/z 561 (M+1 ).
Example 926
Preparation of 2.2.2-trichloro-/V-f1-ethyl-1-r(4-(3-fluorophenvn-4--,2-r(1 R.5SV3-
(2-methyl-1 H-benzimidazol-1 -vn-8-azabicvclor3.2.noct-8-vnethyl)-1- piperidinvDcarbonvnpropyllacetamide
Figure imgf000660_0001
2-Amino-2-ethyl-1-(4-(3-fluoro-phenyl)-4-{2-[3-(2-methyl-benzoimidazol-1-yl)- 8-aza-bicyclo[3.2.1] oct-8-yl]-ethyl}-piperidin-1-yl)-butan-1-one (0.100 g, 0.178 mmol), trichloroacetyl chloride (0.032 g, 0.178 mmol)and DIEA (0.069 g, 0.534 mmol) as outlined in procedure for procedure for Example 890 to give title compound, 2,2,2-trichloro-/V-{1 -ethyl-1 -[(4-(3-fluorophenyl)-4-{2- [(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}- 1-piperidinyl)carbonyl]propyl}acetamide(0.068 g, 54%). ES-LCMS m/z 706 (M+1 ).
Example 927
Preparation of Λ/-f 1 -ethyl-1 -r(4-(3-fluorophenyl)-4-f2-[(1 R.5S)-3-(2-methyl-1 H- benzimidazol-1-yl)-8-azabicvclor3.2.noct-8-vnethyl}-1 -piperidinyl) carbonyllpropyl}-2,2,2-trifluoroacetamide
Figure imgf000660_0002
2-Amino-2-ethyl-1-(4-(3-fluoro-phenyl)-4-{2-[3-(2-methyl-benzoimidazol-1-yl)- 8-aza-bicyclo[3.2.1] oct-8-yl]-ethyl}-piperidin-1-yl)-butan-1-one example 890 (0.100 g, 0.178 mmol), trifluoroacetic anhydirde (0.038 g, 0.178 mmol)and DIEA (0.069 g, 0.534 mmol) as outlined in procedure for procedure for Example 890 to give title compound,_Λ/-{1 -ethyl-1 -[(4-(3-fluorophenyl)-4-{2- [(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}- 1 -piperidinyl) carbonyl]propyl}-2,2,2-trifluoroacetamide(0.061 g, 52%). ES- LCMS m/z 656 (M+1 ).
Example 928
Preparation of I3-(1 -(2.2-dimethylpropanovn-4-f2-r.1 R,5S)-3-(2-methyl-1 H- benzimidazol-1-vπ-8-azabicvclor3.2.noct-8-vnethyl)-4- piperidinvDphenvπmethanol
Figure imgf000661_0001
[3-(4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1 ]oct-8- yl]ethyl}-4-piperidinyl) phenyl]methanol dihydrochloride(0.100 g, 0.188 mmol), Dimethyl-propionyl chloride(0.024 g, 0.188 mmol) and DIEA (0.069 g, 0.534 mmol) were stirred at room temperature in DCM (3 ml) for 2 hours. Solvent was removed and compound was purified by RP-HPLC to give the title compound, [3-(1-(2,2-dimethylpropanoyl)-4-{2-[(1R,5S)-3-(2-methyl-1H- benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4- piperidinyl)phenyl]methanol (0.069 g, 71%). ES-LCMS m/z 543 (M+1). Example 929
Preparation of Λ/-f2.5-dichloro-3-IT4-(3-fluorophenvn-4-f2-r(1 R.5S)-3-(2- methyl-1 H-benzimidazol-1 -yl)-8-azabicvclo[3.2.1loct-8-yllethyl}-1 - piperidinvDcarbonyll phenyl)-1 ,1 ,1-trifluoromethanesulfonamide
Figure imgf000662_0001
Λ/-{2,5-dichloro-3-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H- benzimidazol-1 -yl)-8-azabicyclo[3.2.1 ]oct-8-yl]ethyl}-1 -piperidinyl )carbonyl] phenyl}-1 ,1 ,1-trifluoromethanesulfonamide was obtained through procedure outlined in scheme.
Figure imgf000662_0002
Preparation of methyl 3-amino-2,5-dichlorobenzoate
Figure imgf000662_0003
3-amino-2,5-dichlorobenzoic acid(5.00 g, 24.27 mmol) was stirred in methanol(30 ml) at room temperature. Sulfuric Acid(5 ml) was added dropwise. Reaction stirred for 3 hours and was then diluted with water(30 ml) and basified using sodium hydroxide. Mixture was extracted with ethyl acetate x 3. Solvent was removed to afford methyl 3-amino-2,5- dichlorobenzoate(4.20 g, 79%) as a solid. Preparation of methyl 2,5-dichloro-3-{[(trifluoromethyl) sulfonyl]amino}benzoate
Figure imgf000663_0001
methyl 3-amino-2,5-dichlorobenzoate(2.10 g, 9.55 mmol), DIEA(3.0 ml) were stirred in DCM(40 ml) at 0°C. Triflic anhydride(3.90 g, 14.31 mmol) was added dropwise whike stirring at 0°C. After 2hrs at 0°C, reaction was allowed to warm to room temperature while stirring overnight. Quenched rxn with saturated NH4CI and washed with brine. Organic layer with dried to yeild crude methyl 2,5-dichloro-3-{[(trifluoromethyl) sulfonyl]amino}benzoate(4.0 g) which will be carried on.
Preparation of 2,5-dichloro-3-{[(trifluoromethyl) sulfonyl]amino}benzoic acid hydrochloride
Figure imgf000663_0002
Crude methyl 2,5-dichloro-3-{[(trifluoromethyl) sulfonyl]amino}benzoate(4.0 g) was dissolved in methanol(30 ml) and 4N NaOH(30 ml) was added while stirring at room temperature for 18 hrs. Removed solvent and added 4N
HCI(10 ml). Stirred at room temperature for 4hours. Filtered off solid to give
2,5-dichloro-3-{[(trifluoromethyl) sulfonyl] aminojbenzoic acid hydrochloride in quantitative yield.
Preparation of example 929
Λ/-{2,5-dichloro-3-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H- benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl] phenyl}-1 ,1 ,1-trifluoromethanesulfonamide (0.140 g, 47%)was obtained as a oil from (0.320 g, 1.4 mmol), 2,5-dichloro-3-{[(trifluoromethyl) sulfonyl] aminojbenzoic acid hydrochloride(0.157 g, 0.46 mmol), 1 -(8-{2-[4-(3-Fluoro- phenyl)-piperidin-4-yl]-ethyl}-8-aza-bicyclo[3.2.1]oct-3-yl)-2-methyl-1 H- enzoimidazole dihydrochloride(0.200 g, 0.39 mmol) and HATU(0.150 g, 0.46 mmol) following the procedure outlined in example 5. ES-LCMS m/z 766(M+1).
Example 930
Preparation of Λ/-(2,5-dichloro-3-lϊ4-(3-fluorophenvn-4-{2-r(1 R,5S)-3-(2- methyl-1 H-benzimidazol-1 -vπ-8-azabicvclo [3.2.noct-8-yl1ethyl)-1- piperidinvDcarbonvnphenyl) methanesulfonamide
Figure imgf000664_0001
Preparation of methyl 2,5-dichloro-3-[(methylsulfonyl)amino]benzoate
Figure imgf000664_0002
From common intermediate methyl 3-amino-2,5-dichlorobenzoate following the procedure outlined in scheme. Methyl 3-amino-2,5-dichlorobenzoate(2.10 g, 9.55 mmol), DIEA(3.0 ml) were stirred in DCM(40 ml) at 0°C methanesulfonyl chloride (2.18 g, 19.08 mmol) was added dropwise whike stirring at 0°C. After 2hrs at 0°C, reaction was allowed to warm to room temperature while stirring overnight. Quenched rxn with saturated NH4CI and washed with brine. Organic layer with dried to yeild crude methyl 2,5- dichloro-3-[(methylsulfonyl)amino]benzoate(3.10 g) which will be carried on. methyl 2,5-dichloro-3-[(methylsulfonyl)amino]benzoate(3.10 g) was treated with NaOH, methanol following procedure outlined in scheme to form 2,5- dichloro-3-[(methylsulfonyl)amino]benzoic acid hydrochloride (3.53 g).
Preparation of example 930 A/-f2,5-dichloro-3-r(4-(3-fluorophenvn-4-f2-r(1R.5S)-3-(2-methyl-1H- benzimidazol-1-yl)-8-azabicvclo [3.2.11oct-8-vnethyl)-1- piperidinvDcarbonyllphenyl) methanesulfonamide (0.127 g, 45%)was obtained as a oil from 2,5-dichloro-3-[(methylsulfonyl)amino]benzoic acid hydrochloride
(0.132 g, 0.46 mmol), 1-(8-{2-[4-(3-Fluoro-phenyl)-piperidin-4-yl]-ethyl}-8-aza- bicyclo[3.2.1]oct-3-yl)-2-methyl-1 H-benzoimidazole dihydrochloride(0.200 g,
0.39 mmol) and HATU(0.150 g, 0.46 mmol) following the procedure outlined in example 5. ES-LCMS m/z 712(M+1 ).
Example 931
Preparation of 1 ,1 ,1-trifluoro-Λ/-(f4-f(4-(3-fluorophenvn-4-f2-r(1 R,5S)-3-(2- methyl-1 H-benzimidazol-1 -yl)-8-azabicvclor3.2.1loct-8-vnethyl)-1 -piperidinyl) carbonyllphenyllmethyDmethanesulfonamide
Figure imgf000665_0001
By the procedure outlined in example 929, starting from 4- (aminomethyl)benzoic acid(2.00 g, 13.24 mmol) was treated with sulfuric acid to form methyl 4-(aminomethyl)benzoate(1.20 g, 55%). Methyl 4- (aminomethyl)benzoate(0.600 g, 3.63 mmol) was treated with triflic anhydride(1.512 g, 4.92 mmol) in DCM(20 ml) to give crude methyl 4- ({[(trifluoromethyl)sulfonyl]amino}methyl) benzoate(0.402 g, 37%). Methyl 4- ({[(trifluoromethyl) sulfonyl]amino}methyl) benzoate(0.402 g, 1.35 mmol) was treated with NaOH and methanol to give 4-
({[(trifluoromethyl)sulfonyl]amino}methyl)benzoic acid hydrochloride(0.380 g, 95%). The title compound, 1 ,1 ,1-trifluoro-Λ/-({4-[(4-(3-fluorophenyl)-4-{2- [(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}- 1 -piperidinyl) carbonyl]phenyl}methyl) methanesulfonamide(0.145 g, 52%) was obtained as a oil from 4-({[(trifluoromethyl)sulfonyl]amino}methyl)benzoic acid hydrochloride (0.157 g, 0.46I), 1-(8-{2-[4-(3-Fluoro-phenyl)-piperidin-4-yl]- ethyl}-8-aza-bicyclo[3.2.1]oct-3-yl)-2-methyl-1 H-benzoimidazole dihydrochloride(0.200 g, 0.39 mmol) and HATU(0.150 g, 0.46 mmol) following the procedure outlined in example 5. ES-LCMS m/z 712(M+1).
Example 932
Preparation of Λ/-«4-r(4-(3-fluorophenyl)-4-f2-r(1 R,5S)-3-(2-methyl-1 H- benzimidazol-1-yl)-8-azabicvclo[3.2.noct-8-vnethyl)-1- piperidinvDcarbonyllphenyllmethyl) methanesulfonamide
Figure imgf000666_0001
By the procedure outlined in scheme example 929, starting from 4- (aminomethyl)benzoic acid (2.00 g, 13.24 mmol) was treated with sulfuric acid to form methyl 4-(aminomethyl)benzoate(1.20 g, 55%). Methyl 4- (aminomethyl)benzoate (0.600 g, 3.63 mmol) was treated with methanesulfonyl chloride (0.832 g, 7.26 mmol) ) in DCM(20 ml) to give crude methyl 4-{[(methylsulfonyl)amino] methyl}benzoate(0.398 g, 45%). Methyl 4- {[(methylsulfonyl)amino]methyl}benzoate(0.398 g, 1.63 mmol) was treated with NaOH and methanol to give 4-{[(methylsulfonyl)amino]methyl}benzoic acid hydrochloride(0.370 g, 98%). The title compound, Λ/-({4-[(4-(3- fluorophenyl)-4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]phenyl}methyl) methanesulfonamide
(0.128 g, 50%) was obtained as a oil from 4-
{[(methylsulfonyl)amino]methyl}benzoic acid hydrochloride (0.132 g, 0.46I), 1- (8-{2-[4-(3-Fluoro-phenyl)-piperidin-4-yl]-ethyl}-8-aza-bicyclo[3.2.1]oct-3-yl)-2- methyl-1 H-enzoimidazole dihydrochloride(0.200 g, 0.39 mmol) and HATU(0.150 g, 0.46 mmol) following the procedure outlined in example 5. ES- LCMS m/z 658(M+1).
Example 933
Preparation of 2-chloro-/V-ethyl-3-IT4-(3-fluorophenyl)-4-f2-r(1 R,5S)-3-(2- methyl-1 H-benzimidazol-1 -vπ-8-azabicvclo[3.2.11oct-8-yl]ethyl}piperidin-1- vDcarbonyllbenzenesulfonamide
Figure imgf000667_0001
Preparation of 2-chloro-3-f(ethylamino)sulfonyl1benzoic acid. To a solution of methyl 2-chloro-3-(chlorosulfonyl)benzoate (608 mg, 2.26 mmol) and K2CO3 (770 mg, 5.6 mmol) in 10 mL benzene was added ethylamine (5.6 mL, 11.2 mmol). Purification of the product provided methyl 2-chloro-3- [(ethylamino)sulfonyl]benzoate (335 mg, 53%) as a solid. 1H NMR (400 MHz, CDCIs), D 8.24 (dd, 1 H, J = 8.0, 1.7 Hz), 7.90 (dd, 1 H, J = 7.8, 1.7 Hz), 7.47 (t, 1 H, J = 7.8 Hz), 5.14 (t, 1 H, J = 5.9 Hz), 3.94 (s, 3H), 2.98 (qd, 2H, J = 7.3, 6.0 Hz), 1.09 (t, 3H, J = 7.2 Hz); ESI-MS 278 (M+H), 300 (M+Na). Methyl 2- chloro-3-[(ethylamino)sulfonyl]benzoate was hydrolyzed using aqueous NaOH to provide 2-chloro-3-[(ethylamino)sulfonyl]benzoic acid as a solid, which was used without further purification. ESI-MS 264 (M+H), 286 (M+Na).
2-chloro-W-ethyl-3-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H- benzimidazol-1-yi)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-1- yl)carbonyl]benzenesulfonamide (282 mg, 83%) was obtained as a solid from 2-chloro-3-[(ethylamino)sulfonyl]benzoic acid (51 mg, 0.19 mmol), 1-((1R,5S)- 8-{2-[4-(3-fluorophenyl)piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2- methyl-1 H-benzimidazole dihydrochloride (117 mg, 0.19 mmol) and HATU (80 mg, 0.21 mmol) following the procedure outlined in example 5. 1H NMR (400 MHz, CDCI3), D 8.12 (m, 1 H), 7.64 (m, 1 H), 7.53-7.40 (m, 2 H), 7.38-7.25 (m, 2 H), 7.14 (m, 2 H), 7.05 (m, 1 H), 7.00-6.92 (m, 2 H), 5.80-5.35 (m, 2 H), 4.52 (m, 1 H), 4.20 (m, 1 H), 3.45-2.87 (m, 7 H), 2.52 (m, 3 H, rotamers), 2.40-1.60 (m, 15 H), 1.1 (m, 3H); ESI-MS 692 (M+H).
Example 934
Preparation of 2-chloro-M-cvclopropyl-3-r(4-(3-fluorophenv0-4-{2-[(1 R.5SV3-
(2-methyl-1 H-benzimidazol-1 -vπ-8-azabicvclor3.2.noct-8-vnethyl}piperidin-1- vπcarbonvπbenzenesulfonamide
Figure imgf000669_0001
Preparation of 2-chloro-3-r(cvclopropylamino)sulfonv-1benzoic acid. To a solution of methyl 2-chloro-3-(chlorosulfonyl)benzoate (608 mg, 2.26 mmol) and K2CO3 (770 mg, 5.6 mmol) in 10 mL benzene was added cyclopropylamine (0.78 mL, 11.2 mmol). Purification of the product provided methyl 2-chloro-3-[(cyclopropylamino)sulfonyl]benzoate (355 mg, 54%) as a solid. 1H NMR (400 MHz, CDCI3), D 8.28 (dd, 1 H, J = 7.9, 1.7 Hz), 7.90 (dd, 1H, J = 7.8, 1.7 Hz), 7.48 (t, 1 H, J = 7.8 Hz), 5.63 (s, 1 H), 3.93 (s, 3H), 2.17 (m, 1 H), 0.65-0.58 (m, 2H), 0.57-0.50 (m, 2H); ESI-MS 290 (M+H), 312 (M+Na). Methyl 2-chloro-3-[(cyclopropylamino)sulfonyl]benzoate was hydrolyzed using aqueous NaOH to provide 2-chloro-3- [(cyclopropylamino)sulfonyl]benzoic acid as a solid, which was used without further purification. ESI-MS 276 (M+H), 298 (M+Na).
2-chloro-Λ/-cyclopropyl-3-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H- benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-1- yl)carbonyl]benzenesulfonamide (288 mg, 91%) was obtained as a solid from 2-chloro-3-[(cyclopropylamino)sulfonyl]benzoic acid (41 mg, 0.15 mmol), 1- ((1R,5S)-8-{2-[4-(3-fluorophenyl)piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3- yl)-2-methyl-1 H-benzimidazole dihydrochloride (90 mg, 0.15 mmol) and HATU (62 mg, 0.16 mmol) following the procedure outlined in example 5. 1H NMR
Figure imgf000669_0002
D 8.18 (m, 1 H), 7.65 (m, 1 H), 7.56-7.25 (m, 4H), 7.15 (m, 2H), 7.05 (m, 1 H), 7.01-6.91 (m, 2H), 5.95-5.44 (m, 2H), 4.61 (m, 1H), 4.23 (m, 1H), 3.45-3.05 (m, 5H), 2.56 (s, 1.5H, rotamer), 2.54 (s, 1.5H, rotamer), 2.43-1.74 (m, 15H), 1.70-1.58 (m, 2H), 0.78 (m, 1 H), 0.63-0.50 (m, 2H); ESI-MS 704 (M+H). Example 935
Preparation of 1.1.1-trifluoro-Λ/-r3-(4-(3-fluorophenyl)-4-(2-r(1 .5S)-3-(2- methyl-1 H-benzimidazol-1 -yl)-8-azabicvclor3.2.11oct-8-yl1ethyl}piperidin-1 -vD-
2.2-dimethyl-3-oxopropynmethanesulfonamide
Figure imgf000670_0001
Preparation of 2.2-dimethyl-3-{r(trifluoromethyl)sulfonvnamino)propanoic acid. To a -78 °C solution of methyl 3-amino-2,2-dimethylpropanoate (318 mg, 2.4 mmol) and Et3N (0.34 mL, 2.44 mmol) in 4 mL CH2CI2 was added trifluoromethanesulfonic anhydride (0.81 mL, 4.84 mmol). The reaction was stirred for 4h below -40 °C and quenched with saturated aqueous NaHCO3. The crude methyl 2,2-dimethyl-3-{[(trifluoromethyl)sulfonyl]amino}propanoate was isolated and hydrolyzed using aqueous NaOH to provide 2,2-dimethyl-3- {[(trifluoromethyl)sulfonyl]amino}propanoic acid which was used without further purification.
1 ,1 ,1 -trifluoro-/V-[3-(4-(3-fluorophenyl)-4-{2-[(1 R,5S)-3-(2-methyl-1 H- benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-1-yl)-2,2- dimethyl-3-oxopropyl]methanesulfonamide (41 mg, 44%) was obtained as a solid from 2,2-dimethyl-3-{[(trifluoromethyl)sulfonyl]amino}propanoic acid (100 mg, 0.40 mmol), 1-((1R,5S)-8-{2-[4-(3-fluorophenyl)piperidin-4-yl]ethyl}-8- azabicyclo[3.2.1]oct-3-yl)-2-methyl-1 H-benzimidazole dihydrochloride (83 mg, 0.14 mmol) and HATU (75 mg, 0.20 mmol) following the procedure outlined in example 5. 1H NMR (400 MHz, CDCI3). DD.71 -7.67 (m, 1H), 7.41-7.21 (m, 4H), 7.07 (m, 1 H), 7.02-6.94 (m, 2H), 4.84 (q, 1 H, J = 9.5 Hz), 3.94 (m, 2H), 3.45 (m, 2H), 3.21 (m, 5H), 2.62 (s, 3H). 2.54 (m, 2H), 2.20 (m, 2H), 2.14-1.95 (m, 6H), 1.87 (m, 2H), 1.81-1.71 (m, 4H), 1.33 (s, 6H); ESI-MS 678 (M+H).
Example 936
Preparation of Λ/-(2-chloro-3-r(4-(3-fluorophenyl)-4-f2-f(1 R.5S)-3-(2-methyl-
1 H-benzimidazol-1 -yl)-8-azabicvclo[3.2.1 ]oct-8-yriethyl)piperidin-1 - vDcarbonyllphenyllmethanesulfonamide
Figure imgf000671_0001
Preparation of 2-chloro-3-[(methylsulfonyl)amino1benzoic acid. To a solution of methyl 3-amino-2-chlorobenzoate (517 mg, 2.79 mmol) and pyridine (0.25 mL, 3.06 mmol) in 8mL CH2CI2 was added methanesulfonylchloride (0.24 mL, 3.06 mmol). After washing with 1 M HCl, methyl 2-chloro-3- [(methylsulfonyl)amino]benzoate was isolated as a solid in quantitative yield. 1H NMR (400 MHz, CDCI3), D 7.77 (dd, 1H, J = 8.2, 1.6 Hz), 7.61 (dd, 1H, J = 7.9, 1.6 Hz), 7.33 (t, 1H, J = 7.9 Hz), 7.16 (s, 1H), 3.91 (s, 3H), 2.99 (s, 3H); ESI-MS 262 (M-H). Methyl 2-chloro-3-[(methylsulfonyl)amino]benzoate was hydrolyzed using aqueous NaOH to provide 2-chloro-3- [(methylsulfonyl)amino]benzoic acid as a solid, which was used without further purification. ESI-MS 248 (M-H).
Λ/-{2-chloro-3-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol- 1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-1- yl)carbonyl]phenyl}methanesulfonamide (18 mg, 20%) was obtained as a solid from 2-chloro-3-[(methylsulfonyl)amino]benzoic acid (49 mg, 0.20 mmol), 671
1-((1R,5S)-8-{2-[4-(3-fluorophenyl)piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct- 3-yl)-2-methyl-1 H-benzimidazole dihydrochloride (83 mg, 0.14 mmol) and HATU (75 mg, 0.20 mmol) following the procedure outlined in example 5. 1H NMR (400 MHz, CDCI3), D 7.72-7.63 (m, 2H), 7.41-7.25 (m, 4H), 7.16 (m, 2H), 7.07 (m, 1H), 7.02-6.93 (m, 2H), 4.62 (m, 1H), 4.22 (m, 1H), 3.48-3.09 (m, 5H), 3.07 (2, 1.5H, rotamer), 3.04 (s, 1.5H, rotamer), 2.58-2.53 (m, 3H, rotamers), 2.45-2.24 (m, 3H), 2.18-1.61 (m, 15H); ESI-MS 678 (M+H).
Example 937
Preparation of Λ/-f4-chloro-2-fluoro-5-r(4-(3-fluorophenyl)-4-f2-r(1 R,5S)-3-(2- methyl-1 H-benzimidazol-1 -yl)-8-azabicvclof3.2.noct-8-vπethyl|piperidin-1- yl)carbonyl]phenyl)-1 ,1 ,1 -trifluoromethanesulfonam.de
Figure imgf000672_0001
Preparation of 2-chloro-4-fluoro-5-{[(trifluoromethyl)sulfonyl]amino}benzoic acid. To a -78 °C solution of methyl 5-amino-2-chloro-4-fluorobenzoate (195 mg, 1.0 mmol) and Et3N (0.13 mL, 1.0 mmol) in 2 mL CH2CI2 was added trifluoromethanesulfonic anhydride (0.32 mL, 1.9 mmol). The reaction was stirred for 4h below -40 °C and quenched with saturated aqueous NaHCO3. The crude methyl 2-chloro-4-fluoro-5-
{[(trifluoromethyl)sulfonyl]amino}benzoate (ESI-MS 336 (M+H)) was isolated and hydrolyzed using aqueous NaOH to provide 2-chloro-4-fluoro-5- {[(trifluoromethyl)sulfonyl]amino}benzoic acid (ESI-MS 320 (M-H)) which was used without further purification. Λ/-{4-chloro-2-fluoro-5-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H- benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-1- yl)carbonyl]phenyl}-1 ,1 ,1-trifluoromethanesulfonamide (27 mg, 26%) was obtained as a solid from 2-chloro-4-fluoro-5-
{[(trifluoromethyl)sulfonyl]amino}benzoic acid (90 mg, 0.28 mmol), 1-((1R,5S)- 8-{2-[4-(3-fluorophenyl)piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2- methyl-1 H-benzimidazole dihydrochloride (83 mg, 0.14 mmol) and HATU (75 mg, 0.20 mmol) following the procedure outlined in example 5. 1H NMR (400
Figure imgf000673_0001
D 7.68 (m, 1 H), 7.58-7.46 (m, 1 H), 7.38 (m, 1 H), 7.31-7.19 (m, 3H), 7.14 (m, 1 H), 7.08-6.93 (m, 3H), 5.06 (m, 1 H), 4.12 (m, 1 H), 3.89-3.63 (m, 2H), 3.48- 3.08 (m, 4H), 2.77-2.33 (m, 7H), 2.30-1.76 (m, 12H); ESI-MS 750 (M+H).
Example 938
Preparation of NJ 1 -ethyl-1 -r(4-(3-fluorophenyl)-4-f2-r(1 R.5S)-3-(2-methyl-1 H- benzimidazol-1-yl)-8-azabicvclo[3.2.noct-8-yl1ethyl}piperidin-1- vDcarbonvnpropyDmethanesulfonamide
Figure imgf000673_0002
Preparation of 2-ethyl-2-[(methylsulfonyl)amino]butanoic acid. To a solution of 0 °C solution of diethylglycine (205 mg, 1.56 mmol) in 2mL 1M NaOH was added methanesulfonyl chloride (0.14 mL, 1.81 mmol) with periodic stirring and addition of another 2mL 1M NaOH. The reaction mixture was stirred for 1 h at 0 °C, 4h at room temperature, and then acidified with 1M HCl and extracted into EtOAc to provide the crude 2-ethyl-2- [(methylsulfonyl)amino]butanoic acid (37 mg, 11%) as a solid, which was used without further purification. 1H NMR (400 MHz, CDCI3), D 5.19 (s, 1 H), 3.06 (s, 3H), 2.14 (m, 2H), 1.92 (m, 2H), 0.96 (t, 6H, J = 7.4 Hz).
Λ/-{1 -ethyl-1 -[(4-(3-fluorophenyl)-4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol- 1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-1- yl)carbonyl]propyl}methanesulfonamide (69 mg, 79%) was obtained as a solid from 2-ethyl-2-[(methylsulfonyl)amino]butanoic acid (37 mg, 0.18 mmol), 1- ((1R,5S)-8-{2-[4-(3-fluorophenyl)piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3- yl)-2-methyl-1 H-benzimidazole dihydrochloride (83 mg, 0.14 mmol) and HATU (75 mg, 0.20 mmol) following the procedure outlined in example 5. 1H NMR (400 MHz, CDCI3), D 7.65-7.62 (m, 1 H), 7.39-7.30 (m, 1 H), 7.28 (m, 1 H), 7.19-7.11 (m, 2H), 7.06 (m, 1 H), 7.01-6.91 (m, 2H), 6.35 (s, 0.3H, rotamer), 6.28 (s, 0.7H, rotamer), 4.75 (br. s, 1 H), 4.07-3.96 (m, 2H), 3.39-3.25 (m, 4H), 2.98 (s, 2H, rotamer), 2.97 (s, 1 H, rotamer), 2.57 (s, 3H), 2.48-2.38 (m, 2H), 2.31 (m, 2H), 2.24-2.15 (m, 2H), 2.01-1.91 (m, 4H), 1.90-1.74 (m, 8H), 1.74- 1.63 (m, 2H), 0.96-0.85 (m, 6H); ESI-MS 638 (M+H).
Example 939
Preparation of Λ/-f4-chloro-2-fluoro-5-r(4-(3-fluorophenyl)-4-(2-r(1 R.5S)-3-(2- methyl-1 H-benzimidazol-1 -yl)-8-azabicvclo[3.2. noct-8-yl]ethyl}piperidin-1- vDcarbonyllphenvDmethanesulfonamide
Figure imgf000674_0001
Preparation of 2-chloro-4-fluoro-5-[(methylsulfonyl)amino]benzoic acid. To a solution of methyl 5-amino-2-chloro-4-fluorobenzoate (152 mg, 0.75 mmol) and pyridine (0.07 mL, 0.82 mmol) in 3 mL CH2CI2 was added methanesulfonyl chloride (0.06 mL, 0.82 mmol). After 3 days at room temperature, the reaction mixture was washed with saturated aqueous NaHCO3 and filtered through a silica plug to provide methyl 2-chloro-4-fluoro- 5-[(methylsulfonyl)amino]benzoate (96 mg, 44%) as a solid (ESI-MS 280 (M- H)), which was hydrolyzed using aqueous NaOH to provide 2-chloro-4-fluoro- 5-[(methylsulfonyl)amino]benzoic acid (ESI-MS 266 (M-H)), which was used without further purification.
Λ/-{4-chloro-2-fluoro-5-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H- benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-1- yl)carbonyl]phenyl}methanesulfonamide (15.9 mg, 7%) was obtained as a solid from 2-chloro-4-fluoro-5-[(methylsulfonyl)amino]benzoic acid (91 mg, 0.34 mmol), 1-((1 R,5S)-8-{2-[4-(3-fluorophenyl)piperidin-4-yl]ethyl}-8- azabicyclo[3.2.1]oct-3-yl)-2-methyl-1 H-benzimidazole dihydrochloride (210 mg, 0.34 mmol) and HATU (194 mg, 0.51 mmol) following the procedure outlined in example 5. 1H NMR (400 MHz, CDCI3), D 7.66 (m, 1 H), 7.55 (m, 0.5H, rotamer), 7.42-7.32 (m, 1.5H, rotamer), 7.31-7.27 (m, 1 H), 7.25-7.11 (m, 3H), 7.07 (m, 1 H), 7.02-6.93 (m, 2H), 4.65 (br. s, 1 H), 4.29-4.11 (m, 1 H), 3.47- 3.11 (m, 5H), 3.08 (s, 1.5H, rotamer), 3.05 (s, 1.5H, rotamer), 2.56 (s, 3H), 2.46-2.35 (m, 2H), 2.33-2.24 (m, 1 H), 2.18-2.10 (m, 1 H), 2.00-1.73 (m, 10H), 1.67 (m, 2H); ESI-MS 696 (M+H).
Example 940
Preparation of Λ/-r3-(4-(3-fluorophenyl)-4-f2-,T1 R.5S)-3-(2-methyl-1 H- benzimidazol-1-yl)-8-azabicvclo[3.2.noct-8-vnethyllpiperidin-1-yl)-2,2- dimethyl-3-oxopropyπpropane-2-sulfonamide
Figure imgf000676_0001
Preparation of 3-r(isopropylsulfonyl)amino1-2,2-dimethylpropanoic acid. To a solution of methyl 3-amino-2,2-dimethylpropanoate (200 mg, 1.53 mmol) and Et3N (0.64 mL, 4.59 mmol) in 2 mL CH2CI2 was added isopropylsulfonyl chloride (0.34 mL, 3.05 mmol). The reaction was stirred for 24h, quenched by the addition of saturated aqueous NaHCO3, extracted with CHCI3, and chromatographed (1 :1 hex.EtOAc) to provide methyl 3- [(isopropylsulfonyl)amino]-2,2-dimethylpropanoate (77 mg, 21%) as a solid. 1H NMR (400 MHz, CDCI3), 4.78 (t, 1 H, J = 6.6 Hz), 3.68 (s, 3H), 3.20-3.11 (m, 3H), 1.36 (d, 6H, J = 6.9 Hz), 1.23 (s, 6H). Methyl 3- [(isopropylsulfonyl)amino]-2,2-dimethylpropanoate was hydrolyzed using aqueous NaOH to provide 3-[(isopropylsulfonyl)amino]-2,2-dimethylpropanoic acid, which was used without further purification.
Λ/-[3-(4-(3-fluorophenyl)-4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-1-yl)-2,2-dimethyl-3- oxopropyl]propane-2-sulfonamide (130mg, 74%) was obtained as a solid from 3-[(isopropylsulfonyl)amino]-2,2-dimethylpropanoic acid (60 mg, 0.27 mmol), 1-((1R,5S)-8-{2-[4-(3-fluorophenyl)piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct- 3-yl)-2-methyl-1 H-benzimidazole dihydrochloride (164 mg, 0.27 mmol) and HATU (154 mg, 0.41 mmol) following the procedure outlined in example 5. 1H NMR (400 MHz, CDCI3), D 7.68-7.64 (m, 1 H), 7.36 (m, 1 H), 7.29 (m, 1 H), 7.16 (m, 2H), 7.08 (m, 1 H), 7.00 (m, 1 H), 6.96 (m, 1 H), 5.36 (t, 1 H, J = 6.6 Hz), 4.65 (br. s, 1 H), 3.93 (m, 2H), 3.33-3.20 (m, 4H), 3.15 (m, 1 H), 3.10 (m, 2H), 2.58 (s, 3H), 2.40 (m, 2H), 2.19 (m, 2H), 2.00-1.73 (m, 10H), 1.67 (m, 2H), 1.39 (s, 3H), 1.37 (s, 3H), 1.33 (s, 6H); ESI-MS 652 (M+H). Example 941
Preparation of H-{2.4-difluoro-5-IT4-(3-fluorophenvn-4 2-lϊ1 R.5S)-3-(2-methyl-
1 H-benzimidazol-1 -vπ-8-azabicvclo[3.2.11oct-8-yl1ethyl)piperidin-1- vDcarbonyllphenyllmethanesulfonamide
Figure imgf000677_0001
Preparation of 2,4-difluoro-5-[(methylsulfonyl)amino]benzoic acid. To a solution of methyl 5-amino-2,4-difluorobenzoate (252 mg, 1.35 mmol) and pyridine (0.13 mL, 1.61 mmol) in 5 mL CH2CI2 was added methanesulfonyl chloride (0.12 mL, 1.48 mmol). After 24h at room temperature, the reaction mixture was washed with saturated aqueous NaHCO3 and extracted with CHCI3 to provide crude methyl 2, 4-difluoro-5-[(methylsulfonyl)amino]benzoate as a solid (ESI-MS 264 (M-H)), which was hydrolyzed using aqueous NaOH to provide 2,4-difluoro-5-[(methylsulfonyl)amino]benzoic acid (ESI-MS 250 (M- H)), which was used without further purification.
Λ/-{2,4-difluoro-5-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H- benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-1- yl)carbonyl]phenyl}methanesulfonamide (7.0 mg, 13%) was obtained as a solid from 2,4-difluoro-5-[(methylsulfonyl)amino]benzoic acid (20 mg, 0.08 mmol), 1-((1R,5S)-8-{2-[4-(3-fluorophenyl)piperidin-4-yl]ethyl}-8- azabicyclo[3.2.1]oct-3-yl)-2-methyl-1 H-benzimidazole dihydrochloride (48 mg, 0.08 mmol) and HATU (45 mg, 0.12 mmol) following the procedure outlined in example 5. 1H NMR (400 MHz, CDCI3), D 7.73-7.68 (m, 1H), 7.60 (s, 1H), 7.41 (m, 1 H), 7.25-7.15 (m, 3H), 7.12-7.07 (m, 1 H), 7.04-6.93 (m, 3H), 4.26- 4.11 (m, 1 H), 3.89-3.63 (m, 2H), 3.58-3.43 (m, 2H), 3.29-3.16 (m, 2H), 3.07 (s, 2H, rotamer), 3.02 (s, 1 H, rotamer), 2.70 (s, 3H), 2.41-1.61 (m, 16H); ESI- MS 681 (M+H).
Example 942
Preparation of Λ/-{2,4-difluoro-3-r(4-(3-fluorophenyl)-4 2-lϊ1 R.5S)-3-(2-methyl-
1 H-benzimidazol-1 -yl)-8-azabicvclo[3.2.1 loct-8-yl1ethyl)piperidin-1 - vDcarbonvπphenyllmethanesulfonamide
Figure imgf000678_0001
Preparation of 2.6-difluoro-3-r(methylsulfonyl)amino]benzoic acid. To a solution of methyl 3-amino-2,6-difluorobenzoate (530 mg, 2.83 mmol) and pyridine (0.28 mL, 3.40 mmol) in 10 mL CH2CI2 was added methanesulfonyl chloride (0.24 mL, 3.11 mmol). After 24h at room temperature, the reaction mixture was washed with saturated aqueous NaHCO3 and extracted with CHCI3 to provide crude methyl 2,6-difluoro-3-[(methylsulfonyl)amino]benzoate as a solid (ESI-MS 264 (M-H)), which was hydrolyzed using aqueous NaOH to provide 2,6-difluoro-3-[(methylsulfonyl)amino]benzoic acid (ESI-MS 250 (M- H)), which was used without further purification.
/V-{2,4-difluoro-3-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H- benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-1- yl)carbonyl]phenyl}methanesulfonamide (30.5 mg, 49%) was obtained as a solid from
2,6-difluoro-3-[(methylsulfonyl)amino]benzoic acid (26 mg, 0.10 mmol), 1-
((1R,5S)-8-{2-[4-(3-fluorophenyl)piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3- yl)-2-methyl-1 H-benzimidazole dihydrochloride (56 mg, 0.09 mmol) and HATU
(53 mg, 0.14 mmol) following the procedure outlined in example 5.
1H NMR (400 MHz, CDCI3), D 7.79 (m, 1H), 7.55 (m, 1H), 7.42 (m, 1H), 7.34-
7.23 (m, 3H), 7.13 (m, 1H), 7.05-6.94 (m, 3H), 6.02 (br. s, 1H), 4.13 (m, 1H),
3.98-3.80 (m, 2H), 3.59-3.43 (m, 2H), 3.23 (m, 1H), 3.08 (s, 3H), 2.97-3.85
(m, 2H), 2.82 (s, 3H), 2.61-2.46 (m, 2H), 2.39-1.86 (m, 12H); ESI-MS 681
(M+H).
Example 943
Preparation of Λ/-(2-chloro-4-fluoro-5-r(4-(3-fluorophenvn-4-f2-r(1 R,5S)-3-(2- methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1 "|oct-8-yl]ethyl}piperidin-1 - yl)carbonyl]phenyl|methanesulfonamide
Figure imgf000679_0001
Preparation of 4-chloro-2-fluoro-5-[(methylsulfonyl)amino]benzoic acid. To a solution of methyl 5-amino-4-chloro-2-fluorobenzoate (248 mg, 1.22 mmol) and pyridine (0.12 mL, 1.46 mmol) in 5 mL CH2CI2 was added methanesulfonyl chloride (0.10 mL, 1.34 mmol). After 5 days at room temperature, the reaction mixture was washed with saturated aqueous NaHCO3 and extracted with CHCI3 to provide crude methyl 4-chloro-2-fluoro- 5-[(methylsulfonyl)amino]benzoate as a solid (ESI-MS 280 (M-H)), which was hydrolyzed using aqueous NaOH to provide 4-chloro-2-fluoro-5- [(methylsulfonyl)amino]benzoic acid (ESI-MS 266 (M-H)), which was used without further purification. H-{2-chloro-4-fluoro-5-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H- benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-1- yl)carbonyl]phenyl}methanesulfonamide (56 mg, 59%) was obtained as a solid from 4-chloro-2-fluoro-5-[(methylsulfonyl)amino]benzoic acid (43 mg, 0.16 mmol), 1 -((1 R,5S)-8-{2-[4-(3-fluorophenyl)piperidin-4-yl]ethyl}-8- azabicyclo[3.2.1]oct-3-yl)-2-methyl-1 H-benzimidazole dihydrochloride (83 mg, 0.13 mmol) and HATU (78 mg, 0.20 mmol) following the procedure outlined in example 5. 1H NMR (400 MHz, CDCI3), D 7.68-7.61 (m, 1 H), 7.61 (br. s, 1 H), 7.36 (m, 1 H), 7.31-7.26 (m, 1 H), 7.25-7.21 (m, 1 H), 7.21-7.12 (m, 2H), 7.07 (m, 1H), 7.02-6.93 (m, 2H), 4.68 (br. s, 1H), 4.19 (m, 1H), 3.50-3.15 (m, 5H), 3.04 (s, 3H), 2.58 (s, 3H), 2.51-2.34 (m, 2H), 2.28 (m, 2H), 2.15 (m, 2H), 2.07- 1.76 (m, 10H), 1.69 (m, 2H); ESI-MS 696 (M+H).
Example 944
Preparation of 1-f(1R.5S)-8-(2-f4-(3-fluorophenyl)-1-r3-(1H-1.2.4-triazol-1- yl)benzovnpiperidin-4-yl)ethvπ-8-azabicvclor3.2.11oct-3-vn-2-methyl-1H- benzimidazole
Figure imgf000680_0001
1 -[(1 R,5S)-8-(2-{4-(3-fluorophenyl)-1 -[3-(1 H-1 ,2,4-triazol-1 - yl)benzoyl]piperidin-4-yl}ethyl)-8-azabicyclo[3.2.1]oct-3-yl]-2-methyl-1H- benzimidazole (89 mg, 47%) was obtained as a solid from 3-(1H-1 ,2,4-triazol- 1-yl)benzoic acid (107 mg, 0.56 mmol), 1-((1R,5S)-8-{2-[4-(3- fluorophenyl)piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H- benzimidazole dihydrochloride (160 mg, 0.31 mmol) and HATU (176 mg, 0.46 mmol) following the procedure outlined in example 5. 1H NMR (400 MHz, CDCI3). □ 8.58 (s, 1 H), 8.11 (s, 1H), 7.77-7.72 (m, 2H), 7.67 (d, 1 H, J = 7.9 Hz), 7.56 (t, 1H, J = 7.8 Hz), 7.43-7.24 (m, 3H), 7.17 (m, 2H), 7.09 (d, 1H, J 7.7 Hz), 7.04-6.94 (m, 2H), 4.61 (m, 1 H), 4.19 (m, 1 H), 3.60 (m, 1 H), 3.47- 3.17 (m, 3H), 2.56 (s, 3H), 2.43-2.26 (m, 3H), 2.13 (m, 1H), 2.02-1.55 (m, 12H); ESI-MS 618 (M+H).
Example 945
Preparation of 2-(4-(3-fluorophenvn-4-f2-IT1 R.5S)-3-(2-methyl-1 H- benzimidazol-1-yl)-8-azabicvclo[3.2.noct-8-yl1ethyl}piperidin-1-yl)propanoic acid
Figure imgf000681_0001
To a -78 °C solution of benzyl 2-hydroxypropanoate (250 mg, 1.39 mmol) and 4A molecular sieves in 2 mL CH2CI2 was added trifluoromethanesulfonic anhydride (0.33 mL, 1.97 mmol). After stirring for 10 min at this temperature, 2,6-lutidine (0.31 mL, 2.62 mmol) was added. After 15 min, diisopropylethylamine (0.46 mL, 2.62 mmol) was added and after another 15 min, a solution of 1-((1R,5S)-8-{2-[4-(3-fluorophenyl)piperidin-4-yl]ethyl}-8- azabicyclo[3.2.1]oct-3-yl)-2-methyl-1 H-benzimidazole dihydrochloride (400 mg, 0.66 mmol) in 3 mL CH2CI2 was added. The reaction mixture was stirred at -78 °C, then allowed to warm to room temperature overnight, washed with saturated aqueous NaHCO3, and purified by chromatographaphy (3% (2M NH3 / MeOH) in CHCI3) to provide benzyl 2-(4-(3-fluorophenyl)-4-{2-[(1R,5S)- 3-(2-methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin- 1-yl)propanoate (146 mg, 37%) as a solid. 1H NMR (400 MHz, CDCI3), D 7.68 (m, 1H), 7.37-7.26 (m, 7H), 7.22-7.13 (m, 2H), 7.08 (m, 1H), 6.98 (m, 1H), 6.92 (m, 1H), 5.09 (s, 2H), 4.62 (m, 1H), 3.39-3.17 (m, 2H), 2.89-1.26 (m, 27H); ESI-MS 609 (M+H).
A solution of benzyl 2-(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H- benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-1-yl)propanoate (136 mg, 0.223 mmol) in 8mL MeOH was stirred for 3h under an atmospheric pressure of hydrogen and in the presence of catalytic 5% Pd/C. Filtration and evaporation afforded 2-(4-(3-fluorophenyl)-4-{2-[(1 R,5S)-3-(2-methyl-1 H- benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-1-yl)propanoic acid (90.0 mg, 78%) as a solid. 1H NMR (400 MHz, CDCI3), □ 7.69 (m, 1H), 7.40 (m, 1H), 7.26-7.12 (m, 4H), 7.09-6.95 (m, 2H), 5.37 (m, 1H), 3.85-3.55 (m, 5H), 2.81-1.77 (18H), 2.62 (s, 3H), 1.61-1.41 (3H); ESI-MS 517 (M-H).
Example 946
Preparation of 2-cvclohexyl-2-(4-(3-fluorophenylV4-f2-[f 1 R.5S)-3-(2-methyl-
1 H-benzimidazol-1 -vπ-8-azabicvclof3.2.noct-8-vnethyl>piperidin-1-yl)--V- methylacetamide
Figure imgf000682_0001
Preparation of cvclohexyl(4-(3-fluorophenyl)-4-{2-r(1 R.5S)-3-(2-methyl-1 H- benzimidazol-1-vπ-8-azabicvclor3.2.noct-8-vπethyl)piperidin-1-yl)acetic acid. To a -78 °C solution of benzyl cyclohexyl(hydroxy)acetate (61 mg, 0.25 mmol) and 4A molecular sieves in 1.2 mL CH2CI2 was added trifluoromethanesulfonic anhydride (0.05 mL, 0.30 mmol). After stirring for 10 min at this temperature, 2,6-lutidine (0.06 mL, 0.49 mmol) was added. After 15 min, diisopropylethylamine (0.09 mL, 0.49 mmol) was added and after another 15 min, a solution of 1-((1R,5S)-8-{2-[4-(3-fluorophenyl)piperidin-4- yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1 H-benzimidazole dihydrochloride (153 mg, 0.30 mmol) in 1 mL CH2CI2 was added. The reaction mixture was stirred at -78 °C, then allowed to warm to room temperature overnight, washed with saturated aqueous NaHCO3, and purified by preparatory TLC using 5% MeOH in CHCI3 to afford benzyl cyclohexyl (4-(3- fluorophenyl)-4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-1-yl)acetate (33 mg, 20%) as an oil. 1H NMR (400 MHz, CDCI3), D 7.68 - 7.64 (m, 1H), 7.33-7.23 (m, 7H), 7.20- 7.12 (m, 2H), 7.05 (m, 1 H), 6.97 (m, 1H), 6.89 (m, 1 H), 5.05 (ABq, 2H, J = 12.3 Hz), 4.61 (m, 1 H), 3.26-3.18 (m, 2H), 2.92 (d, 1 H, J = 10.4 Hz), 2.70 (m, 1H), 2.64-2.50 (m, 2H), 2.57 (s, 3H), 2.46-2.30 (m, 3H), 2.12-0.81 (m, 25H); ESI-MS 677 (M+H).
A solution of benzyl cyclohexyl(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl- 1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-1-yl)acetate (23.8 mg, 0.035 mmol) in 3mL MeOH was stirred for 3h under an atmospheric pressure of hydrogen and in the presence of catalytic 5% Pd/C. Filtration and evaporation afforded cyclohexyl(4-(3-fluorophenyl)-4-{2-[(1 R,5S)-3-(2-methyl- 1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-1-yl)acetic acid (17.5 mg, 85%). ESI-MS 585 (M-H).
To a solution of cyclohexyl(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H- benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-1-yl)acetic acid (22.0 mg, 0.037 mmol), methylamine (0.056 mL of a 2M solution in THF, 0.11 mmol), N-hydroxybenzotriazole (10.1 mg, 0.075 mmol) and N- methylmorpholine (0.10 mL, 0.094 mmol) in 1 mL DMF was added EDC (14 mg, 0.075 mmol). The reaction mixture was stirred for 24h, then diluted with 4:1 EtOAc:hex and washed with saturated aqueous NaHCO3, dried (Na2SO4) and chromatographed (5% (2M NH3 / MeOH) in CHCI3) to provide 2- cyclohexyl-2-(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol- 1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-1-yl)-Λ/-methylacetamide (8.1 mg, 36%) as a solid. 1H NMR (400 MHz, CDCI3), D 7.66 (m, 1 H), 7.33-7.27 (m, 2H), 7.20-7.11 (m, 2H), 7.05 (m, 1 H), 6.98 (m, 1 H), 6.90 (m, 1 H), 4.64 (m, 1 H), 3.33-3.20 (m, 2H), 2.80 (d, 3H, J = 4.9 Hz), 2.59 (s, 3H), 2.47-0.79 (m, 27H); ESI-MS 600 (M+H).
Example 947
Preparation of 2-cvclohexyl-2-(4-(3-fluorophenyl)-4-{2-r.1 R,5S)-3-(2-methyl-
1 H-benzimidazol-1 -yl)-8-azabicvclo[3.2.1 ]oct-8-vπethyl}piperidin-1 - vPacetamide
Figure imgf000684_0001
To a solution of cyclohexyl(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H- benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-1-yl)acetic acid (22.0 mg, 0.037 mmol), hydroxylamine (0.2 mL of a 28% solution in water, 3.3 mmol), N-hydroxybenzotriazole (10.1 mg, 0.075 mmol) and N- methylmorpholine (0.10 mL, 0.094 mmol) in 1 mL DMF was added EDC (14 mg, 0.075 mmol). The reaction mixture was stirred for 24h, then diluted with 4:1 EtOAc:hex and washed with saturated aqueous NaHCO3, dried (Na2SO ) and chromatographed (5% (2M NH3 / MeOH) in CHCI3) to provide 2- cyclohexyl-2-(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol- 1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-1-yl)acetamide (7.7 mg, 35%) as a solid. 1H NMR (400 MHz, CDCI3), D 7.66 (m, 1 H), 7.34- 7.27 (m, 2H), 7.20-7.12 (m, 2H), 7.06 (m, 1 H), 6.99 (m, 1 H), 6.90 (m, 1 H), 4.61 (m, 1H), 3.27-3.19 (m, 2H), 2.73-2.62 (m, 2H), 2.58 (s, 3H), 2.47-0.78 (m, 27H); ESI-MS 589 (M+H)
Example 948
Preparation of 2-chloro-3-r(4-(3-fluorophenvn-4-f2-r(1 R.5S)-3-(2-methyl-1 H- benzimidazol-1-yl)-8-azabicvclor3.2.noct-8-vnethyl|piperidin-1-yl)carbonvn-Λ/- methylbenzenesulfonamide
Figure imgf000685_0001
Preparation of 2-chloro-3-r(methylamino)sulfonvπbenzoic acid. To a solution of
To a solution of methyl 2-chloro-3-(chlorosulfonyl)benzoate (608 mg, 2.26 mmol) and K2CO3 (770 mg, 5.6 mmol) in 10 mL benzene was added a 2M solution of methylamine in THF (5.6 mL, 11.2 mmol). Purification of the product (2:1 hex: EtOAc) provided methyl 2-chloro-3- [(methylamino)sulfonyl]benzoate (430 mg, 72%) as a solid. 1H NMR (400 MHz, CDCI3), D 8.23 (dd, 1 H, J = 7.9, 1.7 Hz), 7.90 (dd, 1 H, J = 7.8, 1.7 Hz), 7.48 (t, 1H, J = 7.9 Hz), 5.16 (q, 1 H, J = 5.2 Hz), 3.94 (s, 3H), 2.62 (d, 3H, J = 5.3 Hz); ESI-MS 264 (M+H). Methyl 2-chloro-3-
[(methylamino)sulfonyl]benzoate was hydrolyzed using aqueous NaOH to provide 2-chloro-3-[(methylamino)sulfonyl]benzoic acid as a solid, which was used without further purification. ESI-MS 250 (M+H), 272 (M+Na). 2-chloro-3-[(4-(3-fluorophenyl)-4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 - yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}ρiperidin-1-yl)carbonyl]-Λ/- methylbenzenesulfonamide (87 mg, 62%) was obtained as a solid from 2- chloro-3-[(methylamino)sulfonyl]benzoic acid (52 mg, 0.21 mmol), 1-((1R,5S)- 8-{2-[4-(3-fluorophenyl)piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2- methyl-1 H-benzimidazole dihydrochloride (127 mg, 0.21 mmol) and HATU (87 mg, 0.23 mmol) following the procedure outlined in example 5. 1H NMR (400 MHz, CDCI3), □ 8.40 (m, 1H), 7.62 (m, 1H), 7.53-7.28 (m, 4H), 7.13 (m, 2H), 7.04 (m, 1 H), 6.99-6.90 (m, 2H), 5.92-5.59 (m, 2H), 4.60 (m, 1H), 4.2 (m, 1H), 3.42-3.03 (m, 6H), 2.63-2.58 (m, 3H, rotamers), 2.54 (s, 1.5H, rotamer), 2.52 (s, 1.5H, rotamer), 2.41-2.23 (m, 3H), 2.17-1.58 (m, 11H); ESI-MS 678 (M+H).
Example 949
Preparation of 3-(4-(3-fluorophenyl)-4-f2-r(1 R.5S)-3-(2-methyl-1 H- benzimidazol-1 -yl)-8-azabicvclo[3.2.1 ]oct-8-vπethyl)piperidin-1 -yl)-2,2- dimethyl-3-oxopropan-1 -ol
Figure imgf000686_0001
3-(4-(3-fluorophenyl)-4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-1-yl)-2,2-dimethyl-3-oxopropan-1-ol (63 mg, 88%) was obtained as a solid from 3-hydroxy-2,2-dimethylpropanoic acid (23 mg, 0.20 mmol), 1-((1R,5S)-8-{2-[4-(3-fluorophenyl)piperidin-4- yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1 H-benzimidazole dihydrochloride (80 mg, 0.13 mmol) and HATU (75 mg, 0.20 mmol) following the procedure outlined in example 5. 1H NMR (400 MHz, CDCI3), D 7.67-7.63 686
(m, 1 H), 7.38-7.28 (m, 2H), 7.15 (m, 2H), 7.08 (m, 1H), 7.02-6.92 (m, 2H), 4.60 (m, 1 H), 3.90 (m, 2H), 3.72 (m, 1 H), 3.45 (m, 2H), 3.25 (m, 4H), 2.57 (s, 3H), 2.37 (m, 2H), 2.19 (m, 2H), 1.99-1.85 (m, 6H), 1.85-1.74 (m, 4H), 1.63 (m, 2H), 1.26 (s, 6H); ESI-MS 547 (M+H).
Example 950
Preparation of Λ/-f3-(4-(3-fluorophenyl)-4-f2-r(1 R,5S)-3-(2-methyl-1 H- benzimidazol-1-yl)-8-azabicvclof3.2.1]oct-8-yl1ethyl}piperidin-1-vπ-2.2- dimethyl-3-oxopropyπmethanesulfonamide
Figure imgf000687_0001
Preparation of 2,2-dimethyl-3-[(methylsulfonyl)amino1propanoic acid. To a solution of methyl 3-amino-2,2-dimethylpropanoate (249 mg, 1.90 mmol) and Et N (0.80 mL, 5.70 mmol) in 2 mL CH2CI2 was added methanesulfonyl chloride (0.29 mL, 3.80 mmol). The reaction was stirred for 2 days, quenched by the addition of saturated aqueous NaHCO3, extracted with CHCI3, and chromatographed (1:1 hex.ΕtOAc) to provide methyl 2,2-dimethyl-3- [(methylsulfonyl)amino]propanoate (124 mg, 31%) as a clear oil. 1H NMR (400 MHz, CDCI3), 4.95 (t, 1H, J = 6.8 Hz), 3.69 (s, 3H), 3.16 (d, 2H, J = 6.8 Hz), 2.95 (s, 3H), 1.24 (s, 6H). Methyl 2,2-dimethyl-3-
[(methylsulfonyl)amino]propanoate was hydrolyzed using aqueous NaOH to provide 2,2-dimethyl-3-[(methylsulfonyl)amino]propanoic acid, which was used without further purification. 1H NMR (400 MHz, CDCI3), D 10.28 (br. s, 1H), 5.56 (br. s, 1H), 3.14 (s, 2H), 2.94 (s, 3H), 1.25 (s, 6H). Λ/-[3-(4-(3-fluorophenyl)-4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-1-yl)-2,2-dimethyl-3- oxopropyl]methanesulfonamide (41 mg, 48%) was obtained as a solid from 2,2-dimethyl-3-[(methylsulfonyl)amino]propanoic acid (38 mg, 0.20 mmol), 1- ((1R,5S)-8-{2-[4-(3-fluorophenyl)piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3- yl)-2-methyl-1 H-benzimidazole dihydrochloride (83 mg, 0.14 mmol) and HATU (75 mg, 0.20 mmol) following the procedure outlined in example 5. 1H NMR (400 MHz, CDCI3), D 7.63 (m, 1 H), 7.34 (m, 1 H), 7.28 (m, 1 H), 7.14 (m, 2H), 7.06 (m, 1 H), 6.99 (m, 1 H), 6.94 (m, 1 H), 5.52 (t, 1 H, J = 6.8 Hz), 4.63 (m, 1H), 3.89 (m, 2H), 3.24 (m, 4H), 3.08 (d, 2H, J = 6.8 Hz), 2.93 (s, 3H), 2.56 (s, 3H), 2.37 (m, 2H), 2.18 (m, 2H), 1.92 (m, 6H), 1.78 (m, 4H), 1.64 (m, 2H), 1.32 (s, 6H); ESI-MS 624 (M+H).
Example 951
Preparation of Λ/-f2.6-dichloro-4-r(4-(3-fluorophenyl)-4-f2-r(1 R,5S)-3-(2- methyl-1 H-benzimidazol-1 -yl)-8-azabicvclof3.2.noct-8-yl]ethyl)piperidin-1- vDcarbonyllphenvD-l .1 ,1-trifluoromethanesulfonamide
Figure imgf000688_0001
/V-{2,6-dichloro-4-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H- benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-1- yl)carbonyl]phenyl}-1 ,1 ,1-trifluoromethanesulfonamide (63 mg, 60%) was obtained as an oil from 3,5-dichloro-4-{[(trifluoromethyl)sulfonyl]amino}benzoic acid (70 mg, 0.21 mmol), 1-((1R,5S)-8-{2-[4-(3-fluorophenyl)piperidin-4- yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1 H-benzimidazole dihydrochloride (83 mg, 0.14 mmol) and HATU (75 mg, 0.20 mmol) following the procedure outlined in example 5. 1H NMR (400 MHz, CDCI3), D 7.68-7.64 (m, 1 H), 7.37-7.25 (m, 4H), 7.18 (m, 2H), 7.08 (m, 1 H), 7.01-6.90 (m, 2H), 5.17 (m, 1 H), 4.02 (m, 1 H), 3.52 (m, 1 H), 3.30 (m, 2H), 2.64 (s, 3H), 2.56 (m, 2H), 2.23-1.69 (m, 13H); ESI-MS 766 (M+H).
Example 952
Preparation of Λ/-f2-chloro-3-[(4-(3-fluorophenyl)-4 2-rπ R.5S)-3-(2-methyl- 1 H-benzimidazol-1 -yl)-8-azabicvclo[3.2.noct-8-vnethyl}piperidin-1- yl)carbonyl]phenyl)-1 ,1 ,1-trifluoromethanesulfonamide
Figure imgf000689_0001
A/-{2-chloro-3-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol- 1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-1-yl)carbonyl]phenyl}-1 ,1 ,1- trifluoromethanesulfonamide (12 mg, 12%) was obtained as a solid from 2- chloro-3-{[(trifluoromethyl)sulfonyl]amino}benzoic acid (66 mg, 0.22 mmol), 1- ((1R,5S)-8-{2-[4-(3-fluorophenyl)piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3- yl)-2-methyl-1 H-benzimidazole dihydrochloride (83 mg, 0.14 mmol) and HATU (75 mg, 0.20 mmol) following the procedure outlined in example 5. 1H NMR (400 MHz, CDCI3), D 7.70-7.64 (m, 1H), 7.58 (m, 1H), 7.42-7.28 (m, 2H), 7.25-6.92 (m, 5H), 6.88-6.74 (m, 2H), 5.00-4.70 (m, 1H), 4.32-4.00 (m, 1H), 3.75-3.00 (m, 5H), 2.58 (s, 3H), 2.32-1.20 (m, 17H); ESI-MS 732 (M+H). 689
Example 953
Preparation of 1 -((1 R.5S)-8-f2-[1 -(2-chloro-4-fluoro-5-nitrobenzovn-4-r3- fluorophenyl)piperidin-4-vnethyl)-8-azabicvclor3.2.noct-3-yl)-2-methyl-1H- benzimidazole
Figure imgf000690_0001
1 -((1 R,5S)-8-{2-[1 -(2-chloro-4-fluoro-5-nitrobenzoyl)-4-(3- fluorophenyl)piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1 ]oct-3-yl)-2-methyl-1 H- benzimidazole (14 mg, 16%) was obtained as an oil from 2-chloro-4-fluoro-5- nitrobenzoic acid (39 mg, 0.18 mmol), 1-((1R,5S)-8-{2-[4-(3- fluorophenyl)piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H- benzimidazole dihydrochloride (83 mg, 0.14 mmol) and HATU (75 mg, 0.20 mmol) following the procedure outlined in example 5. 1H NMR (400 MHz, CDCI3), D 7.66 (m, 1H), 7.43-7.27 (m, 3H), 7.16 (m, 2H), 7.07 (m, 1H), 7.03- 6.93 (m, 3H), 4.62 (m, 1H), 4.24 (m, 1H), 3.46-3.07 (m, 6H), 2.57 (s, 3H), 2.44-1.59 (m, 15H); ESI-MS 648 (M+H).
Example 954
Preparation of H-f2,6-dichloro-4-r(4-(3-fluorophenyl)-4-f2-lϊ1 R,5S)-3-(2- meth yl- 1 H-benzim idazol-1 -yl )-8-azabicvclor3.2.1 ]oct-8-yl]eth yllpiperid in- 1 ■ vDcarbonyllphenvDmethanesulfonamide 690
Figure imgf000691_0001
Λ/-{2,6-dichloro-4-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H- benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-1- yl)carbonyl]phenyl}methanesulfonamide (28 mg, 28%) was obtained as a solid from 3,5-dichloro-4-[(methylsulfonyl)amino]benzoic acid (59 mg, 0.21 mmol), 1 -((1 R,5S)-8-{2-[4-(3-fluorophenyl)piperidin-4-yl]ethyl}-8- azabicyclo[3.2.1]oct-3-yl)-2-methyl-1 H-benzimidazole dihydrochloride (83 mg, 0.14 mmol) and HATU (75 mg, 0.20 mmol) following the procedure outlined in example 5. 1H NMR (400 MHz, CDCI3), D 7.62 (m, 1H), 7.37-7.22 (m, 3H), 7.13 (m, 2H), 7.05 (m, 1H), 7.01-6.88 (m, 3H), 4.58 (m, 1H), 4.12 (m, 1H), 3.55-3.22 (m, 5H), 3.21 (m, 3H, rotamers), 2.53 (m, 3H, rotamers), 2.41-1.56 (m, 15H); ESI-MS 712 (M+H).
Additional examples of a the formula below were generated by coupling acids listed in the table using method A in example 5.
Figure imgf000691_0002
Figure imgf000692_0001
Figure imgf000693_0001
Figure imgf000694_0001
Figure imgf000695_0001
Figure imgf000696_0001
Figure imgf000697_0001
Figure imgf000698_0001
Figure imgf000699_0001
Example 958
4-[(4-(3-fluorophenyl)-4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-1-yl)carbonyl]-1 H-pyrazol-3-amine
Example 959
1 -[(1 R,5S)-8-(2-{1 -[(3-chloro-5-methylisoxazol-4-yl)carbonyl]-4- phenylpiperidin-4-yl}ethyl)-8-azabicyclo[3.2.1]oct-3-yl]-2-methyl-1 H- benzimidazole
Figure imgf000700_0002
Example 960
{6-[(4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1]oct-8- yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]-1H-benzimidazol-2-yl}methanol
Figure imgf000701_0001
Example 961
3-methyl-1-[1-methyl-2-(4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)-2-oxoethyl]pyrrolidine-
2,5-dione
Figure imgf000701_0002
Example 962
5-methyl-4-[(4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]isoxazol-3(2H)- one
Figure imgf000702_0001
Example 963
1 -[1 -methyl-2-(4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)-2-oxoethyl]pyridin- 2(1H)-one
Figure imgf000702_0002
Example 964
6-fluoro-3-[(4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]quinoline
Figure imgf000703_0001
Example 965
4-[(4-{2-[(1R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1 ]oct-8- yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]-1 ,3-benzothiazol-2(3H)-one
Figure imgf000703_0002
Example 966
1 -((1 R,5S)-8-{2-[1 -((3S,4S)-3,4-dimethoxy-(2S)-tetrahydrofuran-2-carbonyl)-4- phenylpiperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H- benzimidazole
Figure imgf000704_0001
Example 967
1 -[(1 R,5S)-8-(2-{1 -[(3-methoxy-4-methylisoxazol-5-yl)acetyl]-4- phenylpiperidin-4-yl}ethyl)-8-azabicyclo[3.2.1]oct-3-yl]-2-methyl-1 H- benzimidazole
Figure imgf000704_0002
Example 968
4-[(4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1 ]oct-8- yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]-1 ,3-dihydro-2H-benzimidazol-2-one
Figure imgf000705_0001
Example 969
2-methyl-5-[(4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]pyridin-4-ol
Figure imgf000705_0002
Example 970
1 -[(1 R,5S)-8-(2-{1 -[4-(2-methoxyethoxy)benzoyl]-4-phenylpiperidin-4-yl}ethyl)-
8-azabicyclo[3.2.1]oct-3-yl]-2-methyl-1 H-benzimidazole
Figure imgf000706_0001
Example 971
3-{4-[(4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct- 8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]-2-oxopyrrolidin-1-yl}propanenitrile
Figure imgf000706_0002
Example 972
1 -((1 R,5S)-8-{2-[1 -(2-cyclohexyl-2-methylpropanoyl)-4-phenylpiperidin-4- yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1 H-benzimidazole
Figure imgf000707_0001
Example 973
1 -[(1 R,5S)-8-(2-{1 -[(2,4-dimethyl-1 ,3-oxazol-5-yl)carbonyl]-4-phenylpiperidin-
4-yl}ethyl)-8-azabicyclo[3.2.1 ]oct-3-yl]-2-methyl-1 H-benzimidazole
Figure imgf000707_0002
Example 974
6-[(4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1 ]oct-8- yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]-5H-[1 ,3]thiazolo[3,2-a]pyrimidin-5- one
Figure imgf000708_0001
Example 975
1 -[(1 R,5S)-8-(2-{1 -[(5-chloro-2-methylpyrimidin-4-yl)carbonyl]-4- phenylpiperidin-4-yl}ethyl)-8-azabicyclo[3.2.1]oct-3-yl]-2-methyl-1 H- benzimidazole
Figure imgf000708_0002
Example 976
2-methyl-1 -((1 R,5S)-8-{2-[1 -(1 ,3-oxazol-4-ylcarbonyl)-4-phenylpiperidin-4- yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-1 H-benzimidazole
Figure imgf000709_0001
Example 977
3-methoxy-1 -[1 -methyl-2-(4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1 ]oct-8-yl]ethyl}-4-phenylpiperidin-1 -yl)-2-oxoethyl]pyridin-
2(1 H)-one
Figure imgf000709_0002
Example 978
2-methyl-1 -[(1 R,5S)-8-(2-{4-phenyl-1 -[(2-propyl-1 ,3-thiazol-5- yl)carbonyl]piperidin-4-yl}ethyl)-8-azabicyclo[3.2.1]oct-3-yl]-1 H-benzimidazole
Figure imgf000710_0001
Example 979
N-[1 -methyl-3-(4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1 ]oct-8-yl]ethyl}-4-phenylpiperidin-1 -yl)-3-oxopropyl]-1 H- pyrrole-2-carboxamide
Figure imgf000710_0002
Example 980
4-[(4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1 ]oct-8- yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]-2,1-benzisoxazole
Figure imgf000711_0001
Example 981
8-[(4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1 ]oct-8- yl]ethyl}-4-phenylpiperidin-1 -yl)carbonyl]quinolin-2(1 H)-one
Figure imgf000711_0002
Example 982
N-{3-hydroxy-2-[(4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1- yl)carbonyl]phenyl}acetamide
Figure imgf000712_0001
Example 983
2-[(4-{2-[(1R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1]oct-8- yl]ethyl}-4-phenylpiperid i n- 1 -yl )carbonyl] n icotinon itrile
Figure imgf000712_0002
Example 984
1 -[(1 R,5S)-8-(2-{1 -[(1 -ethyl-5-methyl-1 H-pyrazol-3-yl)carbonyl]-4- phenylpiperidin-4-yl}ethyl)-8-azabicyclo[3.2.1]oct-3-yl]-2-methyl-1H- benzimidazole
Figure imgf000713_0001
Example 985
2-methyl-1 -[(1 R,5S)-8-(2-{1 -[oxo(piperidin-1 -yl)acetyl]-4-phenylpiperidin-4- yl}ethyl)-8-azabicyclo[3.2.1]oct-3-yl]-1 H-benzimidazole
Figure imgf000713_0002
Example 986
2-methyl-1-((1 R,5S)-8-{2-[4-phenyl-1-(2H-1 ,2,3-triazol-2-ylacetyl)piperidin-4- yl]ethyl}-8-azabicyclo[3.2.1 ]oct-3-yl)-1 H-benzimidazole
Figure imgf000714_0001
Example 987
2-methyl-1 -{(1 R,5S)-8-[2-(4-phenyl-1 -{[5-(trifluoromethyl)pyridin-2- yl]carbonyl}piperidin-4-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole
Figure imgf000714_0002
Example 988
1 -[(1 R,5S)-8-(2-{1 -[(4-ethyl-3-methoxyisoxazol-5-yl)acetyl]-4-phenylpiperidin-
4-yl}ethyl)-8-azabicyclo[3.2.1 ]oct-3-yl]-2-methyl-1 H-benzimidazole
Figure imgf000715_0001
Example 989
6-chloro-2-[(4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]imidazo[1 ,2- b]pyridazine
Figure imgf000715_0002
Example 990
3-{2-[(4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1]oct-
8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]piperidin-1-yl}propanenitrile
Figure imgf000716_0001
Example 991
2-[2-(4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-
8-yl]ethyl}-4-phenylpiperidin-1-yl)-2-oxoethyl]cyclohexanone
Figure imgf000716_0002
Example 992 ethyl 3,3-dimethyl-2-[(4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]butanoate
Figure imgf000717_0001
Example 993
4-methyl-7-[(4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]cinnoline
Figure imgf000717_0002
Example 994
1 -((1 R,5S)-8-{2-[1 -(2-isopropyl-4,5-dimethyl-3-furoyl)-4-phenylpiperidin-4- yl]ethyl}-8-azabicyclo[3.2.1 ]oct-3-yl)-2-methyl-1 H-benzimidazole
Figure imgf000718_0001
Example 995
N-{4-hydroxy-3-[(4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]phenyl}urea
Figure imgf000718_0002
Example 996
1-[(1 R,5S)-8-(2-{1-[2-(3-methoxyphenyl)-2-methylpropanoyl]-4- phenylpiperidin-4-yl}ethyl)-8-azabicyclo[3.2.1]oct-3-yl]-2-methyl-1 H- benzimidazole
Figure imgf000719_0001
Example 997
1 -methyl-4-[(4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]-1 ,3-dihydro-
2H-benzimidazol-2-one
Figure imgf000719_0002
Example 998 ,
2-(4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1]oct-8- yl]ethyl}-4-phenylpiperidin-1-yl)-2-oxoethanethioamide
Figure imgf000720_0001
Example 999
5-[(4-{2-[(1R,5S)-3-(2-methyl-1 H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8- yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]nicotinamide
Figure imgf000720_0002
Example 1000
2-methyl-1 -[(1 R,5S)-8-(2-{4-phenyl-1 -[(2,2,2-trifluoroethoxy)acetyl]piperidin-4- yl}ethyl)-8-azabicyclo[3.2.1]oct-3-yl]-1 H-benzimidazole
Figure imgf000721_0001
Example 1001 ethyl (1S,2S)-2-[(4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1 ]oct-8-yl]ethyl}-4-phenylpiperidin-1 - yl)carbonyl]cyclopropanecarboxylate
Figure imgf000721_0002
Example 1002
1-{(1 R,5S)-8-[2-(1-{[(1S,2R)-2-(4-chlorophenyl)cyclopropyl]carbonyl}-4- phenylpiperidin-4-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-2-methyl-1H- benzimidazole
Figure imgf000722_0001
Example 1003
N-[1 -cyclopropyl-2-(4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1 ]oct-8-yl]ethyl}-4-phenylpiperidin-1 -yl)-2-oxoethyl]acetamide
Figure imgf000722_0002
Example 1004
1 -{1 -[(4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1 ]oct-
8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]propyl}cyclohexanol
Figure imgf000723_0001
Example 1005
1-{(1 R,5S)-8-[2-(1-{[(1 R,2R)-2-(4-methoxyphenyl)cyclopropyl]carbonyl}-4- phenylpiperidin-4-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-2-methyl-1H- benzimidazole
Figure imgf000723_0002
Example 1006
2-(dimethylamino)-5-methyl-6-[(4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 - yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]pyrimidin-
4-ol
Figure imgf000724_0001
Example 1007
3-methyl-5-[(4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]pyrimidine-
2,4(1 H,3H)-dione
Figure imgf000724_0002
Example 1008
N-{1 -methyl-1 -[(4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1- yl)carbonyl]propyl}acetamide
Figure imgf000725_0001
Example 1009
1-{3-[(4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1]oct-
8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]pyridin-2-yl}ethanone
Figure imgf000725_0002
Example 1010
7-[2-(4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1 ]oct-
8-yl]ethyl}-4-phenylpiperidin-1-yl)-2-oxoethyl]octahydro-2H-indol-2-one 725
Figure imgf000726_0001
Example 1011
3-(4-(3-fluorophenyl)-4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1 ]oct-8-yl]ethyl}piperidin-1 -yl)-2,2-dimethyl-3-oxo-N-{[3-
(trifluoromethyl)phenyl]sulfonyl}propanamide
Figure imgf000726_0002
Synthesis of 2,2-dimethyl-3-oxo-3-({[3- (trifluoromethyl)phenyl]sulfonyl}amino)propanoic acid
Figure imgf000726_0003
2,2-dimethyl-3-oxo-3-({[3-(trifluoromethyl)phenyl]sulfonyl}amino)propanoic acid was prepared in the same manner as 2,2-dimethyl-3-oxo-3-
[(phenylsulfonyl)amino]propanoic acid starting from 3-
(trifluoromethyl)benzenesulfonyl chloride.
1HNMR (300MHz, Chloroform-D1) δ ppm 1.4 (m,6H) 5.1 (m,1 H) 7.9 (M, 1 H)
8.1 (m, 1H) 8.2 (m, 1 H) 8.3 (m, 1H) 10.0 (s, 1H), Electrospray LC-MS 362
(M+23)
Example 1012
3-(4-(3-fluorophenyl)-4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-1-yl)-2,2-dimethyl-3-oxo-N-
(phenylsulfonyl)propanamide
Figure imgf000727_0001
The synthesis of 2,2-dimethyl-3-oxo-3-[(phenylsulfonyl)amino]propanoic acid
Figure imgf000727_0002
Benzenesulfonamide was made by adding benzenesulfonyl chloride to a solution of ammonia in tetrahydrofuran and evaporating to a solid. Benzenesulfonamide (87 mg, .50 mmole) was added to a shaken suspension of 3-ethoxy-2,2-dimethyl-3-oxopropanoic acid (100 mg, .62 mmole) reactivated on PS-DCC resin (1.62 g, 1.25 mmole) and 1.50 mmole of N,N- dimethylpyridin-4-amine in DCE. When reaction is complete the resin is filtered off and the organic layer washed with 1 N HCl dried and evaporated. The resulting resadue was disolved in 6 ml of ethanol and 6 ml of 1N LiOH was added and heated to 40 C°. The reaction was neutralized with 1 N HCl and evaporated to afford 2,2-dimethyl-3-oxo-3-
[(phenylsulfonyl)amino]propanoic acid as a crude product which was used with no further purification.
1HNMR (300MHz, Chloroform-D1 ) δ ppm 1.4 (m, 6H) 4.9 (s, 1 H) 7.6 (m, 3H) 7.9 (m, 1H) 8.1 (m, 1H) 9.8 (s, 1 H), Electrospray LC-MS 180 (M+23).
Example 1013
3-(4-(3-fluorophenyl)-4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-1-yl)-2,2-dimethyl-3-oxo-N-{[4-
(trifluoromethyl)phenyl]sulfonyl}propanamide
Figure imgf000728_0001
The synthesis of 2,2-dimethyl-3-oxo-3-({[4- (trifluoromethyl)phenyl]sulfonyl}amino)propanoic acid
Figure imgf000729_0001
2,2-dimethyl-3-oxo-3-({[4-(trifluoromethyl)phenyl]sulfonyl}amino)propanoic acid was prepared in the same manner as 2,2-dimethyl-3-oxo-3- [(phenylsulfonyl)amino]propanoic acid starting from 4- (trifluoromethyl)benzenesulfonyl chloride.
1HNMR (300MHz, Chloroform-D1) δ ppm 1.4 (m,6H) 5.1 (s,1H) 7.8 (M, 2H) 8.1 (d, J=8.78 Hz, 1 H) 8.2 (d, J=9.0 Hz, 1 H) 9.9 (s, 1 H)
Example 1014
4-[(4-(3-fluorophenyl)-4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-1-yl)carbonyl]-1 ,2,5-thiadiazol-3-ol
Figure imgf000729_0002
Example 1015
1 -[(1 R,5S)-8-(2-{1 -[2-(1 H-imidazol-4-yl)-2-methylpropanoyl]-4-phenylpiperidin-
4-yl}ethyl)-8-azabicyclo[3.2.1]oct-3-yl]-2-methyl-1 H-benzimidazole
Figure imgf000730_0001
Using Method A (HATU) 2-(1H-imidazol-4-yl)-2-methylpropanoic acid and endo 2-methyl-1-{8-[2-(4-phenylpiperidin-4-yl)ethyl]-8-azabicyclo[3.2.1]oct-3- yl}-1 H-benzimidazole dihydrochloride were coupled to afford 1-[(1R,5S)-8-(2- {1-[2-(1H-imidazol-4-yl)-2-methylpropanoyl]-4-phenylpiperidin-4-yl}ethyl)-8- azabicyclo[3.2.1]oct-3-yl]-2-methyl-1 H-benzimidazole 11.8 mg 42% yeild. 1 H NMR (400 MHz, DMSO-D6) d ppm 1.2 (m, 1 H) 1.5 (m, 8 H) 1.7 (m, 8 H) 2.3 (m, 2 H) 2.5 (m, 3 H) 2.5 (m, 8 H) 3.2 (m, 2 H) 4.5 (m, 1 H) 7.1 (m, 10 H) 11.9 (m, 1 H) Electrospray LC-MS 565 (M+H)
Example 1016
4-methyl-8-[(4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]quinoline
Figure imgf000730_0002
Using Method A (HATU) 4-methylquinoline-8-carboxylic acid and endo 2- methyl-1-{8-[2-(4-phenylpiperidin-4-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1H- benzimidazole dihydrochloride were coupled to afford 4-methyl-8-[(4-{2-
[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1 ]oct-8-yl]ethyl}-
4-phenylpiperidin-1-yl)carbonyl]quinoline 14.8 mg 49% yeild.
1 H NMR (400 MHz, DMSO-D6) d ppm 1.7 (m, 10 H) 2.1 (m, 2 H) 2.3 (m, 6 H)
2.7 (m, 3 H) 2.9 (m, 1 H) 3.2 (m, 4 H) 3.6 (m, 1 H) 4.0 (m, 1 H) 4.5 (m, 1 H)
7.1 (m, 2 H) 7.2 (m, J=2.9 Hz, 1 H) 7.4 (m, 6 H) 7.5 (m, J=5.4 Hz, 1 H) 7.6 (m,
2 H) 8.2 (m, J=5.7, 2.1 Hz, 1 H) 8.7 (m, 1 H)
Electrospray LC-MS 598 (M+H)
Example 1017
4-[(4-{2-[(1R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1 ]oct-8- yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]-1 ,3-benzoxazol-2(3H)-one
Figure imgf000731_0001
Using Method A (HATU) 2-oxo-2,3-dihydro-1 ,3-benzoxazole-4-carboxylic acid and endo 2-methyl-1-{8-[2-(4-phenylpiperidin-4-yl)ethyl]-8- azabicyclo[3.2.1]oct-3-yl}-1 H-benzimidazole dihydrochloride were coupled to afford 4-[(4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]-1 ,3- benzoxazol-2(3H)-one 8.7 mg 30% yeild. 1 H NMR (400 MHz, DMSO-D6) d ppm 1.6 (m, 2 H) 1.8 (m, 9 H) 2.4 (m, 2 H)
2.4 (m, 3 H) 2.5 (m, 7 H) 3.2 (m, 3 H) 4.5 (m, 1 H) 7.2 (m, 5 H) 7.4 (m, 6 H)
7.5 (m, 1 H)
Electrospray LC-MS 590 (M+H)
Example 1018
7-[(4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1]oct-8- yl]ethyl}-4-phenylpiperidin-1 -yl)carbonyl]-1 H-1 ,2,3-benzotriazole
Figure imgf000732_0001
Using Method A (HATU) 1H-1 ,2,3-benzotriazole-7-carboxylic acid and endo 2- methyl-1-{8-[2-(4-phenylpiperidin-4-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1H- benzimidazole dihydrochloride were coupled to afford 7-[(4-{2-[(1R,5S)-3-(2- methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1 ]oct-8-yl]ethyl}-4- phenylpiperidin-1-yl)carbonyl]-1 H-1 ,2,3-benzotriazole 9.9 mg 34% yeild. 1 H NMR (400 MHz, DMSO-D6) d ppm 1.6 (m, 1 H) 1.8 (m, 8 H) 2.4 (m, 4 H) 2.5 (m, 8 H) 3.2 (m, 3 H) 4.0 (m, 1 H) 4.5 (m, 1 H) 7.1 (m, 2 H) 7.2 (m, 1 H) 7.4 (m, 8 H) 8.0 (m, 1 H) Electrospray LC-MS 574 (M+H) Example 1019
6-fluoro-7-[(4-(3-fluorophenyl)-4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 ■ yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-1-yl)carbonyl]-1 H-1 ,2,3- benzotriazole
Figure imgf000733_0001
Using Method A (HATU) 6-fluoro-1 - -1 ,2,3-benzotriazole-7-carboxylic acid and endo-1 -(8-{2-[4-(3-flourophenyl) piperidin-4-yl]ethyl}-8- azabicyclo[3.2.1]oct-3-yl)-2-methyl-1 H-benzimidazole dihydrochloride were coupled to afford 6-fluoro-7-[(4-(3-fluorophenyl)-4-{2-[(1 R,5S)-3-(2-methyl-1 H- benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-1-yl)carbonyl]- 1 H-1 ,2,3-benzotriazole 83.9 mg 62% yeild.
1 H NMR (400 MHz, METHANOL-D4) d ppm 1.7 (m, 1 H) 2.0 (m, 4 H) 2.4 (m, 4 H) 2.8 (m, 3 H) 3.4 (m, 13 H) 4.7 (m, 1 H) 7.2 (m, 10 H) 7.9 (m, 1 H) Electrospray LC-MS 610 (M+H)
Preparation of the ethyl 6-fluoro-1H-1 ,2,3-benzotriazole-7-carboxylate
Figure imgf000733_0002
ethyl 2,3-diamino-6-fluorobenzoate (1.00 g, 5.04 mmole) in 50 ml of water and 10 ml acetic acid was cooled to -10 C°. To this solution was added dropwise sodium nitrite (348 mg, 5.04 mmole) in 30 ml of water. After the-addition the reaction was warmed to 0 C° for 30 min, then to room temperature for 1 hr, and finally 50 C° for 1 hr. The reaction was filtered after stirring over night and washed with water. The dark brownish purple solid was disoved in ethylacetate dried over magnesium sulfate and evaporated to afford ethyl 6- fluoro-1H-1 ,2,3-benzotriazole-7-carboxylate (920 mg, 87% yield) 1 H NMR (400 MHz, METHANOL-D4) D ppm 1.3 (t, J=7.1 Hz, 3 H) 4.4 (q, J=7.0 Hz, 2 H) 7.2 (dd, .7=11.2, 9.0 Hz, 1 H) 8.1 (dd, J=9.1 , 4.1 Hz, 1 H)
Preparation of the 6-fluoro-1 - -1 ,2,3-benzotriazole-7-carboxylic acid
Figure imgf000734_0001
ethyl 6-fluoro-1H-1 ,2,3-benzotriazole-7-carboxylate (920 mg) was heated in 6N HCl untill all of the starting material disappeared. Evaporation of the HCl afforded 718 mg of a brownish solid.
1 H NMR (300 MHz, DMSO-D6) D ppm 7.4 (dd, J=11.2, 9.0 Hz, 1 H) 8.3 (dd, -7=9.1 , 4.1 Hz, 1 H)
Example 1020
5-fluoro-4-[(4-(3-fluorophenyl)-4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 ■ yl)-8-azabicyclo[3.2.1 ]oct-8-yl]ethyl}piperidin-1 -yl)carbonyl]-1 ,3-benzoxazol-
2(3H)-one
Figure imgf000735_0001
Using Method A (HATU) 5-fluoro-2-oxo-2,3-dihydro-1 ,3-benzoxazole-4- carboxylic acid and endo-1 -(8-{2-[4-(3-flourophenyl) piperid in-4-yl]ethyl}-8- azabicyclo[3.2.1]oct-3-yl)-2-methyl-1 H-benzimidazole dihydrochloride were coupled to afford 5-fluoro-4-[(4-(3-fluorophenyl)-4-{2-[(1 R,5S)-3-(2-methyl-1 H- benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-1-yl)carbonyl]- 1 ,3-benzoxazol-2(3H)-one. 1 H NMR (300 MHz, METHANOL-D4) d ppm 1.4 (d, J=6.5 Hz, 1 H) 1.8 (m, 3 H) 2.0 (m, 8 H) 2.2 (m, 3 H) 2.5 (m, 3 H) 3.0 (m, 3 H) 3.5 (m, 4 H) 4.2 (m, 1 H) 7.0 (m, 2 H) 7.3 (m, 7 H) 7.6 (m, 1 H) 8.0 (m, 1 H) Electrospray LC-MS 626(M+H)
Preparation of 2-amino-6-fluoro-3-hydroxybenzoic acid
Figure imgf000735_0002
2-amino-6-fluorobenzoic acid (5.00 g, 32.2 mmole) was dissolved in 30 ml of 2N sodium hydroxide. To this was added dropwise a solution of sodium persulfate (7.67 g, 32.2 mmole) in 80 ml of water. After stirring over night the resulting black solution was extracted with 2 L of ether and 1 L of ethylacetate. Evaporation of the water gave a black solid that was used with no purification. 1 H NMR (400 MHz, DMSO-D6) D ppm 6.2 (dd, J=11.5, 8.6 Hz, 1 H) 6.7 (dd,
J=8.6, 4.9 Hz, 1 H)
LC-MS
5-fluoro-2-oxo-2,3-dihydro-1 ,3-benzoxazole-4-carboxylic acid
Figure imgf000736_0001
To a THF solution of 2-amino-6-fluoro-3-hydroxybenzoic acid (520 mg, 3.04 mmole) and n,n-diisopropylethylamine (942 mg, 7.29 mmole) was added bis(trichloromethyl) carbonate (1.08 g, 3.64 mmole) and stirred. Removal of solvent under vacuum afforded a residue, which was run on reversephase flash chromatography 10 to 90% acetonitrile water (0.01% TFA). The resulting fractions were evaporated. APCI LC-MS 196 (M-H) 198 (M+H)
Examples below were synthesized as follows.
Method AA. Synthesis of functional ized carboxamide carboxylic acids via amination of cyclic anhydrides (Acids 69-79 and 97-153). 1 mmol of anhydride was treated with 10mmol of either a 0.5M solution of NH3 in Dioxane or a 2M solution of either methylamine, ethylamine, isopropylamine or cyclopropylamine in THF at 40°C in a sealed tube for 72h. The reaction mixtures were concentrated to remove solvent and excess amine to give the crude carboxamide carboxylic acid as the salt of the corresponding amine. Crude materials were used without further purification or characterization in the subsequent coupling reaction to generate final compounds.
Figure imgf000737_0001
Method BB. Synthesis of benzimidazole carboxylic acids (Acids 65-68, 88, and 89 )
Step 1 : 50mmol of an appropriately substituted 2-amino-3-nitrobenzoic acid ester in 250mL of EtOH/EtOAc (1 :1) was treated with 980mg of 10%Pd/C and H2(g) (1atm) at ambient temperature for 16h. The catalyst was filtered off and the filtrate concentrated to give the corresponding dianiline as a crystaline solid in quantitative yield. The crude material was carried on to either step 2A or 2B without further purification.
Step 2A: 5.6mmol of the dianiline was treated with 15mL of either triethyl orthoacetate or triethyl orthoformate at 120°C for 16h. The reaction mixture was concentrated to dryness to give the corresponding benzimidazole as a crystaline solid that was carried on to step 3 without further purification. Step2B: Alternatively, 6.0mmol of dianiline was treated with 6.3mmol BrCN in 15mL CH3OH at reflux for 3h. The reaction mixture was cooled to ambient temperature and precipitate was filtered off to give the corresponding 2- aminobenzimidazole.
Step 3: Benzimidazoles obtained from steps 2A and 2B were treated with 6N HCl at 80°C for 8h. The reaction mixtures were concentrated to dryness to give the benzimidazole carboxylic acids which were used without purification in coupling reactions to yield final compounds.
Figure imgf000737_0002
Method CC. Synthesis of carboxamide carboxylic acids by amination of dimethyl malonate (Acids 90-96).
Step 1 : Diethyl dimethylpropanedioate (10g, 53mmol) in 170mL EtOH was treated with 3.00g (53mmol) KOH at ambient temperature for 4 days. The reaction mixture was concentrated to dryness and partitioned between EtOAc and water. The aqueous phase was isolated, combined with fresh EtOAc and the pH adj to 2 with 6N HCl. The organic phase was isolated and the aqueous portion extracted twice with EtOAc. The organic phases were combined, dried over MgSO4, filtered and concentrated to give 6.56g (41 mmol) 3-(ethyloxy)-2,2-dimethyl-3-oxopropanoic acid as a clear oil. 1 H NMR (300 MHz, CDCI3) d 4.20 (q. J=7.1Hz, 2H). 1.46(s, 6H). 1.26ft. .7=7.1 Hz. 3H).
Step 2: 400mg (2.50mmol) ) 3-(ethyloxy)-2,2-dimethyl-3-oxopropanoic acid dissolved in 4mL THF was treated with 1 ,1'-carbonyldiimidazole (405mg, 2.50mmol) at ambient temperature until CO2 evolution ceased (~20min). To this solution was added 7.50mmol (3eq) of either ammonia, methylamine, ethylamine, 2-amino-2-methyl-1 -propanol, cyclopropylamine, isopropylamine, 2-propen-1-ylamine, or N,N-dimethylamine. The reaction mixtures were shaken gently at ambient temperature for 16h, concentrated to dryness, partitioned between DCE (8mL) and 0.5N HCl (10mL), shaken vigorously , organic phases isolated, dried over MgSO4 filtered and concentrated to dryness. Identity of these carboxamide ester intermediates was confirmed by 1 H NMR.
Step 3: The carboxamide esters so obtained were treated with 2.5mL (2.5mmol ) of 1 N LiOH in 2.5mL EtOH at ambient temperature for 16h. The reaction mixtures were concentrated to dryness and used in coupling reations without further purification or characterization.
Figure imgf000738_0001
Method DD: Synthesis of carboxamide carboxylic acids from iodobenzoic acids or ester carboxylic acids (Acids 80-86) as exemplified by synthesis of 3- [({[2,4-bis(methyloxy)phenyl]methyl}amino)carbonyl]-4-chlorobenzoic acid (Acid 84).
Step 1 : 2-Chloro-5-iodobenzoic acid (2g , 7.08mmol) in 25mL THF was treated with 1 ,1'-carbonyldiimidazole (1.15g , 7.08mmol) at ambient temperature until CO2 evolution ceased (~20min). 2,4- Dimethoxybenzylamine (1.18g, 7.08mmol) was added and stirred at ambient temperature for 16h. The reaction mixture was concentrated to dryness, partitioned between EtOAc and saturated NaHCO3, the organic phase isolated, dried over MgSO4, filtered and concentrated to give Λ/-{[2,4- bis(methyloxy)phenyl]methyl}-2-chloro-5-iodobenzamide (3.00g, 6.95mmol) as a pale yellow oil that crystallized on standing. 1 H NMR (300 MHz, CDCI3) d 7.95(d, J=2.2Hz, 1 H), 7.62(dd, J=8.5, 2.2Hz, 1 H), 7.25(m, 1 H), 7.10 (m, 1 H), 6.63(m, 1 H), 6.45 (m, 2H), 4.55(d, J=5.7 Hz, 2H), 3.83(s, 3H), 3.80(s, 3H). LCMS ES+ 431.82, 433.77 (M+H).
Step 2: /V-f[2,4-bis(methvloxv)phenvl1methvl}-2-chloro-5-iodobenzamide (2.78g, 6.44mmol) dissolved in 100mL CH3OH with dicyclohexylamine (3.85mL, 19mmol) was treated with POPd2 catalyst (AC2000) under an atmosphere of CO(g) at 1atm pressure and ambient temperature for 3 days. The catalyst was filtered off and the filtrate concentrated to a small volume, cooled in ice bath, and the resultant precipitate filtered off. A second crop was obtained from the mother liquor and the two batches were combined to give methyl 3-[({[2,4-bis(methyloxy)phenyl]methyl}amino)carbonyl]-4- chlorobenzoate (2.26g, 6.21 mmol) as a white crystaline solid. 1H NMR (300 MHz, DMSO-D6) d 8.82(m, 1 H), 7.96(dd, J=8.3, 2.2Hz, 1 H), 7.91 (m, 1 H), 7.65(d, J=8.3Hz, 1H), 7.19(d, J=8.2Hz, 1H), 6.56 (d, J=2.5Hz, 1H), 6.51 (dd, j=8.3, 2.5Hz, 1 H), 4.34(d, J=5.9Hz, 2H), 3.86(s, 3H), 3.79(s, 3H), 3.74(s, 3H). LCMS ES+ 363.99, 365.97(M+H).
Step 3: Methyl 3-[({[2,4-bis(methyloxy)phenyl]methyl}amino)carbonyl]-4- chlorobenzoate (600mg, 1.65mmol) dissolved in 17mL CH3OH was treated with 16.5mL 1N LiOH at ambient temperature for 16h. The reaction mixture was concentrated to dryness, partitioned between EtOAc and water, the aqueous phase isolated and the pH adjusted to 2 with 6N HCl. The resultant precipitate was cooled in an ice bath with stirring, filtered, and washed with water to give 3-[({[2,4-bis(methyloxy)phenyl]methyl}amino)carbonyl]-4- chlorobenzoic acid (533mg, 1.52mmol) as a white crystaline solid. 1 H NMR (300 MHz, DMSO-D6) d ppm 8.96(m, 1 H), 8.29(d, J=2.2 Hz, 1 H), 8.00(dd, J=8.4, 2.3 Hz, 1 H), 7.65(d, J=8.3 Hz, 1 H), 7.09(d, J=8.3 Hz, 1 H), 6.55(d, J=2.3 Hz, 1 H), 6.50(dd, J=8.3, 2.3 Hz, 1 H), 4.35(d, J=5.6 Hz, 1 H), 3.79(s, 3H), 3.73(s, 3H). LCMS ES+ 349.88, 351.91 (M+H).
Figure imgf000740_0001
Acids 80-83 were synthesized in an analogous fashion from the appropriately substituted iodobenzoic acid and the appropriate amine. Acids 85, 86, and 154 were synthesized from diethyl dimethylpropanedioate, diethyl diethylpropanedioate, or diethyl 1 ,1-cyclobutanedicarboxylate , respectively, and 2,4-Dimethoxybenzylamine using Method CC, step 1 and Method DD steps 1 and 3.
The table below lists acids 55-154, their properties, method of their synthesis as well as yields.
Figure imgf000740_0002
Figure imgf000741_0001
Figure imgf000742_0001
Figure imgf000743_0001
Figure imgf000744_0001
Figure imgf000745_0001
Figure imgf000746_0001
Figure imgf000747_0001
Figure imgf000748_0001
748
Figure imgf000749_0001
Figure imgf000750_0001
Figure imgf000751_0001
Figure imgf000752_0001
Figure imgf000753_0001
Figure imgf000754_0001
Figure imgf000755_0001
Figure imgf000756_0001
Figure imgf000757_0001
O 2004/054
757
Figure imgf000758_0002
The following examples were prepared using acids described elsewhere in this invention
Figure imgf000758_0001
Figure imgf000759_0001
Figure imgf000760_0001
O 2004
760
Figure imgf000761_0001
Figure imgf000762_0001
Figure imgf000763_0001
Figure imgf000764_0001
Figure imgf000765_0001
Figure imgf000766_0001
Figure imgf000767_0001
Figure imgf000768_0001
Figure imgf000769_0001
Figure imgf000770_0001
Figure imgf000771_0001
Figure imgf000772_0002
Figure imgf000772_0001
4-chloro-3-[(4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]benzamide. 1H NMR (300 MHz, CD3OD) δ 7.96-7.07(m, 12H), 4.75(m, 1H), 4.21 (m, 1H), 3.90-3.10(m, 6H), 2.53 (s, 3H), 2.50-1.68 (m, 15H).
Figure imgf000773_0001
4-methyl-3-{[4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-(3-methylphenyl)-1- piperidinyl]carbonyl}benzamide. . 1H NMR (300 MHz, CD3OD) δ 7.96-7.07(m, 11 H), 4.75(m, 1H), 4.31 -4.15(m, 1 H), 3.91 -3.10(m, 6H), 2.53 (s, 3H), 2.50- 1.68 (m, 15H), 2.43(s, 1.5H), 2.38 (s, 3H), 2.25(s, 1.5H).
Example 1023
Figure imgf000773_0002
4-chloro-3-{[4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-(3-methylphenyl)-1- piperidinyl]carbonyl}benzamide. 1H NMR (300 MHz, CD3OD) δ 7.96-7.07(m, 11 H), 4.75(m, 1H), 4.22 (m, 1 H), 3.80-3.16(m, 6H), 2.53 (s, 3H), 2.50-1.68 (m, 15H), 2.38 (s, 3H).
Figure imgf000773_0003
2,2-dimethyl-3-[4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-4-(3-methylphenyl)-1-piperidinyl]-3- oxopropanamide. 1H NMR (300 MHz, CD3OD) δ 7.55-7.06(m, 8H), 4.77(m, 1H), 4.02 (m, 1H), 3.89-3.17(m, 6H), 2.67-1.68 (m, 21 H), 2.56 (s, 3H), 2.37 (s, 3H).
Example 1025
Figure imgf000774_0001
2-chloro-N-cyclopropyl-4-fluoro-5-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2- methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1 ]oct-8-yl]ethyl}-1 - piperidinyl)carbonyl]benzenesulfonamide. 1H NMR (300 MHz, CD3OD) D ppm 8.18(m, 1H), 7.67(d, J=8.8Hz, 1H), 7.58(m, 1H), 7.47(m, 2H), 7.30(s, 1H), 7.29-7.20(m, 3H), 7.05(m, 1H), 4.79(m, 1H), 4.21 (m, 1H), 3.60-3.25(m, 8H), 2.59(s, 3H), 2.52-1.70(m, 15H), 0.56(m, 4H).
Example 1026
Figure imgf000774_0002
2-chloro-4-fluoro-5-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H- benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]-N- methylbenzenesulfonamide. 1H NMR (300 MHz, CD3OD) D ppm 8.09(m, 1H), 7.60(d, J=8.8Hz, 1 H), 7.53(m, 1H), 7.40(m, 2H), 7.25-7.16(m, 4H), 7.00(m, 1 H), 4.75(m, 1 H), 4.16(m, 1 H), 3.53-3.18(m, 8H), 2.55(d, J=9.3Hz, 3H), 2.52- 1.70(m, 16H). Example 1027
H1CJ ;Sγo v,N'
2-chloro-4-fluoro-5-[(4-(3-fluorophenyl)-4-{2-[(1 R,5S)-3-(2-methyl-1 H- benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]-N- (l-methylethyl)benzenesulfonamide. 1H NMR (300 MHz, CD3OD) D ppm 8.11(m, 1 H), 7.60(d, J=8.8Hz, 1H), 7.53(m, 1H), 7.40(m, 2H), 7.25-7.16(m, 4H), 7.00(m, 1 H), 4.74(m, 1 H), 4.17(m, 1 H), 3.53-3.18(m, 8H), 2.53(s, 3H), 2.52-1.70(m, 14H), 1.07 (d, J=6.5Hz, 6H).
Example 1028
Figure imgf000775_0001
2-chloro-4-fluoro-5-[(4-(3-fluorophenyl)-4-{2-[(1 R,5S)-3-(2-methyl-1 H- benzimidazol-1 -yl)-8-azabicyclo[3.2.1 ]oct-8-yl]ethyl}-1 -piperidinyl)carbonyl]-N- (2,2,2-trifluoroethyl)benzenesulfonamide. 1H NMR (300 MHz, CD3OD) D ppm 8.10(m, 1 H), 7.60(d, J=8.8Hz, 1 H), 7.51 (m, 1 H), 7.40(m, 2H), 7.25-7.16(m, 4H), 7.00(m, 1 H), 4.73(m, 1 H), 4.16(m, 1 H), 3.77 (q, J=9.4 Hz, 2 H), 3.53- 3.18(m, 8H), 2.53(s, 3H), 2.52-1.68(m, 13H).
Example 1029
Figure imgf000775_0002
2-chloro-N-(1 , 1 -dimethylethyl)-4-fluoro-5-[(4-(3-fluorophenyl)-4-{2-[(1 R,5S)-3- (2-methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1- piperidinyl)carbonyl]benzenesulfonamide. 1H NMR (300 MHz, CD3OD) D ppm 8.10(m, 1 H), 7.58(d, J=8.8Hz, 1 H), 7.51 (m, 1H), 7.40(m, 2H), 7.25-7.16(m, 4H), 7.00(m, 1 H), 4.74(m, 1 H), 4.17(m, 1 H), 3.53-3.18(m, 8H), 2.53(s, 3H), 2.52-1.69(m, 13H), 1.20(s, 9H).
Example 1030
Figure imgf000776_0001
2-chloro-N-cyclopentyl-4-fluoro-5-[(4-(3-fluorophenyl)-4-{2-[(1 R,5S)-3-(2- methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1 ]oct-8-yl]ethyl}-1 - piperidinyl)carbonyl]benzenesulfonamide. H NMR (300 MHz, CD3OD) D ppm 8.11(m, 1 H), 7.60(d, J=8.8Hz, 1 H), 7.51 (m, 1 H), 7.40(m, 2H), 7.25-7.16(m, 4H), 7.00(m, 1H), 4.72(m, 1H), 4.16(m, 1H), 3.57-3.18(m, 8H), 2.53(s, 3H), 2.52-1.39(m, 22H).
Example 1031
Figure imgf000776_0002
-fluorophenyl)-4-{2-[(1 R,5S)-3-(2-methyl-1 H- benzimidazol-1 -yl)-8-azabicyclo[3.2.1 ]oct-8-yl]ethyl}-1 - piperidinyl)carbonyl]benzenesulfonamide. 1H NMR (300 MHz, CD3OD) D ppm 8.10(m, 1 H), 7.58(d, J=9.0Hz, 1 H), 7.51 (m, 1H), 7.40(m, 2H), 7.25-7.16(m, 4H), 7.00(m, 1 H), 4.73(m, 1 H), 4.16(m, 1 H), 3.52-3.19(m, 8H), 2.53(s, 3H), 2.52-1.69(m, 13H). Example 1032
Figure imgf000777_0001
2-chloro-N-ethyl-4-fluoro-5-[(4-(3-fluorophenyl)-4-{2-[(1 R,5S)-3-(2-methyl-1 H- benzimidazol-1 -yl)-8-azabicyclo[3.2.1 ]oct-8-yl]ethyl}-1 - piperidinyl)carbonyl]benzenesulfonamide. 1H NMR (300 MHz, CD3OD) D ppm 8.09(m, 1 H), 7.59(d, J=9.1 Hz, 1 H), 7.51 (m, 1 H), 7.40(m, 2H), 7.25- 7.16(m, 4H), 7.00(m, 1 H), 4.74(m, 1 H), 4.16(m, 1 H), 3.52-3.19(m, 8H), 2.97(q, J=7.2Hz, 2H), 2.53(s, 3H), 2.52-1.69(m, 13H), 1.06(t, J=7.2Hz, 3H).
Example 1033
Figure imgf000777_0002
N-cyclopentyl-4-fluoro-3-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H- benzimidazol-1 -yl)-8-azabicyclo[3.2.1 ]oct-8-yl]ethyl}-1 - piperidinyl)carbonyl]benzenesulfonamide. 1H NMR (300 MHz, CD3OD) D ppm 7.98(m, 1 H), 7.88(m, 1H), 7.53(m, 1H), 7.41 (m, 3H), 7.25-7.16(m, 4H), 7.00(m, 1H), 4.73(m, 1H), 4.17(m, 1H), 3.60-3.18(m, 8H), 2.52(s, 3H), 2.52- 1.34(m, 22H).
Example 1034
Figure imgf000777_0003
N-(1 ,1-dimethylethyl)-4-fluoro-3-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl- 1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1 ]oct-8-yl]ethyl}-1 - piperidinyl)carbonyl]benzenesulfonamide. 1H NMR (300 MHz, CD3OD) D ppm 8.01(m, 1 H), 7.89(m, 1H), 7.52(m, 1 H), 7.40(m, 3H), 7.25-7.16(m, 4H), 7.00(m, 1H), 4.74(m, 1H), 4.17(m, 1H), 3.52-3.17(m, 8H), 2.53(s, 3H), 2.52- 1.68(m, 13H), 1.19(s, 9H).
Example 1035
Figure imgf000778_0001
1 -[(1 R,5S)-8-(2-{4-(3-fluorophenyl)-1 -[(2-methyl-1 H-benzimidazol-4- yl)carbonyl]-4-piperidinyl}ethyl)-8-azabicyclo[3.2.1]oct-3-yl]-2-methyl-1H- benzimidazole. 1H NMR (300 MHz, CD3OD) D ppm 8.01-6.94(m, 11 H), 4.90- 4.72(m, 1 H), 3.97(m, 1H), 3.70-3.16(m, 8H), 2.65(s, 3H), 2.55(s, 3H), 2.46- 1.38(m, 14H).
Example 1039
Figure imgf000778_0002
2-[(4-(3-fluorophenyl)-4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1 ]oct-8-yl]ethyl}-1 - piperidinyl)carbonyl]cyclopropanecarboxamide. 1H NMR (300 MHz, CD3OD) D ppm 7.53(m, 1 H), 7.40(m, 2H), 7.25-7.14(m, 4H), 6.98(m, 1H), 4.74(m, 1H), 4.11-3.79(m, 2H), 3.52-3.29(m, 7H), 3.08(m, 1 H), 2.55(s, 3H), 2.52-1.17(m, 16H). Example 1040
Figure imgf000779_0001
2-[(4-(3-fluorophenyl)-4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1 ]oct-8-yl]ethyl}-1 -piperidinyl)carbonyl]-1 -cyclopentene-1 - carboxamide. 1H NMR (300 MHz, CD3OD) D ppm 7.53(m, 1 H), 7.41 (m, 2H), 7.25-7.14(m, 4H), 6.97(m, 1 H), 4.74(m, 1H), 4.0(m, 1 H), 3.55(m, 1 H), 3.35- 3.20(m, 5H), 3.00(m, 1 H), 2.54(s, 3H), 2.80-1.17(m, 20H).
Example 1041
Figure imgf000779_0002
5-(4-(3-fluorophenyl)-4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)-3,3-dimethyl-5-oxopentanamide. 1H NMR (300 MHz, CD3OD) D ppm 7.50(m, 1 H), 7.40(m, 2H), 7.25-7.16(m, 4H), 6.98(m, 1 H), 4.74(m, 1 H), 4.00(m, 1 H), 3.83(m, 1 H), 3.42-1.68(m, 24H), 2.55(s, 3H), 1.10(d, J=3.8Hz, 6H). Example 1042
Figure imgf000780_0001
3-[(4-(3-fluorophenyl)-4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1 ]oct-8-yl]ethyl}-1 -piperidinyl)carbonyl]-2-pyrazinecarboxamide. 1H NMR (300 MHz, CD3OD) D ppm 8.78(d, J=2.5Hz, 1 H), 8.73(d, J=2.5Hz, 1 H), 7.52(m, 1 H), 7.40(m, 2H), 7.25-7.16(m, 4H), 6.98(m, 1 H), 4.74(m, 1H), 4.15(m, 1 H), 3.46-1.68(m, 21 H), 2.52(s, 3H).
Example 1043
Figure imgf000780_0002
2-[(4-(3-fluorophenyl)-4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1 ]oct-8-yl]ethyl}-1 - piperidinyl)carbonyl]cyclobutanecarboxamide. 1H NMR (300 MHz, CD3OD) D ppm 7.52(m, 1 H), 7.40(m, 2H), 7.25-7.16(m, 4H), 6.97(m, 1H), 4.73(m, 1H), 4.15-1.68(m, 28H), 2.55(s, 3H).
Figure imgf000780_0003
N-cyclopropyl-5-(4-(3-fluorophenyl)-4-{2-[(1 R,5S)-3-(2-methyl-1H- benzimidazol-1 -yl)-8-azabicyclo[3.2.1 ]oct-8-yl]ethyl}-1 -piperidinyl)-4,4- dimethyl-5-oxopentanamide. 1H NMR (300 MHz, CD3OD) D ppm 7.52(m, 1 H), 7.40(m, 2H), 7.25-7.12(m, 4H), 6.96(m, 1 H), 4.75(m, 1H), 3.98(m, 1H), 3.36- 1.68(m, 28H), 2.55(s, 3H).
Example 1050
Figure imgf000781_0001
{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]-N-methylbenzamide. 1H NMR (300 MHz, CD3OD) D ppm 7.85(m, 1 H), 7.84(m, 1 H), 7.55(m, 3H), 7.40(m, 2H), 7.26-7.16(m, 4H), 7.00(m, 1 H), 4.73(m, 1 H), 4.13(m, 1 H), 3.58(m, 1 H), 3.46-1.68(m, 20H), 2.91 (s, 3H), 2.51 (s, 3H).
Example1051
Figure imgf000781_0002
2-ethyl-2-[(4-(3-fluorophenyl)-4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 ■ yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]butanamide. 1H NMR (300 MHz, CD3OD) δ 7.52(m, 1 H), 7.41 (m, 2H), 7.26-7.16(m, 4H), 6.98(m, 1H), 4.74(m, 1H), 3.97 (m, 1H), 3.67 (m, 1 H), 3.34-3.21 (m, 5H), 2.55(s, 3H), 2.41 (m, 2H), 2.22(m, 2H), 2.03-1.69(m, 15H),0.80(m, 6H). Example 1168
Preparation of
1 -(4-(1 ,3-benzodioxol-5-yl)-4-(2-lϊ1 R.5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicvclo 3.2.1loct-8-vnethyl)piperidin-1-yl)-2-methyl-1-oxopropan-2-ol
Figure imgf000782_0001
A mixture of 1-(8-{2-[4-(1 ,3-benzodioxol-5-yl)piperidin-4-yl]ethyl}-8- azabicyclo[3.2.1]oct-3-yl)-2-methyl-1 H-benzimidazole dihydrochloride (0.20 g, 0.39 mmol), triethylamine (0.17 mL, 1.25 mmol) and 2-hydroxyisobutyric acid (41 mg, 0.39 mmol) in dimethylformamide (1.25 mL) was treated with O-(7- azabenzotriazol-1-yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate (163 mg, 0.43 mmol) and the resulting mixture was stirred for 1 h at rt. The mixture was diluted with water and the resulting precipitate was collected, washed with saturated sodium bicarbonate solution, with water, dried and purified by chromatography on silica gel eluting with a dichloromethane to methanol- dichloromethane 1 :19 gradient to give 1 -(4-(1 ,3-benzodioxol-5-yl)-4-{2- [(1R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1]oct-8- yl]ethyl}piperidin-1-yl)-2-methyl-1-oxopropan-2-ol as a solid (0.1 Og, 44%). HRMS C33H42N4O4 m/z 559.3284 (M+H)Caι. 559.3276 (M+H)0bs..
Example 1169 Preparation of 1 -((1 R.5S)-8 2-\4-(1 ,3-benzodioxol-5-vn-1 -isobu tvιNlpiperidin-4-vnethyll-8- azabicvclof3.2.noct-3-vπ-2-methyl-1 H-benzimidazole 782
Figure imgf000783_0001
A mixture of 1-(8-{2-[4-(1,3-benzodioxol-5-yl)piperidin-4-yl]ethyl}-8- azabicyclo[3.2.1]oct-3-yl)-2-methyl-1 H-benzimidazole dihydrochloride (0.20 g, 0.39 mmol), triethylamine (0.17 mL, 1.25 mmol) and isobutyric acid (34 mg, 0.39 mmol) in dimethylformamide (1.25 mL) was treated with O-(7- azabenzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate (163 mg, 0.43 mmol) and the resulting mixture was stirred for 1 h at rt. The mixture was diluted with water and the resulting precipitate was collected, washed with saturated sodium bicarbonate solution, with water and dried to give 1- ((1 ,5S)-8-{2-[4-(1 ,3-benzodioxol-5-yl)-1 -isobutyrylpiperidin-4-yl]ethyl}-8- azabicyclo[3.2.1]oct-3-yl)-2-methyl-1 H-benzimidazole as a solid (0.15g, 72%). HRMS C33H42N4O3 m/z 543.3335 (M+H)Caι. 543.3322 (M+H)0bs,
Example 1170
Preparation of
3-(4-(1.3-benzodioxol-5-yl)-4-(2-r(1 5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicvclor3.2.11oct-8-vπethyl|piperidin-1 -yl)-2.2-dimethyl-3-oxopropan-1 -ol
Figure imgf000784_0001
A mixture of 1-(8-{2-[4-(1 ,3-benzodioxol-5-yl)piperidin-4-yl]ethyl}-8- azabicyclo[3.2.1]oct-3-yl)-2-methyl-1 H-benzimidazole dihydrochloride (0.20 g, 0.39 mmol), triethylamine (0.17 mL, 1.25 mmol) and 2,2-dimethyl-3- hydroxypropionic acid (46 mg, 0.39 mmol) in dimethylformamide (1.25 mL) was treated with O-(7-azabenzotriazol-1-yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate (163 mg, 0.43 mmol) and the resulting mixture was stirred for 1 h at rt. The mixture was diluted with water and the resulting gummy precipitate was dissolved in dichloromethane, washed with saturated sodium bicarbonate solution, with water, dried and purified by chromatography on silica gel eluting with a dichloromethane to methanol- dichloromethane 1 :9 gradient to give 3-(4-(1 ,3-benzodioxol-5-yl)-4-{2- [(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1 ]oct-8- yl]ethyl}piperidin-1-yl)-2,2-dimethyl-3-oxopropan-1-ol as a solid (0.13g, 59%). 1H NMR (400 MHz, CDCI3) δ 7.66 (m, 1 H), 7.29 (m, 1 H), 7.15 (m, 2H), 6.80 (m, 2H), 6.73 (m, 1 H), 5.97 (s, 2H), 4.62 (m, 1 H), 3.92 (m, 2H), 3.75 (m, 1 H), 3.46 (s, 2H), 3.26 (m, 4H), 2.57 (s, 3H), 2.38 (m, 2H), 2.14 (m, 2H), 1.91 - 2.00 (m, 6H), 1.70 - 1.78 (m, 4H), 1.64 (m, 2H), 1.25 (s, 6H). HRMS C34H44N4O4 m/z 573.3441 (M+H)Caι. 573.3428 (M+H)0bs,
Example 1171
Λ/-(4-chloro-3-r(4-(3-fluorophenvn-4-(2-r3-(2-methyl-1H-benzimidazol-1- yl)-8-azabicvclo 3.2.noct-8-yllethyl)piperidin-1-yl)carbonyllphenyl)-1.1 ,1- trifluoromethanesulfonamide.
Figure imgf000785_0001
a) Preparation of methyl 5-amino-2-chlorobenzoate.
Figure imgf000785_0002
To a solution of 5-amino-2-chlorobenzoic acid (6.0 g, 35 mmol) in anhydrous methanol (100 ml) was added dropwise thionyl chloride (15 ml) with stirring under a nitrogen atmosphere. After stirring for 3 hours the volatiles were removed by spin evaporation in vacuo and the residue was dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate and then water. The organic layer was concentrated by spin evaporation in vacuo with the addition of dichloromethane (3 times) to give methyl 5-amino-2-chlorobenzoate as a white solid (6.2 g, 95%). 1 H-NMR (400 MHz, DMSO-c/e): δ 7.20-7.14 (m, 1 H), 7.13-7.02 (m, 1 H), 6.73-6.67 (m. 1 H), 3.89 (s, 3H). ES-LCMS m/z 186 (M+H).
b) Preparation of methyl 2-chloro-5- {[(trifluoromethyl)sulfonyl]amino}benzoate.
Figure imgf000786_0001
Triflic anhydride (1.53 g, 5.39 mmol) was added dropwise to a solution of methyl 5-amino-2-chlorobenzoate (2.0 g, 10.8 mmol) in dichloromethane (35 ml) at 0 °C while stirring under a nitrogen atmosphere. After warming to room temperature over 1 hour, the thick slurry was diluted with additional dichloromethane (200 ml) and washed with aqueous 1 N hydrochloric acid and then water. The dichloromethane layer was dried with MgSO4 and the volatiles were removed by spin evaporation in vacuo to give methyl 2-chloro- 5-{[(trifluoromethyl)sulfonyl]amino}benzoate as a tan oil (1.7 g, 100%). 1H- NMR (400 MHz, DMSO-c/6): δ 9.43 (s, 1H), 7.55-7.18 (m, 5H), 3.92-3.82 (m, 2H), 3.31-3.18 (m, 2H), 2.40-1.92 (m, 4H), and 1.38 (s, 9H). ES-LCMS m/z 317 (M+H).
c) Preparation of2-chloro-5-{[(trifluoromethyl)sulfonyl]amino}benzoic acid.
Figure imgf000786_0002
A solution of methyl 2-chloro-5- {[(trifluoromethyl)sulfonyl]amino}benzoate (1.0 g, 3.15 mmol), sodium hydroxide (378 mg, 9.44 mmol), methanol (6 ml) and water (6 ml) was stirred for 1 hour. Removal of the volatiles by spin evaporation in vacuo gave a residue that was dissolved in 1 N aqueous hydrochloric acid. The aqueous solution was extracted with ethyl acetate (3 times) and the organic layers were combined, washed with water, and concentrated by spin evaporation in vacuo to give 2-chloro-5-{[(trifluoromethyl)sulfonyl]amino}benzoic acid as a crystalline solid (0.78 g, 82%). 1H-NMR (400 MHz, DMSO-c/e): δ 7.63-7.60 (m, 1H), 7.59-7.54 (m, 1H), 7.40-7.35 (m, 1H). ES-LCMS m/z 304 (M+H). d) Preparation of N-{4-chloro-3-[(4-(3-fluorophenyl)-4-{2-[3-(2~methyl-1H- benzimidazol-1'yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-1- yl)carbonyl]phenyl}-1, 1, 1 -trifluoromethanesulfonamide.
Figure imgf000787_0001
Λ/-{4-Chloro-3-[(4-(3-fluorophenyl)-4-{2-[3-(2-methyl-1H-benzimidazol- 1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-1-yl)carbonyl]phenyl}-1 ,1 ,1- trifluoromethanesulfonamide (43m g, 23 %) was obtained as a solid from 1-(8- {2-[4-(3-fluorophenyl)-4-piperidinyl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2- methyl-1 H-benzimidazole (150 mg, 246 mmol), 2-chloro-5- {[(trifluoromethyl)sulfonyl]amino}benzoic acid (82 mg. 270 mmol), HATU (140 mg, 389 mmol), and DIEA (95 mg, 738 mmol) following the procedure outlined in example 5. 1H-NMR (400 MHz, DMSO-c/e): 8.6 (bs, 1H), 7.56-7.38 (m, 3H), 7.32-7.06 (m, 6H), 6.96-6.77 (m, 2H), 4.90-4.76 (bs, 1 H), 4.04-3.82 (m, 3H), 3.40-3.15 (m, 5H+H2O), 3.07-2.94 (m, 1 H), 2.64-2.36 (m, 2H+DMSO), 2.23- 1.68 (m, 14H). ES-LCMS m/z 732 (M+H).
Example 1172
1.1.1 -Trifluoro-A/-(3-r(4-(3-fluorophenyl)-4-(2-r3-(2-methyl-1 H-benzimidazol-1 ■ vn-8-azabicvclof3.2.1 loct-δ-yllethvD-l - piperidinyl)carbonyl1phenyl}methanesulfonamide
Figure imgf000787_0002
Figure imgf000788_0001
aj Preparation of methyl 3-amino-benzoate.
Figure imgf000788_0002
To a solution of 3-amino-benzoic acid (10.0 g, 72 mmol) in anhydrous methanol (100 ml) was added dropwise acetyl chloride (15 ml) with stirring under a nitrogen atmosphere. After stirring for 3 hours the volatiles were removed by spin evaporation in vacuo and the residue was dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate and then water. The organic layer was concentrated by spin evaporation in vacuo with the addition of dichloromethane (3 times) give methyl 5-amino-2- chlorobenzoate as a white solid. (9.8 g, 89%). 1 H-NMR (400 MHz, DMSO-c/e. δ 7.92-7.78 (m, 2H), 7.50-7.44 (m, 1H), 7.4-7.36 (m, 1H), 3.94 (s, 3H) ES- LCMS m/z 152 (M+H).
b) Preparation of methyl 3-{bis[(trifluoromethyl)sulfonyl]amino}benzoate.
Figure imgf000788_0003
Triflic anhydride (3.73 g, 13.2 mmol) was added dropwise to a solution of methyl 3-amino-benzoate (2.0 g, 13.2 mmol) and DIEA (2.3 ml) in dichloromethane (50 ml) at 0 °C while stirring under a nitrogen atmosphere. After warming to room temperature over 1 hour, the thick slurry was diluted with additional dichloromethane (200 ml) and washed with aqueous 1 N hydrochloric acid and the water. The dichloromethane layer was dried with MgSO4 and the volatiles were removed by spin evaporation in vacuo to give methyl 3-bis[(trifluoromethyl)sulfonyl]amino}benzoate as a tan oil (5.4 g, 100%). 1H-NMR (400 MHz, DMSO-c/e): δ 7.73-7.65 (m, 2H), 7.55-7.50 (m, 1 H), 7.44-7.36 (m, 1 H), 3.95 (s, 3H). ES-LCMS m/z 416 (M+H).
c) Preparation of3-{[(trifluoromethyl)sulfonyl]amino}benzoic acid.
Figure imgf000789_0001
A solution of methyl 3-{bis[(trifluoromethyl)sulfonyl]amino}benzoate (5.4 g, 13.0 mmol), sodium hydroxide (3.12 g, 78.0 mmol), methanol (125 ml) and water (125 ml) was stirred for 2 hours. The solution from concentration to 75 ml by spin evaporation in vacuo and dilution with 100 ml water was extracted with ethyl acetate. The aqueous layer was acidified with 12 N hydrochloric acid and again extracted with ethyl acetate. The organic layer was washed with water and concentrated by spin evaporation in vacuo, with the addition of dichloromethane (3 times) to give a residue that was dissolved in 1 N aqueous hydrochloric acid. The aqueous solution was extracted with ethyl acetate (3 times) and the organic layers were combined, washed with water, and concentrated by spin evaporation in vacuo to 3-
{[(trifluoromethyl)sulfonyl]amino}benzoic acid as a solid (2.3 g, 66%). 1 H-NMR (400 MHz, DMSO-c/e): ): δ 7.83-7.78 (m, 2H), 7.55-7.50 (m, 1 H), 7.50-7.46 (m, 1 H). ES-LCMS m/z 269 (M+H).
d) Preparation of 1,1,1-trifluoro~N-{3~[(4-(3-fluorophenyl)-4-{2-[3-(2- methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1~ piperidinyl)carbonyl]phenyl}methanesulfonamide.
Figure imgf000790_0001
1 ,1 ,1 -Trifluoro-Λ/-{3-[(4-(3-fluorophenyl)-4-{2-[3-(2-methyl-1 H- benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1- piperidinyl)carbonyl]phenyl}methanesulfonamide (72 mg, 100%) was obtained as a solid from 1-(8-{2-[4-(3-fluorophenyl)-4-piperidinyl]ethyl}-8- azabicyclo[3.2.1]oct-3-yl)-2-methyl-1 H-benzimidazole (150 mg, 246 mmol), 3- {[(trifluoromethyl)sulfonyl]amino}benzoic acid (73 mg. 270 mmol), HATU (140 mg, 369 mmol), and DIEA (95 mg, 738 mmol) following the procedure outlined in example 5. 1 H-NMR (400 MHz, DMSO-c/e): δ 8.83-8.68 (bs, 1 H), 7.58-7.49 (m, 1 H), 7.59-7.49 (m, 2H),7.49-7.38 (m, 2H), 7.21-7.05 (m, 4H), 7.02-6.91 (m, 2H), 6.79-6.67 (m, 1 H), 5.03-4.76 (m, 1 H), 4.13-3.96 (m, 3H), 3.57-3.01 (m, 6H), 2.54-2.39 (M, 5H), 2.24-1.97 (m, 8H), 1.97-1.68 (m, 3H), 1.31-1.14 (m, 2H). ES-LCMS m/z 698 (M+H).
Example 1173
/V-(3-r(4-(3-Fluorophenvn-4-(2-r3-(2-methyl-1H-benzimidazol-1-vn-8- azabicvclor3.2.11oct-8-vnethyl)-1 - piperidinvDcarbonvnphenyljmethanesulfonamide
Figure imgf000790_0002
a) Preparation of3-[(methylsulfonyl)amino]benzoic acid.
Figure imgf000791_0001
To a solution of methyl 3-amino-benzoate (2.0 g, 13.2 mmol) and pyridine (2.30 g, 29.1 mmol) in dichloromethane (50 ml) at -10 °C under a nitrogen atmosphere was slowly added methanesulfonyl chloride (2.25 ml, 29.1 mmol) by syringe. After 2 hours, water was added and the volatiles were removed by spin evaporation in vacuo. A solution of the residue and sodium hydroxide (3.175 g, 79.4 mmol) in methanol (50 ml) and water (50 ml) was stirred for 18 hours. The residue after removal of the volatiles by spin evaporation in vacuo was dissolved in 1 N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and the volatiles were removed by spin evaporation in vacuo to give 3- [(methylsulfonyl)amino]benzoic acid as an oil. (1.32 g, 46 %). 1 H-NMR (400 MHz, DMSO-c/e): δ 7.83-7.78 (m, 2H), 7.55-7.50 (m, 1 H), 7.50-7.46 (m, 1 H), 3.80 (s, 3H). ES-LCMS m/z 216 (M+H).
b) Preparation of N-{3-[(4-(3-fluorophenyl)-4-{2-[3-(2-methyl-1H- benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1- piperidinyl)carbonyl]phenyl}methanesulfonamide.
Figure imgf000791_0002
Λ/-{3-[(4-(3-Fluorophenyl)-4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-1- piperidinyl)carbonyl]phenyl}methanesulfonamide (72 mg, 100%) was obtained as a solid from 1-(8-{2-[4-(3-fluorophenyl)-4-piperidinyl]ethyl}-8- azabicyclo[3.2.1]oct-3-yl)-2-methyl-1 H-benzimidazole (150 mg, 246 mmol 3- [(methylsulfonyl)amino]benzoic acid (73 mg. 270 mmol), HATU (140 mg, 369 mmol), and DIEA (95 mg, 738 mmol) following the procedure outlined in example 5. 1 H-NMR (400 MHz, DMSO-c/e): δ 9.90 (bs 1H), 7.49-7.49 (m, 1H), 7.44-7.31 (m, 3H), 7.27-7.20 (m, 3H), 7.19-7.15 (m, 1 H), 7.14-7.00 (m, 4H), 4.55-4.39 (m, 1 H), 3.91-3.79 (m, 1 H), 3.53-3.40 (m, 1 H), 3.40-3.09 (m, 2H), 3.03-2.96 (m, 3H), 2.51-2.45 (m, 5H), 2.44-2.40 (m, 3H), 2.40-2.30 (m, 2H), 2.17-1.96 (m, 2H), 1.91-1.70 (m, 4H), 1.64-1.52 (m, 2H), 1.25-1.10 (m, 1H). ES-LCMS m/z 644 (M+H).
Example 1174
Λ/-(3-Chloro-4-f(4-(3-fluorophenvn-4-l2-r3-(2-methyl-1H-benzimidazol-1-vn-8- azabicvclor3.2.11oct-8-yllethyl)-1 - piperidinvDcarbonvπphenvDmethanesulfonamide.
Figure imgf000792_0001
a) Preparation of methyl 4-amino-2-chlorobenzoate.
Figure imgf000792_0002
Methyl 4-amino-2-chlorobenzoate (5.1 g, 94 %) was obtained as solid from 4-amino-2-chlorobenzic acid (5.0 g, 29.1 mmol) ) following the procedure outlined for methyl 5-amino-2-chlorobenzoate. 1 H-NMR (400 MHz, DMSO- dβ): δ 7.64-7.57 (m, 1H), 6.65-6.57 (m, 1H), 6.51-6.39 (m, 1H), 6.16 (bs, 2H), 3.71 (s, 3H). ES-LCMS m/z 186 (M+H).
b) Preparation of2-chloro-4-[(methylsulfonyl)amino]benzoic acid.
Figure imgf000793_0001
2-Chloro-4-[(methylsulfonyl)amino]benzoic acid (5.1 g, 94 %) was obtained as an oil from methyl 4-amino-2-chlorobenzoate (5.0 g, 29.1 mmol) ) following the procedure outlined for 3-[(methylsulfonyl)amino]benzoic acid. 1 H-NMR (400 MHz, DMSO-c/e): δ 13.11 (bs, 1 H), 10.29 (bs, 1 H), 7.83-7.80 (m, 1H), 7.24-7.22 (m, 1H), 7.21-7.18 (m, 1 H), 3.11 (s, 3H). ES-LCMS m/z 250 (M+H).
c) Preparation of N-{3-chloro-4-[(4-(3-fluorophenyl)-4-{2-[3-(2-methyl-1H- benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1- piperidinyl)carbonyl]phenyl}methanesulfonamide.
Figure imgf000793_0002
Λ/-{3-Chloro-4-[(4-(3-fluorophenyl)-4-{2-[3-(2-methyl-1H-benzimidazol- 1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1- piperidinyl)carbonyl]phenyl}methanesulfonamide (29 mg, 17.4%) was obtained as a solid from 1-(8-{2-[4-(3-fluorophenyl)-4-piperidinyl]ethyl}-8- azabicyclo[3.2.1]oct-3-yl)-2-methyl-1 H-benzimidazole (150 mg, 246 mmol), 2- chloro-4-[(methylsulfonyl)amino]benzoic acid (68 mg. 0.270 mmol), HATU (140 mg, 369 mmol), and DIEA (95 mg, 738 mmol) following the procedure outlined in example 5. 1H-NMR (400 MHz, DMSO-c/e): δ 7.55-7.44 )m, 1 H0,7.44-7.27 (m, 3H), 7.27-6.98 (m, 8H), 4.56-4.42 (m, 1 H), 3.97-3.82 (m, 1 H), 3.39-3.17 (m, 3H), 3.10-2.93 (m, 5H), 2.44-2.40 (m, 3H), 2.39-2.29 (m, 2H), 2.19-2.02 (m, 3H), 1.93-1.69 (m, 6H), 1.62-1.54 (m, 2H), 1.24-1.07 (m, 2H), 0.98-0.91 (m, 1 H). ES-LCMS m/z 678 (M+H).
Example 1175
Λ/-(4-chloro-3-r(4-(3-fluorophenvn-4-(2-f3-(2-methyl-1H-benzimidazol-1-yl)-8- azabicvclor3.2.11oct-8-vπethviyi - piperidinyl)carbonyl1phenyl}methanesulfonamide
Figure imgf000794_0001
Figure imgf000794_0002
a) Preparation of2-chloro-5-[(methylsulfonyl)amino]benzoic acid.
Figure imgf000794_0003
2-Chloro-5-[(methylsulfonyl)amino]benzoic acid (1.83 g, 68 %) was obtained as an oil from methyl 5-amino-2-chlorobenzoate (2.0 g, 10.8 mmol) ) following the procedure outlined for 2-chloro-4-
[(methylsulfonyl)arnino]benzoic acid. 1 H-NMR (400 MHz, DMSO-c/e): δ 13.46 (bs, 1 H), 10.05 (s, 1 H), 7.62-7.55 (m, 1H), 7.50-7.45 (m, 1 H), 7.37-7.30 (m, 1 H), 3.02 (s, 3H). ES-LCMS m/z 249 (M+H).
b) Preparation of N-{4-chloro-3-[(4-(3-fluorophenyl)-4-{2-[3-(2-methyl-1H- benzimidazol-1-yl)-8-azabicyclo[3.2.1Joct-8-yl]ethyl}-1- piperidinyl)carbonyl]phenyl}methanesulfonamide.
Figure imgf000795_0001
Λ/-{4-Chloro-3-[(4-(3-fluorophenyl)-4-{2-[3-(2-methyl-1H-benzimidazol- 1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1- piperidinyl)carbonyl]phenyl}methanesulfonamide (103 mg, 61.6 %) was obtained as a solid from 1-(8-{2-[4-(3-fluorophenyl)-4-piperidinyl]ethyl}-8- azabicyclo[3.2.1]oct-3-yl)-2-methyl-1 H-benzimidazole (150 mg, 246 mmol 2- chloro-5-[(methylsulfonyl)amino]benzoic acid (68 mg. 0.270 mmol), HATU (140 mg, 369 mmol), and DIEA (95 mg, 738 mmol) following the procedure outlined in example 5. 1 H-NMR (400 MHz, DMSO-c e): δ 10.00 (bs, 1 H), 7.57- 7.47 (m, 2H), 7.45-7.34 (m, 2H), 7.28-7.21 (m, 3H),7.18-7.02 (m, 4H), 4.57- 4.43 (m, 1 H), 3.98-3.83 (m, 1 H), 3.45-3.21 (m, 8H), 3.11-2.99 (m, 4H), 2.46- 2.41 (m, 3H), 2.41-2.30 (m, 2H), 2.21-2.02 (m, 2H), 1.99-1.72 (m, 6H), 1.65- 1.56 (m, 2H). ES-LCMS m/z 678 (M+H). Example 1176 Λ/-{3-Fluoro-4-[(4-(3-fluorophenyl)-4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8- azabicyclo[3.2.1 ]oct-8-yl]ethyl}-1 - piperidinyl)carbonyl]phenyl}methanesulfonamide.
Figure imgf000796_0001
a) Preparation of methyl 4-amino-2-fluorobenzoate.
Figure imgf000796_0002
Methyl 4-amino-2-fluorobenzoate (1.98 g, 98 %) was obtained as solid from 4-amino-2-fluorobenzic acid (2.0 g, 12.90 mmol) ) following the procedure outlined for methyl 5-amino-2-chlorobenzoate. 1 H-NMR (400 MHz, DMSO-c/e): δ 7.61-7.58 (m, 1H), 6.42-6.37 (m, 1H), 6.32-6.25 (m, 3H), 3.72 (s, 3H). ES-LCMS m/z 170 (M+H).
b) Preparation of2-fluoro-4-[(methylsulfonyl)amino]benzoic acid.
Figure imgf000796_0003
2-Fluoro-4-[(methylsulfonyl)amino]benzoic acid (5.1 g, 94 %) was obtained as an oil from methyl 4-amino-2-fluorobenzoate (5.0 g, 29.1 mmol) ) following the procedure outlined in example 3- [(methylsulfonyl)aminojbenzoic acid. 1 H-NMR (400 MHz, DMSO-c/e): δ 7.69-7.59 (m, 1 H), 6.45-6.40 (m, 1 H), 6.40-6.32 (m, 3H), 3.72 (s, 3H). ES- LCMS m/z 234 (M+H).
c) Preparation of N-{3-fluoro-4-[(4-(3-fluorophenyl)-4-{2-[3-(2-methyl-1H- benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1- piperidinyl)carbonyl]phenyl}methanesulfonamide.
Figure imgf000797_0001
Λ/-{3-Fluoro-4-[(4-(3-fluorophenyl)-4-{2-[3-(2-methyl-1H-benzimidazol- 1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1- piperidinyl)carbonyl]phenyl}methanesulfonamide (26 mg, 15%) was obtained as a solid from 1-(8-{2-[4-(3-fluorophenyl)-4-piperidinyl]ethyl}-8- azabicyclo[3.2.1]oct-3-yl)-2-methyl-1 H-benzimidazole (150 mg, 246 mmol), 2- chloro-4-[(methylsulfonyl)amino]benzoic acid (U20375/163/1 ) (68 mg. 0.270 mmol), HATU (140 mg, 369 mmol), and DIEA (95 mg, 738 mmol) following the procedure outlined in example 5. 1H-NMR (400 MHz, DMSO-c/6): δ 7.49- 7.45 (m, 1 H), 7.43-7.28 (m, 3H), 7.25-7.01 (m, 8H), 4.54-4.42 (m, 1H), 3.95- 3.83 (m, 1 H), 3.38-3.196 (m, 5H+H2O), 3.08-2.97 (m, 4H), 2.51-2.40 (m, 2H), 2.39-2.29 (m, 2H), 2.18-2.01 (m, 3H), 1.91-1.70 (m, 6H), 1.62-1.55 (m, 2H), 1.23-1.10 (m, 2H), 0.98-0.92 (m, 1H). ES-LCMS m/z 662 (M+H).
Example 1177
Λ/-(3-Chloro-4-r(4-(3-fluorophenvn-4-(2-r3-(2-methyl-1H-benzimidazol-1-yl)-8- azabicvclor3.2.11oct-8-yl1ethyll-1 -piperidinvDcarbonvnphenylM .1.1- trifluoromethanesulfonamide
Figure imgf000798_0001
b) Preparation of methyl 4-{bis[(trifluoromethyl)sulfonyl]amino}-2- chlorobenzoate.
Figure imgf000798_0002
Triflic anhydride (3.73 g, 13.2 mmol) was added dropwise to a solution of methyl 4-amino-2-chlorobenzoate (2.45 g, 13.2 mmol) and ethyl[bis(1- methylethyl)]amine (2.3 ml) in dichloromethane (50 ml) at 0 °C while stirring under a nitrogen atmosphere. After warming to room temperature over 1 hour, the thick slurry was diluted with additional dichloromethane (200 ml) and washed with aqueous 1 N hydrochloric acid and the water. The dichloromethane layer was dried with MgSO and the volatiles were removed by spin evaporation in vacuo to give methyl 4- {bis[(trifluoromethyl)sulfonyl]amino}-2-chlorobenzoate as a tan oil (5.9 g, 100 %). ES-LCMS m/z 450 (M+H).
c) Preparation of 2-chloro-4-{[(trifluoromethyl)sulfonyl]amino}benzoic acid.
Figure imgf000799_0001
A solution of methyl 4-{bis[(trifluoromethyl)sulfonyl]amino}-2- chlorobenzoate (5.9 g, 13.1 mmol), sodium hydroxide (3.12 g, 78.0 mmol), methanol (125 ml) and water (125 ml) was stirred for 2 hours. The solution from concentration to 75 ml by spin evaporation in vacuo and dilution with 100 ml water was extracted with ethyl acetate. The aqueous layer was acidified with 12 N hydrochloric acid and again extracted with ethyl acetate. The organic layer was washed with water and concentrated by spin evaporation in vacuo, with the addition of dichloromethane (3 times) to give a residue that was dissolved in 1 N aqueous hydrochloric acid. The aqueous solution was extracted with ethyl acetate (3 times) and the organic layers were combined, washed with water, and concentrated by spin evaporation in vacuo 2-chloro-4- {[(trifluoromethyl)sulfonyl]amino}benzoic acid as a solid (3.6 g, 61 %). ES- LCMS A77/z 304 (M+H).
d) Preparation of N-{3-chloro-4-[(4-(3-fluorophenyl)-4-{2-[3-(2-methyl-1 H- benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1- piperidinyl)carbonyl]phenyl}-1 , 1 ,1 -trifluoromethanesulfonamide.
Figure imgf000799_0002
Λ/-{3-chloro-4-[(4-(3-fluorophenyl)-4-{2-[3-(2-methyl-1H-benzimidazol-1- yl)-8-azabicyclo[3.2.1 ]oct-8-yl]ethyl}-1 -piperidinyl)carbonyl]phenyl}-1 ,1 ,1- trifluoromethanesulfonam.de (35 mg, 19%) was obtained as a solid from 1-(8- {2-[4-(3-fluorophenyl)-4-piperidinyl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2- methyl-1 H-benzimidazole (150 mg, 246 mmol), 2-chloro-4- {[(trifluoromethyl)sulfonyl]amino}benzoic (82 mg. 270 mmol), HATU (140 mg, 369 mmol), and DIEA (95 mg, 738 mmol) following the procedure outlined in example 5. ES-LCMS m/z 732 (M+H).
Example 1178
1.1.1 -Trifluoro-Λ/-(2-fluoro-4-r(4-(3-fluorophenvn-4-(2-r3-(2-methyl-1 H- benzimidazol-1 -yl)-8-azabicvclor3.2.1loct-8-yllethyl)-1 - piperidinyl)carbonyllphenyl)methanesulfonamide.
Figure imgf000800_0001
a) Preparation of Methyl 4-amino-3-fluorobenzoate.
Figure imgf000800_0002
Methyl 4-amino-3-fluorobenzoate (1.01 g, 92 %) was obtained as solid from 4-amino-3-fluorobenzic acid (1.0 g, 6.4 mmol) following the procedure outlined in example 1171. ES-LCMS m/z 170 (M+H). b) Preparation of 3-fluoro-4-{[(trifluoromethyl)sulfonyl]amino}benzoic acid.
Figure imgf000801_0001
3-Fluoro-4-{[(trifluoromethyl)sulfonyl]amino}benzoic acid (0.892 g, 97 %) was obtained as an oil from methyl 4-amino-3-fluorobenzoate (1.80 g, 6.39 mmol) ) following the procedure outlined in example 1174. ES-LCMS m/z 288 (M+H).
c) Preparation of 1,1,1-trifluoro-N-{2-fluoro-4-[(4-(3-fluorophenyl)-4-{2-[3- (2-methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1- piperidinyl)carbonyl]phenyl}methanesulfonamide.
Figure imgf000801_0002
1,1 ,1-Trifluoro-Λ/-{2-fluoro-4-[(4-(3-fluorophenyl)-4-{2-[3-(2-methyl-1H- benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1- piperidinyl)carbonyl]phenyl}methanesulfonamide (85 mg, 48%) was obtained as a solid from 1-(8-{2-[4-(3-fluorophenyl)-4-piperidinyl]ethyl}-8- azabicyclo[3.2.1]oct-3-yl)-2-methyl-1 H-benzimidazole (150 mg, 246 mmol), 3- fluoro-4-{[(trifluoromethyl)sulfonyl]amino}benzoic acid (78 mg. 270 mmol), HATU (140 mg, 369 mmol), and DIEA (95 mg, 738 mmol) following the procedure outlined in example 5. ES-LCMS m/z 716 (M+H). Example 1179
1.1.1 -Trifluoro-Λ/-(3-fluoro-4-r(4-(3-fluorophenvn-4-{2-r3-(2-methyl-1 H- benzimidazol-1-vπ-8-azabicvclor3.2.noct-8-vnethyl}-1- piperidinvπcarbonvπphenyllmethanesulfonamide.
Figure imgf000802_0001
aj Preparation of methyl 4-amino-2-fluorobenzoate.
Figure imgf000802_0002
Methyl 4-amino-2-fluorobenzoate (1.85 g, 84 %) was obtained as solid from 4-amino-2-fluorobenzic acid (2.0 g, 12.90 mmol) ) following the procedure outlined in example 1171. ES-LCMS m/z 170 (M+H).
b) Preparation of2-fluoro-4-{[(trifluoromethyl)sulfonyl]amino}benzoic acid.
Figure imgf000802_0003
2-Fluoro-4-{[(trifluoromethyl)sulfonyl]amino}benzoic acid (1.32 g, 74 %) was obtained as an oil from methyl 4-amino-2-fluorobenzoate (1.05 g, 6.2 mmol) ) following the procedure outlined in example 1174. ES-LCMS m/z 288 (M+H).
c) Preparation of 1,1,1-trifluoro-N-{3-fluoro-4-[(4-(3-fluorophenyl)-4-{2-[3- (2-methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1- piperidinyl)carbonyl]phenyl}methanesulfonamide.
Figure imgf000803_0001
1 ,1 ,1 -Trifluoro-Λ/-{3-fluoro-4-[(4-(3-fluorophenyl)-4-{2-[3-(2-methyl-1 H- benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1- piperidinyl)carbonyl]phenyl}methanesulfonamide (85 mg, 48%) was obtained as a solid from 1-(8-{2-[4-(3-fluorophenyl)-4-piperidinyl]ethyl}-8- azabicyclo[3.2.1]oct-3-yl)-2-methyl-1 H-benzimidazole (150 mg, 246 mmol), 2- fluoro-4-{[(trifluoromethyl)sulfonyl]amino}benzoic acid (78 mg. 270 mmol), HATU (140 mg, 369 mmol), and DIEA (95 mg, 738 mmol) following the procedure outlined in example 5. ES-LCMS m/z 716 (M+H).
Example 1180 Λ/-(2-fluoro-4-r(4-(3-fluorophenvn-4-(2-r3-(2-methyl-1H-benzimidazol-1-yl)-8- azabicvclor3.2.11oct-8-vπethyl)-1 - piperidinvOcarbonvHphenyllmethanesulfonamide.
Figure imgf000804_0001
a) Preparation of methvl 4-amino-3-fluorobenzoate
Figure imgf000804_0002
Methyl 4-amino-3-fluorobenzoate (0.98 g, 90.0 %) was obtained as solid from 4-amino-3-fluorobenzic acid (1.0 g, 6.45 mmol) ) following the procedure outlined in example 1171. ES-LCMS m/z 170 (M+H).
b) Preparation of3-fluoro-4-[(methylsulfonyl)amino]benzoic acid.
3-Fluoro-4-[(methylsulfonyl)amino]benzoic acid (490 mg, 66 %) was obtained as an oil from methyl 4-amino-3-fluorobenzoate (0.54 g, 3.19 mmol) ) following the procedure outlined in example 1174. ES-LCMS m/z 234 (M+H).
c) Preparation ofN- {2-fluoro-4- [(4-(3-fluorophenyl)-4-{2-[3-(2-methyl-1 H- benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1- piperidinyl)carbonyl]phenyl}methanesulfonamide.
Figure imgf000805_0001
Λ/-{2-Fluoro-4-[(4-(3-fluorophenyl)-4-{2-[3-(2-methyl-1H-benzimidazol- 1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1- piperidinyl)carbonyl]phenyl}methanesulfonamide (92 mg, 52 %) was obtained as a solid from 1-(8-{2-[4-(3-fluorophenyl)-4-piperidinyl]ethyl}-8- azabicyclo[3.2.1]oct-3-yl)-2-methyl-1 H-benzimidazole (150 mg, 246 mmol), 3- fluoro-4-[(methylsulfonyl)amino]benzoic acid (U20375/147/1) (78 mg. 270 mmol), HATU (140 mg, 369 mmol), and DIEA (95 mg, 738 mmol) following the procedure outlined in example 5. ES-LCMS m/z 662 (M+H).
Example 1181
N-{4-[(4-(3-fluorophenyl)-4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1 ]oct-8-yl]ethyl}-1 - piperidinyl)carbonyl]phenyl}methanesulfonamide
Figure imgf000805_0002
The synthesis of 4-[(methylsulfonyl)amino]benzoic acid
Figure imgf000806_0001
Figure imgf000806_0002
2.1 g (15.6 mmol) of 4-aminobenzoic acid was dissolved in anhydrous MeOH, added 14.47g (123.3 mmol) of thionyl chloride dropwise under N2 while stirring at rt. After dtiring for four hours, solvents were removed and redissolved in 100 mL EtOAc and 40 mL of saturated NaHCO3 aq, stirred 30 min, separated and washed with 3 x 20 mL water. Organics were dried yielding 2.17g (yield 92.1 %) of methyl 4-aminobenzoate. 1 H NMR (300 MHz, CDCI3): 7.88 (2H, d, J=8.6 Hz), 6.66 (2H, d, J=8.6 Hz), 4.19 (2H, broad s), 3.88 (3H, s). 13C NMR (300 MHz, CDCI3): 167.8 (C=O), 151.4 (Cq), 131.9 (2x CH), 120.0 (Cq), 113.8 (2x CH), 50.9 (CH3).
1.13g (7.48 mmol) of methyl 4-aminobenzoate was dissolved in 20 mL of anhydrous DCM and 1.97g (17.19 mmol) of mesyl chloride was added at 4 deg C, followed by the 2.22 g (17.19 mmol) of the diethylisopropylamine. Reaction was carried out overnight at room temperature resulting methyl 4- [(methylsulfonyl)amino]benzoate, which was used in the next step without additional purification. 3.6 g (90 mmol) of NaOH was added to the solution of methyl 4- [(methylsulfonyl)amino]benzoate in 40 mL methanol and 20 mL water and stirred overnight at room temperature. Solvents were then removed and the product purified by ethyl acetate extraction from 1 N aqueous hydrochloric acid, providing 1.2g (yield 74.6%) of the 4-[(methylsulfonyl)amino]benzoic acid. 1 H NMR in d-chloroform: 8.03 (2H, d, J=8.7 Hz), 7.34 (2H, d, J=8.7 Hz), 3.09 (3H, s). 13C NMR in d-chloroform: 131.2, 117.9, 38.6.
The synthesis of N-{4-[(4-(3-fluorophenyl)-4-{2-[(1R, 5S)-3-(2-methyl-1 H- benzimidazol- 1 -yl) -8-azabicyclo[3.2.1]oct-8-yl]ethyl}- 1 - piperidinyl)carbonyl]phenyl}methanesulfonamide
270 mg (0.61 mmol) of 1-((1 R,5S)-8-{2-[4-(3-fluorophenyl)-4-piperidinyl]ethyl}- 8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1 H-benzimidazole dihydrochloride salt trihydrate was dissolved in the dichloromethane, and added 195 mg (0.91 mmol) of the 4-[(methylsulfonyl)amino]benzoic acid, 440 mg (0.91 mmol) of HATU and 391 mg (3.03 mmol) of the diethylisopropylamine an the reaction carried out as described in example 5, resulting in title N-{4-[(4-(3- fluorophenyl)-4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-1- piperidinyl)carbonyl]phenyl}methanesulfonamide, yield 32% after HPLC purification.
1 H NMR (d4-methanol, 400 MHz): 7.53 (1 H, m), 7.40 (4H, m), 7.31 (2H, d, J=7.7 Hz), 7.22 (4H), 6.99 (1 H, m), 4.74 (1 H, m), 4.09 (1H, broad s), 3.68 (1 H, broad s), 3.39 (4H, m), 3.03 (4H, m), 2.52 (s, 3H), 2.45 (2H, m), 2.32 (1 H, broad s), 2.23 (1 H, broad s), 1.95 (10H, m), 1.71 (1H, m) Example 1074
Figure imgf000808_0001
3-[(4-(3-fluorophenyl)-4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1 ]oct-8-yl]ethyl}-1 -piperidinyl)carbonyl]-/V-hydroxybenzamide
Example 1074 was prepared according to scheme below.
Figure imgf000808_0002
1-((1R,5S)-8-{2-[4-(3-fluorophenyl)-4-piperidinyl]ethyl}-8-azabicyclo[3.2.1]oct- 3-yl)-2-methyl-1 H-benzimidazole (500mg, 0.962mmol) was combined with 3- [(methyloxy)carbonyl]benzoic acid (173mg, 0.962mmol) and DIPEA (373mg, 2.88mmol) in 8mL DMF and treated with HATU (366mg, 0.962mmol) at ambient temperature for 16h. The reaction mixture was treated with satd. NaHCO3 which yielded a solid precipitate that was filtered off, washed with water and dried to give methyl 3-[(4-(3-fluorophenyl)-4-{2-[(1ft,5S)-3-(2- methyl-1 H-benzimidazol-1 -yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1- piperidinyl)carbonyl]benzoate (395mg, 0.649mmol, 67%) as a white solid. ES- LCMS m/z 609.1 (M+H).
Hydroxylamine.HCI (26mg, 0.360mmol) dissolved in 5mL EtOH was cooled in an ice bath and treated with 0.5M NaOCH3 (1.92mL, 0.96mmol) for 15min with stirring. Methyl 3-[(4-(3-fluorophenyl)-4-{2-[(1ft,5S)-3-(2-methyl-1H- benzimidazol-1 -yl)-8-azabicyclo[3.2.1 ]oct-8-yl]ethyl}-1 - piperidinyl)carbonyl]benzoate (183mg, 0.300mmol) was added to the reaction mixture and allowed to stir 16h at ambient temperature. The reaction mixture was concentrated to dryness and purified by RP-HPLC on a C-18 column eluted with 0- 50%CH3CN in H2O with 0.1% formic acid buffer. The appropriate fractions were combined and concentrated to give 3-[(4-(3- fluorophenyl)-4-{2-[(1 R,5S)-3-(2-methyl-1 H-benzimidazol-1 -yl)-8- azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]-Λ/-hydroxybenzamide (20mg, 0.032mmol, 9%) as a clear glass. ES-LCMS m/z 610.14 (M+H), 608.21 (M-1).
CC-Chemokine Receptor-5 Binding by Scintillation Proximity Assay The compounds of this invention were evaluated as antagonists of CCR5 by high-throughput screening using scintillation proximity assay (SPA) binding that measures inhibition of binding of 125I-MIP1 D to the human CCR5 chemokine receptor.
Human CCR5 receptors were expressed in Chinese Hamster Ovary (CHO) cells. Cells were grown in suspension and 50 to 80 ml CCR5 cell pellets were prepared.
Membranes were prepared according to the following procedure: 1) weighed pellet; 2) prepared an ice-cold 50 mM HEPES buffer, containing 0.0025 mg/ml Pefabloc, 0.0001 mg/ml Pepstatin A, 0.0001 mg/ml Leupeptin, 0.0001 mg/ml Aprotinin (protease inhibitor cocktail), pH 7.4; 3) homogenized pellet in 5 volumes of HEPES buffer; 4) homogenized again with a glass homogenizer for 10 to 20 strokes; 5) centrifuged homogenate at 18,000 rpm in a F28/36 rotor using a Sorvall RC26 PIUS refrigerated Centrifuge for 30 minutes; 6) discarded supernatant and resuspended pellet in 3 volumes of HEPES buffer; 7) homogenized and centrifuged again using steps 4-6 for two more times; 8) re-weighed pellet and homogenize in three times weight-to- volume of HEPES buffer; 9) placed aliquot 0.5 to 1.5 ml of the membrane preparation into small vials and stored at -80°C; 10) determined the protein concentration of the membrane preparation using the Bio-Rad or BCA method; and 11 ) characterized the membrane homogenate for the assay conditions including protein concentration, optimal protein-to-bead ratio in SPA, and saturation curve to determine Kd and Bmax (number of binding sites) in SPA.
The saturation curve binding experiment was performed by adding varying amounts of [125l]MIP1α (0-8.5 nM) to membranes and beads in concentrations chosen from the optimal protein/bead ratio. The data was analyzed using a non-linear curve-fitting program. The Kd and Bmaχ were derived from the curve.
Bacitracin 50 mg/ml was dissolved in deionized water, brought to a boil for 5 minutes (to destroy protease activity) and cooled. One milliliter aliquots were prepared and stored at -80°C.
Protease inhibitor cocktail was prepared by dissolving 25 mg/ml of Pefabloc, 1 mg/ml of Leupeptin, 1 mg/ml of Aprotinin and 1 mg/ml of Pepstatin A in 100% DMSO. The cocktail could be aliquoted and stored frozen at -20 °C until needed.
Any reagent bottles and reservoirs that come in contact with the radioligand were treated with Sigmacote to reduce sticking. Containers were rinsed with undiluted Sigmacote and with deionized water for several times and allowed to air dry before using.
Color quench assay was performed with a [125l] SPA PVT color quench kit (Cat. No. RPAQ 4030, Amersham Ltd.). A color quench curve was generated for each Packard TopCount and was stored in each counting protocol specific for the assay. This was done to prevent colored compounds from quenching the scintillation counts.
Compounds of this invention were prepared for SPA according to the following protocol. Compounds for a single concentration determination (one shots) were delivered in 96 well Packard Optiplates containing 1 μl of compound in 100% DMSO in columns A1-H10 (80 compounds/plate). Column A11 to H11 was used for total binding (Bo: zero standard - bound radioactive counts in the absence of added inhibitor or test compound) (vehicle-5 μl of the appropriate DMSO concentration) and column A12 to D12 was used for determination of nonspecific binding (NSB). No further preparation was required. Compounds for concentration-response curves (10 points) were delivered in 96- Packard Optiplates containing 1 μl of compound in 100% DMSO in columns A1-H10. A 10-point concentration-response curve was desired for each compound with a starting high concentration of 30 μM (in the assauy final). Column A11 to H11 was used for total binding (Bo) (vehicle-5 μl of the appropriate DMSO concentration) and column A12 to D12 was used for determination of nonspecific binding. No further preparation was required.
Assay buffer was prepared by mixing 50 mM HEPES buffer (pH 7.4), 1 mM CaCI2ι 5 mM MgCI2 which could be made ahead as a 100X stock, 1% BSA (bovine serum albumin), 0.5 mg/ml Bacitracin, and protease inhibitor cocktail (100 uL/100 ml). DMSO was added to equal a final concentration of 2% per well (includes compound %DMSO) if needed.
[125l]MIP1 radioligand dilutions was prepared in containers treated with Sigmacote. Each 50 μCi vial was reconstituted with 0.5 ml of deionized water and stored at 4°C. The specific activity was 2,000 Ci/mmol. 50 μL (-60,000 cpm; 0.17 nM) of [125l]MIP1α was added to each assay well.
Zero standard (Bo) was prepared by making a 20% DMSO solution and adding 5 μl of 20% DMSO solution to each well in columns A11-H11. This gave a final 2% DMSO concentration for the well when added to the 1 % in the assay buffer.
A stock dilution of MIP1α at 100uM was made using deionized water and aliquoted and frozen. The MIP-1α stock solution was diluted to a concentration of 2 μM in the same 20% DMSO solution used above. 5 μl of the resultant solution was added to the wells in column A12 to D12 to give a final assay concentration of 100 nM. This procedure was conducted in a Sigmacote-treated container.
The final assay concentration for the membrane was 15 μg per well. SPA beads were prepared by adding 5 ml of assay buffer to a 500 mg vial. The final concentration of SPA beads in the assay was 0.25 mg/well. Membranes and beads were premixed as a 1 :1 (membrane:bead) mixture and maintained at mixture at 4°C with constant stirring. 50 μl of the mixture was added to each assay well. After all reagents had been added to the plates (total assay volume 100 μl), plates were shaken for 4 hours at room temperature. After 4 hours, the plates were placed on the TopCount in a count the plates on the TopCount for 30 sec per well using an appropriate program (i.e., one with a quench curve established for the conditions of the assay).
Data reduction was performed using the Microsoft Excel Addins Robofit or Robosage. For single concentration assays (one shots), the result of each test well was expressed as % inhibition using the following formula: 100*(1- (U1-C2)/(C1-C2)), where U1 was the unknown sample in cpm observed in a particular well, C1 was the average of column 12 cpm observed in the absence of any added inhibitor, and C2 was the average of column 11 cpm observed in the presence of 1 uM of MIP1α. For concentration-response assays, the result of each test well was expressed as %B/Bo (% total specific binding) using the following formula: 100* (U1-C2)/C1-C2). Curves were generated by plotting the %B/Bo versus the concentration and the IC50 was derived using the equation y=Vmax*(1-(xΛn/(kΛn+xΛn))).
For controls and standards, each plate contained 12 wells of total binding (column A11-H11). The cpm/well were averaged and used in data reduction as value C1. Each plate also contained 4 wells of non-specific binding (wells A12-D12). The counts of these wells were averaged and used in data reduction as value C2. A standards plate was included in each experiment. This plate contained a 14-point concentration-response curve (in triplicate) for the standard compound MIP1α at a starting concentration of 1 μM. The average historical pKj obtained with MIP1α was 7.6.
The relevant biological response field for a single concentration (one shots) was % inhibition. Inhibition values of >40 or >50% were considered positive responses. The relevant biological response field for a concentration- response experiment was pKj. HOS Assay (Also referred to as HOS-LTR-Luciferase Assay)
HOS-CD4.CCR5-LTR-Luciferase (Bioresource Registration # 21164): Human Osteosarcoma cell line was engineered to overexpress human CD4 and human CCR5 (AIDS Repository cat# 3318) stabily transfected with HIV-1 - LTR-Luciferase reporter.
Growth and Maintenance of the HOS-CD4.CCR5-LTR-Luciferase cell line: The cells were propagated in DMEM containing 2% FBS. Cells were split by standard trypsinization when confluency reached 80% (roughly every 2 to 3 days).
Titering of virus stocks: HIV-1 virus stocks were titered in the assay system in order to obtain an estimate of the number of infectious particles per unit volume (described as RLU/ml). Virus stocks were diluted into DMEM containing 2% FBS and assayed as described in the "procedure" section below.
Procedure: Black-walled 96-well tissue culture plates were seeded with HOS-CD4.CCR5-LTR-Luciferase @ 0.6 to 1.2 x 103 cells per well in 50μl DMEM containing 2% FBS and placed in a humidified incubator @ 37°C, 5% CO2 overnight. The following day, test compounds were titrated 4-fold at 2X the final concentration in DMEM + 2% FBS + 0.2% DMSO. 50DI of titrated compound was transferred to the HOS cells and the plates were placed in a humidified incubator at 37°C, 5% CO2for 1 hr. An additional 60DI of 2X titrated compound was transferred to a clear-walled 96-well tissue culture plate and 60DI of HIV (diluted to appropriate m.o.i.) was added to each well and thoroughly mixed. 100DI of the HIV/compound mixture was transferred to the black-walled plates containing 100DI of cells/compound. The plates were placed in a humidified incubator at 37°C, 5% CO for 72hr. Following the 72 hour incubation, 150DI of supernatant was removed and 50DI of reconstituted LUCLITE (kit reagent) was added to each well. Each plate was sealed and read in a Topcount (Packard) luminometer at 1s/well.
Data Reduction: Relative Light Units (RLU) were expressed as % control (RLU at drug concentration / RLU no drug)*100 = % Control. IC50 values were determined by any one of the following four nonlinear regression models: y=Vmax*(1 -(xΛn/(KΛn+xΛn)))+Y2; y=Vmax*(1 -(xΛn/(KΛn+xΛn))); y=Vmax*(1 -(x/(K+x)))+Y2; y=Vmax*(1-(x/(K+x))); where K is IC50, Y2 is baseline, and N is Hill Coefficient.
Each of the compounds of the present invention provides a plCso value of at least 5 when tested in each of the above-described assays.
Test compounds are employed in free or salt form.
While we have hereinbefore presented a number of embodiments of this invention, it is apparent that our basic construction can be altered to provide other embodiments which utilize the compounds and methods of this invention. Therefore, it will be appreciated that the scope of the invention is to be defined by the appended claims rather than by the specific embodiments which have been represented by way of example.

Claims

What is Claimed is:
1. A compound of formula (I):
Figure imgf000815_0001
or a pharmaceutically acceptable derivative thereof, wherein:
R1 is alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl, wherein said alkyl is optionally substituted by one or more R7, said carbocyclyl or heterocyclyl is optionally substituted by one or more R8 and said aryl or heteroaryl is optionally substituted by one or more R6; or R1 and X taken together form a saturated, partially saturated or aromatic 5-7 membered ring, having 0-3 heteroatoms chosen from oxygen, sulfur, nitrogen and phosphorus, that is fused to Ring A;
X is a C-ι-5 alkylene chain, wherein said Cι_5 alkylene chain is optionally substituted by one or more groups chosen from =O, =S and halo, and wherein said C1-5 alkylene chain optionally contains 1 -3 heteroatoms chosen from oxygen, sulfur, nitrogen and phosphorus;
Ring A is a saturated, partially saturated or aromatic 5-6 membered monocyclic or 8-10 membered bicyclic ring having 0-5 ring heteroatoms chosen from oxygen, sulfur and nitrogen; each R2 is independently chosen from -OR0, -C(O)R°, -C(O)N(R°)2, -N(R°)(-Vm-R+), -S(O)2-R°, -S(O)2-N(R°)2, -(CH2)a-N(R°)(-Vb-R+), -(CH2)a-(-Vb-R+), halo, alkyl, aryl, carbocyclyl, heteroaryl and heterocyclyl, wherein said alkyl is optionally substituted by one or more R7, said aryl or heteroaryl is optionally substituted by one or more R6, and said carbocyclyl or heterocyclyl is optionally substituted by one or more R8; or two adjacent R2s on Ring A are optionally taken together to form a fused, saturated, partially saturated or aromatic 4-7 membered ring having 0-3 heteroatoms chosen from oxygen, sulfur, nitrogen and phosphorus; or two geminal R2s are optionally taken together to form a spiro, saturated, partially saturated or aromatic 5-6 membered ring having 0-3 heteroatoms chosen from oxygen, sulfur and nitrogen, said fused or spiro ring being optionally substituted by one or more groups chosen from oxo, alkyl optionally substituted by one or more R7, and aryl optionally substituted by one or more R6; each a is independently 0-3; each b is independently 0 or 1 ;
V is alkyl, -C(O)-, -S(0)2-, -C(O)O-, or -C(O)-N(R0)- (when V is attached to R+ through the right hand side of the radical;
R+ is alkyl, aralkyl, aryl, heteroaryl, heteroaralkyl, wherein said alkyl is optionally substituted by one or more R7 and said aralkyl or aryl is optionally substituted by one or more R6; m is 0 or 1 ; n is 0-5;
R3 is H, halo, -N(R°)2, -N(R°)C(O)R°, -CN, -CF3, alkyl optionally substituted by one or more groups chosen from R7 and -S-aryl optionally substituted by -(CH2)ι-6-N(R0)SO2(R°), carbocyclyl, aryl, heteroaryl or heterocyclyl, wherein said carbocyclyl or heterocyclyl is optionally substituted by one or more R8, and said aryl or heteroaryl is optionally substituted by one or more R6;
Y is -(CR4R5)p- -C(O)-, -C(O)C(O)-, -C(S)-, -O-(CH2)o-4-C(O)-, -N(R°)-C(O)-, -C(O)-N(R0)-, -N(R°)-C(S)-, -S(O)r. -O-C(=N-CN)-, -O-C(=N-R0)-, -S-C(=N-CN)-, -N(R°)-C(=N-CN)-, -C(=N-CN)-, -N(R°)-C[=N-C(O)-R0]-, -N(R°)-C[=N-S(O)t-R0]-, -N(R°)-C(=N-OR°)->
-N(R°)-C(=N-R0)-, -C(=N-R0)-, -(CH2)o-4-C(O)-O-, -C(=N-CN)-O-, -C(=N-R°)-O-, or -C(=N-CN)-S- when Y is attached to R3 through the left hand side of the radical; each R4 is independently H or alkyl optionally substituted by R7; each R5 is independently chosen from H, -C(O)-OR°, aryl optionally substituted by R6, -C(O)-OR6, -C(O)-N(R°)2, -S(O)2-N(R°)2, -S(O)2-R°, and heteroaryl optionally substituted by R6; p is 1-5; t is 1 or 2; each R6 is independently chosen from halo, -CF3, -OCF3, -OR0, -SR°, -SCF3, -R°, methylenedioxy, ethylenedioxy, -NO2, -CN, -N(R°)2, -NR°C(O)R°, -NR°C(O)N(R°)2, -NR°C(S)N(R°)2, -NR°CO2R0, -NR°NR°C(O)R°, -NR°NR0C(O)N(R0)2, -NR°NR°CO2R°, -C(O)C(O)R°, -C(O)CH2C(O)R°, -CO2R°, -O-C(O)R°, -C(O)R°, -C(O)N(R°)2, -OC(O)N(R°)2) -S(O)tR°, -S(O)t-OR°, -SO2N(R°)C(O)R0, -NR°SO2N(R0)2, -NR°SO2R0, -C(=S)N(R°)2> -C(=NH)-N(R°)2, -C(=N-OR°)-N(R°)2, -O-(CH2)0.6-SO2N(R0)2, -(CH2)1.6NHC(O)R°, -SO2N(R°)2, -(CH2)ι-6-OR0, -(CH2)ι.6-SR0, -(CH2)ι-6-CN, -(CH2)1.6-N(R°)2, -(CH2)i.6CO2R0, -C(O)N(R°)N(R°)2, -C(O)N(R°)OH, -C(O)N(R0)SO2R0, -S(O)tN(R°)OR, and -(CH2)ι-6-C(O)R°, wherein the two R°s on the same nitrogen optionally taken together forming a 5-8 membered saturated, partially saturated or aromatic ring having additional 0-4 ring heteroatoms chosen from oxygen, nitrogen, sulfur and phosphorus; each R7 is independently chosen from halogen, -CF3, -R°, -OR0, -SR°, aryl optionally substituted by R6, -NO2, -CN, -N(R°)2, -NR°C(O)R°, -NR°C(O)N(R0)2, -N(R°)C(S)N(R°)2, -NR°CO2R0, -NR°NR°C(O)R°, -NR°NR°C(O)N(R°)2, -NR°NR0CO2R0, -C(O)C(O)R°, -C(O)CH2C(O)R°, -CO2R0, -C(O)R°, -C(O)N(R0)-N(R°)2, -C(O)N(R°)2, -C(O)NR°SO2R0, -OC(O)N(R°)2) -S(O)tR°, -NR°SO2N(R0)2) -NR0SO2R°, -C(=S)N(R°)2, -C(=NH)-N(R°)2, -(CH2)ι-6-C(O)R°, -SO2N(R0)2j -OCF3j -SCF3, -(CH2)ι.6-SR0, methylenedioxy, ethylenedioxy, -(CH2)ι-6-CN, -(CH2)ι-6-N(R°)2, -S(O)tN(R°)OR°, -(CH^-e-CfOJR0, -C(=N-OR0)-N(R°)2, -O-(CH2)o-6-SO2N(R0)2, and -(CH2)ι-6-NHC(O)R°, wherein the two R°s on the same nitrogen optionally taken together form a 5-8 membered saturated, partially saturated or aromatic ring having additional 0-4 ring heteroatoms chosen from oxygen, nitrogen, sulfur and phosphorous; each R8 is independently chosen from R7, =O, =S, =N(R°), and =N(CN); each R >o is independently chosen from R*, -C(O)-aralkyl, -S(O) heteroaryl, carbocyclylalkyl, aralkyl, heteroaralkyl, and heterooyclylalkyl, wherein each member of R° except H is optionally substituted by one or more groups chosen from R*, -OR*, N(R*)2, =O, =S, halo, -CF3, -NO2, -CN, -C(O)R*, -CO2R*. -C(O)-aryl, -C(O)-heteroaryl, -O-aryl, aralkyl, -S(O)t-aryl, -NR*SO2R*, -NR*C(0)R*, -NR*C(O)N(R*)2) -N(R*)C(S)N(R*)2, -NR*CO2R*, -NR*NR*C(O)R*, -NR*NR*C(O)N(R*)2, -NR*NR*CO2R*, -C(O)C(O)R*, -C(O)CH2C(O)R*, -C(O)N(R*)N(R*)2, -C(O)N(R*)2, -C(O)NR*SO2R*, -OC(O)N(R*)2) -S(O)tR*, -NR*SO2N(R*)2, and -SO2N(R*)2 wherein the two R*s on the same nitrogen optionally taken together form a 5-8 membered saturated, partially saturated or aromatic ring having additional 0-4 ring heteroatoms chosen from oxygen, nitrogen, sulfur and phosphorus; and each R* is independently H, alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl.
2. The compound according to claim 1 having one or more of the features selected from the group consisting of:
(a) R1 is alkyl, aryl, heteroaryl or heterocyclyl, wherein said alkyl is optionally substituted by one or more R7, said aryl or heteroaryl is optionally substituted by one or more R6, and said heterocyclyl is optionally substituted by one or more R8;
(b) X is a C-1-5 alkylene chain optionally substituted by one or more groups chosen from =O and halo;
(c) Ring A is an 8-10 membered bicyclic ring having 0-5 ring heteroatoms chosen from oxygen, sulfur and nitrogen;
(d) R2 is aryl, heteroaryl or heterocyclyl, wherein said aryl or heteroaryl is optionally substituted by one or more R6 and said heterocyclyl is optionally substitued by one or more R8;
(e) Y is -C(R°)[C(O)OR0]-, -C(O)-, -O-C(O)-, -N(R°)-C(O)-, -S(O)2-, -O-C(=N-CN)-, -S-C(=N-CN)-, -N(R°)-C(=N-CN)-, -C(=N-CN)-, -N(R°)-C(S)-, -N(R°)-C(=N-OR0)-, -N(R°)-C[=N-S(O)rR0], -O-C(=N-R0)-( -N(R°)-C[=N-C(O)-R°], -N(R°)-C(=N-R0)-, or -C(=N-R0)-; wherein each R° is independently R* and m is 1 ; and
(f) R3 is alkyl, aryl, heteroaryl, heterocyclyl or carbocyclyl, wherein said alkyl is optionally substituted by one or more R7, said aryl or heteroaryl is optionally substituted by one or more R6, and said heterocyclyl or carbocyclyl is optionally substituted by one or more R8.
3. The compound according to claim 2, wherein:
(a) R1 is aryl optionally substituted by one or more R6;
(b) X is a C2 alkylene chain optionally substituted by one or more groups chosen from =O and halo;
(c) Ring A is an 8-9 membered bicyclic ring having one ring nitrogen and 0-4 additional ring heteroatoms chosen from oxygen, sulfur and nitrogen;
(d) R2 is heteroaryl optionally substituted by one or more Rβ, or heterocyclyl optionally substituted by one or more R8;
(e) Y is -C(R°)[C(O)OR0]-, -CH(COOH)-, -0(0)-, -O-C(O)-, S(0)t-, -N(R°)-C(0)-, -0-C(=N-CN)-, or -N(R°)-C(S)-; wherein each R° is independently R* and m is 1 ; and
(f) R3 is alkyl optionally substituted by one or more R7, aryl or heteroaryl wherein said aryl or heteroaryl is optionally substituted by one or more R6.
4. The compound of claim 1 wherein R1 is optionally substitued aryl.
5. The compound of claim 4 wherein R1 is phenyl mono- or di- substituted with halogen.
6. The compound of claim 5 wherein R is phenyl substituted with F.
7. The compound of claim 1 wherein m is 1 , Y is selected from the group consisting of
Figure imgf000820_0001
8. The compound of claim 1 wherein m is 1 , and Y-R3 selected from the group consisting of
Figure imgf000820_0002
Figure imgf000821_0001
Figure imgf000822_0001
Figure imgf000823_0001
Figure imgf000823_0002
Figure imgf000823_0004
Figure imgf000823_0003
Figure imgf000824_0001
. The compound of claim 1 wherein m is 1 , Y-R3 is selected from the group consisting of
Figure imgf000825_0001
10. The compound of claim 1 wherein m is 0, R is directly attached to N, and R3 is optionally substituted aryl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, or optionally substituted heterocyclyl.
11. The compound of claim 1 wherein m is 1 , Y-R3 is selected from the group consisting of
Figure imgf000825_0002
12. The compound of claim 1 wherein m is 1 , Y is -0(O)O-, and R3 is optionally substituted alkyl or optionally substituted aryl.
13. The compound of claim 1 where X is -(CH2)-, -(CH2-CH2)-, or — (CH2-CH2-CH2)-.
14. The compound of claim 13 wherein X is optionally substituted by one or more halogen or oxo.
15. The compound of claim 14 wherein X is disubstituted with halogen.
16. The compound of claim 15 wherein X is disubstituted with fluoro.
17. The compound of claim 16 wherein X is -(CF2-CH2)-.
18. The compound of claim 13 wherein X optionally has 1-3 heteroatoms selected from oxygen, phosphorus, sulfur, and nitrogen.
19. The compound of claim 1 wherein the A ring is selected from, where the asterisk (*) indicates the preferred, but not limiting point(s) of substitution,
Figure imgf000827_0001
Figure imgf000827_0002
Figure imgf000827_0003
20. The compound of claim 1 wherein each R2, with an asterisk indicating a point of substitution from ring A, independently is selected from the group consisting of
Figure imgf000828_0001
-Y O - uft *γ u> *~ ott -ft u »
Figure imgf000828_0002
Figure imgf000828_0003
Figure imgf000829_0001
Figure imgf000830_0001
21. The compound of claim 1 wherein the A ring, with two geminal R2s, is selected from the group consisting of
Figure imgf000831_0001
22. The compound of claim 1 wherein the A ring is tropane or piperidine, either optionally substituted with one or more R2.
23. The compound of claim 22 wherein the A ring in combination with R2 is
Figure imgf000831_0002
Figure imgf000832_0001
Figure imgf000833_0001
Figure imgf000834_0001
24. The compound according to claim 1 selected from among the group consisting of:
Figure imgf000835_0001
Figure imgf000836_0001
Figure imgf000837_0001
Figure imgf000838_0001
Figure imgf000839_0001
Figure imgf000840_0001
Figure imgf000841_0001
Figure imgf000842_0001
Figure imgf000843_0001
843
Figure imgf000844_0001
844
Figure imgf000845_0001
O 2004/054974
845
Figure imgf000846_0001
O 20040
846
Figure imgf000847_0001
847
Figure imgf000848_0001
O 2004/054974
Figure imgf000849_0001
849
Figure imgf000850_0001
O 2004
850
Figure imgf000851_0001
Figure imgf000851_0002
Figure imgf000851_0003
Figure imgf000852_0001
25. A composition comprising a compound according to Claim 1 and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
26. The composition according to claim 25 further comprising a second therapeutic agent.
27. The composition according to claim 25 in the form of a tablet or capsule.
28. The composition according to claim 25 in the form of a liquid.
29. The composition according to claim 26, wherein said second therapeutic agent is chosen from (1 -alpha, 2-beta, 3-alpha)-9-[2,3-bis(hydroxy methyl)cyclobutyl]guanine [(-)BHCG, SQ-34514, lobucavir], 9-[(2R,3R,4S)- 3,4-bis(hydroxy methyl)-2-oxetanosyl]adenine (oxetanocin-G), acyclic nucleosides, ribonucleotide reductase inhibitors, nucleoside reverse transcriptase inhibitors, protease inhibitors, interferons, renal excretion inhibitors, nucleoside transport inhibitors, immunomodulators, non- nucleoside reverse transcriptase inhibitors, glycoprotein 120 antagonists, cytokine antagonists, integrase inhibitors, and fusion inhibitors.
30. The composition according to claim 29, wherein said acyclic nucleoside is chosen from acyclovir, valaciclovir, famciclovir, ganciclovir, penciclovir, acyclic nucleoside phosphonates, (S)-1-(3-hydroxy-2-phosphonyl- methoxypropyl)cytosine (HPMPC), [[[2-(6-amino-9H-purin-9- yl)ethoxy]methyl]phosphinylid-ene]bis(oxymethylene)-2,2- dimethylpropanoic acid (bis-POM PMEA, adefovir dipivoxil), [[(1 R)-2-(6- amino-9H-purin-9-yl)-1 -methylethoxy]methyl]phosphonic acid (tenofovir) and (R)-[[2-(6-Amino-9H-purin-9-yl)-1-methylethoxy]methyl]phosphonic acid bis-(isopropoxycarbonyloxymethyl)ester (bis-POC-PMPA).
31. The composition according to claim 29, wherein said ribonucleotide reductase inhibitor is chosen from 2-acetylpyridine 5-[(2-chloroanilino) thiocarbonyl)thiocarbonohydrazone and hydroxyurea.
32. The composition according to claim 29, wherein said nucleoside reverse transcriptase inhibitor is chosen from 3'-azido-3'-deoxythymidine (AZT, zidovudine), 2',3'-dideoxycytidine (ddC, zalcitabine), 2',3'- dideoxyadenosine, 2',3'-dideoxyinosine (ddl, didanosine), 2',3'-didehydro thymidine (d4T, stavudine), (-)-beta-D-2,6-diamino purine dioxolane (DAPD), 3'-azido-2',3'-dideoxy thymidine-5'-H-phosphophonate (phosphonovir), 2'-deoxy-5-iodo-uridine (idoxuridine), (-)-cis-1 -(2-hydroxy methyl)-1 ,3-oxathiolane 5-yl)-cytosine (lamivudine), cjs-1-(2- (hydroxymethyl)-l ,3-oxathiolan-5-yl)-5-fluorocytosine (FTC), 3'-deoxy-3'- fluorothymidine, 5-chloro-2',3'-dideoxy-3'-fluorouridine, (-)-cis-4-[2-amino- 6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1 -methanol (abacavir), 9-[4-hydroxy-2-(hydroxymethyl)but-1-yl]-guanine (H2G), and ABT-606 (2HM-H2G) ribavirin.
33. The composition according to claim 29, wherein said protease inhibitor is chosen from indinavir, ritonavir, nelfinavir, amprenavir, saquinavir, fosamprenavir, (R)-N-tert-butyl-3-[(2S,3S)-2-hydroxy-3-N-[(R)-2-N- (isoquinolin-5-yloxyacetyl) amino-3-methylthiopropanoyl]amino-4- phenylbutanoyl]-5,5-dimethyl-1 ,3-thiazolidine-4-carboxamide (KNI-272), 4R-(4alpha,5alpha,6beta)]-1 ,3-bis[(3-aminophenyl) methyl]hexahydro-5,6- dihydroxy-4,7-bis(phenylmethyl)-2H-1 ,3-diazepin-2-one dimethanesulfonate (mozenavir), 3-[1 -[3-[2-(5-trifluoromethylpyridinyl)- sulfonylamino] phenyl]propyl]-4-hydroxy-6alpha-phenethyl-6beta-propyl- 5,6-dihydro-2-pyranone (tipranavir), N'-[2(S)-Hydroxy-3(S)-[N- (methoxycarbonyl)-l-tert-leucylamino]-4- phenylbutyl-Nalpha- (methoxycarbonyl)-N'-[4-(2-pyridyl)benzyl]-L-tert-leucylhydrazide (BMS- 232632), 3-(2(S)-Hydroxy-3(S)-(3-hydroxy-2-methylbenzamido)-4- phenylbutanoyl)-5,5-dimethyl-N-(2-methylbenzyl) thiazolidine-4(R)- carboxamide (AG-1776), and N-(2(R)-hydroxy-1(S)-indanyl)-2(R)-phenyl- methyl-4(S)-hydroxy-5-(1-(1-(4-benzo[b]furanylmethyl)-2(S)-N,-(tert- butylcarboxamido)piperazinyl)pentanamide (MK-944A).
34. The composition according to claim 29, wherein said interferon is α- interferon.
35. The composition according to claim 29, wherein said renal excretion inhibitor is probenecid.
36. The composition according to claim 29, wherein said nucleoside transport inhibitor is chosen from dipyridamole, pentoxifylline, N- acetylcysteine (NAC), Procysteine, α -trichosanthin and phosphono-formic acid.
37. The composition according to claim 29, wherein said immunomodulator is chosen from interleukin II, thymosin, granulocyte macrophage colony stimulating factors, erythropoetin, soluble CD4 and genetically engineered derivatives thereto.
38. The composition according to claim 29, wherein said non-nucleoside reverse transcriptase inhibitor (NNRTI) is chosen from nevirapine (BI-RG- 587), alpha-((2-acetyl-5-methyl phenyl)amino)-2,6-dichloro- benzeneacetamide (loviride), 1-[3-(isopropyl amino)-2-pyridyl]-4-[5- (methane-sulfonamido)-1H-indol-2-ylcarbonyl]piperazine monomethanesulfonate (delavirdine), (10R, 11S, 12S)-12-hydroxy-6, 6, 10, 11-tetramethyl-4-propyl-11 ,12-dihydro-2H, 6H, 10H-benzo(1 , 2-b:3, 4- b':5, 6-b")tripyran-2-one ((+) calanolide A), (4S)-6-chloro-4-[1 E)- cyclopropylethenyl)-3,4- dihydro-4-(trifluoro-methyl)-2(1 H)-quinazolinone (DPC-083), (S)-6-chloro-4-(cyclopropylethynyl)-1 ,4-dihydro-4- (trifluoromethyl)-2H-3,1-benzoxazin-2-one (efavirenz, DMP 266), 1- (ethoxymethyl)-5-(1-methylethyl)-6-(phenylmethyl)-2,4(1H,3H)- pyrimidinedione (MKC-442), and 5-(3,5-dichlorophenyl)thio-4-isopropyl-1- (4-pyridyl)methyl-1 H-imidazol-2-ylmethyl carbamate (capravirine).
39. The composition according to claim 29, wherein said glycoprotein 120 antagonist is chosen from PRO-2000, PRO-542, and 1 ,4-bis[3-[(2,4- dichlorophenyl) carbonylamino]-2-oxo-5,8-disodiumsulfanyl]naphthalyl-2, 5-dimethoxyphenyl-1 ,4-dihydrazone (FP-21399).
40. The composition according to claim 29, wherein said cytokine antagonists is chosen from reticulose (Product-R), 1 ,1'-azobis-formamide (ADA), and 1 ,11-(1 ,4-phenylene bis(methylene))bis-1 ,4,8,11-tetraaza cyclotetradecane octahydrochloride (AMD-3100).
41. The composition according to claim 33, wherein said protease inhibitor is ritonavir.
42. A method of antagonizing a chemokine CCR-5 receptor activity in a patient in need thereof comprising administering to said patient a therapeutically effective amount of a composition according to claim 25.
43. A method of antagonizing a chemokine CCR-5 receptor activity in a biological sample, comprising contacting the biological sample with an effective amount of a compound according to Claim 1 or a composition according to claim 25.
44. A method of treating a viral infection in a patient comprising administering to said patient a therapeutically effective amount of a composition according to claim 25.
45. The method according to claim 44 wherein the viral infection is an HIV infection.
46. A method of treating of a viral infection in a patient comprising administering to said patient a therapeutically effective amount of a composition according to Claim 26.
47. The method according to claim 33 wherein the viral infection is an HIV infection.
48. A method of treating a disease or disorder selected from AIDS related complex, progressive generalized lymphadenopathy, Kaposi's sarcoma, thromobocytopenic purpura, AIDS-related neurological conditions, multiple sclerosis, tropical paraperesis, anti-HIV antibody-positive, or HIV-positive conditions in a patient in need thereof comprising administering to said patient a therapeutically effective amount of a composition according to claim 25.
49. The method according to claim 48, wherein said disease or disorder is AIDS related complex, Kaposi's sarcoma or AIDS dementia.
50. A method of treating a disease or disorder selected from AIDS related complex, progressive generalized lymphadenopathy, Kaposi's sarcoma, thromobocytopenic purpura, AIDS-related neurological conditions, multiple sclerosis, tropical paraperesis, anti-HIV antibody-positive, or HIV-positive conditions in a patient in need thereof comprising administering to said patient a therapeutically effective amount of a composition according Claim 26.
51. The method according to claim 50, wherein said disease or disorder is AIDS related complex, Kaposi's sarcoma or AID dementia.
52. A method of treating or preventing multiple sclerosis, rheumatoid arthritis, autoimmune diabetes, chronic implant rejection, asthma, rheumatoid arthritis, Crohns Disease, inflammatory bowel disease, chronic inflammatory disease, glomerular disease, nephrotoxic serum nephritis, kidney disease, Alzheimer's Disease, autoimmune encephalomyelitis, arterial thrombosis, allergic rhinitis, arteriosclerosis, Sjogren's syndrome, systemic lupus erythematosus, graft rejection, cancers with leukocyte infiltration of the skin or organs, human papilloma virus infection, prostate cancer, wound healing, amyotrophic lateral sclerosis, immune-mediated disorders, or bacterial infections in a patient in need thereof comprising administering to said patient a therapeutically effective amount of a composition according to claim 25.
53. A method of treating or preventing multiple sclerosis, rheumatoid arthritis, autoimmune diabetes, chronic implant rejection, asthma, rheumatoid arthritis, Crohns Disease, inflammatory bowel disease, chronic inflammatory disease, glomerular disease, nephrotoxic serum nephritis, kidney disease, Alzheimer's Disease, autoimmune encephalomyelitis, arterial thrombosis, allergic rhinitis, arteriosclerosis, Sjogren's syndrome (dermatomyositis), systemic lupus erythematosus, graft rejection, cancers with leukocyte infiltration of the skin or organs, human papilloma virus infection, prostate cancer, wound healing, amyotrophic lateral sclerosis or immune-mediated disorders in a patient in need thereof comprising administering to said patient a therapeutically effective amount of a composition according to Claim 26.
54. A compound according to any one of claims 1-24 for use in medical therapy.
55. Use of a compound according to any one of claims 1-24 in the manufacture of a medicament for the treatment of a viral infection.
56. The use according to claim 55 wherein the viral infection is an HIV infection.
57. Use of a compound according to any one of claims 1-24 in the manufacture of a medicament for the treatment or prophylaxis of a disease or disorder selected from AIDS related complex, progressive generalized lymphadenopathy, Kaposi's sarcoma, thromobocytopenic purpura, AIDS- related neurological conditions, multiple sclerosis, tropical paraperesis, anti-HIV antibody-positive, and HIV-positive conditions.
58. The use according to claim 57 wherein said disease or disorder is AIDS related complex, Kaposi's sarcoma or AID dementia.
59. A use of a compound according to any one of claims 1-24 in the manufacture of a medicament for the treatment of multiple sclerosis, rheumatoid arthritis, autoimmune diabetes, chronic implant rejection, asthma, rheumatoid arthritis, Crohns Disease, inflammatory bowel disease, chronic inflammatory disease, glomerular disease, nephrotoxic serum nephritis, kidney disease, Alzheimer's Disease, autoimmune encephalomyelitis, arterial thrombosis, allergic rhinitis, arteriosclerosis, Sjogren's syndrome, systemic lupus erythematosus, graft rejection, cancers with leukocyte infiltration of the skin or organs, human papilloma virus infection, prostate cancer, wound healing, amyotrophic lateral sclerosis or immune-mediated disorders.
60. The use according to any one of claims 55-59, said medicament further comprises a second therapeutic agent.
61. The use according to claim 60 wherein said second therapeutic agent is chosen from (1 -alpha, 2-beta, 3-alpha)-9-[2,3-bis(hydroxy methyl)cyclobutyl] guanine [(-)BHCG, SQ-34514, lobucavir], 9- [(2R,3R,4S)-3,4-bis(hydroxy methyl)-2-oxetanosyl]adenine (oxetanocin-G), acyclic nucleosides, ribonucleotide reductase inhibitors, nucleoside reverse transcriptase inhibitors, protease inhibitors, interferons, renal excretion inhibitors, nucleoside transport inhibitors, immunomodulators, non-nucleoside reverse transcriptase inhibitors, glycoprotein 120 antagonists, cytokine antagonists, integrase inhibitors, and fusion inhibitors.
PCT/US2003/039644 2002-12-13 2003-12-12 Piperidine derivatives as ccr5 antagonists WO2004054974A2 (en)

Priority Applications (8)

Application Number Priority Date Filing Date Title
JP2004560838A JP2006511554A (en) 2002-12-13 2003-12-12 Piperidine derivatives as CCR5 antagonists
US10/538,144 US7645771B2 (en) 2002-12-13 2003-12-12 CCR5 antagonists as therapeutic agents
AU2003300902A AU2003300902A1 (en) 2002-12-13 2003-12-12 Piperidine derivatives as CCR5 antagonists
EP03813419A EP1569646A2 (en) 2002-12-13 2003-12-12 Piperidine derivatives as ccr5 antagonists
CA002509711A CA2509711A1 (en) 2002-12-13 2003-12-12 Piperidine derivatives as ccr5 antagonists
BR0317230-9A BR0317230A (en) 2002-12-13 2003-12-12 Compound, composition, methods of antagonizing a ccr-5 chemokine receptor activity, and treating a viral infection in a patient, and use of a compound
MXPA05006354A MXPA05006354A (en) 2002-12-13 2003-12-12 Piperidine derivatives as ccr5 antagonists.
NO20052739A NO20052739L (en) 2002-12-13 2005-06-07 CCR5 antagonists as drugs

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US43363402P 2002-12-13 2002-12-13
US60/433,634 2002-12-13

Publications (2)

Publication Number Publication Date
WO2004054974A2 true WO2004054974A2 (en) 2004-07-01
WO2004054974A3 WO2004054974A3 (en) 2004-09-02

Family

ID=32595222

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2003/039644 WO2004054974A2 (en) 2002-12-13 2003-12-12 Piperidine derivatives as ccr5 antagonists

Country Status (15)

Country Link
US (1) US7645771B2 (en)
EP (1) EP1569646A2 (en)
JP (1) JP2006511554A (en)
KR (1) KR20050087832A (en)
CN (1) CN1744899A (en)
AU (1) AU2003300902A1 (en)
BR (1) BR0317230A (en)
CA (1) CA2509711A1 (en)
CO (1) CO5580771A2 (en)
MA (1) MA27647A1 (en)
MX (1) MXPA05006354A (en)
NO (1) NO20052739L (en)
RU (1) RU2005118407A (en)
WO (1) WO2004054974A2 (en)
ZA (1) ZA200505600B (en)

Cited By (64)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004108662A1 (en) * 2003-05-15 2004-12-16 Kumiai Chemical Industry Co., Ltd. Phenylsulfonyl carbamate derivative and plant disease control agent for agricultural or horticultural use
WO2005101989A2 (en) * 2004-04-23 2005-11-03 Astrazeneca Ab Piperidine derivatives as modulators of chemokine receptor ccr5
WO2006001751A1 (en) * 2004-06-24 2006-01-05 Astrazeneca Ab Chemical compounds i
JP2007517010A (en) * 2003-12-24 2007-06-28 プロシディオン・リミテッド Heterocyclic derivatives as GPCR receptor agonists
WO2007107565A1 (en) * 2006-03-22 2007-09-27 Glaxo Group Limited Benzimidazoles which have activity at m1 receptor and their uses in medicine
WO2007130712A1 (en) * 2006-01-31 2007-11-15 Janssen Pharmaceutica, Nv Substituted dipiperidine as ccr2 antagonists for the treatment of inflammatory diseases
WO2007138974A1 (en) * 2006-05-26 2007-12-06 Toyama Chemical Co., Ltd. Novel heterocyclic compound or salt thereof and intermediate thereof
WO2008004100A2 (en) 2006-07-05 2008-01-10 Pfizer Products Inc. Therapeutic compounds
WO2008011453A2 (en) * 2006-07-20 2008-01-24 Amgen Inc. SUBSTITUTED AZOLE AROMATIC HETEROCYCLES AS INHIBITORS OF LLβ-HSD-1
WO2008034731A1 (en) * 2006-09-18 2008-03-27 F. Hoffmann-La Roche Ag Octahydropyrrolo [3, 4-c] pyrrole derivatives an their use as antiviral agents
WO2008075070A1 (en) * 2006-12-21 2008-06-26 Astrazeneca Ab Sulfonamide derivatives for therapeutic use as fatty acid synthase inhibitors
WO2009049113A1 (en) * 2007-10-11 2009-04-16 Glaxo Group Limited Piperidinylhydroxyethylpiperidines as modulators of chemokine receptors
WO2009051112A1 (en) 2007-10-15 2009-04-23 Takeda Pharmaceutical Company Limited Amide compounds and use of the same
US7576106B2 (en) 2005-10-11 2009-08-18 Chemocentryx, Inc. Piperidine derivatives and methods of use
WO2009111278A2 (en) * 2008-02-29 2009-09-11 Array Biopharma Inc. Raf inhibitor compounds and methods of use thereof
WO2010018131A1 (en) 2008-08-11 2010-02-18 Smithkline Beecham Corporation Purine derivatives for use in the treatment of allergic, inflammatory and infectious diseases
WO2010080864A1 (en) 2009-01-12 2010-07-15 Array Biopharma Inc. Piperidine-containing compounds and use thereof
WO2011011652A1 (en) 2009-07-24 2011-01-27 Glaxosmithkline Llc Therapeutic compounds
EP2322515A1 (en) * 2008-08-29 2011-05-18 JSR Corporation N-carboxy amino acid anhydride and amino acid carbamate compound production method
US7956184B2 (en) 2006-07-07 2011-06-07 Gilead Sciences, Inc. Pyridazine compound and use thereof
WO2011098451A1 (en) 2010-02-10 2011-08-18 Glaxosmithkline Llc Purine derivatives and their pharmaceutical uses
WO2011098452A1 (en) 2010-02-10 2011-08-18 Glaxosmithkline Llc 6-amino-2-{ [ (1s)-1-methylbutyl] oxy}-9-[5-(1-piperidinyl)-7,9-dihydro-8h-purin-8-one maleate
US8012955B2 (en) 2006-12-28 2011-09-06 Rigel Pharmaceuticals, Inc. N-substituted-heterocycloalkyloxybenzamide compounds and methods of use
US8097610B2 (en) 2005-08-26 2012-01-17 Shionogi & Co., Ltd. Derivative having PPAR agonistic activity
US8119809B2 (en) 2007-11-16 2012-02-21 Rigel Pharmaceuticals, Inc. AMPK-activating heterocycloalkyloxy(hetero)aryl carboxamide, sulfonamide and amine compounds and methods for using the same
US8129390B2 (en) 2007-12-12 2012-03-06 Rigel Pharmaceuticals, Inc. Carboxamide, sulfonamide and amine compounds and methods for using the same
WO2012017166A3 (en) * 2010-07-19 2012-07-19 Vaxconsulting Benzenesulfonamide-compound treatment of a pathological condition linked to an excessive effect of tnf
US8283364B2 (en) 2005-09-30 2012-10-09 Glaxo Group Limited Compounds which have activity at M1 receptor and their uses in medicine
US8288412B2 (en) 2005-09-30 2012-10-16 Glaxo Group Limited Compounds which have activity at M1 receptor and their uses in medicine
US8288413B2 (en) 2005-09-30 2012-10-16 Glaxo Group Limited Benzimidazolones which have activity at M1 receptor
US8314107B2 (en) 2008-04-23 2012-11-20 Rigel Pharmaceuticals, Inc. Carboxamide compounds and methods for using the same
US8344000B2 (en) 2007-09-20 2013-01-01 Glaxo Group Limited Compounds which have activity at M1 receptor and their uses in medicine
WO2013090664A1 (en) 2011-12-16 2013-06-20 Glaxosmithkline Llc Derivatives of betulin
US8598164B2 (en) 2010-05-06 2013-12-03 Vertex Pharmaceuticals Incorporated Heterocyclic chromene-spirocyclic piperidine amides as modulators of ion channels
WO2014062044A1 (en) 2012-10-15 2014-04-24 Vilnius University Fluorinated benzenesulfonamides as inhibitors of carbonic anhydrase
US8796321B2 (en) 2008-04-21 2014-08-05 Path Drug Solutions Compounds, compositions and methods comprising oxadiazole derivatives
US8828996B2 (en) 2011-03-14 2014-09-09 Vertex Pharmaceuticals Incorporated Morpholine-spirocyclic piperidine amides as modulators of ion channels
US8916565B2 (en) 2011-02-02 2014-12-23 Vertex Pharmaceuticals Incorporated Pyrrolopyrazine-spirocyclic piperidine amides as modulators of ion channels
WO2015031722A1 (en) * 2013-08-30 2015-03-05 Ramot At Tel-Aviv University Ltd. Method for treating amyotrophic lateral sclerosis by inhibition of cxcr4/cxcl12 signaling
AU2012200933B2 (en) * 2005-06-22 2015-04-30 Plexxikon, Inc. Pyrrolo [2, 3-B] pyridine derivatives as protein kinase inhibitors
WO2015124591A1 (en) 2014-02-20 2015-08-27 Glaxosmithkline Intellectual Property (No.2) Limited Pyrrolo[3,2] pyrimidine derivatives as inducers of human interferon
EP2395004B1 (en) * 2005-06-22 2016-01-20 Plexxikon Inc. Pyrrolo [2,3-b]pyridine derivatives as protein kinase inhibitors
EP3000813A1 (en) 2008-08-11 2016-03-30 GlaxoSmithKline LLC Purine derivatives for use in the treatment of allergic, inflammatory and infectious diseases
WO2016075661A1 (en) 2014-11-13 2016-05-19 Glaxosmithkline Biologicals Sa Adenine derivatives which are useful in the treatment of allergic diseases or other inflammatory conditions
EP2930170A4 (en) * 2012-12-06 2016-05-25 Kyowa Hakko Kirin Co Ltd Pyridone compound
WO2016073774A3 (en) * 2014-11-05 2016-07-07 Flexus Biosciences, Inc. Immunoregulatory agents
WO2017017505A1 (en) 2015-07-28 2017-02-02 Vilnius University Selective inhibitors of carbonic anhydrase
US9624213B2 (en) 2011-02-07 2017-04-18 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
US9663517B2 (en) 2009-04-03 2017-05-30 Plexxikon Inc. Compositions and uses thereof
WO2017093933A1 (en) 2015-12-03 2017-06-08 Glaxosmithkline Intellectual Property Development Limited Cyclic purine dinucleotides as modulators of sting
US9695169B2 (en) 2012-05-31 2017-07-04 Plexxikon Inc. Synthesis of heterocyclic compounds
WO2017175147A1 (en) 2016-04-07 2017-10-12 Glaxosmithkline Intellectual Property Development Limited Heterocyclic amides useful as protein modulators
WO2017175156A1 (en) 2016-04-07 2017-10-12 Glaxosmithkline Intellectual Property Development Limited Heterocyclic amides useful as protein modulators
EP3246030A1 (en) 2008-08-11 2017-11-22 GlaxoSmithKline LLC Novel adenine derivatives
US10106556B2 (en) 2015-03-30 2018-10-23 Takeda Pharmaceutical Company Limited Heterocyclic compound
US10112939B2 (en) 2014-08-21 2018-10-30 Bristol-Myers Squibb Company Tied-back benzamide derivatives as potent rock inhibitors
WO2019069270A1 (en) 2017-10-05 2019-04-11 Glaxosmithkline Intellectual Property Development Limited Modulators of stimulator of interferon genes (sting)
WO2019069269A1 (en) 2017-10-05 2019-04-11 Glaxosmithkline Intellectual Property Development Limited Modulators of stimulator of interferon genes (sting) useful in treating hiv
US10385070B2 (en) 2011-02-18 2019-08-20 Vertex Pharmaceuticals Incorporated Chroman-spirocyclic piperidine amides as modulators of ion channels
WO2019219820A1 (en) 2018-05-16 2019-11-21 Ctxt Pty Limited Substituted condensed thiophenes as modulators of sting
WO2020232378A1 (en) 2019-05-16 2020-11-19 Silicon Swat, Inc. Benzo[b][1,8]naphthyridine acetic acid derivatives and methods of use
WO2020232375A1 (en) 2019-05-16 2020-11-19 Silicon Swat, Inc. Oxoacridinyl acetic acid derivatives and methods of use
WO2021009365A1 (en) 2019-07-18 2021-01-21 Ctxt Pty Limited Benzothiophene, thienopyridine and thienopyrimidine derivatives for the modulation of sting
WO2021009362A1 (en) 2019-07-18 2021-01-21 Ctxt Pty Limited Benzothiophene, thienopyridine and thienopyrimidine derivatives for the modulation of sting

Families Citing this family (38)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB0215293D0 (en) * 2002-07-03 2002-08-14 Rega Foundation Viral inhibitors
ATE405269T1 (en) * 2002-12-13 2008-09-15 Smithkline Beecham Corp CYCLOHEXYL COMPOUNDS AS CCR5 ANTAGONISTS
WO2005063744A2 (en) * 2003-12-22 2005-07-14 K.U. Leuven Research & Development IMIDAZO[4,5-c]PYRIDINE COMPOUNDS AND METHODS OF ANTIVIRAL TREATMENT
PL1841765T3 (en) * 2004-12-21 2009-08-31 Gilead Sciences Inc Imidazo[4,5-c]pyridine compound and method of antiviral treatment
US20080124355A1 (en) 2006-09-22 2008-05-29 David Gordon Bermudes Live bacterial vaccines for viral infection prophylaxis or treatment
WO2008063888A2 (en) 2006-11-22 2008-05-29 Plexxikon, Inc. Compounds modulating c-fms and/or c-kit activity and uses therefor
AR064181A1 (en) * 2006-12-06 2009-03-18 Genzyme Corp UNION COMPOUNDS TO CHEMIOKIN RECEPTORS
UA99466C2 (en) 2007-07-06 2012-08-27 Гилиад Сайенсиз, Инк. Crystalline pyridazine compound
WO2009058923A1 (en) * 2007-10-31 2009-05-07 Smithkline Beecham Corporation Ccr5 antagonists as therapeutic agents
WO2009058924A1 (en) * 2007-10-31 2009-05-07 Smithkline Beecham Corporation Ccr5 antagonists as therapeutic agents
WO2009075960A1 (en) * 2007-12-12 2009-06-18 Smithkline Beecham Corporation Ccr5 antagonists as therapeutic agents
US20110237528A1 (en) * 2008-09-19 2011-09-29 Institute For Oneworld Health Compositions and methods comprising imidazole and triazole derivatives
US20110016543A1 (en) * 2008-12-04 2011-01-20 Sigma-Aldrich Co. Genomic editing of genes involved in inflammation
US8241623B1 (en) 2009-02-09 2012-08-14 David Bermudes Protease sensitivity expression system
WO2010129681A1 (en) * 2009-05-05 2010-11-11 Van Andel Research Institute Methods for treating autophagy-related disorders
AR076936A1 (en) * 2009-06-02 2011-07-20 Vitae Pharmaceuticals Inc CARBAMATE AND UREA INHIBITORS OF THE 11 BETA HYDROXIESTEROID DEHYDROGENASE 1
ES2470329T3 (en) * 2009-08-28 2014-06-23 Daiichi Sankyo Company, Limited 3- (baryloxy) priopinic acid derivative
AU2010315126B2 (en) 2009-11-06 2015-06-25 Plexxikon, Inc. Compounds and methods for kinase modulation, and indications therefor
US9597379B1 (en) 2010-02-09 2017-03-21 David Gordon Bermudes Protease inhibitor combination with therapeutic proteins including antibodies
US8771669B1 (en) 2010-02-09 2014-07-08 David Gordon Bermudes Immunization and/or treatment of parasites and infectious agents by live bacteria
US8524220B1 (en) 2010-02-09 2013-09-03 David Gordon Bermudes Protease inhibitor: protease sensitivity expression system composition and methods improving the therapeutic activity and specificity of proteins delivered by bacteria
WO2014102594A2 (en) 2012-12-27 2014-07-03 Purdue Pharma L.P. Substituted benzimidazole-type piperidine compounds and uses thereof
US9593339B1 (en) 2013-02-14 2017-03-14 David Gordon Bermudes Bacteria carrying bacteriophage and protease inhibitors for the treatment of disorders and methods of treatment
WO2014139144A1 (en) * 2013-03-15 2014-09-18 Agios Pharmaceuticals, Inc. Therapeutic compounds and compositions
CN103497162B (en) * 2013-09-24 2015-08-26 西安近代化学研究所 The synthetic method of 2-(4,6-dimethyl pyrimidine-2-base carbamoylamino alkylsulfonyl) methyl benzoate
US8853407B1 (en) * 2013-12-07 2014-10-07 Muhammed Majeed Synthesis of 4-aryl 4-acyl piperidine, its salts and analogs using indium metal
JP2017525753A (en) 2014-06-06 2017-09-07 フレクサス・バイオサイエンシーズ・インコーポレイテッドＦｌｅｘｕｓ Ｂｉｏｓｃｉｅｎｃｅｓ， Ｉｎｃ． Immunomodulator
JP2017538678A (en) 2014-11-05 2017-12-28 フレクサス・バイオサイエンシーズ・インコーポレイテッドＦｌｅｘｕｓ Ｂｉｏｓｃｉｅｎｃｅｓ， Ｉｎｃ． Immunomodulator
UY36390A (en) 2014-11-05 2016-06-01 Flexus Biosciences Inc MODULATING COMPOUNDS OF INDOLAMINE ENZYME 2,3-DIOXYGENASE (IDO), ITS SYNTHESIS METHODS AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
MX2018005215A (en) 2015-11-06 2018-08-01 Neurocrine Biosciences Inc N-[2-(1 -benzylpiperidin-4-yl)ethyl]-4-(pyrazin-2-yl)-piperazine- 1 -carboxamide derivatives and related compounds as muscarinic receptor 4 (m4) antagonists for treating neurological diseases.
US11129906B1 (en) 2016-12-07 2021-09-28 David Gordon Bermudes Chimeric protein toxins for expression by therapeutic bacteria
EP3551047A1 (en) 2016-12-07 2019-10-16 Progenity, Inc. Gastrointestinal tract detection methods, devices and systems
US11180535B1 (en) 2016-12-07 2021-11-23 David Gordon Bermudes Saccharide binding, tumor penetration, and cytotoxic antitumor chimeric peptides from therapeutic bacteria
EP3554541B1 (en) 2016-12-14 2023-06-07 Biora Therapeutics, Inc. Treatment of a disease of the gastrointestinal tract with a chemokine/chemokine receptor inhibitor
TW202340155A (en) * 2017-12-29 2023-10-16 美商拜奧馬林製藥公司 Glycolate oxidase inhibitors for the treatment of disease
CN116726362A (en) 2018-11-19 2023-09-12 比奥拉治疗股份有限公司 Methods and devices for treating diseases with biologic therapeutic agents
CN115666704A (en) 2019-12-13 2023-01-31 比奥拉治疗股份有限公司 Ingestible device for delivery of therapeutic agents to the gastrointestinal tract
US11116737B1 (en) 2020-04-10 2021-09-14 University Of Georgia Research Foundation, Inc. Methods of using probenecid for treatment of coronavirus infections

Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2248018A (en) * 1939-03-30 1941-07-01 Winthrop Chem Co Inc 4-aryl-piperidine-ketones and a process of preparing them
US2773870A (en) * 1953-06-04 1956-12-11 Sterling Drag Inc 1-(lower alkyl)-4-phenyl-4-(tertiaryaminoalkoxymethyl- and tertiary-aminoalkoxy) piperidines and their preparation
US3334106A (en) * 1964-10-20 1967-08-01 Aldrich Chem Co Inc N(aryl)n(hydrocarbyl)-omega-(4-phenyl-4-piperidinocarbonylheteroamine) alkanoamide
US3539580A (en) * 1967-06-26 1970-11-10 Janssen Pharm 4-aryl-4-aminoalkoxy-piperidines
US5340822A (en) * 1991-05-03 1994-08-23 Elf Sanofi Polycyclic amine compounds and their enantiomers, their method of preparation and pharmaceutical compositions in which they are present
WO1998025605A1 (en) * 1996-12-13 1998-06-18 Merck & Co., Inc. Spiro-substituted azacycles as modulators of chemokine receptor activity
WO1998025604A1 (en) * 1996-12-13 1998-06-18 Merck & Co., Inc. Spiro-substituted azacycles as modulators of chemokine receptor activity
WO1999004794A1 (en) * 1997-07-25 1999-02-04 Merck & Co., Inc. Cyclic amine modulators of chemokine receptor activity
WO2000038680A1 (en) * 1998-12-23 2000-07-06 Pfizer Limited Azabicycloalkanes as ccr5 modulators
WO2002079190A1 (en) * 2001-03-29 2002-10-10 Smithkline Beecham P.L.C. 3-substituted indoles as chemokine antagonists

Family Cites Families (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NL130088C (en) * 1960-03-14
ZA852235B (en) * 1984-03-26 1986-11-26 Janssen Pharmaceutica Nv Anti-virally active pyridazinamines
SE8904298D0 (en) * 1989-12-21 1989-12-21 Astra Ab NEW COMPOUNDS
SE9400447D0 (en) * 1994-02-11 1994-02-11 Astra Ab New compounds
NZ501615A (en) * 1997-06-17 2002-02-01 Schering Corp Benzo[5,6]cyclohepta[1,2-b] pyridine derivatives useful for inhibition of farnesyl protein transferase
ID29137A (en) * 1998-07-27 2001-08-02 Schering Corp HIGH AFINITY LIGANS FOR ORL-1 NOSISEPTIN RECEPTORS
US6518286B1 (en) * 1999-03-26 2003-02-11 Astrazeneca Ab Compounds
JP3894729B2 (en) * 1999-05-04 2007-03-22 シェーリング コーポレイション Piperazine derivatives useful as CCR5 antagonists
JP2002348288A (en) * 2001-05-28 2002-12-04 Ono Pharmaceut Co Ltd Spiroheterocycle derivative and medicine having the same as active ingredient
TW200403058A (en) * 2002-04-19 2004-03-01 Bristol Myers Squibb Co Heterocyclo inhibitors of potassium channel function

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2248018A (en) * 1939-03-30 1941-07-01 Winthrop Chem Co Inc 4-aryl-piperidine-ketones and a process of preparing them
US2773870A (en) * 1953-06-04 1956-12-11 Sterling Drag Inc 1-(lower alkyl)-4-phenyl-4-(tertiaryaminoalkoxymethyl- and tertiary-aminoalkoxy) piperidines and their preparation
US3334106A (en) * 1964-10-20 1967-08-01 Aldrich Chem Co Inc N(aryl)n(hydrocarbyl)-omega-(4-phenyl-4-piperidinocarbonylheteroamine) alkanoamide
US3539580A (en) * 1967-06-26 1970-11-10 Janssen Pharm 4-aryl-4-aminoalkoxy-piperidines
US5340822A (en) * 1991-05-03 1994-08-23 Elf Sanofi Polycyclic amine compounds and their enantiomers, their method of preparation and pharmaceutical compositions in which they are present
WO1998025605A1 (en) * 1996-12-13 1998-06-18 Merck & Co., Inc. Spiro-substituted azacycles as modulators of chemokine receptor activity
WO1998025604A1 (en) * 1996-12-13 1998-06-18 Merck & Co., Inc. Spiro-substituted azacycles as modulators of chemokine receptor activity
WO1999004794A1 (en) * 1997-07-25 1999-02-04 Merck & Co., Inc. Cyclic amine modulators of chemokine receptor activity
WO2000038680A1 (en) * 1998-12-23 2000-07-06 Pfizer Limited Azabicycloalkanes as ccr5 modulators
WO2002079190A1 (en) * 2001-03-29 2002-10-10 Smithkline Beecham P.L.C. 3-substituted indoles as chemokine antagonists

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
DATABASE WPI Section Ch, Week 200335 Derwent Publications Ltd., London, GB; Class B02, AN 2003-367209 XP002283279 -& JP 2002 348288 A (ONO PHARM CO LTD) 4 December 2002 (2002-12-04) *
REHSE K ET AL: "Platelet aggregation inhibiting and anticoagulant effects of oligoamines, 1: N-(4-piperidinyl)methanamines" ARCHIV DER PHARMAZIE, VCH VERLAGSGESELLSCHAFT MBH, WEINHEIM, DE, vol. 319, no. 319, 1986, pages 505-515, XP001085385 ISSN: 0365-6233 *
STEVENTON ET AL: "4,4-disubstituted Piperidine High-Affinity NK1 Antagonists: Structure-Activity Relationships and in Vivo Activity" JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 41, no. 23, 1998, pages 4623-4622, XP002173109 ISSN: 0022-2623 *

Cited By (107)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004108662A1 (en) * 2003-05-15 2004-12-16 Kumiai Chemical Industry Co., Ltd. Phenylsulfonyl carbamate derivative and plant disease control agent for agricultural or horticultural use
JP2007517010A (en) * 2003-12-24 2007-06-28 プロシディオン・リミテッド Heterocyclic derivatives as GPCR receptor agonists
WO2005101989A2 (en) * 2004-04-23 2005-11-03 Astrazeneca Ab Piperidine derivatives as modulators of chemokine receptor ccr5
WO2005101989A3 (en) * 2004-04-23 2006-04-27 Astrazeneca Ab Piperidine derivatives as modulators of chemokine receptor ccr5
US7615555B2 (en) 2004-04-23 2009-11-10 Astrazeneca Ab Piperidine derivatives as modulators of chemokine receptor CCR5
WO2006001751A1 (en) * 2004-06-24 2006-01-05 Astrazeneca Ab Chemical compounds i
AU2012200933B2 (en) * 2005-06-22 2015-04-30 Plexxikon, Inc. Pyrrolo [2, 3-B] pyridine derivatives as protein kinase inhibitors
EP2395004B1 (en) * 2005-06-22 2016-01-20 Plexxikon Inc. Pyrrolo [2,3-b]pyridine derivatives as protein kinase inhibitors
US8097610B2 (en) 2005-08-26 2012-01-17 Shionogi & Co., Ltd. Derivative having PPAR agonistic activity
US8288413B2 (en) 2005-09-30 2012-10-16 Glaxo Group Limited Benzimidazolones which have activity at M1 receptor
US8283364B2 (en) 2005-09-30 2012-10-09 Glaxo Group Limited Compounds which have activity at M1 receptor and their uses in medicine
US8288412B2 (en) 2005-09-30 2012-10-16 Glaxo Group Limited Compounds which have activity at M1 receptor and their uses in medicine
US7576218B2 (en) * 2005-10-11 2009-08-18 Chemocentryx, Inc. 4-phenylpiperdine-pyrazole CCR1 antagonists
US7576106B2 (en) 2005-10-11 2009-08-18 Chemocentryx, Inc. Piperidine derivatives and methods of use
WO2007130712A1 (en) * 2006-01-31 2007-11-15 Janssen Pharmaceutica, Nv Substituted dipiperidine as ccr2 antagonists for the treatment of inflammatory diseases
CN103058990A (en) * 2006-03-22 2013-04-24 葛兰素集团有限公司 Benzimidazoles which have activity at m1 receptor and uses thereof in medicine
WO2007107565A1 (en) * 2006-03-22 2007-09-27 Glaxo Group Limited Benzimidazoles which have activity at m1 receptor and their uses in medicine
KR101409261B1 (en) * 2006-05-26 2014-06-18 다이쇼 세이야꾸 가부시끼가이샤 Novel heterocyclic compound or salt thereof and intermediate thereof
US8211908B2 (en) 2006-05-26 2012-07-03 Toyama Chemical Co., Ltd. Heterocyclic compound or salt thereof and intermediate thereof
WO2007138974A1 (en) * 2006-05-26 2007-12-06 Toyama Chemical Co., Ltd. Novel heterocyclic compound or salt thereof and intermediate thereof
US8367831B2 (en) 2006-05-26 2013-02-05 Toyama Chemical Co., Ltd. Heterocyclic compound or salt thereof and intermediate thereof
AU2007268749B2 (en) * 2006-05-26 2012-07-26 Taisho Pharmaceutical Co., Ltd. Novel heterocyclic compound or salt thereof and intermediate thereof
JP5171618B2 (en) * 2006-05-26 2013-03-27 富山化学工業株式会社 Novel heterocyclic compounds or salts thereof and intermediates thereof
WO2008004100A2 (en) 2006-07-05 2008-01-10 Pfizer Products Inc. Therapeutic compounds
US7956184B2 (en) 2006-07-07 2011-06-07 Gilead Sciences, Inc. Pyridazine compound and use thereof
US8569487B2 (en) 2006-07-07 2013-10-29 Gilead Sciences, Inc. Pyridazine compound and use thereof
WO2008011453A3 (en) * 2006-07-20 2009-04-16 Amgen Inc SUBSTITUTED AZOLE AROMATIC HETEROCYCLES AS INHIBITORS OF LLβ-HSD-1
US7666888B2 (en) 2006-07-20 2010-02-23 Amgen Inc. Substituted azole aromatic heterocycles as inhibitors of 11β-HSD-1
WO2008011453A2 (en) * 2006-07-20 2008-01-24 Amgen Inc. SUBSTITUTED AZOLE AROMATIC HETEROCYCLES AS INHIBITORS OF LLβ-HSD-1
JP2010503714A (en) * 2006-09-18 2010-02-04 エフ．ホフマン−ラ ロシュ アーゲー Octahydropyrrolo [3,4-C] pyrrole derivatives, their use as antiviral agents
US7625905B2 (en) 2006-09-18 2009-12-01 Roche Palo Alto Llc Octahydro-pyrrolo[3,4-c]pyrrole CCR5 receptor antagonists
WO2008034731A1 (en) * 2006-09-18 2008-03-27 F. Hoffmann-La Roche Ag Octahydropyrrolo [3, 4-c] pyrrole derivatives an their use as antiviral agents
WO2008075070A1 (en) * 2006-12-21 2008-06-26 Astrazeneca Ab Sulfonamide derivatives for therapeutic use as fatty acid synthase inhibitors
US8012955B2 (en) 2006-12-28 2011-09-06 Rigel Pharmaceuticals, Inc. N-substituted-heterocycloalkyloxybenzamide compounds and methods of use
US9181220B2 (en) 2006-12-28 2015-11-10 Rigel Pharmaceuticals, Inc. N-substituted-heterocycloalkyloxybenzamide compounds and methods of use
US8697727B2 (en) 2006-12-28 2014-04-15 Rigel Pharmaceuticals, Inc. N-substituted-heterocycloalkyloxybenzamide compounds and methods of use
US8344000B2 (en) 2007-09-20 2013-01-01 Glaxo Group Limited Compounds which have activity at M1 receptor and their uses in medicine
WO2009049113A1 (en) * 2007-10-11 2009-04-16 Glaxo Group Limited Piperidinylhydroxyethylpiperidines as modulators of chemokine receptors
US8329691B2 (en) 2007-10-15 2012-12-11 Takeda Pharmaceutical Company Limited Amide compounds and use of the same
WO2009051112A1 (en) 2007-10-15 2009-04-23 Takeda Pharmaceutical Company Limited Amide compounds and use of the same
US8119809B2 (en) 2007-11-16 2012-02-21 Rigel Pharmaceuticals, Inc. AMPK-activating heterocycloalkyloxy(hetero)aryl carboxamide, sulfonamide and amine compounds and methods for using the same
US9174964B2 (en) 2007-11-16 2015-11-03 Rigel Pharmaceuticals, Inc. AMPK-activating piperidinyloxy-substituted 2,3-dihydro-1H-indene-1-amine compounds and pharmaceutical compositions including the same
US8569340B2 (en) 2007-11-16 2013-10-29 Rigel Pharmaceuticals, Inc. AMPK-activating piperidinyloxypyiridine carboxamide and sulfonamide compounds and methods for using the same
US8557822B2 (en) 2007-12-12 2013-10-15 Rigel Pharmaceuticals, Inc. Carboxamide, sulfonamide and amine compounds and methods for using the same
US8129390B2 (en) 2007-12-12 2012-03-06 Rigel Pharmaceuticals, Inc. Carboxamide, sulfonamide and amine compounds and methods for using the same
US8895578B2 (en) 2007-12-12 2014-11-25 Rigel Pharmaceuticals, Inc. Carboxamide, sulfonamide and amine compounds and methods for using the same
WO2009111278A2 (en) * 2008-02-29 2009-09-11 Array Biopharma Inc. Raf inhibitor compounds and methods of use thereof
WO2009111278A3 (en) * 2008-02-29 2010-07-15 Array Biopharma Inc. Raf inhibitor compounds and methods of use thereof
US8338452B2 (en) 2008-02-29 2012-12-25 Array Biopharma Inc. Raf inhibitor compounds and methods of use thereof
US8796321B2 (en) 2008-04-21 2014-08-05 Path Drug Solutions Compounds, compositions and methods comprising oxadiazole derivatives
US9353111B2 (en) 2008-04-23 2016-05-31 Rigel Pharmaceuticals, Inc. Carboxamide compounds and methods for using the same
US9062052B2 (en) 2008-04-23 2015-06-23 Rigel Pharmaceuticals, Inc. Carboxamide compounds and methods for using the same
US9255085B2 (en) 2008-04-23 2016-02-09 Rigel Pharmaceuticals, Inc. Carboxamide compounds and methods for using the same
US8871770B2 (en) 2008-04-23 2014-10-28 Rigel Pharmaceuticals Inc. Carboxamide compounds and methods for using the same
US8314107B2 (en) 2008-04-23 2012-11-20 Rigel Pharmaceuticals, Inc. Carboxamide compounds and methods for using the same
US8785449B2 (en) 2008-04-23 2014-07-22 Rigel Pharmaceuticals, Inc. Carboxamide compounds and methods for using the same
EP3246030A1 (en) 2008-08-11 2017-11-22 GlaxoSmithKline LLC Novel adenine derivatives
EP3000813A1 (en) 2008-08-11 2016-03-30 GlaxoSmithKline LLC Purine derivatives for use in the treatment of allergic, inflammatory and infectious diseases
WO2010018131A1 (en) 2008-08-11 2010-02-18 Smithkline Beecham Corporation Purine derivatives for use in the treatment of allergic, inflammatory and infectious diseases
EP2322515A1 (en) * 2008-08-29 2011-05-18 JSR Corporation N-carboxy amino acid anhydride and amino acid carbamate compound production method
EP2322515A4 (en) * 2008-08-29 2011-12-21 Jsr Corp N-carboxy amino acid anhydride and amino acid carbamate compound production method
CN102123994B (en) * 2008-08-29 2014-09-24 Jsr株式会社 N-carboxy amino acid anhydride and amino acid carbamate compound production method
CN102123994A (en) * 2008-08-29 2011-07-13 Jsr株式会社 N-carboxy amino acid anhydride and amino acid carbamate compound production method
WO2010080864A1 (en) 2009-01-12 2010-07-15 Array Biopharma Inc. Piperidine-containing compounds and use thereof
US8809538B2 (en) 2009-01-12 2014-08-19 Array Biopharma Inc. Piperidine-containing compounds and use thereof
US9663517B2 (en) 2009-04-03 2017-05-30 Plexxikon Inc. Compositions and uses thereof
WO2011011652A1 (en) 2009-07-24 2011-01-27 Glaxosmithkline Llc Therapeutic compounds
WO2011098451A1 (en) 2010-02-10 2011-08-18 Glaxosmithkline Llc Purine derivatives and their pharmaceutical uses
WO2011098452A1 (en) 2010-02-10 2011-08-18 Glaxosmithkline Llc 6-amino-2-{ [ (1s)-1-methylbutyl] oxy}-9-[5-(1-piperidinyl)-7,9-dihydro-8h-purin-8-one maleate
US8598164B2 (en) 2010-05-06 2013-12-03 Vertex Pharmaceuticals Incorporated Heterocyclic chromene-spirocyclic piperidine amides as modulators of ion channels
WO2012017166A3 (en) * 2010-07-19 2012-07-19 Vaxconsulting Benzenesulfonamide-compound treatment of a pathological condition linked to an excessive effect of tnf
US8975399B2 (en) 2010-07-19 2015-03-10 Jean-Francois Zagury Benzenesulfon amide-compound treatment of a pathological condition linked to an excessive effect of TNF
US8916565B2 (en) 2011-02-02 2014-12-23 Vertex Pharmaceuticals Incorporated Pyrrolopyrazine-spirocyclic piperidine amides as modulators of ion channels
US9511067B2 (en) 2011-02-02 2016-12-06 Vertex Pharmaceuticals Incorporated Substituted spiro[piperidine-4,1'-pyrrolo[1,2-a]pyrazine]s as modulators of ion channels
US9624213B2 (en) 2011-02-07 2017-04-18 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
US11337976B2 (en) 2011-02-07 2022-05-24 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
US10385070B2 (en) 2011-02-18 2019-08-20 Vertex Pharmaceuticals Incorporated Chroman-spirocyclic piperidine amides as modulators of ion channels
US9181273B2 (en) 2011-03-14 2015-11-10 Vertex Pharmaceuticals Incorporated Morpholine-spirocyclic piperidine amides as modulators of ion channels
US8828996B2 (en) 2011-03-14 2014-09-09 Vertex Pharmaceuticals Incorporated Morpholine-spirocyclic piperidine amides as modulators of ion channels
WO2013090664A1 (en) 2011-12-16 2013-06-20 Glaxosmithkline Llc Derivatives of betulin
US9695169B2 (en) 2012-05-31 2017-07-04 Plexxikon Inc. Synthesis of heterocyclic compounds
WO2014062044A1 (en) 2012-10-15 2014-04-24 Vilnius University Fluorinated benzenesulfonamides as inhibitors of carbonic anhydrase
US9643952B2 (en) 2012-12-06 2017-05-09 Kyowa Hakko Kirin Co., Ltd. Pyridone compound
EP2930170A4 (en) * 2012-12-06 2016-05-25 Kyowa Hakko Kirin Co Ltd Pyridone compound
WO2015031722A1 (en) * 2013-08-30 2015-03-05 Ramot At Tel-Aviv University Ltd. Method for treating amyotrophic lateral sclerosis by inhibition of cxcr4/cxcl12 signaling
WO2015124591A1 (en) 2014-02-20 2015-08-27 Glaxosmithkline Intellectual Property (No.2) Limited Pyrrolo[3,2] pyrimidine derivatives as inducers of human interferon
US10112939B2 (en) 2014-08-21 2018-10-30 Bristol-Myers Squibb Company Tied-back benzamide derivatives as potent rock inhibitors
WO2016073774A3 (en) * 2014-11-05 2016-07-07 Flexus Biosciences, Inc. Immunoregulatory agents
KR20170097643A (en) * 2014-11-05 2017-08-28 플렉서스 바이오사이언시스, 인크. Immunoregulatory agents
KR102647639B1 (en) * 2014-11-05 2024-03-15 플렉서스 바이오사이언시스, 인크. Immunoregulatory agents
WO2016075661A1 (en) 2014-11-13 2016-05-19 Glaxosmithkline Biologicals Sa Adenine derivatives which are useful in the treatment of allergic diseases or other inflammatory conditions
US10106556B2 (en) 2015-03-30 2018-10-23 Takeda Pharmaceutical Company Limited Heterocyclic compound
WO2017017505A1 (en) 2015-07-28 2017-02-02 Vilnius University Selective inhibitors of carbonic anhydrase
US11312682B2 (en) 2015-07-28 2022-04-26 Vilnius University Selective inhibitors of carbonic anhydrase
WO2017093933A1 (en) 2015-12-03 2017-06-08 Glaxosmithkline Intellectual Property Development Limited Cyclic purine dinucleotides as modulators of sting
EP3366691A1 (en) 2015-12-03 2018-08-29 GlaxoSmithKline Intellectual Property Development Limited Cyclic purine dinucleotides as modulators of sting
WO2017175156A1 (en) 2016-04-07 2017-10-12 Glaxosmithkline Intellectual Property Development Limited Heterocyclic amides useful as protein modulators
EP4032885A1 (en) 2016-04-07 2022-07-27 GlaxoSmithKline Intellectual Property Development Limited Heterocyclic amides useful as protein modulators
WO2017175147A1 (en) 2016-04-07 2017-10-12 Glaxosmithkline Intellectual Property Development Limited Heterocyclic amides useful as protein modulators
WO2019069269A1 (en) 2017-10-05 2019-04-11 Glaxosmithkline Intellectual Property Development Limited Modulators of stimulator of interferon genes (sting) useful in treating hiv
WO2019069270A1 (en) 2017-10-05 2019-04-11 Glaxosmithkline Intellectual Property Development Limited Modulators of stimulator of interferon genes (sting)
WO2019219820A1 (en) 2018-05-16 2019-11-21 Ctxt Pty Limited Substituted condensed thiophenes as modulators of sting
US11613525B2 (en) 2018-05-16 2023-03-28 Ctxt Pty Limited Substituted condensed thiophenes as modulators of sting
WO2020232378A1 (en) 2019-05-16 2020-11-19 Silicon Swat, Inc. Benzo[b][1,8]naphthyridine acetic acid derivatives and methods of use
WO2020232375A1 (en) 2019-05-16 2020-11-19 Silicon Swat, Inc. Oxoacridinyl acetic acid derivatives and methods of use
WO2021009365A1 (en) 2019-07-18 2021-01-21 Ctxt Pty Limited Benzothiophene, thienopyridine and thienopyrimidine derivatives for the modulation of sting
WO2021009362A1 (en) 2019-07-18 2021-01-21 Ctxt Pty Limited Benzothiophene, thienopyridine and thienopyrimidine derivatives for the modulation of sting

Also Published As

Publication number Publication date
KR20050087832A (en) 2005-08-31
WO2004054974A3 (en) 2004-09-02
JP2006511554A (en) 2006-04-06
NO20052739L (en) 2005-08-19
BR0317230A (en) 2005-10-25
MA27647A1 (en) 2005-12-01
ZA200505600B (en) 2006-09-27
CO5580771A2 (en) 2005-11-30
US20060229336A1 (en) 2006-10-12
NO20052739D0 (en) 2005-06-07
CN1744899A (en) 2006-03-08
CA2509711A1 (en) 2004-07-01
EP1569646A2 (en) 2005-09-07
US7645771B2 (en) 2010-01-12
MXPA05006354A (en) 2005-08-26
RU2005118407A (en) 2006-03-10
AU2003300902A1 (en) 2004-07-09

Similar Documents

Publication Publication Date Title
US7645771B2 (en) CCR5 antagonists as therapeutic agents
EP1720856B1 (en) Hiv integrase inhibitors
US6489338B2 (en) Imidazopyridine and imidazopyrimidine antiviral agents
US7569579B2 (en) Cyclopropyl compounds as ccr5 antagonists
US6586430B1 (en) CCR5 modulators
US7589207B2 (en) Cyclohexyl compounds as CCR5 antagonists
AU2001272906A1 (en) Imidazopyridine and imidazopyrimidine antiviral agents
WO2004055016A1 (en) Pyrrolidine and azetidine compounds as ccr5 antagonists
EP1386920A1 (en) Benzimidazolone derivatives
WO2004055011A1 (en) Heterocyclic compounds as ccr5 antagonists
MXPA04009220A (en) Tropane derivatives as ccr5 modulators.
JP5730871B2 (en) Therapeutic compound
AU2010282506A1 (en) Process for the preparation of Cathepsin S inhibitors

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): BW GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
WWE Wipo information: entry into national phase

Ref document number: 168958

Country of ref document: IL

WWE Wipo information: entry into national phase

Ref document number: 2003813419

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 2006229336

Country of ref document: US

Ref document number: 540645

Country of ref document: NZ

Ref document number: 10538144

Country of ref document: US

WWE Wipo information: entry into national phase

Ref document number: 2004560838

Country of ref document: JP

Ref document number: 2509711

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 1020057010809

Country of ref document: KR

Ref document number: 1020057010807

Country of ref document: KR

Ref document number: PA/a/2005/006354

Country of ref document: MX

WWE Wipo information: entry into national phase

Ref document number: 1-2005-501130

Country of ref document: PH

WWW Wipo information: withdrawn in national office

Ref document number: 1020057010807

Country of ref document: KR

WWE Wipo information: entry into national phase

Ref document number: 2003300902

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: 1328/KOLNP/2005

Country of ref document: IN

WWE Wipo information: entry into national phase

Ref document number: 2005/05600

Country of ref document: ZA

Ref document number: 05068493

Country of ref document: CO

Ref document number: 200505600

Country of ref document: ZA

Ref document number: DZP2005000249

Country of ref document: DZ

ENP Entry into the national phase

Ref document number: 2005118407

Country of ref document: RU

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 1200500976

Country of ref document: VN

WWE Wipo information: entry into national phase

Ref document number: 20038A96285

Country of ref document: CN

WWP Wipo information: published in national office

Ref document number: 1020057010809

Country of ref document: KR

WWP Wipo information: published in national office

Ref document number: 2003813419

Country of ref document: EP

ENP Entry into the national phase

Ref document number: PI0317230

Country of ref document: BR

WWP Wipo information: published in national office

Ref document number: 10538144

Country of ref document: US