WO2013074386A2 - Hcv ns3 protease inhibitors - Google Patents

Hcv ns3 protease inhibitors Download PDF

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Publication number
WO2013074386A2
WO2013074386A2 PCT/US2012/064270 US2012064270W WO2013074386A2 WO 2013074386 A2 WO2013074386 A2 WO 2013074386A2 US 2012064270 W US2012064270 W US 2012064270W WO 2013074386 A2 WO2013074386 A2 WO 2013074386A2
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WIPO (PCT)
Prior art keywords
alkyl
optionally substituted
methyl
cyclopropyl
carboxamide
Prior art date
Application number
PCT/US2012/064270
Other languages
French (fr)
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WO2013074386A3 (en
Inventor
Michael T. Rudd
John Mccauley
Nigel Liverton
Christiane GRISE-BARD
Marie-Christine BROUCHU
Sylvie Charron
Virender AULAKH
Benoit Bachand
Patrick Beaulieu
Helmi ZAGHDANE
Yongxin Han
Marco Ferrara
Steven Harper
Vincenzo Summa
Samuel Chackalamannil
Srikanth Venkatraman
Unmesh Shah
Francisco Velazquez
Original Assignee
Merck Sharp & Dohme Corp.
Merck Canada Inc.
Istituto Di Ricerche Di Biologia Molecolare P. Angeletti S.R.L.
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Application filed by Merck Sharp & Dohme Corp., Merck Canada Inc., Istituto Di Ricerche Di Biologia Molecolare P. Angeletti S.R.L. filed Critical Merck Sharp & Dohme Corp.
Priority to US14/358,050 priority Critical patent/US9328138B2/en
Priority to EP12850713.4A priority patent/EP2780026B1/en
Publication of WO2013074386A2 publication Critical patent/WO2013074386A2/en
Publication of WO2013074386A3 publication Critical patent/WO2013074386A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/7056—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing five-membered rings with nitrogen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/005—Enzyme inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/06—Tripeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/21—Interferons [IFN]
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
    • C07K5/0808—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0812—Tripeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0821—Tripeptides with the first amino acid being heterocyclic, e.g. His, Pro, Trp
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C

Definitions

  • the present invention relates to macrocyclic compounds that are useful as inhibitors of the hepatitis C virus (HCV) NS3 protease, the synthesis of such compounds, and the use of such compounds for treating HCV infection and/or reducing the likelihood or severity of symptoms of HCV infection.
  • HCV hepatitis C virus
  • HCV infection is a major health problem that leads to chronic liver disease, such as cirrhosis and hepatocellular carcinoma, in a substantial number of infected individuals, estimated to be 2-15% of the world's population.
  • HCV human immunodeficiency virus
  • WHO World Health Organization
  • NS3 protease is located in the N-terminal domain of the NS3 protein.
  • the NS3 protease is considered a prime drug target.
  • Previous research has identified classes of peptides, such as hexapeptides as well as tripeptides discussed in U.S. Patent Application Publications Nos. US2005/0020503, US2004/0229818, and US2004/00229776, showing degrees of activity in inhibiting the NS3 protease. Additional HSV NS3 protease inhibitors have been described in International Patent Applicaton Publication Nos. WO2008/057208 and
  • the aim of the present invention is to provide further compounds which exhibit activity against the HCV NS3 protease.
  • the present invention relates to novel macrocyclic compounds of formula (I) and/or pharmaceutically acceptable salts or hydrates thereof. These compounds are useful in the inhibition of HCV (hepatitis C virus) NS3 (non-structural 3) protease, the prevention or treatment of one or more of the symptoms of HCV infection, either as compounds or their pharmaceutically acceptable salts or hydrates (when appropriate), or as pharmaceutical composition ingredients.
  • HCV hepatitis C virus
  • NS3 non-structural 3
  • pharmaceutical composition ingredients these compounds, salts and hydrates may be the primary active therapeutic agent, and, when appropriate, may be combined with other therapeutic agents including but not limited to other HCV antivirals, anti- infectives, immunomodulators, antibiotics or vaccines. More particularly, the present invention relates to a compound of formula (I) and/or a pharmaceutically acceptable salt thereof:
  • Y is CH or N
  • R 1 is:
  • alkyl is optionally substituted with 1 or 2 fluoro substituents
  • said phosphate group is optionally substituted with 1, 2 or 3 C 1-6 alkyl
  • aryl selected from phenyl or napthyl optionally substituted with 1 or 2 substituents selected from -OH, Cr 6 alkyl, or halo;
  • heteroaryl selected from 5- and 6-membered aromatic rings having 1, 2 or 3 heteroatoms independently selected from N, O and S, wherein said heteroaryl is attached through a ring atom selected from C or N and optionally substituted with 1 or 2 substituents independently selected from C h alky! and -OH; or
  • R a and R b are independently selected from H; d- 6 alkyl; t-Boc; aryl; C 3 - 6 cycloalkyl optionally substituted with 1 or 2 fluoro substituents; C ealko y-Ci-ealkyl; tetrahydropyranyl; C ⁇ ealkyl-OH; C 1 - 6 alkyl-aryl; Q- 6 alkyl-C(OH)-aryl; Q-ealkyl-imidazolyl optionally substituted with methyl, C ealkyl-benzimidazolyl optionally substituted with methyl; Crealkyl-pyrazolyl; Crealkyl-dihydrotriazole optionally substituted with oxo; or d-ealkyl-pyrrolidinyl optionally substituted with oxo;
  • m is 0 or 1 to 4;
  • aryl is phenyl, naphthalenyl, tetrahydronapthalenyl, or 7-10 membered fused bicyclic ring structure wherein at least one of the rings is aromatic and is optionally substituted with 2 -OH;
  • said tetrahydropyranyl is optionally substituted with 1 oxo;
  • R 2 is Ci-ealkyl, C 2 - 6 alkenyl, C 3 -C 6 cycloalkyl or NR c R d ;
  • the C 3-6 cycloalkyl is optionally substituted with C 1-6 alkyl optionally substituted with -OH, morpholinyl, C 1-6 alkoxy, C 1-6 alkoxy-C 1-6 alkoxy, C 1-6 alkoxy-phenyl, or C 1-6 alkenyl;
  • R c and R d are independently H or C 1- alkyl, or may be taken together, with the N to which they are attached, to form a 4-7-membered monocyclic ring;
  • R is C ⁇ alkyl, C 2 - alkenyl, C3-C 6 cycloalkyl, CF 2 or CF 3 ;
  • R 4 is Ci-8 alkyl, C 3 -g cycloalkyl, Ci-8 alkyl-C 3 - 8 cycloalkyl, adamantyl, dihydroindenyl, or a 4-8 membered heterocycloalkyl having 1 or 2 heteroatoms selected from N, O, or S, wherein R 4 is optionally substituted with one or two substituents independently selected from (Ci- C 6 )alkyl, halo, and -0(C 1 -C 6 )alkyl; or
  • Z is C or N
  • R 5 is H or d- 6 alkyl; or R 5 is absent when Z is N;
  • W is a bond, O or NR
  • R is H or d- 6 alkyl
  • X is absent or is halo, CF 3 , -OCHF 2 , -OCH 2 F, -OCD 2 F, -OCDF 2 , C C 6 alkyl, Crealkoxy, aryl, heteroaryl, or -0(CH 2 ) 1-6 NR a R b ;
  • A is absent, O or N;
  • B is (CH 2 ) m ;
  • n 1-4.
  • the present invention also includes pharmaceutical compositions containing a compound of the present invention and methods of preparing such pharmaceutical compositions.
  • the present invention further includes methods of treating or reducing the likelihood or severity of one or more symptoms of HCV infection.
  • Other embodiments, aspects and features of the present invention are either further described in or will be apparent from the ensuing description, examples and appended claims.
  • the present invention relates to compounds of Formula (I) and pharmaceutically acceptable salts thereof, as defined above and a first embodiment of the invention. Different embodiments further describing Formula (I) variables are described below.
  • the present invention relates to c mpounds, or a pharmaceutically acceptable salt thereof, having a formula of
  • the present invention relates to compounds of Formula (I), (la), (lb), (Ic), (Id) or (le) and pharmaceutically acceptable salts thereof, wherein Z is C and the other variables are as provided for in the first or second embodiments.
  • the present invention relates to compounds of Formula
  • the present invention relates to compounds of Formula (I), (la), (lb), (Ic), (Id), (Ie), (If), (Ig) and (Ih) and pharmaceutically acceptable salts thereof, wherein R is ethyl, ethylene, or cyclopropyl and the other variables are as provided for in the first or sixth embodiments.
  • R 3 is ethylene.
  • the present invention relates to compounds of Formula (I), (la), (lb), (Ic), (Id), (Ie), (If), (Ig) and (Ih) and pharmaceutically acceptable salts thereof, wherein R 4 is propyl, t-butyl, cyclopentyl, cyclohexyl optionally substituted with 1 or 2 F, cyclohexylmethyl, methylcyclohexyl, methylcyclopentyl,
  • R 4 is t-butyl, cyclopentyl, or cyclohexyl, 1 -methylcyclohexyl, propan-2-yl, 2,3 -dihydroindenyl, tetrahydro- 2H-pyranyl, or cyclohexylmethyl.
  • R 4 is t-butyl, cyclopentyl, or cyclohexyl, 1 -methylcyclohexyl, 2,3 -dihydroindenyl, or tetrahydro-2H-pyranyl.
  • the present invention relates to compounds of Formula (I), (la), (lb), (Ic), (Id), (Ie), (If), (Ig) and (Ih) and pharmaceutically acceptable salts thereof, wherein n is 1 or 3, and the other variables are as provided for in any of the first or sixth to eighth embodiments.
  • R 2 is cyclopropyl, N(CH 3 ) 2 , (methyl)cyclopropyl,
  • R 2 is cyclopropyl, N(C3 ⁇ 4) 2 , (methyl)cyclopropyl, or l-(methoxymethyl)cyclopropyl.
  • R a and R b are independently
  • heti is phenyl; oxazepanyl; oxooxazolidinyl; pyridinyl; pyrazolyl; pyrrolyl;
  • tetrahydropyranyl triazolyl optionally substituted with C 1-6 alkyl; dioxolanyl; oxoimidazolidinyl; morpholinyl optionally substituted with dimethyl or ethyl; pyrrolidinyl optionally substituted with 1 or 2 substituents independently selected from oxo, Boc, C 1-6 alkyl, OH, C(0)NH 2 , dimethylamino, and methylsulfomyl; piperidinyl optionally substituted with 1 or 2 substituents independently selected from C 1-6 alkyl, C 1-6 alkoxy, Q-ealkoxy-C ⁇ alkyl optionally substituted with CF 3 , cyclopropyl-C 1-6 alkyl, cyclopropyl, -(CH 2 )mF, OH, -C 1-6 alkyl-S0 2 C 1-6 alkyl,
  • oxaazaspiroheptyl optionally substituted with methoxyethyl; azetidinyl optionally substituted with 1 or 2 substituents independently selected from C 1-6 alkyl, Q-ealkoxy, cyano, fluoro, OH, phenyl and Boc; dioxidothiomorpholinyl; piperazinyl optionally substituted with 1 or 2 substituents independently selected from C 1-6 alkyl, C 1-6 alkyl-cyclopropyl, CF 3 , methylsulfonyl, Boc, and oxo; azabicyclooctyl substituted with C 1-6 alkyl, Q-ealkoxy-C ⁇ alkyl, -COOC 1-6 alkyl, or -(CH 2 ) m CF 3 ; oxaazabicyclononyl optionally substituted with Boc, C 1-6 alkyl, -COOC 1- alkyl, C 1-6 alkoxy-C 1-6 al
  • the present invention relates to compounds of Formula (I), (la), (lb), (Ic), (Id), (Ie), (If), (Ig) and (Ih) and pharmaceutically acceptable salts thereof, wherein X is absent or selected from -Br, -CI, -F, methoxy, methyl, propanyl and CF 3 , and the other variables are as provided for in any of the first or sixth through eleventh embodiments.
  • compositions comprising an effective amount of a compound of formula (I), in any of the described embodiments, and a pharmaceutically acceptable carrier.
  • the second therapeutic agent is ribavirin.
  • HCV antiviral agent is an antiviral selected from the group consisting of HCV protease inhibitors and HCV NS5B polymerase inhibitors.
  • HCV antiviral agent is an antiviral selected from the group consisting of HCV protease inhibitors and HCV NS5B polymerase inhibitors.
  • HCV antiviral agent is an antiviral selected from the group consisting of HCV protease inhibitors and HCV NS5B polymerase inhibitors.
  • a method of inhibiting HCV NS3 protease in a subject in need thereof which comprises administering to the subject the pharmaceutical composition of (a), (b), or (c) or the combination of (d) or (e).
  • the present invention also includes a compound of the present invention for use (i) in, (ii) as a medicament for, or (iii) in the preparation of a medicament for: (a) inhibiting HCV NS3 protease, or (b) treating HCV infection and/or reducing the likelihood or severity of symptoms of HCV infection.
  • the compounds of the present invention can optionally be employed in combination with one or more second therapeutic agents selected from HCV antiviral agents, anti-infective agents, and immunomodulators.
  • the second therapeutic agent is ribavirin.
  • Additional embodiments of the invention include the pharmaceutical compositions, combinations and methods set forth in (a)-(k) above and the uses set forth in the preceding paragraph, wherein the compound of the present invention employed therein is a compound of one of the embodiments, aspects, classes, sub-classes, or features of the
  • the compound may optionally be used in the form of a pharmaceutically acceptable salt or hydrate as appropriate.
  • the dotted line is an optional bond.
  • the bond in its entirety
  • the bond in its entirety
  • the bond in its entirety
  • the bond in its entirety
  • the bond is a single bond.
  • Each such bond is independently a single bond or a double bond.
  • two such bonds when two such bonds are adjacent to each other, it can represent two single bonds, two double bonds, a single bond adjacent to a double bond, or a double bond adjacent to a single bond.
  • alkyl refers to any linear or branched chain alkyl group having a number of carbon atoms in the specified range.
  • C 1-6 alkyl (or “Ci-Ce alkyl”) refers to all of the hexyl alkyl and pentyl alkyl isomers as well as n-, iso-, sec- and t-butyl, n- and isopropyl, ethyl and methyl.
  • CM alkyl refers to n-, iso-, sec- and t-butyl, n- and isopropyl, ethyl and methyl. Alkyl groups may be substituted as indicated.
  • alkoxy refers to an "alkyl-O-" group. Alkoxy groups may be substituted as indicated.
  • alkylene refers to any linear or branched chain alkylene group (or alternatively “alkanediyl”) having a number of carbon atoms in the specified range.
  • -C ⁇ alkylene- refers to any of the C ⁇ to C 6 linear or branched alkylenes.
  • a class of alkylenes of particular interest with respect to the invention is -(CH 2 ) 1-6 -, and sub-classes of particular interest include -( ⁇ 1 ⁇ 4) -, -( ⁇ 3 ⁇ 4) 1-3 -, -(CH 2 ) 1-2 -, and -CH 2 -.
  • alkylene -CH(CH 3 )- is also of interest.
  • Alkylene groups may be substituted as indicated.
  • cycloalkyl refers to any monocyclic or bicyclic ring structure of an alkane or alkene having a number of carbon atoms in the specified range.
  • C 3-8 cycloalkyl (or “C 3 -C 8 cycloalkyl”) includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • cycloalkoxy refers to a "cycloalkyl-O-" group. Cycloalkyl groups may be substituted as indicated.
  • Carbocyclyl as used herein, unless otherwise indicated, refers to (i) a C 3 to C 8 monocyclic, saturated or unsaturated ring or (ii) a C 7 to C 12 bicyclic saturated or unsaturated ring system.
  • Each ring in (ii) is either independent of, or fused to, the other ring, and each ring is saturated or unsaturated.
  • Carbocycle groups may be substituted as indicated, for example with C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, aryl, halogen, -NH 2 or -OH.
  • the carbocycle may be attached to the rest of the molecule at any carbon atom which results in a stable compound.
  • a subset of the fused bicyclic unsaturated carbocycles are those bicyclic carbocycles in which one ring is a benzene ring and the other ring is saturated or unsaturated, with attachment via any carbon atom that results in a stable compound.
  • Depicted ring systems include, where appropriate, able to
  • Variable R 5 is shown as a floating variable which can be attached to any ring atom, provided that such attachment results in formation of a stable ring.
  • each ring in (ii) and (iii) is independent of, or fused to, the other ring or rings and each ring is saturated or unsaturated, and the monocyclic ring, bicyclic ring system or tricyclic ring system contains one or more heteroatoms (e.g., from 1 to 6 heteroatoms, or from 1 to 4 heteroatoms) independently selected from N, O and S and a balance of carbon atoms (the monocyclic ring typically contains at least one carbon atom and the bicyclic and tricyclic ring systems typically contain at least two carbon atoms); and wherein any one or more of the nitrogen and sulfur heteroatoms is optionally oxidized, and any one or more of the nitrogen heteroatoms is optionally quaternized.
  • heteroatoms e.g., from 1 to 6 heteroatoms, or from 1 to 4 heteroatoms
  • the monocyclic ring typically contains at least one carbon atom and the bicyclic and tricyclic ring systems typically contain at least two carbon atoms
  • heterocyclic ring may be attached at any heteroatom or carbon atom, provided that attachment results in the creation of a stable structure.
  • Heterocycle groups may be substituted as indicated, and unless otherwise specified, the substituents may be attached to any atom in the ring, whether a heteroatom or a carbon atom, provided that a stable chemical structure results.
  • Representative examples include piperidinyl, piperazinyl, azepanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl (or tetrahydrofuranyl).
  • heterocyclics include 4-8 membered heterocycloalkyls having 1 to 2 heteroatoms selected from N, O, and S.
  • heteroaromatic rings include pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienyl (or thiophenyl), thiazolyl, furanyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isooxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, and thiadiazolyl.
  • bicyclic heterocycles include benzotriazolyl, indolyl, isoindolyl, indazolyl, indolinyl, isoindolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, chromanyl, isochromanyl, tetrahydroquinolinyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl,
  • 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzo-l,4-dioxinyl i.e., CO ⁇
  • imidazo(2,l-6)(l,3)thiazole i.e., )
  • aanndd bbeennzzoo--ll,,33--ddiiooxxoollyyll ((ii..ee..,, ).
  • phenyl having as a substituent methylenedioxy attached to two adjacent carbon atoms.
  • a reference to a compound of formula (I) is a reference to the compound per se, or to any one of its tautomers per se, or to mixtures of two or more tautomers.
  • Isotopically-enriched compounds within generic Formula I can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents and/or intermediates.
  • the compounds of the present inventions are useful in the inhibition of HCV protease (e.g., HCV NS3 protease) and the treatment of HCV infection and or reduction of the likelihood or severity of symptoms of HCV infection.
  • HCV protease e.g., HCV NS3 protease
  • the compounds of this invention are useful in treating infection by HCV after suspected past exposure to HCV by such means as blood transfusion, exchange of body fluids, bites, accidental needle stick, or exposure to patient blood during surgery.
  • Suitable salts include acid addition salts which may, for example, be formed by mixing a solution of the compound of the present invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, or benzoic acid.
  • a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, or benzoic acid.
  • suitable pharmaceutically acceptable salts thereof can include alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., calcium or magnesium salts), and salts formed with suitable organic ligands such as quaternary ammonium salts.
  • suitable organic ligands such as quaternary ammonium salts.
  • pharmaceutically acceptable esters can be employed to modify the solubility or hydrolysis characteristics of the compound.
  • Solid preparations suitable for oral administration can be prepared according to techniques known in the art and can employ such solid excipients as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like.
  • Parenteral compositions can be prepared according to techniques known in the art and typically employ sterile water as a carrier and optionally other ingredients, such as solubility aids.
  • injectable solutions can be prepared according to methods known in the art wherein the carrier comprises a saline solution, a glucose solution or a solution containing a mixture of saline and glucose. Further description of methods suitable for use in preparing pharmaceutical compositions of the present invention and of ingredients suitable for use in said compositions is provided in Remington's Pharmaceutical Sciences, 18 edition (ed. A. R. Gennaro, Mack Publishing Co., 1990).
  • the present invention also relates to a method of inhibiting HCV NS3 protease, inhibiting HCV replication, treating HCV infection and/or reducing the likelihood or severity of symptoms of HCV infection with a compound of the present invention in combination with one or more therapeutic agents and a pharmaceutical composition comprising a compound of the present invention and one or more therapeutic agents selected from the group consisting of a HCV antiviral agent, an immunomodulator, and an anti-infective agent.
  • Amgen's recombinant consensus interferon has the brand name Infergen®.
  • Levovirin is the L-enantiomer of ribavirin which has shown immunomodulatory activity similar to ribavirin.
  • Viramidine represents an analog of ribavirin disclosed in International Patent Application Publication No. WO 01/60379.
  • the individual components of the combination can be administered separately at different times during the course of therapy or concurrently in divided or single combination forms.
  • the compounds of the present invention may also be administered in combination with an agent that is an inhibitor of HCV NS3 serine protease.
  • HCV NS3 serine protease is an essential viral enzyme and has been described to be an excellent target for inhibition of HCV replication. Both substrate and non-substrate based inhibitors of HCV NS3 protease inhibitors are disclosed in International Patent Application Publication Nos.
  • WO 98/22496 WO 98/46630, WO 99/07733, WO 99/07734, WO 99/38888, WO 99/50230, WO 99/64442, WO 00/09543, WO 00/59929, WO 02/48116 and WO 02/48172, British Patent No. GB 2 337 262, and U.S. Patent No. 6,323,180.
  • Ribavirin, levovirin, and viramidine may exert their anti-HCV effects by modulating intracellular pools of guanine nucleotides via inhibition of the intracellular enzyme inosine monophosphate dehydrogenase (IMPDH).
  • IMPDH inosine monophosphate dehydrogenase
  • Ribavirin is readily
  • the compounds of the present invention may also be administered in combination with an inhibitor of IMPDH, such as VX-497, which is disclosed in International Patent Application Publication Nos. WO 97/41211 and WO 01/00622; another IMPDH inhibitor, such as that disclosed in International Patent Application Publication No. WO 00/25780; or mycophenolate mofetil. See Allison et i, 1993, Agents Action 44 (Suppl.):165.
  • the compounds of the present invention may also be administered in combination with the antiviral agent amantadine (1-aminoadamantane).
  • amantadine 1-aminoadamantane
  • the compounds of the present invention may also be combined for the treatment of HCV infection with antiviral 2'-C-branched ribonucleosides disclosed in Harry-O'Kuru et ah, 1997, J. Org. Chem. 62:1754-59; Wolfe et al, 1995, Tet. Lett. 36:7611-14; U.S. Patent No. 3,480,613; and International Patent Application Publication Nos. WO 01/90121, WO 01/92282, WO 02/32920, WO 04/002999, WO 04/003000 and WO 04/002422.
  • Such 2'-C-branched ribonucleosides include, but are not limited to, 2'-C-methyl-cytidine, 2'-C-methyl-uridine, -C- methyl-adenosine, 2'-C-methyl-guanosine, and 9-(2-C-methyl-P-D-ribofuranosyl)-2,6- diaminopurine, and the corresponding amino acid ester of the ribose C-2', C-3', and C-5' hydroxyls and the corresponding optionally substituted cyclic 1,3 -propanediol esters of the 5'- phosphate derivatives.
  • the compounds of the present invention may also be combined for the treatment of HCV infection with other nucleosides having anti-HCV properties, such as those disclosed in International Patent Application Publication Nos. WO 02/51425, WO 01/79246, WO 02/32920, WO 02/48165, WO05/003147 (including R1656, (2'i?)-2'-deoxy-2'-fluoro-2'-C-methylcytidine), WO 01/68663, WO 99/43691, WO 02/18404, WO06/021341, WO 02/100415, WO 03/026589, WO 03/026675, WO 03/093290, WO 04/011478, WO 04/013300 and WO 04/028481, and U.S.
  • Patent Application Publication Nos. US2005/0038240 including 4'-azido nucleosides such as R1626, 4'-azidocytidine), US2002/0019363, US2003/0236216, US2004/0006007 and
  • the compounds of the present invention may also be administered in combination with an agent that is an inhibitor of HCV NS5B polymerase.
  • HCV NS5B polymerase inhibitors that may be used as combination therapy include, but are not limited to, those disclosed in International Patent Application Publication Nos.
  • HCV polymerase inhibitors include, but are not limited to, valopicitabine (NM-283; Idenix) and 2'-F-2'-beta-methylcytidine (see also International Patent Application Publication No. WO 05/003147).
  • nucleoside HCV NS5B polymerase inhibitors that are used in combination with the present HCV NS3 protease inhibitors are selected from the following compounds: 4-amino-7-(2-C-methyl-P-D-arabinofuranosyl)-7H-pyrrolo[2,3-if]pyrimidine; 4- amino-7-(2-C-methyl-P-D-ribofiiranosyl)-7H-pyrrolo[2,3-i ]pyrimidine; 4-methylamino-7-(2-C- methyl-P-D-ribofuranosyl)-7H-pyrrolo[2,3-£ ]pyrimidine; 4-dimethylamino-7-(2-C-methyl-P-D- ribofuranosyl)-7H-pyrrolo[2,3-cf
  • the compounds of the present invention may also be combined for the treatment of HCV infection with non-nucleoside inhibitors of HCV polymerase such as HCV-796 (Viropharma Inc.) and those disclosed in International Patent Application Publication Nos. WO 01/77091; WO 01/47883; WO 02/04425; WO 02/06246; WO 02/20497; and WO 05/016927 (in particular JTK003).
  • HCV-796 Viropharma Inc.
  • non-nucleoside HCV NS5B polymerase inhibitors that are used in combination with the present HCV NS3 protease inhibitors are selected from the following compounds: 14-cyclohexyl-6-[2-(dimethylamino)ethyl]-7-oxo-5,6,7,8- tetrahydroindolo[2,l-a][2,5]benzodiazocine-l 1-carboxylic acid; 14-cyclohexyl-6-(2-morpholin- 4-ylethyl)-5,6,7,8-tetrahydroindolo[2,l-o][2,5]benzodiazocine-l 1-carboxylic acid; 14- cyclohexyl-6-[2-(dimethylamino)ethyl]-3-methoxy-5,6,7,8-tetrahydroindolo[2,l- ]
  • [2,5]benzodiazocine-l 1-carboxylic acid 6-allyl-14-cyclohexyl-3-methoxy-5,6,7,8- tetrahydroindolo[2,l-a][2,5]benzodiazocine-l 1-carboxylic acid; 14-cyclopentyl-6-[2- (dimethylamino)ethyl]-5,6,7,8-tetrahydroindolo[2,l- ][2,5]benzodiazocine-l 1-carboxylic acid; 14-cyclohexyl-6-[2-(dimethylamino)ethyl]-5,6,7,8-tetrahydroindolo[2,l-a][2,5]benzodiazoc 11-carboxylic acid; 13-cyclohexyl-5-methyl-4,5,6,7-tetrahydrofuro[3',2':6,7][l,4]diazocino[l,8-
  • the HCV NS3 protease inhibitory activity of the present compounds may be tested using assays known in the art.
  • One such assay is HCV NS3 protease time-resolved fluorescence (TRF) assay as described below and in International Patent Application Publication No. WO2006/102087.
  • TRF time-resolved fluorescence
  • Other examples of such assays are described in e.g., International Patent Application Publication No. WO2005/046712.
  • the assay is performed in a final volume of 100 ⁇ in assay buffer containing 50 mM HEPES, pH 7.5, 150 mM NaCl, 15 % glycerol, 0.15 % Triton X-100, 10 mM DTT, and 0.1 % PEG 8000.
  • NS3 protease is pre-incubated with various concentrations of inhibitors in DMSO for 30 minutes. The reaction is initiated by adding the TRF peptide substrate (final concentration 100 nM). NS3 mediated hydrolysis of the substrate is quenched after 1 hour at room temperature with 100 ⁇ of 500 mM MES, pH 5.5. Product fluorescence is detected using either a VICTOR V2 or FUSION fluorophotometer (Perkin Elmer Life and Analytical Sciences) with excitation at 340 nm and emission at 615 nm with a 400 ⁇ 8 delay. Testing concentrations of different enzyme forms are selected to result in a signal to background ratio (S/B) of 10-30. IC 50 values are derived using a standard four-parameter fit to the data. Kj values are derived from IC 50 values using the following formula,
  • the present invention also includes processes for making compounds of formula (I).
  • the compounds of the present invention can be readily prepared according to the following reaction schemes and examples, or modifications thereof, using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants which are themselves known to those of ordinary skill in this art, but are not mentioned in greater detail. Furthermore, other methods for preparing compounds of the invention will be readily apparent to the person of ordinary skill in the art in light of the following reaction schemes and examples. Unless otherwise indicated, all variables are as defined above.
  • Olefin metathesis catalysts include the following Ruthenium based species:
  • Step 1 tert-butyl [(lR,2S)-2-ethenyl-l-( ⁇ [l- carbamoyl)cyclopropyl]carbamate
  • Step 2 (lR,2S)-l-amino-2-ethenyl-N- ⁇ [l-(prop-l-en-2-yl)cyclopropyl]sulfonyl ⁇
  • Step 1 tert-butyl ⁇ (1 R,2S)-1 -[( ⁇ 1 -[(benzyloxy)methylJcyclopropyl ⁇ sulfonyl)carbamoyl]-2- ethenylcyclopropyljcarbamate
  • Step 2 (lR,2S)-l-amino-N-( ⁇ l-[(benzyloxy)methyl]cyclopropyl ⁇ sulfonyl)-2- ethenylcyclopropanecarboxamide hydrochloride
  • Step 1 tert-butyl ( ⁇ l-[(2-methoxyethoxy)methyl]cyclopropyl ⁇ sulfonyl)carbamate BuLi 2.5 M in hexanes (7.53 ml) was added dropwise to the solution of tert-butyl
  • Step 2 l-[(2-methoxyethoxy)methyl]cyclopropanesulfonamide
  • Step 4 (lR,2S)-l-amino-2-ethenyl-N-( ⁇ l-[(2- sulfonyl)cyclopropanecarboxamide hydrochloride
  • Step 1 tert-butyl ⁇ (lR,2S)-2-ethenyl-l-[( ⁇ l-[2-(morpholin-4- yl)ethyl]cyclopropyl ⁇ sulfonyl)carbamoyl]cyclopropyl ⁇ carbamate
  • Step 2 benzyl ⁇ [l-(2-hydroxypropan-2-yl)cyclopropyl]sulfonyl ⁇ carbamate
  • Step 2 methyl (2S)-[( ⁇ [(lR,2S)-2-(but-3-en-l-yl)-l- methylcyclopentyl]oxy ⁇ carbonyl)amino](cyclopentyl)ethanoate and methyl (2S)-[( ⁇ [(lS,2R)-2- (but-3-en-l-yl)-l-methylcyclopentyl]oxy ⁇ carbonyl)amino] (cyclopentyl)ethanoate
  • DMAP (0.59 g) was added to a stirred mixture of the product of Step 1 (0.75 g) and methyl (2S)-cyclopentyl(isocyanato)ethanoate (1.34 g) (See International Patent Application Publication No.: WO08/057209) in toluene (24 ml).
  • DIPEA (3.40 mL) was then added and the mixture was stirred at 100°C for 22 hours. Since the reaction wasn't complete, methyl (25)- cyclopentyl(isocyanato)ethanoate (0.6 g), DIPEA (1.5 mL) and DMAP (0.3 g) were added and the mixture was stirred at 100°C for 8 hours.
  • Step 3 (2S)-[( ⁇ [(lR,2R)-2-(but-3-en-l-yl)-l- methylcyclopropyl]oxy ⁇ carbonyl)amino](cyclopentyl)ethanoic acid and (2S)-[( ⁇ [(lS,2S)-2-(but- -en-l-yl)-l-me ethanoic acid
  • Step 2 (2S)-cyclopentyl[( ⁇ [(lR,2R)-2-(pent-4-yn-l-yl)cyclopropyl]oxy ⁇ carbonyl)
  • Steps 1-2 methyl (2S)-cyclopentyl[( ⁇ [(lR,2R)-2-(pent-4-yn-l-yl)cyclopropyl]
  • Step 1 (4S)-4- ⁇ [(4-bromophenyl)sulfonyl]oxy ⁇ -l-(tert-butoxycarbonyl)-L-proline
  • Step 2 tert-butyl (2S,4S)-4- ⁇ [(4-bromophenyl)sulfonyl]oxy ⁇ -2- ⁇ [(lR,2S)-2-ethenyl-l- (ethoxycarbonyl)cyclopropyl]carbamoyl ⁇ pyrrolidine-l-carboxylate
  • HATU 49.6 g was added to the solution of the acid from Step 1 (53.4 g), (lR,2S)-cyclopropanecarboxylic acid, l-amino-2-ethenyl-, ethyl ester, hydrochloride
  • Step 3 ethyl (lR,2S)-l- ⁇ [(4S)-4- ⁇ [(4-bromophenyl)sulfonyl]oxy ⁇ -L-prolyl]amino ⁇ -2- ethenylcyclopropanecarboxylate
  • Step 4 ethyl (lR,2S)-l- ⁇ [(4S)-4- ⁇ [(4-bromophen l)sidfo ⁇
  • Step 5 ethyl (lR,2S)-l- ⁇ [(4S)-4- ⁇ [(4-bromophenyl)sulfonyl]oxy ⁇ -l- ⁇ (2S)-2-[(tert- butoxycarbonyl)amino]non-8-enoyl ⁇ -L-prolyl](tert-butoxycarbonyl)amino ⁇ -2- ethenylcyclopropanecarboxylate
  • Di-tert-butyl dicarbonate (17.54 ml) was added at 0°C to the solution of the product of Step 4 (37.3 g) and DMAP (1.85 g) in ethyl acetate (504 ml). The solution was stirred at room temperature for 4 hours. At this point, another 2.5 g of di-tert-butyl dicarbonate was added and the solution was stirred at room temperature for 2 hours. The reaction was quenched with water and the mixture was extracted with ethyl acetate (3x). The combined organic fractions were dried over magnesium sulfate, filtered and concentrated.
  • Step 6 15-tert-butyl 14a-ethyl (2S,6S, 12Z, 13aS, 14aR, 16aS)-2- ⁇ [(4-bromophenyl)sulfonyl]oxy ⁇ - 6-[ (tert-butoxycarbonyl)amino J-5, 16-dioxo-2, 3, 6, 7, 8, 9, 10,11,13a, 14, 16,16a-dodecahydro c clopropafe Jpyrrolof 1, 2-a][ 1, 4 ]diazacyclopentadecine-14a, 15(1H, 5H)-dicarboxylate
  • Step 1 ethyl 3-[(4-bromophenyl)amino]-3-oxopropanoate
  • Step 1 The product of Step 1 (16.63 g) was dissolved in THF (150 mL) and 2N NaOH
  • Step 2 The product of Step 2 (14.7 g) was added to polyphosphoric acid (55.3 mL) and mixture was heated to 140°C for 3 hrs. The reaction mixture was cooled slightly and poured into 3N HC1 (168 mL). The pH was adjusted to 4 with 3N NaOH and resulting solid was filtered after cooling the reaction mixture to 10°C. The cake was washed with water and then slurried in 400 mL of 50% isopropanol/water for 18 hours. The solids were filtered, air dried to give a pasty solid which was dried in vacuo at 90°C for 4 hours, ground in mortar/pestle and re-dried at 90°C for another 18 hours to give 15 g of the desired product. Step 4: 6-bromo-4-hydroxy-3-(prop-2-en-l-yl)quinolin-2(lH)-one
  • Step 5 4-(benzyloxy)-6-bromo-3-(prop-2-en-l-yl)quinolin-2(lH)-one
  • Step 1 To the product of Step 1 (3.75 g) in a flask was added a solution of methanesulfonic acid (8 ml) containing phosphorus pentoxide (0.8 g) and the mixture was warmed to 170°C for 1 hour. The reaction was cooled and poured into 50 g of ice. The mixture was allowed to stir then it was diluted with water and solids were filtered. The solid was dissolved with 0.5N sodium hydroxide and washed with toluene (2X). The pH was adjusted to 3 with concentrated HCl to give solids which were filtered and washed with water to give 2.1 g of an orange solid. The material was clean but it was a 1 :1 mixture of regioisomers. LRMS (ES+) m/z (M+H) + 196.1.
  • Step 3 7-chloro-3-(prop-2-en-l-yl)quinoline-2,4-diol and 5-chloro-3-(prop-2-en-l-yl)quinoline- 2 4-diol
  • Step 4 7-chloro-4-methoxy-3-(prop-2-en-l-yl)quinolin-2-ol (A) and 5-chloro-4-methoxy-3- rop-2-en-l-yl)quinolin-2-ol (B)
  • N-bromosuccinimide (2.21 g) was added to the solution of 2,4- dihydroxyquinoline (2 g) in DCM (50 ml). The mixture was stirred at room temperature for 3 days. The mixture was filtrated and the solid was triturated with isopropanol. After filtration, toluene was added to the solid and the solvent was evaporated under reduced pressure to give the desired product (1.92 g) as a beige solid. LRMS (ES+) m/z 240.1 (M+H) + .
  • Step 1 ethyl 3-[(2-fluorophenyl)amino]-3-oxopropanoate
  • Step 5 4-(benzyloxy)-3-bromo- 7-(trifluoromethyl)quinolin-2(lH)-one
  • Step 2 tert-butyl ((lR,2S)-l-(((l-methylcyclopropyl)sulfonyl)carbamoyl)-2- vinylcyclopropyl)carbamate
  • the mixture was heated (oil bath at 75°C) overnight.
  • the reaction mixture was treated with aq 1M HC1 (20 mL) and water (50 mL).
  • the product was extracted into ethyl acetate (400 mL).
  • the organic layer was washed with aq 1M HCl/water (1 :2, 80 mL), and brine (80 mL), dried over magnesium sulfate, filtered and concentrated in rotavap.
  • Step 3 (lR,2S)-l-amino-N-((l-methylcyclopropyl)sulfonyl)-2-vinylcyclopropanecarboxam hydrochloride
  • Boc-L-indanylglycine (Chem-Impex International Inc., Wood Dale, IL) (4.2 g, 14.42 mmol) was treated with 4M hydrochloric acid (80 ml, 320 mmol) in dioxane at room temperature. The resulting slurry was stirred for 2 hours. TLC showed complete reaction and the mixture was concentrated to dryness in rotavap. The residue was dried under vacuum to give the product D5 (3.3 g, 101 %) as a white powder.
  • the HCV NS3 protease inhibitory activity was measured using the protease time- resolved fluorescence (TRF) assay as described below and in International Patent Application Publication No. WO 2006/102087.
  • TRF protease time- resolved fluorescence
  • the assay was performed with HCV genotype lb (BK) NS3 modified enzyme with a R155K mutation and genotype 3a (3A-1).
  • the assay was performed in a final volume of 50 ⁇ in assay buffer containing 50 mM HEPES, pH 7.5, 150 mM NaCl, 15% glycerol, 0.15% TRITON X-100, 10 mM DTT, and 0.1 % PEG 8000.
  • NS3 and NS4A protease is pre-incubated with various concentrations of inhibitors in DMSO for 10 minutes.
  • the reaction was initiated by adding the TRF peptide substrate (final concentration 25 nM) and NS3 mediated hydrolysis of the substrate proceeds for 6 hours at room temperature.
  • Product fluorescence is detected using an Envision plate reader (Perkin Elmer) with excitation at 340 nm and emission at 615 nm with a 400 delay. Testing concentrations of the enzymes were selected to result in a signal to background ratio (S/B) of 5- 20.
  • S/B signal to background ratio
  • the Ki values can be obtained using the following protocol:
  • the assay is performed in a final volume of 100 ⁇ in assay buffer containing 50 mM HEPES, pH 7.5, 150 mM NaCl, 15% glycerol, 0.15% TRITON X-100, 10 mM DTT, and 0.1 % PEG 8000.
  • NS3 and NS4A protease is pre-incubated with various concentrations of inhibitors in DMSO for 30 minutes. The reaction is initiated by adding the TRF peptide substrate (final concentration 100 nM).
  • NS3 mediated hydrolysis of the substrate is quenched after 1 hour at room temperature with 100 ⁇ of 500 mM MES, pH 5.5.
  • Example 1 (3a ?JS,10S.12i?.21E.24aS)-7-cvclopentyl-N-story?,2S)-l- (cvclopropylsulfonyl carbamoyll-2-ethenylcvclopropy -19-ethoxy-5,8-dioxo- 1.2.3.3a.5.6.7.8.11.12,20,23,24,24a-tetradecahvdro-10H-9.12-methanocvclo
  • Step 1 1-tert-butyl 2 -methyl (2S,4R)-4- ⁇ [4-ethoxy-3-(prop-2-en-l-yl)quinolin-2- yl]oxy ⁇ pyrrolidine-l,2-dicarboxylate
  • Step 3 methyl (4R)-l- ⁇ (2S)-2-[( ⁇ [(lR,2S)-2-(but-3-en-l-yl)cyclopentyl]oxy ⁇ carbonyl) cyclopentylacetyl ⁇ -4- ⁇ [4-ethoxy-3-(prop-2-en-l-yl)quinolin-2-yl]oxy ⁇ -L-prolinate
  • Step 4 methyl (3aR, 7S,10S,12R,21Z,24aS)-7-cyclopentyl-19-ethoxy-5,8-dioxo- 1, 2, 3, 3a, 5, 6, 7, 8, 11,12, 20, 23, 24, 24a-tetradecahydro-l OH-9, 12-methanocyclopenta
  • Step 5 (3aR, 7S, 1 OS, 12R,21E, 24aS)- 7-cyclopentyl-19-ethoxy-5, 8-dioxo-l, 2, 3, 3a, 5, 6, 7, 8, 11, 12,20, 23, 24, 24a-tetradecahydro-l OH-9, 12-methanocyclopenta[18,19][l,10, 3, 6]
  • Example 8 (19 mg) was treated with TFA (1 ml) in a sealed tube and warmed to 55°C. After 30 minutes, the reaction was concentrated and the residue was dissolved in ACN and purified by reverse phase HPLC to provide the desired product as a white foam (13 mg). LRMS (ES+) m/z (M+H) + 790.2.
  • Example 18 (3ai?.7S.10S.12i?.21E,25aj? -7-cvclopentyl-N-(aj?,25)-l-r(cvclopropyl sulfonvncarbamoyll ⁇ -ethenylcvclopro yU-ig-hvdroxy-S.S-dioxo ⁇ .S a.S.ej.S.l l. .
  • Example 19 riai?.5 ⁇ 8 .10i?J9E,22ai?V5-cvclopentyl-N- ⁇ (lj?.2S)-l-r(cvclopropyl sulfonyl)carbamoyl]-2-ethenylcyclopropyl ⁇ - 17-hydroxy- 1 a-methyl-3 ,6-dioxo-
  • Example 21 (3ai?.7 l S l ,10S.12i?.21E.24a ⁇ -7-cvclopentyl-N-r(lS.2igV2- (cvclopropyl sulfonyDcarbamoyl -l.r-bi cyclopropyD ⁇ -yll- ⁇ -hvdroxy-S ⁇ -dioxo- 1.2.3 ,3a.5.6.7.8.11.12.20.23.24.24a-tetradecahvdro- 1 OH-9.12-methanocyclopentar 18, 191
  • Example 22 (3ai?JSq0Sa2i?,21E,24aS)-17-bromo-7-cvclopentyl-N-i( ' li?,2S)-l- (cyclopropylsulfonvncarbamovn-2-ethenylcyclopropyl ⁇ -19-hydroxy-5,8-dioxo- l,2,3,3a,5,6J.8Jia2.20,23,24.24a-tetradecahvdro-10H-9,12-methanocvclopentari8J91 ⁇ ⁇ 03 ,6]dioxadiazacvclononadecino 11 , 12-b] quinoline- 10-carboxamide
  • Example 23 (3ai?JSJ0SJ2i?.21E.24ay)-7-cvclopentyl-N-r(li?,2 ⁇ -2-ethenyl-l- ⁇ r(l- methylcvclopropyl)sulfonyl1carbamoyl>cvclopropyl]-19-hvdroxy-5,8-dioxo-L2,3, 3a.5.6.7.8.11.12,20,23, 24.24a-tetradecahvdro- 10H-9.12-methanocvclopentar 18.191
  • Example 24 r3a j ?.7 ⁇ .10S.12i?,24ai?)-7-cvclopentyl-N-(ni?,2 ⁇ -l-r(cvclopropyl sulfonvDcarbarnoyll-2-ethenylcyclopropyU - 19-ethoxy-5,8-dioxo- 1 ,2,3 ,3a,5,6,7,8, 1 1,12, 20,21 ,22.23 ,24.24a-hexadecahvdro- 1 OH-9.12-methanocvclopentar 18, 191 ⁇ 1 , 10.3.61dioxa diazacyclononadecino ⁇ 11 , 12-61quinoline- 10-carboxamide
  • Step 1 methyl (3aR, 7S,10S,12R,24aR)-7-cyclopentyl-19-ethoxy-5,8-dioxo-
  • Step 2 (3aR, 7S,10S,12R,24aR)-7-cyclopentyl-19-ethoxy-5,8-dioxo-l,2,3,3a,5,6, 7,8, 11,
  • Step 3 (3aR, 7S, 10S,12R,24aR)-7-cyclopentyl-N- ⁇ (lR,2S)-l-[(cyclopropylsulfonyl) carbamoyl] - 2-ethenylcyclopropyl ⁇ -19-ethoxy-5, 8-dioxo-l, 2, 3, 3a, 5, 6, 7, 8, 11,12, 20, 21, 22, 23, 24, 24a-hexadeca hydro-10H-9, 12-methanocyclopenta[18, 19] [1, 10,3, 6] dioxadiazacyclononadecinofl 1, 12-b] quinoline-10-carboxamide
  • Example 29 (3aig.7S.10S.12i?.24ai?V7-cvclopentyl-N-(rii?.2S)-l-rrcvclopropylsulfonvn carbamoyl]-2-ethenylcvclopropyl ⁇ -19-hvdroxy-3a-methyl-5,8-dioxo-l,2,3,3a,5,6,7,8J l, 12,20,21 ,22,23 ,24,24a-hexadecahydro- lQH-9,12-methano cvclopentai 18,191 ⁇ 1.10.3 ,6] dioxadiazacyclononadecino [11,12-b] quinoline- 10-carboxamide
  • Step 1 (3aR, 7S, 10S, 12R,24aR)-7-cyclopentyl-19-hydroxy-3a-methyl-5,8-dioxo-
  • Step 2 (3aR, 7S, 10S, 12R,24aR)-7-cydopentyl ⁇ N- ⁇ (lR,2S)-l-[(cyclopropylsulfonyl) carbamoyl]- 2-ethenylcyclopropyl ⁇ -19-hydroxy-3a-methyl-5, 8-dioxo-l, 2, 3, 3a, 5, 6, 7, 8, 11,
  • Example 29 By following the procedures outlined in Example 29 and using the appropriate A, B and C intermediates (depicted below the structure as Int.), the following compounds were prepared.
  • Example 38 (-3ai?.7S.10SJ2 ⁇ ,21E.24aS)-7-cvclopentyl-10-ridj?.2S)-l- [(cvclopropylsulfonyl carbamoyl]-2-ethenylcvclopropyl
  • Example 39 r3ai?.7S.10S.12i?.21E,24aS)-7-cvclopentyl-10-( ' i(1 ⁇ .2S -l-r( ' cvclopropyl sulfonyl)carbamoyl1-2-ethenylcvclopropyl
  • Example 40 r3a ? J ⁇ 10 l S.12i?.21E.24a ⁇ -7-cvclopentyl-10-r ⁇ nig.2 ( ⁇ -l-r(cvclopropyl sulfonyf)carbamoyll-2-ethenylcyclopropyl ⁇ carbamoyl ' )-5,8-dioxo-L2,3,3a,5,6,7,8,l l,
  • Example 41 r3ai?.7S.10S.12j?.21E.24aS -7-cvclopentyl-10-(((lj?.2S)-l-r( ' cvclopropyl sulfonyl)carbamoyll-2-ethenylcvclopropyl ⁇ carbamoylV5.8-dioxo-1.2.3.3a.5.6.7.8.11.
  • Example 42 r3a ?.7S.10S.12i;.21E,24aS)-7-cvclopentyl-N- ⁇ rii?.2S)-l-rrcvclopropyl sulfonyl)carbamoyll-2-ethenylcvclopropyl ⁇ -5,8-dioxo-19- 2-(2-oxo-l,3-oxazolidin-3- vnethoxyl-1.2 .3a.5.6.7.8.11.12,20,23,24,24a-tetradecahvdro-10H-9,12-methanocvclo
  • Example 42 By following the procedures outlined in Example 42 and using the appropriate A, B and C intermediates and reagent (depicted below the structure as Int. and Rg., respectively), the following compounds were prepared.
  • Example 61 (3ai?JSJ0S.12i?.24ai? -7-tert-butyl-N-r( ' li?.2S)-2-ethenyl-l-( ' ⁇ ri-(methoxy methvDcvclopropyll sulfonyl ⁇ carbamo vDcyclopropyl] - 19- [2-(morpholin-4-yl')ethoxyl -5 ,8-dioxo- 1.2.3.3 a.5.6.7,8, 11 , 12,20.21.22.23 ,24.24a-hexadecahvdro- 1 OH-9.12-methano
  • Example 61 By following the procedures outlined in Example 61 and using the appropriate A, B and C intermediates and reagent (depicted below the structure as Int. and Rg., respectively), the following compounds were prepared.
  • Example 66 (r(3aj?.7S.10S.12i?.21E.24aS -7-cvclopentyl-10-( ⁇ (lj?.2S)-l-r(cvclor>ropyl sulfonyl carbamoyl]-2-ethenylcvclopropyl
  • Step 1 methyl ⁇ [(3aR,7S,10S,12R,21E,24aS)-7-cyclopentyl-10-( ⁇ (lR,2S)-l- [(cyclopropylsulfonyl)carbamoyl]-2-ethenylcyclopropyl ⁇ carbamoyl)-5,8-dioxo- 1 ,2,3 ,3a,5,6,7,8, 11 , 12,20,23 ,24,24a-tetradecahydro- 1 OH-9, 12-methanocyclopenta
  • Step 2 ⁇ [(3aR, 7S, 10S, 12R,21E,24aS)-7-cyclopentyl-10-( ⁇ (lR,2S)-l- [( cyclopropylsulfonyl)carbamoyl ]-2-ethenylcyclopropyl ⁇ carbamoyl)-5, 8-dioxo- 1, 2, 3, 3a, 5, 6, 7, 8, 11,12, 20, 23, 24, 24a-tetradecahydro-l OH-9, 12-methanocyclopenta
  • Step 1 The product of Step 1 (43 mg) was dissolved in THF (1 ml) and methanol (0.2 ml). Water (0.5 ml) and LiOH (11.95 mg) were added and the reaction was stirred until complete conversion. The reaction was quenched with IN HC1 (0.4 mL) and 5% KHS0 4 was added until the pH was 3. The mixture was extracted with ether then ethyl acetate. The combined organics were washed with water (5x) then brine, dried over magnesium sulfate, filtered and concentrated to yield 42 mg of pure product. HRMS (ES+) m/z 848.3522 (M+H) + .
  • Example 67 (3ai?,7S,10SJ2i?,21E,24aS)-7-cvclopentyl-N- ⁇ (l ?,2S)-l-r(cvclopropyl sulfonyl)carbamoyll-2-ethenylcvclopropyU-5,8-dioxo-19- 2-oxo-2-(pyrrolidin-l-yl)ethoxyl- 1 ,2.3.3a.5.6,7,8, 11.12.20,23 ,24.24a-tetradecahvdro- 1 OH-9.12-methanocvclopenta
  • Step 1 (SaR, 7S,10S,12R,21E,24aS)-19-(4- ⁇ [tert-butyl(dimethyl)silyl]oxy ⁇ butoxy)-7-cyclopentyl- N- ⁇ (lR,2S)-l-[(cyclopropylsulfonyl)carbamoyl]-2-ethenylcyclopropyl ⁇ -5,8-dioxo- 1, 2, 3, 3a, 5, 6, 7, 8, 11,12, 20, 23, 24, 24a-tetradecahydro-l OH-9, 12-methanocyclo
  • Step 2 (3aR, 7S,10S,12R,21E,24aS)-7-cyclopentyl-N- ⁇ (lR,2S)-l-[(cyclopropyl
  • Example 69 r3ai?.7 ⁇ 10 ,12i?.21E.24aS , )-7-cvclopentyl-N-i(Ti?,2 -l-rfcvclopropyl sulfonyl)carbamoyll-2-ethenylcvclopropyl
  • Example 70 (Z ⁇ R SSQSA2R ⁇ E2 ⁇ aS)-l-tert ⁇ uty ⁇ -N-U ⁇ R2S) - ( c ⁇ o )roO ⁇
  • the title compound was prepared using the same method as Example 70, using 3- bromopropanol-TBS ether and (3ai?,7S,105,12 ⁇ ,21E,24aS)-7-tert-butyl-N- ⁇ (lJ?,2S)-l- [(cyclopropylsulfonyl)carbamoyl]-2-ethenylcyclopropyl ⁇ -19-hydroxy-5,8-dioxo- l,2,3,3a,5,6,7,8,l l ,12,20,23,24,24a-tetradecahydro-10H-9,12-methanocyclo
  • Example 71 (3aR SA0SA2R21E24aS)-7-tert-butyl-N- ⁇ (lR2S)-2-et enylA-m ⁇ methylcvclopropyDsulfonyllcarbamoyllcvclopropy ⁇ -ig-O-hvdroxypropoxy ⁇ -S ⁇ -dioxo-
  • Example 72 r3aig.7SJ0S,12i?.21E,24aS)-7-cvclopentyl-N-(rii?,2 ⁇ )-l-rrcvclopropyl sulfonvDcarbamoyll -2-ethenylcyclopropyl ⁇ - 19-(3-hydroxypropoxy)-5 , 8-dioxo- L2,3 a,5.6.7,8,lia2.20.23.24.24a-tetradecahvdro-10H-9J2-methanocyclo
  • Example 74 3-t ⁇ (3aR SA0SA2R2 ⁇ E24aS)-7-CYc ⁇ opentyl-l0-(UlR2S)-l- lYcyclopropyl sulfonvDcarbamoyll -2-ethenylcvclopropyl ⁇ carbamoyl)-5 , 8-dioxo- 1.2.3.3 a.5.6.7.8.11.12,20.23.24,24a-tetradecahydro- 1 OH-9.12-methanocvclo
  • Example 72 To a solution of Example 72 (31 mg) in dichloromethane (0.5 mL) was added ⁇ , ⁇ -dimethylglycine (11.3 mg) then triethylamine (0.015 ml), A N'-dicyclo hexylcarbodiimide (18.9 mg) and DMAP (1.1 mg). The solution was stirred at room temperature for 3 days. The mixture was diluted with ether and the solids that were formed were filtered off. The filtrate was concentrated in vacuo. Purification by reverse phase HPLC (30-100% ACN/water w/ 0.15% TFA) yielded 21 mg of the desired product after workup with NaHC0 3 and ethyl acetate.
  • Example 75 By following the procedures outlined in Example 75 and using the appropriate A, B and C intermediates and reagent (depicted below the structure as Int. and Rg., respectively), the following compounds were prepared.
  • Example 93 ( , 3ai?.7S,10Sa2i?,21E,24aS)-7-cvclopentyl-10- rii?.2S -l-r( ' cvclo propylsulfonvDcarbamoyl] -2-ethenylcyclopropyl ⁇ carbamovD-5 ,8-dioxo- 1 ,2 ,3 ,3a, 5,6,7,8,1 l,12,20,23.24.24a-tetradecahvdro-10H-9,12-methanocvclopentari8.191 ⁇ 1 , 10,3 ,6]dioxadiazacyclononadecino [11,12-6]quinolin- 19-yl propan-2-ylcarbamate
  • Example 17 enta[18,19][l ,10,3,6]dioxadiazacyclononadecino[l l,12- )]quinoline-10-carboxamide (Example 17) (30 mg) in dichloroethane (0.6 mL) was added isopropylisocyanate (0.037 mL) then DMAP (4.6 mg). The reaction mixture was heated to 50°C for 1 hour. After cooling back to room temperature, the mixture was diluted with ethyl acetate and water was added. The mixture was extracted with ethyl acetate (3x). The combined organics were dried over magnesium sulfate, filtered and concentrated.
  • Example 94 (3ai?JS,10 ⁇ ,12ig.21E,24ay)-19-(3-aminopropoxyV7-cvclopentyl-N- ⁇ (li?,25 f )-l- [(cvclopropylsulfonyl)carbamoyll -2-ethenylcyclopropyl > -5 , 8 -dioxo-

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Abstract

The present invention relates to macrocyclic compounds of formula (I) that are useful as inhibitors of the hepatitis C virus (HCV) NS3 protease, their synthesis, and their use for treating or preventing HCV infections.

Description

TITLE OF THE APPLICATION
HCV NS3 PROTEASE INHIBITORS
FIELD OF THE INVENTION
The present invention relates to macrocyclic compounds that are useful as inhibitors of the hepatitis C virus (HCV) NS3 protease, the synthesis of such compounds, and the use of such compounds for treating HCV infection and/or reducing the likelihood or severity of symptoms of HCV infection. BACKGROUND OF THE INVENTION
Hepatitis C virus (HCV) infection is a major health problem that leads to chronic liver disease, such as cirrhosis and hepatocellular carcinoma, in a substantial number of infected individuals, estimated to be 2-15% of the world's population. There are an estimated 3.9 million infected people in the United States alone, according to the U.S. Center for Disease Control, roughly five times the number of people infected with the human immunodeficiency virus (HIV). According to the World Health Organization, there are more than 170 million infected individuals worldwide, with at least 3 to 4 million people being infected each year. Once infected, about 20% of people clear the virus, but about 80% of those infected harbor HCV the rest of their lives. Ten to 20% of chronically infected individuals eventually develop liver- destroying cirrhosis or cancer. The viral disease is transmitted parenterally by contaminated blood and blood products, contaminated needles, or sexually and vertically from infected mothers or carrier mothers to their off-spring.
Current treatments for HCV infection, which are restricted to immunotherapy with recombinant interferon-a alone or in combination with the nucleoside analog ribavirin, are of limited clinical benefit. Moreover, there is no established vaccine for HCV. Consequently, there is an urgent need for improved therapeutic agents that effectively combat chronic HCV infection. The current state of the art in the treatment of HCV infection has been discussed in the following references: Dymock et al, 2000, Antiviral Chem. & Chemotherapy 11 :79-96; Rosen et al, 1999, Molec. Med. Today 5:393-399; Moradpour et al, 1999, Euro. J. Gastroenterol.
Hepatol. 11 :1189-1202; Bartenschlager, 1997, Intervirology 40(5-6):378-393; Lauer et al, 2001, N. Engl. J. Med. 345:41-52; Dymock, 2001, Emerging Drugs 6:13-42; and Crabb, 2001, Science 294:506-507. Several virally-encoded enzymes are putative targets for therapeutic intervention, including a metalloprotease (NS2-3), a serine protease (NS3), a helicase (NS3), and an RNA- dependent R A polymerase (NS5B). The NS3 protease is located in the N-terminal domain of the NS3 protein. Because it is responsible for an intramolecular cleavage at the NS3/4A site and for downstream intermolecular processing at the NS4A 4B, NS4B/5A and NS5A/5B junctions, the NS3 protease is considered a prime drug target. Previous research has identified classes of peptides, such as hexapeptides as well as tripeptides discussed in U.S. Patent Application Publications Nos. US2005/0020503, US2004/0229818, and US2004/00229776, showing degrees of activity in inhibiting the NS3 protease. Additional HSV NS3 protease inhibitors have been described in International Patent Applicaton Publication Nos. WO2008/057208 and
WO2008/057209. The aim of the present invention is to provide further compounds which exhibit activity against the HCV NS3 protease.
SUMMARY OF THE INVENTION
The present invention relates to novel macrocyclic compounds of formula (I) and/or pharmaceutically acceptable salts or hydrates thereof. These compounds are useful in the inhibition of HCV (hepatitis C virus) NS3 (non-structural 3) protease, the prevention or treatment of one or more of the symptoms of HCV infection, either as compounds or their pharmaceutically acceptable salts or hydrates (when appropriate), or as pharmaceutical composition ingredients. As pharmaceutical composition ingredients, these compounds, salts and hydrates may be the primary active therapeutic agent, and, when appropriate, may be combined with other therapeutic agents including but not limited to other HCV antivirals, anti- infectives, immunomodulators, antibiotics or vaccines. More particularly, the present invention relates to a compound of formula (I) and/or a pharmaceutically acceptable salt thereof:
Figure imgf000005_0001
(I) wherein:
Y is CH or N;
R1 is:
-OH,
-OCi-6alkyl,
-OC1-6alkyl-het1,
-Od-6alkyl-OH,
-OC 6alkyl-NRaRb,
-O-het!,
-OC1-6alkylC02H,
-OC1-6alkylC(=0)-het1,
-0(CH2)1-6OC(=0)CH2NRaRb,
-OC i -6alkyl-C i -6alkoxy,
-OC \ -6alkyl-C \ -6alkoxy-C \ -6alkoxy,
-OC(0)Cr6alkyl,
-OC(0)NRaRb,
-Od-ealkyl-S-het!,
-OC i - alkyl-phosphate, a phosphate group,
-(CH2)1-6-het!,
pyridinyl, or
thiazolyl; said alkyl is optionally substituted with 1 or 2 fluoro substituents, said phosphate group is optionally substituted with 1, 2 or 3 C1-6alkyl;
Figure imgf000006_0001
a) aryl selected from phenyl or napthyl optionally substituted with 1 or 2 substituents selected from -OH, Cr6alkyl, or halo;
b) heteroaryl selected from 5- and 6-membered aromatic rings having 1, 2 or 3 heteroatoms independently selected from N, O and S, wherein said heteroaryl is attached through a ring atom selected from C or N and optionally substituted with 1 or 2 substituents independently selected from Chalky! and -OH; or
c) heterocycle selected from 4-7 membered monocyclic or 6-10
membered polycyclic bridged, linearly fused or spirocyclic saturated or unsaturated non-aromatic rings having 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, wherein said heterocycle is attached through a ring atom selected from C or N and optionally substituted with 1 or 2 substituents independently selected from C1-6alkyl, oxo, -(CH2)mF, Boc, -(CH2)mCF3,
-(C¾)mOCF3, -OH, -NRaRb, -C1-6alkoxy, -(CH2)mS02CH3, aryl, -Q-ealkoxy-Ci-ealkyl, -C1-6alkyl-C1-6alkoxy optionally substituted with CF3, cyano, C(=0)NH2, C3-6cycloalkyl,
-C1-6alkyl-C3-6cycloalkyl, -COOC1-6alkyl,
-C1-6alkyl-S02C1-6alkyl, and benzimidazolyl wherein the benzimidazolyl is optionally substituted with F;
Ra and Rb are independently selected from H; d-6 alkyl; t-Boc; aryl; C3-6cycloalkyl optionally substituted with 1 or 2 fluoro substituents; C ealko y-Ci-ealkyl; tetrahydropyranyl; C^ealkyl-OH; C1-6alkyl-aryl; Q-6 alkyl-C(OH)-aryl; Q-ealkyl-imidazolyl optionally substituted with methyl, C ealkyl-benzimidazolyl optionally substituted with methyl; Crealkyl-pyrazolyl; Crealkyl-dihydrotriazole optionally substituted with oxo; or d-ealkyl-pyrrolidinyl optionally substituted with oxo;
wherein m is 0 or 1 to 4;
said aryl is phenyl, naphthalenyl, tetrahydronapthalenyl, or 7-10 membered fused bicyclic ring structure wherein at least one of the rings is aromatic and is optionally substituted with 2 -OH;
said tetrahydropyranyl is optionally substituted with 1 oxo;
R2 is Ci-ealkyl, C2-6alkenyl, C3-C6cycloalkyl or NRcRd;
wherein
the C3-6cycloalkyl is optionally substituted with C1-6alkyl optionally substituted with -OH, morpholinyl, C1-6alkoxy, C1-6alkoxy-C1-6alkoxy, C1-6alkoxy-phenyl, or C1-6alkenyl;
Rc and Rd are independently H or C1- alkyl, or may be taken together, with the N to which they are attached, to form a 4-7-membered monocyclic ring;
R is C^alkyl, C2- alkenyl, C3-C6cycloalkyl, CF2 or CF3;
R4 is Ci-8 alkyl, C3-g cycloalkyl, Ci-8 alkyl-C3-8 cycloalkyl, adamantyl, dihydroindenyl, or a 4-8 membered heterocycloalkyl having 1 or 2 heteroatoms selected from N, O, or S, wherein R4 is optionally substituted with one or two substituents independently selected from (Ci- C6)alkyl, halo, and -0(C1-C6)alkyl; or
R3 and R4 together form heptene;
Z is C or N;
R5 is H or d-6alkyl; or R5 is absent when Z is N;
W is a bond, O or NR;
R is H or d-6alkyl;
X is absent or is halo, CF3, -OCHF2, -OCH2F, -OCD2F, -OCDF2, C C6alkyl, Crealkoxy, aryl, heteroaryl, or -0(CH2)1-6NRaRb;
A is absent, O or N;
B is (CH2)m; and
n is 1-4.
The present invention also includes pharmaceutical compositions containing a compound of the present invention and methods of preparing such pharmaceutical compositions. The present invention further includes methods of treating or reducing the likelihood or severity of one or more symptoms of HCV infection. Other embodiments, aspects and features of the present invention are either further described in or will be apparent from the ensuing description, examples and appended claims. DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to compounds of Formula (I) and pharmaceutically acceptable salts thereof, as defined above and a first embodiment of the invention. Different embodiments further describing Formula (I) variables are described below.
In a second embodiment of the invention, the present invention relates to c mpounds, or a pharmaceutically acceptable salt thereof, having a formula of
Figure imgf000008_0001
Figure imgf000009_0001
and pharmaceutically acceptable salts thereof, where all variables as provided for in the first embodiment.
In a third embodiment of the invention, the present invention relates to compounds of Formula (I), (la), (lb), (Ic), (Id) or (le) and pharmaceutically acceptable salts thereof, wherein Z is C and the other variables are as provided for in the first or second embodiments.
In a fourth embodiment of the invention, the present invention relates to compounds of Formula
Figure imgf000009_0002
and pharmaceutically acceptable salts thereof, wherein the variables are as provided for in the first embodiment.
In a fifth embodiment of the invention, the present invention relates to a compound having the formula of
Figure imgf000010_0001
and pharmaceutically acceptable salts thereof, wherein the variables are as provided for in the first embodiment.
In a sixth embodiment of the invention, the present invention relates to compounds of Formula (I), (la), (lb), (Ic), (Id), (Ie), (If), (Ig) and (Ih) and pharmaceutically acceptable salts thereof, wherein R5 is H or CH3 wherein the other variables are as provided for in the first embodiment
In a seventh embodiment of the invention, the present invention relates to compounds of Formula (I), (la), (lb), (Ic), (Id), (Ie), (If), (Ig) and (Ih) and pharmaceutically acceptable salts thereof, wherein R is ethyl, ethylene, or cyclopropyl and the other variables are as provided for in the first or sixth embodiments. In one aspect of this embodiment, R3 is ethylene.
In a eighth embodiment of the invention, the present invention relates to compounds of Formula (I), (la), (lb), (Ic), (Id), (Ie), (If), (Ig) and (Ih) and pharmaceutically acceptable salts thereof, wherein R4 is propyl, t-butyl, cyclopentyl, cyclohexyl optionally substituted with 1 or 2 F, cyclohexylmethyl, methylcyclohexyl, methylcyclopentyl,
dihydroindenyl, or tetrahydro-2H-pyranyl, and the other variables are as provided for in any of the first, sixth or seventh embodiments. In one aspect of this embodiment, R4 is t-butyl, cyclopentyl, or cyclohexyl, 1 -methylcyclohexyl, propan-2-yl, 2,3 -dihydroindenyl, tetrahydro- 2H-pyranyl, or cyclohexylmethyl. In another aspect of this embodiment, R4 is t-butyl, cyclopentyl, or cyclohexyl, 1 -methylcyclohexyl, 2,3 -dihydroindenyl, or tetrahydro-2H-pyranyl.
In a ninth embodiment of the invention, the present invention relates to compounds of Formula (I), (la), (lb), (Ic), (Id), (Ie), (If), (Ig) and (Ih) and pharmaceutically acceptable salts thereof, wherein n is 1 or 3, and the other variables are as provided for in any of the first or sixth to eighth embodiments. In a tenth embodiment of the invention, the present invention relates to compounds of Formula (I), (la), (lb), (Ic), (Id), (le), (If), (Ig) and (Ih) and pharmaceutically acceptable salts thereof, wherein R is cyclopropyl, N(CH3)2, or azetidinyl, wherein the cyclopropyl is optionally substituted with methyl, CH(CH3)2, C(CH3)=CH2; C(CH3)2OH, CH2CH2-morpholinyl, CH2OCH3, CH2OCH2CH2OCH3, or CH2OCH2-phenyl, and the other variables are as provided for in any of the first or sixth through ninth embodiments. In one aspect of this embodiment, R2 is cyclopropyl, N(CH3)2, (methyl)cyclopropyl,
(methoxymethyl)cyclopropyl, [(benzyloxy)methyl] cyclopropyl, l-(prop-l -en-2-yl)cyclopropyl, or l-[2-(morpholin-4-yl)ethyl]cyclopropyl. In another aspect of this embodiment, R2 is cyclopropyl, N(C¾)2, (methyl)cyclopropyl, or l-(methoxymethyl)cyclopropyl.
In an eleventh embodiment of the invention, the present invention relates to compounds of Formula (I), (la), (lb), (Ic), (Id), (le), (If), (Ig) and (Ih) and pharmaceutically acceptable salts thereof, wherein R1 is is -OH; -0-C1-6alkyl; -OC(0)Ci-6alkyl; -OC!-6alkyl- heti; -OCrealkyl-d-ealkoxy; -OCrealkyl-Crealkoxy-C ealkoxy; -OCH2C(=0)-het1;
-0(CH2)1-6 OC(=0)CH2NRaRb; -OC(0)NRaRb; -OCrealkyl-phosphate; -OCrealkyl-S-heti ; -O-heti; -O-d-ealkyl-OH optionally substituted with 1 or 2 fluoro substituents; or
-Od-ealkyl-NR'R1'
wherein Ra and Rb are independently
H,
Ci-6 alkyl, t-Boc,
C3-6cycloalkyl optionally substituted with 1 or 2 fluoro substituents,
Ci-6 alkyl-Ci-6alkoxy,
C ealkyl-OH, phenyl,
Q-ealkyl-phenyl, tetrahydropyranyl, Ci-6alkyl-C(OH>-phenyl,
naphthalenyl,
C i -6alkyl-naphthalenyl, C i -6alkyl-dihydrooxopyrrolidinyl,
Crealkyl-benzimidazolyl optionally substituted with methyl, C i -6alkyl-pyrazolyl, d-ealkyl-triazole optionally substituted with oxo, or d-ealkyl-imidazolyl optionally substituted with methyl, and the other variables are as provided for in any of the first or sixth through tenth embodiments. In one aspect of this embodiment, heti is phenyl; oxazepanyl; oxooxazolidinyl; pyridinyl; pyrazolyl; pyrrolyl;
tetrahydropyranyl, triazolyl optionally substituted with C1-6alkyl; dioxolanyl; oxoimidazolidinyl; morpholinyl optionally substituted with dimethyl or ethyl; pyrrolidinyl optionally substituted with 1 or 2 substituents independently selected from oxo, Boc, C1-6alkyl, OH, C(0)NH2, dimethylamino, and methylsulfomyl; piperidinyl optionally substituted with 1 or 2 substituents independently selected from C1-6alkyl, C1-6alkoxy, Q-ealkoxy-C^alkyl optionally substituted with CF3, cyclopropyl-C1-6alkyl, cyclopropyl, -(CH2)mF, OH, -C1-6alkyl-S02C1-6alkyl,
-(CH2)mCF3, -COOC1-6alkyl, Boc, and benzimidazol; imidizolyl; thiazolyl optionally substituted with methyl; azabicycloheptyl; azaspiroheptyl; azaspirononyl; oxaazabiocycloheptyl;
oxaazaspiroheptyl optionally substituted with methoxyethyl; azetidinyl optionally substituted with 1 or 2 substituents independently selected from C1-6alkyl, Q-ealkoxy, cyano, fluoro, OH, phenyl and Boc; dioxidothiomorpholinyl; piperazinyl optionally substituted with 1 or 2 substituents independently selected from C1-6alkyl, C1-6alkyl-cyclopropyl, CF3, methylsulfonyl, Boc, and oxo; azabicyclooctyl substituted with C1-6alkyl, Q-ealkoxy-C^alkyl, -COOC1-6alkyl, or -(CH2)mCF3; oxaazabicyclononyl optionally substituted with Boc, C1-6alkyl, -COOC1- alkyl, C1-6alkoxy-C1-6alkyl or cyclopropylC1-6alkyl; or azabicyclooctanyl optionally substituted with C1-6alkyl. In one aspect of the invention, R1 is -OH; -OC(0)CH3; methoxy; ethoxy;
2-(tert-butylamino)ethoxy; 3-aminopropoxy; 2-methoxyethoxy; 3-methoxypropoxy;
3-(2-methoxyethoxy)propoxy; 3-(2-azabicyclo[2.2.1 ]hept-2-yl)propoxy;
2- (2-azaspiro[3.3]hept-2-yl)ethoxy; 3-(2-azaspiro[3.3]hept-2-yl)propoxy;
3- (2-azaspiro[4.4]non-2-yl)propoxy; azetidin-3-yloxy; 2-(azetidin-l-yl)ethoxy;
3 -(azetidin- 1 -yl)propoxy ; 3 - { [2-( 1 H-benzimidazol-2-yl)ethyl] (ethyl)amino }propoxy;
3-[benzyl(2-hydroxyethyl)amino]propoxy; 3-[bis(2-methoxyethyl)amino]propoxy;
3-[(2i?)-2-carbamoylpyrrolidin-l-yl]propoxy; 3-(3-cyanoazetidin-l-yl)propoxy;
3 -(cyclobutylamino)propoxy; 3 -(cyclopentylamino)propoxy; 2-(cyclopropylamino)ethoxy ; [ 1 -(cyclopropylmethyl)piperidin-4-yl]oxy; ( 1 -cyclopropylpiperidin-4-yl)oxy;
3-(cyclopropylamino)propoxy; [l-(cyclopropylmethyl)azetidin-3-yl]oxy;
3 -(3 ,3 -difluoroazetidin- 1 -yl)propoxy ; 2,2,-difluoro-3 -hydroxypropoxy ;
3-{[2-(3,4-dihydroxyphenyl)-2-hydroxyethyl](propan-2-yl)amino}propoxy;
2-(dimethylamino)ethoxy; 3-(dimethylamino)propoxy; 2-(2,2-dimethylmorpholin-4-yl)ethoxy; ( 1 ,4-dimethylpiperazin-2-yl)methoxy; 3 -(dimethylamino)pyrrolidin- 1 -yl;
2- ( 1 ,3 -dioxalan-2-yl)ethoxy; 2-( 1 , 1 -dioxidothiomorpholin-4-yl)ethoxy ;
3- (l , 1 -dioxidothiomorpholin-4-yl)propoxy; 2-(2,5-dioxopyrrolidin- 1 -yl)ethoxy;
(4-ethylmorpholin-2-yl)methoxy; 1 -ethylpiperidin-3-yl)methoxy;
(1 -ethylpiperidin-4-yl)methoxy; ( 1 -ethylpiperidin-4-yl)oxy; 3 -(3 -fluoroazetidin- 1 -yl)propoxy; 3- [2-(5-fluoro- 1 H-benzimidazol-2-yl)piperidin- 1 -yl]propoxy; 3 -(3 -fluoropiperidin- 1 -yl)propoxy ;
2- (3-hydroxyazetidin-l-yl)ethoxy; 4-hydroxybutoxy; 2-hydroxyethoxy;
3 - hydroxy-3 -methylbutoxy; 2-(4-hydroxy-4-methylpiperidin-l-yl)ethoxy;
3-(3 -hydroxy-3 -methylpyrrolidin- 1 -yl)propoxy ; 3-(3 -hydroxy-3 -phenylazetidin- 1 -yl)propoxy ; 3 - [( 1 -hydroxy- 1 -phenylpropan-2-yl)(methyl)amino]propoxy; 3 -hydroxypropoxy;
3 -[(3if)-3 -hydroxy pyrrolidin-1 -yljpropoxy; 2-(lH-imidazol-l-yl)ethoxy;
3-[(lH-imidazol-2-ylmethyl)(methyl)amino]propoxy; 3-(lH-imidazol-l-yl)propoxy;
3 -(3 -methoxy azetidin- 1 -yl)propoxy ;
[(li?,4i?,5i?)-2-(2-methoxyethyl)-2-azabicyclo[2.2.1]hept-5-yl]oxy;
1 -(2-methoxyethyl)piperidin-4-yl]methoxy; [1 -(2-methoxyethyl)piperidin-4-yl]oxy;
3 -(4-methoxypiperidin- 1 -yl)propoxy; 3 - [( 1 -methoxypropan-2-yl)amino]propoxy;
3-(methylamino)propoxy; (l-methylazetidin-3-yl)methoxy;
3 - {methyl [(5 -methyl- 1 H-benzimidazol-2-yl)methyl] amino } propoxy ;
3 - { methyl [(5 -methyl 1 H-imidazol-2-yl)methyl] amino } propoxy;
3-{methyl[(5-oxo-4,5-dihydro-lH-l,2,4-triazol-3-yl)methyl]amino}propoxy;
3-(4-methyl-3-oxopiperazin-l-yl)propoxy;
3-{methyl[(5-oxopyrrolidin-2-yl)methyl]amino}propoxy; 3-(4-methylpiperazin-l-yl)propoxy; ( 1 -methylpiperidin-2-yl)oxy; ( 1 -methylpiperidin-4-yl)oxy ;
3-[methyl(lH-pyrazol-5-ylmethyl)amino]propoxy; (l-methylpyrrolidin-3-yl)methoxy;
3-[4-(methylsulfonyl)piperazin-l-yl]propoxy; 3-[3-(methyl sulfonyl)pyrrolidin-l -yljpropoxy; 3-[(4-methyl-4H-l,2,4-triazol-3-yl)sulfanyl]propoxy; (2i?)-morpholin-2-ylmethoxy;
2-(morpholin-4-yl)ethoxy ; 3 -(morpholin-4-yl)propoxy; 4-(morpholin-4-yl)butoxy; 3 - { [2-(naphthalen- 1 -yl)ethyl] amino } propoxy ;
3-[(lS,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]propoxy;
3-(2-oxa-6-azaspiro[3.3]hept-6-yl)propoxy; 3-(l ,4-oxazepan-4-yl)propoxy;
3 -(2-oxoimidazolidin- 1 -yl-propoxy ; (2-oxo- 1 ,3 -oxazolidin-3-yl)ethoxy;
2-oxo-2-(pyrrolidin-l-yl)ethoxy; 2-(2-oxopyrrolidin-l-yl)ethoxy;
3- { [2-(2-oxopyrrolidin- 1 -yl)ethyl]amino}propoxy; 3-(2-oxopyrrolidin- 1 -yl)propoxy;
3-[(4-phenylbutyl)amino]propoxy; 2-(piperidin-l -yl)ethoxy; 3-(piperidin-l -yl)propoxy;
3 -(propan-2-ylamino)propoxy; 2-( 1 H-pyrazol- 1 -yl)ethoxy; 2-(pyridin-2-yl)ethoxy;
2- (pyridin-3-yl)ethoxy; 2-(pyridine-4-yl)ethoxy; 2-(lH-pyrrol-l-yl)ethoxy;
3-(lH-pyrrol-l-yl)propoxy; 2-(pyrrolidin-l-yl)ethoxy; 3-(pyrrolidin-l-yl)propoxy;
3- (l,2,3, 4-tetrahydronaphthalen-l-ylamino)propoxy;
3-(tetrahydro-2H-pyran-4-ylamino)propoxy; 3-(4H-l,2,4-triazol-4-yl)propoxy;
3-[3-(trifluoromethyl)piperazin-l-yl]propoxy; -0(CH2)3OC(=0)CH2N(CH3)2; -0(CH2)3NHBoc;
-OC(=0)NHCH(CH3)2; -0(CH2)3OP(-0)(OH)2;
[l-(tert-butoxycarbonyl)pyrrolidin-4-yl]methoxy, [l-(2,2,2-trifluoroethyl)piperidin-4-yl]oxy;
[ 1 -(tert-butoxycarbonyl)piperidin-4-yl]oxy ; 3 - [(3 ,3 -difluorocyclobutyl)amino]propoxy;
pyridin-2-yl; pyridine-3-yl; pyridine-4-yl; l,3-thiazol-2-yl; (morpholin-4-yl)methoxy;
tetrahydro-2H-pyran-4-yloxy; [7-(tert-butoxycarbonyl)-3-oxa-7-azabicyclo[3.3.1]non-9-yl]oxy;
[7-(cyclopropylmethyl)-3 -oxa-7-azabicyclo[3.3.1 ]non-9-yl]oxy;
[7-(2-methoxyethyl)-3-oxa-7-azabicyclo[3.3.1 ]non-9-yl]oxy;
3-oxa-7-azabicyclo[3.3.1 ]non-9-yl} oxy; (7-ethyl-3-oxa-7-azabicyclo[3.3.1 ]non-9-yl)oxy;
{l-[2-(trifluoromethoxy)ethyl]piperidin-4-yl}oxy; (8-methyl-8-azabicyclo[3.2.1]oct-3-yl)oxy;
[ 1 -(tert-butoxycarbonyl)piperazin-4-yl]propoxy; (4-methylpiperazin- 1 -yl)methoxy;
piperidin-4-yloxy; { 1 -[2-(methylsulfonyl)ethyl]piperidin-4-yl}oxy;
[(2-fluoroethyl)piperidin-4-yl]oxy; [8-(tert-butoxycarbonyl)-8-azabicyclo[3.2.1 ]oct-3-yl]oxy;
(8-azabicyclo[3.2.1]oct-3-yl)oxy; [8-(2,2,2-trifluoroethyl)-8-azabicyclo[3.2.1]oct-3-yl]oxy;
[8-(2-methoxyethyl)-8-azabicyclo[3.2.1]oct-3-yl]oxy; (8-ethyl-8-azabicyclo[3.2.1]oct-3-yl)oxy;
[9-(tert-butoxycarbonyl)-3-oxa-9-azabicyclo[3.3.1 ]non-7-yl]oxy;
3 -oxa-9-azabicyclo [3.3.1 ]non-7-yloxy ;
[9-(2-methoxyethyl)-3-oxa-9-azabicyclo[3.3.1]non-7-yl]oxy;
[9-ethyl)-3-oxa-9-azabicyclo[3.3.1]non-7-yl]oxy; [l-(tert-butoxycarbonyl)-3-fluoro-piperidin-4-yl]oxy; (3-fluoropiperidin-4-yl)oxy; and (3 -fluoro- 1 -methylpiperidin-4-yl)oxy .
In a twelveth embodiment of the invention, the present invention relates to compounds of Formula (I), (la), (lb), (Ic), (Id), (Ie), (If), (Ig) and (Ih) and pharmaceutically acceptable salts thereof, wherein X is absent or selected from -Br, -CI, -F, methoxy, methyl, propanyl and CF3, and the other variables are as provided for in any of the first or sixth through eleventh embodiments.
In a thirteenth embodiment of the invention, the compound of the invention is selected from the exemplary species depicted in Examples 1 through 306 shown below (or a pharmaceutically acceptable salt thereof).
In a fourteenth embodiment of the invention, the compound of the invention is
Figure imgf000015_0001
Figure imgf000016_0001
Figure imgf000017_0001
Figure imgf000018_0001
Figure imgf000019_0001
harmaceutically acceptable salt of any of the above.
In a fifteenth embodiment of the invention, the compound of the invention is one of the following compounds:
( 1 aR,5S, 1 1 Z, 12aS, 13aR, 16S, 19R,27E,31 aR)-N-[(l -methylcyclopropyl)sulfonyl]- 3,15,33-trioxo-26-[2-^iperidin-l-yl)ethoxy]-l ,la,3,4,5,6,7,8,9,10,12a,13,15,16,l ^
31 a-icosahydro-5,17: 16,19-dimethanodicyclopropa[12,13:28,29][l,20,3,14,17]
dioxatriazacyclononacosino [21 ,22-b]quinoline- 13a(l 4H)-carboxamide;
( 1 ai?,5S, 11 Z, 12aS, 13 ai?, 16S, 19i?,27E,31 ^
26-[2-(morpholin-4-yl)ethoxy]-3,15,33-trioxo-l ,la,3,4,5,6,7,8,9,10,12a,13,15,16,18,19,29,30,3 31a- icosahydro-5,17: 16,19-dimethanodicyclopropa[12,13:28,29][l,20,3,14,17]
dioxatriazacyclononacosino [21 ,22-6] quinoline- 13 a( 14H)-carboxamide; (1 &R,5S, 1 lZ,12aS, 13aR,l 6S, 19i?,27E,31 a ?)-N-[(l -methylcyclopropyl)sulfonyl]- 26-[3-(morpholin-4-yl)propoxy]-3,15,33-trioxo-l,la,3,4,5,6,7,8,9,10,12a,13,15,16,18,19,2 31,31a-icosahydro-5,17: 16,19-dimethanodicyclopropa[12,13:28,29][l,20,3,14,17]
dioxatriazacyclononacosino[21,22-0]quinoline-13a(14H)-carboxamide; (la^,55,l lZ,12a5,13ai?,16S,19i?,27E,31ai?)-N-[(l-methylcyclopropyl)sulfonyl] 3,15,33-trioxo-26-[2-(pyrrolidin-l-yl)ethoxy]-l,la,3,4,5,6,7,8,9,10,12a,13,15,16,18,^
31a-icosahydro-5,17:16,19-dimethanodicyclopropa[12,13:28,29][l,20,3, 14,17]
dioxatriazacyclononacosino[21 ,22-Z>] quinoline- 13a( 14H)-carboxamide;
(loR,5S, 11Z, 12aS,l 3aR, 16S, 19i?,27E,31 a£)-26-methoxy-N-[(l - methylcyclopropyl)sulfonyl]-3,15,33-trioxo-l,la,3,4,5,6,7,8,9,10,12a,13,15,16,18,19,2
31 a-icosahydro-5 , 17:16,19-dimethanodicyclopropa[ 12, 13 :28,29] [ 1 ,20,3 , 14, 17]
dioxatriazacyclononacosino [21 ,22-£] quinoline- 13a( 14H)-carboxamide;
(1 a ,5S, 11Z,12aS, 13aR, 16S, 19R,3 laR)-N-[(l -methylcyclopropyl)sulfonyl]-26- [2-(morpholin-4-yl)ethoxy^
31,31a-docosahydro-5,17:16,19-dimethanodicyclopropa[12,13:28,29][l,20,3, 14,17]
dioxatriazacyclononacosino[21 ,22-b]quinoline- 13a(l 4H)-carboxamide;
( 1 aR,5S, 11 Z, 12aS, 13aJ?, 16S, 19i?,27E,31 aR)-N-[( 1 -methylcyclopropyl)sulfonyl]- 3,15,33-trioxo-26-[3-(piperidin-l^
31 a-icosahydro-5 , 17:16,19-dimethanodicyclopropa[ 12, 13 :28,29] [ 1 ,20,3 , 14, 17]
dioxatriazacyclononacosino [21 ,22-b] quinoline- 13a( 14H)-carboxamide;
(1 aR,5S, 11Z, 12aS, 13ai?,l 6S, 19i?,27E,31 ai?)-N-[(l -methylcyclopropyl)sulfonyl]- 3,15,33-trioxo-26-[3-(pyrrolidin-l-yl)propoxy]-l,la,3,4,5,6,7,8,9,10,12a,13, 15,16,18,19,29, 30,31 ,31 a-icosahydro-5, 17: 16, 19-dimethanodicyclopropa[l 2, 13 :28,29] [1 ,20,3, 14, 17]dioxatriaza cyclononacosino[21 ,22-Z>] quinoline- 13a(l 4H)-carboxamide; or
(la#,5S,l \Z,\2aS,l3aR,l6S,l9R,27E,3 lai?)-N-[(l-methylcyclopropyl)sulfonyl]-
26-[3-(4-methylpiperazin-l-yl)propoxy]-3,15,33-trioxo-l,la,3,4,5,6,7,8,9,10,12a,13,15,l^ 19,29,30,31,31a-icosahydro-5,17:16,19-dimethanodicyclopropa[12,13:28,29][l,20,3,14,17] dioxatriazacyclononacosino [21 ,22-b] quinoline- 13a( 14H)-carboxamide, or
a pharmaceutically acceptable salt of any of the above.
Other embodiments of the present invention include the following: (a) A pharmaceutical composition comprising an effective amount of a compound of formula (I), in any of the described embodiments, and a pharmaceutically acceptable carrier.
(b) The pharmaceutical composition of (a), further comprising a second therapeutic agent selected from the group consisting of HCV antiviral agents,
immunomodulators, and anti-infective agents. In one aspect of the invention, the second therapeutic agent is ribavirin.
(c) The pharmaceutical composition of (b), wherein the HCV antiviral agent is an antiviral selected from the group consisting of HCV protease inhibitors and HCV NS5B polymerase inhibitors.
(d) A pharmaceutical combination which is (i) a compound of formula (I) and (ii) a second therapeutic agent selected from the group consisting of HCV antiviral agents, immunomodulators, and anti-infective agents; wherein the compound of formula (I) and the second therapeutic agent are each employed in an amount that renders the combination effective for inhibiting HCV NS3 protease, or for treating HCV infection and/or reducing the likelihood or severity of symptoms of HCV infection.
(e) The combination of (d), wherein the HCV antiviral agent is an antiviral selected from the group consisting of HCV protease inhibitors and HCV NS5B polymerase inhibitors.
(f) A method of inhibiting HCV NS3 protease in a subject in need thereof which comprises administering to the subject an effective amount of a compound of formula (I).
(g) A method of treating HCV infection and/or reducing the likelihood or severity of symptoms of HCV infection in a subject in need thereof which comprises
administering to the subject an effective amount of a compound of formula (I).
(h) The method of (g), wherein the compound of formula (I) is administered in combination with an effective amount of at least one second therapeutic agent selected from the group consisting of HCV antiviral agents, immunomodulators, and anti- infective agents.
(i) The method of (h), wherein the HCV antiviral agent is an antiviral selected from the group consisting of HCV protease inhibitors and HCV NS5B polymerase inhibitors. (j) A method of inhibiting HCV NS3 protease in a subject in need thereof which comprises administering to the subject the pharmaceutical composition of (a), (b), or (c) or the combination of (d) or (e).
(k) A method of treating HCV infection and/or reducing the likelihood or severity of symptoms of HCV infection in a subject in need thereof which comprises
administering to the subject the pharmaceutical composition of (a), (b), or (c) or the combination of (d) or (e).
In the embodiments of the compounds provided above, it is to be understood that each embodiment may be combined with one or more other embodiments, to the extent that such a combination provides a stable compound and is consistent with the description of the embodiments. It is further to be understood that the embodiments of compositions and methods provided as (a) through (k) above are understood to include all embodiments of the compounds, including such embodiments as result from combinations of embodiments.
The present invention also includes a compound of the present invention for use (i) in, (ii) as a medicament for, or (iii) in the preparation of a medicament for: (a) inhibiting HCV NS3 protease, or (b) treating HCV infection and/or reducing the likelihood or severity of symptoms of HCV infection. In these uses, the compounds of the present invention can optionally be employed in combination with one or more second therapeutic agents selected from HCV antiviral agents, anti-infective agents, and immunomodulators. In one aspect of the invention, the second therapeutic agent is ribavirin.
Additional embodiments of the invention include the pharmaceutical compositions, combinations and methods set forth in (a)-(k) above and the uses set forth in the preceding paragraph, wherein the compound of the present invention employed therein is a compound of one of the embodiments, aspects, classes, sub-classes, or features of the
compounds described above. In all of these embodiments, the compound may optionally be used in the form of a pharmaceutically acceptable salt or hydrate as appropriate.
As used herein, all ranges are inclusive, and all sub-ranges are included within such ranges, although not necessarily explicitly set forth. In addition, the term "or," as used herein, denotes alternatives that may, where appropriate, be combined; that is, the term "or" includes each listed alternative separately as well as their combination.
As used herein, represents a bond where the dotted line is an optional bond. When the optional bond is present, the bond (in its entirety) is a double bond. When the optional bond is absent, the bond (it its entirety) is a single bond. Each such bond is independently a single bond or a double bond. Thus, when two such bonds are adjacent to each other, it can represent two single bonds, two double bonds, a single bond adjacent to a double bond, or a double bond adjacent to a single bond.
As used herein, the term "alkyl" refers to any linear or branched chain alkyl group having a number of carbon atoms in the specified range. Thus, for example, "C1-6 alkyl" (or "Ci-Ce alkyl") refers to all of the hexyl alkyl and pentyl alkyl isomers as well as n-, iso-, sec- and t-butyl, n- and isopropyl, ethyl and methyl. As another example, "CM alkyl" refers to n-, iso-, sec- and t-butyl, n- and isopropyl, ethyl and methyl. Alkyl groups may be substituted as indicated.
The term "halogenated" refers to a group or molecule in which a hydrogen atom has been replaced by a halogen. Similarly, the term "haloalkyl" refers to a halogenated alkyl group. The term "halogen" (or "halo") refers to atoms of fluorine, chlorine, bromine and iodine
(alternatively referred to as fluoro, chloro, bromo, and iodo).
The term "alkoxy" refers to an "alkyl-O-" group. Alkoxy groups may be substituted as indicated.
The term "alkylene" refers to any linear or branched chain alkylene group (or alternatively "alkanediyl") having a number of carbon atoms in the specified range. Thus, for example, "-C^ alkylene-" refers to any of the C\ to C6 linear or branched alkylenes. A class of alkylenes of particular interest with respect to the invention is -(CH2)1-6-, and sub-classes of particular interest include -(Ώ¼) -, -(ϋ¾)1-3-, -(CH2)1-2-, and -CH2-. Also of interest is the alkylene -CH(CH3)-. Alkylene groups may be substituted as indicated.
The term "cycloalkyl" refers to any monocyclic or bicyclic ring structure of an alkane or alkene having a number of carbon atoms in the specified range. Thus, for example, "C3-8 cycloalkyl" (or "C3-C8 cycloalkyl") includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. The term "cycloalkoxy" refers to a "cycloalkyl-O-" group. Cycloalkyl groups may be substituted as indicated.
The term "carbocycle" (and variations thereof such as "carbocyclic" or
"carbocyclyl") as used herein, unless otherwise indicated, refers to (i) a C3 to C8 monocyclic, saturated or unsaturated ring or (ii) a C7 to C12 bicyclic saturated or unsaturated ring system.
Each ring in (ii) is either independent of, or fused to, the other ring, and each ring is saturated or unsaturated. Carbocycle groups may be substituted as indicated, for example with C1-6 alkyl, C1-6 alkenyl, C1-6 alkynyl, aryl, halogen, -NH2 or -OH. The carbocycle may be attached to the rest of the molecule at any carbon atom which results in a stable compound. The fused bicyclic carbocycles are a subset of the carbocycles; i.e., the term "fused bicyclic carbocycle" generally refers to a C7 to C10 bicyclic ring system in which each ring is saturated or unsaturated and two adjacent carbon atoms are shared by each of the rings in the ring system. A fused bicyclic carbocycle in which both rings are saturated is a saturated bicyclic ring system. Saturated carbocyclic rings are also referred to as cycloalkyl rings, e.g., cyclopropyl, cyclobutyl, etc. A fused bicyclic carbocycle in which one or both rings are unsaturated is an unsaturated bicyclic ring system. A subset of the fused bicyclic unsaturated carbocycles are those bicyclic carbocycles in which one ring is a benzene ring and the other ring is saturated or unsaturated, with attachment via any carbon atom that results in a stable compound. Representative examples
Figure imgf000024_0001
Depicted ring systems include, where appropriate, able to
which a particular ring atom is attached. For example, the indole
Figure imgf000024_0002
shows ring atom 2 is directly attached to variable X and ring atom 4 is directly attached to variable Z.
Variable R5 is shown as a floating variable which can be attached to any ring atom, provided that such attachment results in formation of a stable ring.
The term "aryl" refers to aromatic mono- and poly-carbocyclic ring systems, also referred to as "arenes," wherein the individual carbocyclic rings in the polyring systems are fused or attached to each other via a single bond. Suitable aryl groups include phenyl, naphthyl, and biphenylenyl. Aryl groups may be substituted as indicated.
Unless indicated otherwise, the term "heterocycle" (and variations thereof such as
"heterocyclic" or "heterocyclyl") broadly refers to (i) a stable 4- to 8-membered, saturated or unsaturated monocyclic ring, (ii) a stable 7- to 12-membered bicyclic ring system, or (iii) a stable
11- to 15-membered tricyclic ring sty stem, wherein each ring in (ii) and (iii) is independent of, or fused to, the other ring or rings and each ring is saturated or unsaturated, and the monocyclic ring, bicyclic ring system or tricyclic ring system contains one or more heteroatoms (e.g., from 1 to 6 heteroatoms, or from 1 to 4 heteroatoms) independently selected from N, O and S and a balance of carbon atoms (the monocyclic ring typically contains at least one carbon atom and the bicyclic and tricyclic ring systems typically contain at least two carbon atoms); and wherein any one or more of the nitrogen and sulfur heteroatoms is optionally oxidized, and any one or more of the nitrogen heteroatoms is optionally quaternized. Unless otherwise specified, the heterocyclic ring may be attached at any heteroatom or carbon atom, provided that attachment results in the creation of a stable structure. Heterocycle groups may be substituted as indicated, and unless otherwise specified, the substituents may be attached to any atom in the ring, whether a heteroatom or a carbon atom, provided that a stable chemical structure results.
Saturated heterocyclics form a subset of the heterocycles. Unless expressly stated to the contrary, the term "saturated heterocyclic" generally refers to a heterocycle as defined above in which the entire ring system (whether mono- or poly-cyclic) is saturated. The term "saturated heterocyclic ring" refers to a 4- to 8-membered saturated monocyclic ring, a stable 7- to 12-membered bicyclic ring system, or a stable 11- to 15-membered tricyclic ring system, which consists of carbon atoms and one or more heteroatoms independently selected from N, O and S. Representative examples include piperidinyl, piperazinyl, azepanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl (or tetrahydrofuranyl). Saturated
heterocyclics include 4-8 membered heterocycloalkyls having 1 to 2 heteroatoms selected from N, O, and S.
Unsaturated heterocyclics form another subset of the heterocycles. Unless expressly stated to the contrary, the term "unsaturated heterocyclic" generally refers to a heterocycle as defined above in which the entire ring system (whether mono- or poly-cyclic) is not saturated, i.e., such rings are either unsaturated or partially unsaturated. Unless expressly stated to the contrary, the term "heteroaromatic ring" refers a stable 5- or 6-membered monocyclic aromatic ring, a stable 7- to 12-membered bicyclic ring system, or a stable 11- to 15-membered tricyclic ring system, which consists of carbon atoms and one or more heteroatoms selected from N, O and S. In the case of substituted heteraromatic rings containing at least one nitrogen atom (e.g., pyridine), such substitutions can be those resulting in N-oxide formation. Representative examples of heteroaromatic rings include pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienyl (or thiophenyl), thiazolyl, furanyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isooxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, and thiadiazolyl.
Representative examples of bicyclic heterocycles include benzotriazolyl, indolyl, isoindolyl, indazolyl, indolinyl, isoindolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, chromanyl, isochromanyl, tetrahydroquinolinyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl,
2,3-dihydrobenzofuranyl, 2,3-dihydrobenzo-l,4-dioxinyl (i.e., CO υ ), imidazo(2,l-6)(l,3)thiazole, (i.e.,
Figure imgf000026_0001
)),, aanndd bbeennzzoo--ll,,33--ddiiooxxoollyyll ((ii..ee..,, ). In
Figure imgf000026_0002
is alternatively referred to as phenyl having as a substituent methylenedioxy attached to two adjacent carbon atoms.
Unless expressly stated to the contrary, all ranges cited herein are inclusive. For example, a heteroaryl ring described as containing from "1 to 3 heteroatoms" means the ring can contain 1, 2, or 3 heteroatoms. It is also to be understood that any range cited herein includes within its scope all of the sub-ranges within that range. The oxidized forms of the heteroatoms N and S are also included within the scope of the present invention.
When any variable (e.g., R7 and R10) occurs more than one time in any constituent or in formula (I) or in any other formula depicting and describing compounds of the invention, its definition on each occurrence is independent of its definition at every other occurrence. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
Unless expressly stated to the contrary, substitution by a named substituent is permitted on any atom in a ring (e.g., aryl, a heteroaromatic ring, or a saturated heterocyclic ring) provided such ring substitution is chemically allowed and results in a stable compound. A "stable" compound is a compound which can be prepared and isolated and whose structure and properties remain or can be caused to remain essentially unchanged for a period of time sufficient to allow use of the compound for the purposes described herein (e.g., therapeutic or prophylactic administration to a subject).
As a result of the selection of substituents and substituent patterns, certain of the compounds of the present invention can have asymmetric centers and can occur as mixtures of stereoisomers, or as individual diastereomers, or enantiomers. All isomeric forms of these compounds, whether isolated or in mixtures, are within the scope of the present invention.
As would be recognized by one of ordinary skill in the art, certain of the compounds of the present invention can exist as tautomers. For the purposes of the present invention a reference to a compound of formula (I) is a reference to the compound per se, or to any one of its tautomers per se, or to mixtures of two or more tautomers.
In the compounds of generic Formula I, the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. The present invention is meant to include all suitable isotopic variations of the compounds of generic Formula I. For example, different isotopic forms of hydrogen (H) include protium ( H) and deuterium ( H). Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples.
Isotopically-enriched compounds within generic Formula I can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents and/or intermediates.
The compounds of the present inventions are useful in the inhibition of HCV protease (e.g., HCV NS3 protease) and the treatment of HCV infection and or reduction of the likelihood or severity of symptoms of HCV infection. For example, the compounds of this invention are useful in treating infection by HCV after suspected past exposure to HCV by such means as blood transfusion, exchange of body fluids, bites, accidental needle stick, or exposure to patient blood during surgery.
The compounds of this invention are useful in the preparation and execution of screening assays for antiviral compounds. For example, the compounds of this invention are useful for isolating enzyme mutants, which are excellent screening tools for more powerful antiviral compounds. Furthermore, the compounds of this invention are useful in establishing or determining the binding site of other antivirals to HCV protease, e.g., by competitive inhibition. Thus, the compounds of this invention may be commercial products to be sold for these purposes. The compounds of the present invention may be administered in the form of pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" refers to a salt which possesses the effectiveness of the parent compound and which is not biologically or otherwise undesirable (e.g., is neither toxic nor otherwise deleterious to the recipient thereof). Suitable salts include acid addition salts which may, for example, be formed by mixing a solution of the compound of the present invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, or benzoic acid. Many of the compounds of the invention carry an acidic moiety, in which case suitable pharmaceutically acceptable salts thereof can include alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., calcium or magnesium salts), and salts formed with suitable organic ligands such as quaternary ammonium salts. Also, in the case of an acid (-COOH) or alcohol group being present, pharmaceutically acceptable esters can be employed to modify the solubility or hydrolysis characteristics of the compound.
The term "administration" and variants thereof (e.g., "administering" a compound) in reference to a compound of the invention mean providing the compound or a prodrug of the compound to the individual in need of treatment. When a compound of the invention or a prodrug thereof is provided in combination with one or more other active agents (e.g., antiviral agents useful for treating HCV infection), "administration" and its variants are each understood to include concurrent and sequential provision of the compound or salt (or hydrate) and other agents.
As used herein, the term "prodrug" is intended to encompass an inactive drug form or compound that is converted into an active drug form or compound by the action of enzymes, chemicals or metabolic processes in the body of an individual to whom it is administered.
As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients, as well as any product which results, directly or indirectly, from combining the specified ingredients.
By "pharmaceutically acceptable" is meant that the ingredients of the
pharmaceutical composition must be compatible with each other and not deleterious to the recipient thereof. The term "subject" (alternatively referred to herein as "patient") as used herein refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.
The term "effective amount" as used herein means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician. In one embodiment, the effective amount is a "therapeutically effective amount" for the alleviation of one or more symptoms of the disease or condition being treated. In another embodiment, the effective amount is a "prophylactically effective amount" for reduction of the severity or likelihood of one or more symptoms of the disease or condition. The term also includes herein the amount of active compound sufficient to inhibit HCV NS3 protease and thereby elicit the response being sought (i.e., an "inhibition effective amount"). When the active compound (i.e., active ingredient) is administered as the salt, references to the amount of active ingredient are to the free acid or free base form of the compound.
For the purpose of inhibiting HCV NS3 protease and treating HCV infection and/or reducing the likelihood or severity of symptoms of HCV infection, the compounds of the present invention, optionally in the form of a salt or a hydrate, can be administered by any means that produces contact of the active agent with the agent's site of action. They can be
administered by any conventional means available for use in conjunction with pharmaceuticals, either as individual therapeutic agents or in a combination of therapeutic agents. They can be administered alone, but typically are administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice. The compounds of the invention can, for example, be administered orally, parenterally (including subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion
techniques), by inhalation (such as in a spray form), or rectally, in the form of a unit dosage of a pharmaceutical composition containing an effective amount of the compound and conventional non-toxic pharmaceutically-acceptable carriers, adjuvants and vehicles. Liquid preparations suitable for oral administration (e.g., suspensions, syrups, elixirs and the like) can be prepared according to techniques known in the art and can employ any of the usual media such as water, glycols, oils, alcohols and the like. Solid preparations suitable for oral administration (e.g., powders, pills, capsules and tablets) can be prepared according to techniques known in the art and can employ such solid excipients as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like. Parenteral compositions can be prepared according to techniques known in the art and typically employ sterile water as a carrier and optionally other ingredients, such as solubility aids. Injectable solutions can be prepared according to methods known in the art wherein the carrier comprises a saline solution, a glucose solution or a solution containing a mixture of saline and glucose. Further description of methods suitable for use in preparing pharmaceutical compositions of the present invention and of ingredients suitable for use in said compositions is provided in Remington's Pharmaceutical Sciences, 18 edition (ed. A. R. Gennaro, Mack Publishing Co., 1990).
The compounds of this invention can be administered orally in a dosage range of 0.001 to 1000 mg/kg of mammal (e.g., human) body weight per day in a single dose or in divided doses. One dosage range is 0.01 to 500 mg/kg body weight per day orally in a single dose or in divided doses. Another dosage range is 0.1 to 100 mg/kg body weight per day orally in single or divided doses. For oral administration, the compositions can be provided in the form of tablets or capsules containing 1.0 to 500 mg of the active ingredient, particularly 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, and 500 mg of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. The specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.
As noted above, the present invention also relates to a method of inhibiting HCV NS3 protease, inhibiting HCV replication, treating HCV infection and/or reducing the likelihood or severity of symptoms of HCV infection with a compound of the present invention in combination with one or more therapeutic agents and a pharmaceutical composition comprising a compound of the present invention and one or more therapeutic agents selected from the group consisting of a HCV antiviral agent, an immunomodulator, and an anti-infective agent. Such therapeutic agents active against HCV include, but are not limited to, ribavirin, levovirin, viramidine, thymosin alpha- 1, R7025 (an enhanced interferon (Roche)), interferon-β, interferon- a, pegylated interferon-a (peginterferon-a), a combination of interferon- and ribavirin, a combination of peginterferon-a and ribavirin, a combination of interferon-α and levovirin, and a combination of peginterferon-α and levovirin. Interferon-α includes, but is not limited to, recombinant interferon-a2a (such as Roferon interferon available from Hoffmann-LaRoche, Nutley, NJ), pegylated interferon-a2a (Pegasys™), interferon-a2b (such as Intron-A interferon available from Schering Corp., Kenilworth, NJ), pegylated interferon-a2b (Peglntron™), a recombinant consensus interferon (such as interferon alphacon-1), albuferon (interferon-a bound to human serum albumin (Human Genome Sciences), and a purified interferon-α product.
Amgen's recombinant consensus interferon has the brand name Infergen®. Levovirin is the L-enantiomer of ribavirin which has shown immunomodulatory activity similar to ribavirin. Viramidine represents an analog of ribavirin disclosed in International Patent Application Publication No. WO 01/60379. In accordance with the method of the present invention, the individual components of the combination can be administered separately at different times during the course of therapy or concurrently in divided or single combination forms.
For the treatment of HCV infection, the compounds of the present invention may also be administered in combination with an agent that is an inhibitor of HCV NS3 serine protease. HCV NS3 serine protease is an essential viral enzyme and has been described to be an excellent target for inhibition of HCV replication. Both substrate and non-substrate based inhibitors of HCV NS3 protease inhibitors are disclosed in International Patent Application Publication Nos. WO 98/22496, WO 98/46630, WO 99/07733, WO 99/07734, WO 99/38888, WO 99/50230, WO 99/64442, WO 00/09543, WO 00/59929, WO 02/48116 and WO 02/48172, British Patent No. GB 2 337 262, and U.S. Patent No. 6,323,180.
Ribavirin, levovirin, and viramidine may exert their anti-HCV effects by modulating intracellular pools of guanine nucleotides via inhibition of the intracellular enzyme inosine monophosphate dehydrogenase (IMPDH). IMPDH is the rate-limiting enzyme on the biosynthetic route in de novo guanine nucleotide biosynthesis. Ribavirin is readily
phosphorylated intracellularly and the monophosphate derivative is an inhibitor of IMPDH. Thus, inhibition of IMPDH represents another useful target for the discovery of inhibitors of HCV replication. Therefore, the compounds of the present invention may also be administered in combination with an inhibitor of IMPDH, such as VX-497, which is disclosed in International Patent Application Publication Nos. WO 97/41211 and WO 01/00622; another IMPDH inhibitor, such as that disclosed in International Patent Application Publication No. WO 00/25780; or mycophenolate mofetil. See Allison et i, 1993, Agents Action 44 (Suppl.):165.
For the treatment of HCV infection, the compounds of the present invention may also be administered in combination with the antiviral agent amantadine (1-aminoadamantane). For a comprehensive description of this agent, see Kirschbaum, 1983, Anal. Profiles Drug Subs. 12:1-36.
For the treatment of HCV infection, the compounds of the present invention may also be administered in combination with the antiviral agent polymerase inhibitor R7128
(Roche).
The compounds of the present invention may also be combined for the treatment of HCV infection with antiviral 2'-C-branched ribonucleosides disclosed in Harry-O'Kuru et ah, 1997, J. Org. Chem. 62:1754-59; Wolfe et al, 1995, Tet. Lett. 36:7611-14; U.S. Patent No. 3,480,613; and International Patent Application Publication Nos. WO 01/90121, WO 01/92282, WO 02/32920, WO 04/002999, WO 04/003000 and WO 04/002422. Such 2'-C-branched ribonucleosides include, but are not limited to, 2'-C-methyl-cytidine, 2'-C-methyl-uridine, -C- methyl-adenosine, 2'-C-methyl-guanosine, and 9-(2-C-methyl-P-D-ribofuranosyl)-2,6- diaminopurine, and the corresponding amino acid ester of the ribose C-2', C-3', and C-5' hydroxyls and the corresponding optionally substituted cyclic 1,3 -propanediol esters of the 5'- phosphate derivatives.
The compounds of the present invention may also be combined for the treatment of HCV infection with other nucleosides having anti-HCV properties, such as those disclosed in International Patent Application Publication Nos. WO 02/51425, WO 01/79246, WO 02/32920, WO 02/48165, WO05/003147 (including R1656, (2'i?)-2'-deoxy-2'-fluoro-2'-C-methylcytidine), WO 01/68663, WO 99/43691, WO 02/18404, WO06/021341, WO 02/100415, WO 03/026589, WO 03/026675, WO 03/093290, WO 04/011478, WO 04/013300 and WO 04/028481, and U.S. Patent Application Publication Nos. US2005/0038240 (including 4'-azido nucleosides such as R1626, 4'-azidocytidine), US2002/0019363, US2003/0236216, US2004/0006007 and
US2004/0063658.
For the treatment of HCV infection, the compounds of the present invention may also be administered in combination with an agent that is an inhibitor of HCV NS5B polymerase. Such HCV NS5B polymerase inhibitors that may be used as combination therapy include, but are not limited to, those disclosed in International Patent Application Publication Nos.
WO 02/057287, WO 02/057425, WO 03/068244, WO 04/000858, WO 04/003138 and
WO 04/007512; U.S. Patent No. 6,777,392 and U.S. Patent Application Publication No.
US2004/0067901. Other such HCV polymerase inhibitors include, but are not limited to, valopicitabine (NM-283; Idenix) and 2'-F-2'-beta-methylcytidine (see also International Patent Application Publication No. WO 05/003147).
In one embodiment, nucleoside HCV NS5B polymerase inhibitors that are used in combination with the present HCV NS3 protease inhibitors are selected from the following compounds: 4-amino-7-(2-C-methyl-P-D-arabinofuranosyl)-7H-pyrrolo[2,3-if]pyrimidine; 4- amino-7-(2-C-methyl-P-D-ribofiiranosyl)-7H-pyrrolo[2,3-i ]pyrimidine; 4-methylamino-7-(2-C- methyl-P-D-ribofuranosyl)-7H-pyrrolo[2,3-£ ]pyrimidine; 4-dimethylamino-7-(2-C-methyl-P-D- ribofuranosyl)-7H-pyrrolo[2,3-cf|pyrimidine; 4-cyclopropylamino-7-(2-C-methyl-P-D- ribofuranosyl)-7H-pyrrolo[2,3-fii]pyrimidine; 4-amino-7-(2-C-vinyl-P-D-ribofuranosyl)-7H- pyrrolo[2,3-fif]pyrimidine; 4-amino-7-(2-C-hydroxymethyl-P-D-ribofuranosyl)-7H- pyrrolo[2,3-fii]pyrimidine; 4-amino-7-(2-C-fluoromethyl-P-D-ribofuranosyl)-7H- pyrrolo[2,3-i ]pyrimidine; 4-amino-5-methyl-7-(2-C-methyl-P-D-ribofuranosyl)-7H-
Figure imgf000033_0001
4-amino-7-(2-C-methyl-P-D-ribofuranosyl)-7//- pyrrolo[2,3-i¾pyrimidine-5-carboxylic acid; 4-amino-5-bromo-7-(2-C-methyl-P-D- ribofuranosyl)-7H-pyrrolo[2,3-i ]pyrimidine; 4-amino-5-chloro-7-(2-C-methyl-P-D- ribofuranosyl)-7H-pyrrolo[2,3-<i]pyrimidine; 4-amino-5-fluoro-7-(2-C-methyl-P-D- ribofuranosyl)-7H-pyrrolo[2,3-<flpyrimidine; 2,4-diamino-7-(2-C-methyl-P-D-ribofuranosyl)- 7H-pyrrolo[2,3-cf]pyrimidine; 2-amino-7-(2-C-methyl-P-D-ribofuranosyl)-7H- pyrrolo[2,3-(i]pyrimidine; 2-amino-4-cyclopropylamino-7-(2-C-methyl-P-D-ribofuranosyl)-7H- pyrrolo[2,3-i ]pyrimidine; 2-amino-7-(2-C-methyl-P-D-ribofuranosyl)-7H- pyrroloP^-^pyrimidin^pHj-one; 4-amino-7-(2-C-ethyl-P-D-ribofuranosyl)-7H- pyrrolo[2,3-i ]pyrimidine; 4-amino-7-(2-C,2-0-dimethyl-P-D-ribofuranosyl)-7H- pyrrolo[2,3-<i]pyrimidine; 7-(2-C-methyl-P-D-ribofuranosyl)-7H-pyn-olo[2,3-^pyrimidin-4(3H)- one; 2-amino-5-methyl-7-(2-C, 2-0-dimethyl-P-D-ribof iranosyl)-7H-pyrrolo[2,3-i ]pyrimidin- 4(3H)-one; 4-amino-7-(3-deoxy-2-C-methyl-P-D-ribofuranosyl)-7H-pyrrolo[2,3-^pyrimidine; 4-amino-7-(3-deoxy-2-C-methyl-P-D-arabinofuranosyl)-7H-pyrrolo[2,3-i ]pyrimidine; 4-amino- 2-fluoro-7-(2-C-methyl-p-D-ribofuranosyl)-7H-pyrrolo[2,3-i/]pyrimidine; 4-amino-7-(3-C- methyl-P-D-ribofuranosyl)-7H-pyrrolo[2,3-i ]pyrimidine; 4-amino-7-(3-C-methyl-P-D- xylofuranosyl)-7H-pyrrolo[2,3-^pyrimidine; 4-amino-7-(2,4-di-C-methyl-P-D-ribofuranosyl)- 7H-pyrrolo[2,3- ]pyrimidine; 4-amino-7-(3-deoxy-3-fluoro-2-C-methyl-P-D-ribofuranosyl)-7H- pyrrolo[2,3-c¾pyrimidine; and the corresponding 5'-triphosphates; or a pharmaceutically acceptable salt thereof. The compounds of the present invention may also be combined for the treatment of HCV infection with non-nucleoside inhibitors of HCV polymerase such as HCV-796 (Viropharma Inc.) and those disclosed in International Patent Application Publication Nos. WO 01/77091; WO 01/47883; WO 02/04425; WO 02/06246; WO 02/20497; and WO 05/016927 (in particular JTK003).
In one embodiment, non-nucleoside HCV NS5B polymerase inhibitors that are used in combination with the present HCV NS3 protease inhibitors are selected from the following compounds: 14-cyclohexyl-6-[2-(dimethylamino)ethyl]-7-oxo-5,6,7,8- tetrahydroindolo[2,l-a][2,5]benzodiazocine-l 1-carboxylic acid; 14-cyclohexyl-6-(2-morpholin- 4-ylethyl)-5,6,7,8-tetrahydroindolo[2,l-o][2,5]benzodiazocine-l 1-carboxylic acid; 14- cyclohexyl-6-[2-(dimethylamino)ethyl]-3-methoxy-5,6,7,8-tetrahydroindolo[2,l- ]
[2,5]benzodiazocine-l 1-carboxylic acid; 14-cyclohexyl-3-methoxy-6-methyl-5,6,7,8- tetrahydroindolo[2,l-a][2,5]benzodiazocine-l 1-carboxylic acid; methyl ({[(14-cyclohexyl-3- methoxy-6-methyl-5,6,7,8-tetrahydroindolo[2,l-a][2,5]benzodiazocin-l l- yl)carbonyl] amino } sulfonyl)acetate; ( { [( 14-cyclohexyl-3 -memoxy-6-methyl-5 ,6,7,8- tetrahydroindolo[2,l-a][2,5]benzodiazocin-l l-yl)carbonyl] amino }sulfonyl)acetic acid; 14- cyclohexyl-N-[(dimethylamino)sulfonyl]-3-methoxy-6-methyl-5,6,7,8-tetrahydroindolo[2,l-a] [2,5]benzodiazocine-l l-carboxamide; 3-chloro-14-cyclohexyl-6-[2-(dimethylamino)ethyl]-7- oxo-5,6,7,8-tetrahydroindolo[2,l-a][2,5]benzodiazocine 11-carboxylic acid; iV-(l l-carboxy-14- cyclohexyl-7,8-dihydro-6H-indolo[l,2-e][l,5]benzoxazocin-7-yl)-N,iV-dimethylethane-l,2- diaminium bis(trifluoroacetate); 14-cyclohexyl-7,8-dihydro-6H-indolo[ 1 ,2-e] [1,5]
benzoxazocine-11-carboxylic acid; 14-cyclohexyl-6-methyl-7-oxo-5,6,7,8-tetrahydroindolo [2, 1 -a] [2,5]benzodiazocine-l 1-carboxylic acid; 14-cyclohexyl-3-methoxy-6-methyl-7-oxo- 5,6,7,8-tetrahydroindolo[2, 1 -a] [2,5]benzodiazocine-l 1-carboxylic acid; 14-cyclohexyl-6-[2- (dimethylamino)ethyl]-3-methoxy-7-oxo-5,6,7,8-tetrahydroindolo[2, 1 -a] [2,5]benzodiazocine- 11-carboxylic acid; 14-cyclohexyl-6-[3-(dimethylamino)propyl]-7-oxo-5,6,7,8-tetrahydroindolo [2,1 -a] [2,5]benzodiazocine- 11 -carboxylic acid; 14-cyclohexyl-7-oxo-6-(2-piperidin- 1 -ylethyl)- 5,6,7,8-tetrahydroindolo[2,l- ][2,5]benzodiazocine-l 1-carboxylic acid; 14-cyclohexyl-6-(2- morpholin-4-ylethyl)-7-oxo-5, 6,7,8-tetrahydroindolo [2,1 -a] [2,5]benzodiazocine-l 1-carboxylic acid; 14-cyclohexyl-6-[2-(diethylamino)ethyl]-7-oxo-5,6,7,8-tetrahydroindolo[2,l-a]
[2,5]benzodiazocine-l 1-carboxylic acid; 14-cyclohexyl-6-(l-methylpiperidin-4-yl)-7-oxo- 5,6,7,8-tetrahydroindolo[2,l-a][2,5]benzodiazocine-l 1-carboxylic acid; 14-cyclohexyl-N- [(dimethylamino)sulfonyl]-7-oxo-6-(2-piperidin-l-ylethyl)-5,6,7,8-tetrahydroind
[2,5]benzodiazocine-l l-carboxamide; 14-cyclohexyl-6-[2-(dimethylamino)ethyl]-N- [(dimethylamino)sulfonyl]-7-oxo-5,6,7,8-tetrahydroindolo[2,l-a][2,5]benzodiazocm^ carboxamide; 14-cyclopentyl-6-[2-(dimethylamino)ethyl]-7-oxo-5,6,7,8-tetrahydroindolo[2,l-a] [2,5]benzodiazocine-l 1 -carboxylic acid; 14-cyclohexyl-5,6,7,8-tetrahydroindolo[2,l -a]
[2,5]benzodiazocine-l 1-carboxylic acid; 6-allyl-14-cyclohexyl-3-methoxy-5,6,7,8- tetrahydroindolo[2,l-a][2,5]benzodiazocine-l 1-carboxylic acid; 14-cyclopentyl-6-[2- (dimethylamino)ethyl]-5,6,7,8-tetrahydroindolo[2,l- ][2,5]benzodiazocine-l 1-carboxylic acid; 14-cyclohexyl-6-[2-(dimethylamino)ethyl]-5,6,7,8-tetrahydroindolo[2,l-a][2,5]benzodiazoc 11-carboxylic acid; 13-cyclohexyl-5-methyl-4,5,6,7-tetrahydrofuro[3',2':6,7][l,4]diazocino[l,8- a] indole- 10-carboxy lie acid; 15-cyclohexyl-6-[2-(dimethylamino)ethyl]-7-oxo-6,7,8,9- tetrahydro-5H-indolo[2,l-«][2,6]benzodiazonine-12-carboxylic acid; 15-cyclohexyl-8-oxo- 6,7,8,9-tetrahydro-5H-indolo[2,l- ][2,5]benzodiazonine-12-carboxylic acid; 13-cyclohexyl-6- oxo-6,7-dihydro-5H-indolo[l,2-if][l,4]benzodiazepine-10-carboxylic acid; and pharmaceutically acceptable salts thereof.
The HCV NS3 protease inhibitory activity of the present compounds may be tested using assays known in the art. One such assay is HCV NS3 protease time-resolved fluorescence (TRF) assay as described below and in International Patent Application Publication No. WO2006/102087. Other examples of such assays are described in e.g., International Patent Application Publication No. WO2005/046712. The assay is performed in a final volume of 100 μΐ in assay buffer containing 50 mM HEPES, pH 7.5, 150 mM NaCl, 15 % glycerol, 0.15 % Triton X-100, 10 mM DTT, and 0.1 % PEG 8000. NS3 protease is pre-incubated with various concentrations of inhibitors in DMSO for 30 minutes. The reaction is initiated by adding the TRF peptide substrate (final concentration 100 nM). NS3 mediated hydrolysis of the substrate is quenched after 1 hour at room temperature with 100 μΐ of 500 mM MES, pH 5.5. Product fluorescence is detected using either a VICTOR V2 or FUSION fluorophotometer (Perkin Elmer Life and Analytical Sciences) with excitation at 340 nm and emission at 615 nm with a 400 μ8 delay. Testing concentrations of different enzyme forms are selected to result in a signal to background ratio (S/B) of 10-30. IC50 values are derived using a standard four-parameter fit to the data. Kj values are derived from IC50 values using the following formula,
IC5o = Ki (l + [S] / KM), Eqn (l),
where [S] is the concentration of substrate peptide in the reaction and KM is the Michaelis constant. See Gallinari et al, 1999, Biochem. 38:5620-32; Gallinari et al., 1998, J Virol.
72:6758-69; Taliani et al, 1996, Anal. Biochem. 240:60-67.
The present invention also includes processes for making compounds of formula (I). The compounds of the present invention can be readily prepared according to the following reaction schemes and examples, or modifications thereof, using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants which are themselves known to those of ordinary skill in this art, but are not mentioned in greater detail. Furthermore, other methods for preparing compounds of the invention will be readily apparent to the person of ordinary skill in the art in light of the following reaction schemes and examples. Unless otherwise indicated, all variables are as defined above.
Olefin metathesis catalysts include the following Ruthenium based species:
Miller et al, 1996, J Am. Chem. Soc. 118:9606; Kingsbury et al, 1999, J Am. Chem. Soc.
121 :791; Scholl et al, 1999, Org. Lett. 1 :953; U.S. Patent Application Publication
US2002/0107138; Furstner et al, 1999, J Org. Chem. 64:8275. The utility of these catalysts in ring closing metathesis is well known in the literature (e.g. Trnka et al, 2001, Acc. Chem. Res.
Figure imgf000036_0001
G H j
(Zhan catalyst 1 A, Zannan Pharma Ltd.)
Figure imgf000037_0001
K Zhan ruthenium metathesis catalyst RC-303
(Zhan catalyst IB, RC-303,
Zannan Pharma Ltd.)
The following reaction schemes and examples serve only to illustrate the invention and its practice. The examples are not to be construed as limitations on the scope or spirit of the invention.
List of Abbreviations
ACN Acetonitrile
Aq. Aqueous
ACN Acetonitrile
Bn Benzyl
BOC (also Boc) t-Butyloxycarbonyl
BuLi Butyl lithium
CDC13 Deuterio-trichloromethane
DBU l,8-Diazabicyclo[5.4.0]undec-7-ene
DCM Dichloromethane
DIPEA Diisopropylethylamine
DMA Dimethylacetamide
DMAP 4-Dimethylamine pyridine
DMF Dimethylformamide
DMSO Dimethyl sulfoxide
ES Electronspray ionization
Et20 Diethyl ether
EtOAc Ethyl acetate
HC1 Hydrochloric acid HATU O-(7-Azabenzotriazol- 1 -yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate
HF-TEA Hydrogen fluoride triethylamine
HPLC High performance liquid chromatography
HRMS High resolution mass spectrometry
Int. Intermediate
KHMDS Potassium hexamethyldisilazane
KHSO4 Potassium bisulfate
LiOH Lithium hydroxide
LCMS High performance liquid chromatography - mass spectrometry
LRMS Low resolution mass spectrometry
MeOH Methanol
MES 2-(N-morpholino)ethanesulfonic acid
NaOH Sodium hydroxide
NaHC03 Sodium hydrogen carbonate (sodium bicarbonate)
Na2C03 Sodium carbonate
NMM N-methylmorpholine
Pd/C Palladium on carbon
Pd(Ph3P)4 Tetrakis(triphenylphosphine)palladium(0)
PPh3 Triphenylphosphine
Rh/C Rhodium on carbon
TBS tert-Butyldimethylsilyl
TEA Triethylamine
TFA Trifluoroacetic acid
THF Tetrahydrofuran
TLC Thin Layer Chromatography
Tosyl p-Toluenesulfonyl
General methods
For Intermediates A, various salt forms have been used for the coupling reaction.
These include but are not limited to tosylate and TFA salts. For the final products, they have been isolated either in their free form or a salt derivative (TFA", MeS(0)20", K+, Na+, etc.).
General methods
Figure imgf000039_0001
Figure imgf000039_0002
Scheme 2
Figure imgf000040_0001
Figure imgf000040_0002
Figure imgf000041_0001
-39- Synthesis of Intermediates
Intermediates A
Figure imgf000042_0002
Intermediate A6 : ai?,2S)-l-amino-2-ethenyl-iV-(ri- (methoxymethyl cvclopropyl] sulfonyl } cyclopropanecarboxamide trifluoroacetate
Figure imgf000042_0001
Step 1 : tert-butyl [(lR,2S)-2-ethenyl-l-({[l- carbamoyl)cyclopropyl]carbamate
Figure imgf000043_0001
A solution of (li?,2S)-l-[(tert-butoxycarbonyl)amino]-2- ethenylcyclopropanecarboxylic acid (132 mg) in THF (3 mL) was added 1,1'- carbonyldiimidazole (283 mg). The mixture was stirred 4 hours at reflux. The mixture was cooled to room temperature and a solution of l-(methoxymethyl)cyclopropanesulfonamide (125 mg; Li et al, 2006, Synlett 5:725) and DBU (0.438 mL) in THF (3 mL) was added via cannula. The mixture was stirred for 40 hours at room temperature. The reaction was quenched with IN HC1 and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (ISCO) to give the desired product (120 mg). Ή NMR (400 MHz, CDC13): 5.71-5.62 (m, 1H), 5.29 (d, 1H), 5.16 (d, 1H), 3.36 (s, 2H), 2.15 (dt, 1H), 1.89 (dd, 1H), 1.75-1.68 (m, 2H), 1.49 (s, 9H), 1.34- 1.30 (m, 1H), 1.08-1.03 (m, 2H).
Step 2 : (lR,2S)-l-amino-2-ethenyl-N-{[l-
(methoxymethyl)cyclopropyl]sulfonyl}cyclopropanecarboxamide trifluoroacetate
Figure imgf000043_0002
To a 0°C solution of the product of Step 1 (120 mg) in DCM (1 mL) at 0°C was added TFA (ImL). The mixture was slowly warmed to room temperature and stirred for 3 hours. The solvent was removed in vacuo and the crude product was used in the next step. Ή NMR (400 MHz, CDC13): δ (ppm) 5.82 (ddd, 1 H), 5.44 (d, 1H), 5.43 (d, 1 H), 3.67 (d, 1H), 3.63 (d, 1H), 3.35 (s, 3H), 2.64 (dt, 1H), 1.92 (dd, 1H), 1.83 (dd, 1H), 1.76-1.70 (m, 1H), 1.67-1.60 (m, 1H), 1.14-1.02 (m, 2H). Intermediate A7 : ai?,2y)-l-amino-2-ethenyl-N-(il-(prop-l-en-2-vncvclopropyl1
sulfonyl cyclopropanecarboxamide hydrochloride
Figure imgf000044_0001
Step 1 : tert-butyl [(lR,2S)-2-ethenyl-l-({[l-(prop-l-en-2-yl)cyclopropyl]sulfonyl}
carbamo l) cyclopropyl] carbamate
Figure imgf000044_0002
The title compound was prepared using the same method as described for
Intermediate A6, Step 1 using l-(prop-l-en-2-yl)cyclopropanesulfonamide. Ή NMR (500 MHz, CDC13): δ (ppm) 5.66-5.59 (m, 1 H), 5.30 (d, IH), 5.24 (s, 1 H), 5.22 (s, IH), 5.16 (d, IH), 5.16 (s, IH), 2.14 (dt, IH), 1.96 (s, 3H), 1.90-1.80 (m, 3H), 1.48 (s, 9H), 1.33-1.30 (m, 1 H), 1.12- 1.08 (s, 2 H).
Step 2 : (lR,2S)-l-amino-2-ethenyl-N-{[l-(prop-l-en-2-yl)cyclopropyl]sulfonyl}
cyclopropanecarboxamide hydrochloride
Figure imgf000044_0003
The product of step 1 (136 mg) was dissolved in a solution of HC1 in dioxane (1.5 mL). The mixture was stirred for 3 hours at room temperature. The solvent was removed in vacuo and the crude product was used in the next step. Ή NMR (400 MHz, CDCI3): δ (ppm) 5.69-5.62 (m, IH), 5.41 (d, IH), 5.26 (d, IH), 5.23 (s, IH), 5.21 (s, IH), 2.77-2.72 (m, IH), 2.02- 1.98 (m, IH), 1.95 (s, 3H), 1.93-1.84 (m, 2H), 1.74-1.69 (m, IH), 1.17-1.06 (m, 2H).
Figure imgf000044_0004
ethenylcyclopropanecarboxamide hydrochloride
Step 1 : tert-butyl {(1 R,2S)-1 -[({1 -[(benzyloxy)methylJcyclopropyl}sulfonyl)carbamoyl]-2- ethenylcyclopropyljcarbamate
Figure imgf000045_0001
The title compound was prepared using the same method as described for Intermediate A6, Step 1 using l-[(benzyloxy)methyl]cyclopropanesulfonamide. See
International Patent Publication No. WO 09/061699. Ή NMR (500 MHz, CDC13): δ (ppm) 7.40-7.33 (m, 5Η), 5.67-5.57 (m, 1 Η), 5.25 (d, IH), 5.12 (d, IH), 4.55 (d, IH), 4.50 (d, IH), 3.85 (d, IH), 3.77 (d, IH), 1.96 (br s, 1 H), 1.80 (dd, IH), 1.74-1.72 (m, 2 H), 1.46 (s, 9H), 1.12 (dd, IH), 1.08-1.01 (m, 2 H).
Step 2 : (lR,2S)-l-amino-N-({l-[(benzyloxy)methyl]cyclopropyl}sulfonyl)-2- ethenylcyclopropanecarboxamide hydrochloride
Figure imgf000045_0002
The title compound was prepared using the same method as described for Intermediate A7, Step 2. The crude product was used without further purification. Intermediate A9: (lig.2S -l-amino-2-ethenyl-N-((l-r(2-
Figure imgf000045_0003
Step 1 : tert-butyl ({l-[(2-methoxyethoxy)methyl]cyclopropyl}sulfonyl)carbamate
Figure imgf000045_0004
BuLi 2.5 M in hexanes (7.53 ml) was added dropwise to the solution of tert-butyl
(cyclopropylsulfonyl)carbamate (1.81 g) in THF (40 ml) at -78°C. This solution was stirred at -78°C for 1 hour then 2-methoxyethoxymethyl chloride (1.85 ml) was added dropwise. The reaction was allowed to warm to room temperature and was stirred for 3 days. The solvent was evaporated under reduced pressure and the residue was diluted with ethyl acetate. At this point, HC1 (1 M) was added and the mixture was extracted with ethyl acetate (3x). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and the solvent was evaporated under reduced pressure. The residue was purified by flash chromatography (ISCO, 0 to 100% ethyl acetate in hexanes) to give the desired product (0.630 g) as a clear oil. LRMS (ES+) m/z 332.2 (M+Na)+.
Step 2: l-[(2-methoxyethoxy)methyl]cyclopropanesulfonamide
Figure imgf000046_0001
TFA (5 ml) was added to the solution of the product of Step 1 (0.63 g) in dichloromethane (5 ml) at 0°C. The reaction was allowed to warm to room temperature and was stirred for 1.5 hour. The solvent was removed under reduced pressure to give the desired product (0.426 g) as a light brown oil. Ή NMR (400 MHz, CDC13): δ (ppm) 6.80-6.21 (m, 2H), 3.75 (s, 2H), 3.66-3.64 (m, 2H), 3.56-3.53 (m, 2H), 3.36 (s, 3H), 1.42-1.39 (m, 2H), 0.91-0.89 (m, 2H) Step 3: tert-butyl {(lR,2S)-2-ethenyl-l-[({l-[(2- methox ethoxy)methyl]cyclopropyl}sulfonyl)carbamoyl]cyclopropyl}carbamate
Figure imgf000046_0002
The title compound was prepared using the same method as described for
Intermediate A6, Step 1. LRMS (ES+) m/z 441.2 (M+Na)+.
Step 4: (lR,2S)-l-amino-2-ethenyl-N-({l-[(2- sulfonyl)cyclopropanecarboxamide hydrochloride
Figure imgf000046_0003
The title compound was prepared using the same method as described for
Intermediate A7, Step 2. LRMS (ES+) m/z 341.2 (M+Na)+.
Intermediate A10: (lR.2S l-amino-2-ethenyl-N-((l-r2-(mo holin-4- yDethyl] cyclopropyl } sulfonvOcyclopropanecarboxamide dihydrochloride
Step 1 : tert-butyl {(lR,2S)-2-ethenyl-l-[({l-[2-(morpholin-4- yl)ethyl]cyclopropyl}sulfonyl)carbamoyl]cyclopropyl}carbamate
Figure imgf000047_0001
The title compound was prepared using the same method as described for
th 4-(2-bromoethyl)morpholine. LRMS (ES+) m/z 444.4 (M+H)+.
Figure imgf000047_0002
H-CI
The title compound was prepared using the same method as described for Intermediate A7, Step 2. The crude product was used directly in the next step. Intermediate Al l : 3- 4H-l,2,4-triazol-4-yl)propyl 4-methylbenzenesulfonate
Figure imgf000047_0003
To a solution of 3-(4H-l,2,4-triazol-4-yl)propan-l-ol (100 mg) in pyridine (2.62 mL) under nitrogen at 0 °C was added Tosyl-Cl (165 mg). The reaction was stirred for 18 hours. Pyridine was removed in vacuo and the remaining oil and solids were dissolved in ethyl acetate and washed several times with an aqueous solution of KHS04. The combined aqueous layers were back extracted with ethyl acetate. The combined organics were dried over magnesium sulfate, filtered and concentrated to provide a clear oil. Since the product was still in the aqueous layer, the pH of the aqueous phases was adjusted to 10 using 4.0 N NaOH. The mixture was extracted (3x) with ethyl acetate. The combined organics were dried over magnesium sulfate, filtered and concentrated. Purification of the reaction mixture by flash chromatography (ISCO, 0 to 50% ethyl acetate in hexanes) provided the desired product (50 mg). LRMS (ES+) m/z 282.2 (M+H)+.
Intermediate A12 : 3-(3,3-difluoropiperidin-l-yl)propan-l-ol
-(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)-3!3-difluoropiperidine
Figure imgf000048_0001
To a solution of 3,3-difluoropiperidine hydrochloride (518 mg) in DMF (15 mL) was added cesium carbonate (3.21 g) and (3-bromopropoxy)-tert-butyldimethylsilane (0.838 mL). The resulting reaction mixture was heated to 50°C for 1.5 hours before cooling back to room temperature. Water and ethyl acetate were added to the reaction mixture. The mixture was extracted with ethyl acetate (2x). The combined organics were washed with water (2x), brine, dried over magnesium sulfate, filtered and concentrated. Purification by flash chromatography (ISCO, 0 to 40% ethyl acetate in hexanes with 1% triethylamine) gave the desired product (612 mg). Ή NMR (400 MHz, CDC13): δ (ppm) 4.20 (t, 1H), 3.71-3.64 (m, 2H), 3.46 (t, 1H), 2.62 (t, 1H), 2.50-2.47 (m, 1H), 2.44-2.42 (m, 1H), 2.05-1.98 (m, 1H), 1.91-1.82 (m, 2H), 1.77-1.67 (m, 4H), 0.89 (d, 9H), 0.05 (s, 3H), 0.04 (s, 3H).
-(3,3-difluoropiperidin-l-yl)propan-l-0l
Figure imgf000048_0002
To a solution of the product of Step 1 (612 mg) in THF (20 mL) was added HF-
TEA (13.58 mL) at room temperature. The solution was heated to 50°C for 45 minutes. The reaction mixture was concentrated to remove THF and then diluted with ethyl acetate (100 mL) and water was added (100 mL). To that mixture was added Na2C03 (14.4 g) portion wise at 0°C When the quench was complete, the layers were separated. The organic layer was washed with 10% Na2C03, water and brine. The aqueous layer was re-extracted with ethyl acetate (2x). The combined organics were dried over magnesium sulfate, filtered and concentrated. The crude product (350 mg) was used directly in the next step. HRMS (ES+) m/z 180.1202 (M+H)+.
Intermediate A13 : l-(2-hvdroxypropan-2-yl cvclopropanesulfonamide ulfonyl) carbamate
Figure imgf000049_0001
To a solution of cyclopropanesulfonamide (6.51 g, triethylamine (40 mL) and
DMAP (0.656 g) in DCM (150 mL) was slowly added benzyl chloroformate (12 mL). The mixture was stirred at room temperature for 18 hours. The mixture was washed with 1 N HC1. The aqueous layer (pH 1) was extracted with EtOAc (x2). The combined organics were washed with brine, dried over anhydrous MgS04 and concentrated. The resulting residue was purified by flash chromatography (ISCO, 0-10% methanol in dichloromethane) to afford the desired product (7.8 g). Ή NMR (400 MHz, CDC13): δ (ppm) 7.56-7.44 (m, 1H), 7.38 (s, 5H), 5.22 (s, 2H), 2.92-2.84 (m, 1H), 1.40-1.35 (m, 2H), 1.12-1.06 (m, 2H).
Step 2 : benzyl {[l-(2-hydroxypropan-2-yl)cyclopropyl]sulfonyl}carbamate
Figure imgf000049_0002
The title compound was prepared using the same method as described for
Intermediate A9, Step 1 using acetone. Ή NMR (400 MHz, CDC13): δ (ppm) 8.03-7.83 (m, 1H), 7.36 (s, 5H), 5.18 (s, 2H), 1.72-1.68 (m, 2H), 1.36 (s, 6H), 1.10-1.06 (m, 2H).
-(2-hydroxypropan-2-yl)cyclopropanesulfonamide
Figure imgf000049_0003
To a solution of the product of Step 2 (995 mg) in methanol (30 mL) under nitrogen was added Pd/C (169 mg). The flask was purged with hydrogen and stirred for 3 hours. Celite was added to the reaction mixture and it was filtered through a pad of Celite. The solvent was removed in vacuo. The resulting residue was purified by flash chromatography (ISCO, 0 to 10 % methanol in dichloromethane) to afford the desired product (391 mg). Ή NMR (400 MHz, CDC13): 5 (ppm) 4.88 (br s, 2H), 2.58 (s, 1H), 1.44-1.41 (m, 2H), 1.41 (s, 6H), 1.06-1.03 (m,
2H). Intermediate A14 : l-(r({(lig.2j?V2-rr4E)-5-(4,4,5,5-tetramethyl-1.3.2-dioxaborolan-2-vnpent-4- - 1 -yl] cyclopropyl } oxy)carbonyll oxy) pyrrolidine-2 ,5 -dione
Figure imgf000050_0001
-[({[(lR,2R)-2-(pent-4-yn-l-yl)cyclopropyl]oxy}carbonyl)oxy]pyrrolidine-2,5-dione
Figure imgf000050_0002
To a solution of (li?,2i?)-2-(pent-4-en-l-yl)cyclopropanol (see International Patent Application Publication No. WO 08/057209) (17.1 g) in acetonitrile (193 mL) was added Ν,Ν'- disuccinimidyl carbonate (49.3 g) then triethylamine (53.7 mL). The mixture was heated to 40°C for 18 hours. The reaction mixture was cooled to room temperature and the solids were removed by filtration. The solvent was removed in vacuo. The residue was purified by flash chromatography (ISCO, 10 to 70% ethyl acetate in hexanes) to give the desired product (18 g). Ή NMR (500 MHz, CDC13): δ (ppm) 4.06-4.03 (m, IH), 2.87 (s, 4H), 2.28-2.25 (m, 2H), 1.98- 1.97 (m, IH), 1.72-1.63 (m, 2H), 1.44-1.39 (m, 2H), 1.30-1.25 (m, IH), 1.12-1.08 (m, IH), 0.72- 0.68 (m, IH).
Step 2 : l-{[({(lR,2R)-2-[(4E)-5-(4 ,5,5-tetramethyl-l,3,2-dioxaboro
yl ]cyclopropyl}oxy)carbonyl ]oxy}pyrrolidine-2, 5-dione
Figure imgf000051_0001
Cyclohexene (1.09 mL) was added to a 10 M dimethyl sulfide solution of borane (0.58 mL). Upon addition, a white solid had formed and 3 mL of degassed heptane was added to suspend it. The mixture was stirred for 5 minutes at room temperature. At this point, alkyne from Step 1 (15.5 g) in THF (55 mL) was added dropwise to the reaction mixture. After complete addition, the mixture was warmed to 40 °C for 20 minutes. Pinacolborane (8.48 mL) was added slowly to reaction mixture and the heating was continued for 2 hours at 40°C. The reaction mixture was cooled to room temperature and quenched with brine (100 mL). The mixture was extracted with ethyl acetate (3x). The combined organics were dried over magnesium sulfate, filtered and concentrated to provide the desired compound. Ή NMR (500 MHz, CDC13): δ (ppm) 6.66-6.58 (m, 1H), 5.45 (d, 1H), 4.02-3.99 (m, 1H), 2.87 (s, 4H), 2.22- 2.17 (m, 2H), 1.61-1.54 (m, 3H), 1.32-1.23 (m, 2H), 1.29 (s, 12H), 1.09-1.05 (m, 1H), 0.68-0.63 (m, 1H). Intermediate Al 5: l-(r({(Tj?,2i?V2-r5-(4,4,5,5-tetramethyl-L3,2-dioxaborolan-2- vPpentyl] cyclopropyl > oxy)carbonyll oxy } p yrrolidine-2, 5 -dione
Figure imgf000051_0002
To a degassed suspension of Pd/C (812 mg) in ethyl acetate (51 mL) was added vinyl boronate (intermediate A14, 10 g). After degassing, the mixture was purged and re-filled with hydrogen (balloon, 1 atm). The reaction mixture was stirred at room temperature for 2 hours. The atmosphere was carefully exchanged for nitrogen and the mixture was filtered over celite (rinsing with ethyl acetate). The solvent was removed in vacuo. The residue was purified by flash chromatography (ISCO, 0 to 50% ethyl acetate in hexanes) to give the desired product (7 g). 'HNMR (500 MHz, CDC13): δ (ppm) 4.03-4.00 (m, 1H), 2.87 (s, 4H), 1.46-1.39 (m, 4H), 1.35-1.24 (m, 5H), 1.26 (s, 12H), 1.07-1.03 (m, 1H), 0.81-0.77 (m, 2H), 0.67-0.63 (m, 1H).
Synthesis of Intermediates B
Figure imgf000052_0001
Figure imgf000053_0001
To a stirred solution of (li?,2S)-2-(but-3-en-l-yi)cyclopentanol (see International Patent Application Publication No. WO2009/134624) (2.1 g) and DIPEA (5.3 mL) in anhydrous 1,4-dioxane (51 ml), at 10°C and under nitrogen, was added a solution of triphosgene (1.5 g) in dioxane (51 ml). This reaction was stirred at 22°C for 1.5 hour and 3 -methyl-L- valine (2 g) and NaOH (1M, 30.5 mL) were added, then stirred at 70°C for 15 hours. At 22 °C, the reaction solution was acidified to pH 3 with 1 N HC1 and extracted with (3 x 100 ml) ether. The combined organic layer were washed with water (100 ml), brine (70 ml), dried over Na2S04, filtered and concentrated. The residue was purified by flash chromatography (silica gel, eluting with 10 to 100% EtOAc in hexane) to give the desired product (3.26 g). LRMS (ES+) M/Z (M+Na)+ 320.1.
Figure imgf000053_0002
methylcvclopentylloxylcarbonvDaminoi cvclopentvnethanoic acid and (2S)- ({\(lS2R)-2-(but- -en- 1 -vD- 1 -methylcyclopentylloxy} carbonypaminol (cyclopentyl ethanoic acid
Figure imgf000053_0003
±)-(lR,2S)-2-(but-3-en-l-yl)-l-methylcyclopentanol
Figure imgf000053_0004
(+/-)
To a 0°C solution of butenyl magnesium chloride (45.6 mL, 0.5 M) was added copper(I) chloride (0.113 g) followed by methylcyclopropane oxide (1.12 g) in diethyl ether (5 ml). The reaction mixture was warmed to room temperature and stirred for 20 hours. The mixture was cooled back to 0°C before pouring into a saturated solution of ammonium chloride (at 0°C). The mixture was extracted with ethyl acetate (3x). The combined organic fractions were dried over magnesium sulfate, filtered and concentrated carefully. The residue was purified by flash chromatography (ISCO, 0 to 30% ethyl acetate in hexanes) to give the desired product (1.3 g). Ή NMR (400 MHz, CDC13): δ (ppm) 5.86-5.79 (m, 1H), 5.05-4.99 (m, 1H), 4.97-4.93 (m, 1H), 2.20-2.09 (m, 1H), 2.02-1.92 (m, 2H), 1.73-1.50 (m, 7H), 1.31-1.10 (m, 5H).
Step 2 : methyl (2S)-[({[(lR,2S)-2-(but-3-en-l-yl)-l- methylcyclopentyl]oxy}carbonyl)amino](cyclopentyl)ethanoate and methyl (2S)-[({[(lS,2R)-2- (but-3-en-l-yl)-l-methylcyclopentyl]oxy}carbonyl)amino] (cyclopentyl)ethanoate
Figure imgf000054_0001
DMAP (0.59 g) was added to a stirred mixture of the product of Step 1 (0.75 g) and methyl (2S)-cyclopentyl(isocyanato)ethanoate (1.34 g) (See International Patent Application Publication No.: WO08/057209) in toluene (24 ml). DIPEA (3.40 mL) was then added and the mixture was stirred at 100°C for 22 hours. Since the reaction wasn't complete, methyl (25)- cyclopentyl(isocyanato)ethanoate (0.6 g), DIPEA (1.5 mL) and DMAP (0.3 g) were added and the mixture was stirred at 100°C for 8 hours. The reaction mixture was worked up with ethyl acetate and 5% KHS04. The organic layer was washed with a saturated solution of sodium bicarbonate, then brine, dried over magnesium sulfate and the solvent was removed in vacuo to give crude product. The residue was purified by flash chromatography (ISCO, 0 to 20% ethyl acetate in hexanes) to give the desired product (1.17 g) as a 1 :1 mixture of diastereomers. LRMS (ES+) M/Z (M+H)+ 360.4.
Step 3 : (2S)-[({[(lR2S)-2-(but-3-en-l-yl)-l- methylcyclopentyl]oxy}carbonyl)amino](cyclopentyl)ethanoic acid and (2S)-[({[(lS,2R)-2-(but- -en-l-yl)-l-methylcyclopentyl]oxy}carbonyl)amino](cyclopentyl)ethanoic acid
Figure imgf000054_0002
To a solution of the product of Step 2 (1.17 g) in THF (10 mL), methanol (1 ml), and water (2 ml) was added LiOH (0.415 g). After 1 hour 45 min, the reaction was done. The pH was adjusted (13 mL IN HCl, then 5% KHS04 until pH 3), and then extracted with Et20 and then EtOAc. The combined organic layers were dried over magnesium sulfate and the solvent was removed in vacuo to yield 1.2 g of the desired product. HRMS (ES+) M/Z (M+Na)+ 346.1988.
Intermediate B8 : (2^-Γ((Γ(ϋ?.2^ -2-^ΐ-3-6η-1-ν1)-1- methylcvclopropyl oxy)carbonyl aminol(cvclopentyl)ethanoic acid and (25f)-[({[(lS,2S)-2-(but- -en- 1 -yl)- 1 -methylcyclopropylloxy} carbonyl aminol(cyclopentyl ethanoic acid
Figure imgf000055_0001
±)-(lR,2R)-2-(but-3-en-l-yl)-l-methylcyclopropanol
Figure imgf000055_0002
(+/-)
In a dry sure seal, ethyl acetate (2 mL) was added to THF (204 mL) followed by 1,5-hexadiene (7.28 ml) and chlorotitanium triisopropoxide (20.43 ml). At this point, cyclohexylmagnesium chloride (46.0 mL) was added via a syringe pump over 1 hour. The mixture was stirred 1 hour.
It was then slowly poured into ice water and ether. The mixture was extracted with ether (3x). The combined organic layers were washed with brine, dried over magnesium sulfate and the solvent was removed in vacuo. The residue was purified by flash
chromatography on silica gel (0 to 40% diethyl ether in hexanes) to give the desired product (1.4 g). Ή NMR (400 MHz, CDC13): δ (ppm) 5.88-5.79 (m, 1H), 5.05-5.00 (m, 1H), 4.98-4.94 (m,
1H), 2.17-2.12 (m, 2H), 1.79 (s. 1H), 1.46-1.39 (m, 2H), 1.32-1.15 (m, 3H), 1.04-0.96 (m, 1H),
0.90-0.84 (m, 1H), 0.10-0.07 (m, 1H). Step 2 : methyl (2S)-[({[(lR,2R)-2-(but-3-en-l-yl)-l- methylcyclopropyl]oxy}carbonyl)amino](cyclopentyl)ethanoate and methyl (2S)-[({[(lS,2S)-2- but-3-en-l -yl)-l -methylcyclopropyl]oxy}carbonyl)amino] ' (cyclopentyl) ethanoate
Figure imgf000056_0001
The title compound was prepared using the same method as described for
Intermediate B6, Step 2. LRMS (ES+) M/Z (M+H)+ 310.4.
Step 3 : (2S)-[({[(lR,2R)-2-(but-3-en-l-yl)-l- methylcyclopropyl]oxy}carbonyl)amino](cyclopentyl)ethanoic acid and (2S)-[({[(lS,2S)-2-(but- -en-l-yl)-l-me ethanoic acid
Figure imgf000056_0002
The title compound was prepared using the same method as described for Intermediate B7, Step 3. LRMS (ES+) M/Z (M+K)+ 334.1417.
Intermediate B9 : iV-(([(l ?,2i? -2-(but-3-en-l-ylVl-methylcvclopropylloxy|carbonyl)-3-methyl- L-valine and N-( ( [( 1 S2S)-2-(but-3 -en- 1 -ylV 1 -methylcyclopropylloxy ) carbonyl)-3 -methyl-L- valine
Figure imgf000056_0003
The title compound was prepared using the same method as described for Intermediate B8, Steps 1 to 3 using methyl 3 -methyl -N-(oxomethylidene)-L-valinate (See International Patent Application Publication No. WO 10/11566). LRMS of ester (ES+) M/Z (M+K)+ 336.1573. Intermediate BIO : 3-methyl-iV-({[(li?,2i?')-2-(pent-4-vn-l-yl')cvclopropyl]oxylcarbonyl)-L- valine - N-benzyl-l-phenylmethanamine (1 :1)
Figure imgf000057_0001
The title compound was synthesized in a manner similar to the synthesis of the corresponding terminal alkene-bearing intermediate described in WO2008/057209.
Intermediate Bl l : (2S)-cyclohexyl[({[(li?,2i?)-2-(pent-4-vn-l-yl)cvclopropylloxy} carbonyl) amino ethanoic acid
Figure imgf000057_0002
-[({[(lR R)-2-^ent-4-yn-l-yl)cyclopropyl]oxy}carbonyl)oxy]pyrrolidine-2,5-dione
Figure imgf000057_0003
To a solution of (li?,2R)-2-(pent-4-en-l-yl)cyclopropanol (See International Patent Application Publication No. WO08/057209) (2.13 g; 70 % wt) in acetonitrile (20 ml) was added pyridine (1.5 ml), followed by Ν,Ν'-disuccinimidyl carbonate (3.74 g) and a crystal of DMAP. The mixture was stirred at 40°C overnight. After cooling to room temperature, the reaction mixture was diluted with ether and washed with HC1 IN, water and brine and dried over sodium sulfate. The organic layer was filtered and concentrated to provide the desired product (2.88 g) as an oil. Ή NMR (500 MHz, CDC13): δ (ppm) 4.06-4.03 (m, 1H), 2.87 (s, 4H), 2.28- 2.25 (m, 2H), 1.98-1.97 (m, 1H), 1.72-1.65 (m, 2H), 1.46-1.40 (m, 2H), 1.31-1.24 (m, 1H), 1.12- 1.08 (m, 1H), 0.72-0.68 (m, 1H).
Step 2 : (2S)-cyclopentyl[({[(lR,2R)-2-(pent-4-yn-l-yl)cyclopropyl]oxy}carbonyl)
amino] ethanoic acid
Figure imgf000058_0001
To a solution of the product of Step 1 (457 mg) in acetonitrile (6 ml) was added (25)-amino(cyclohexyl)ethanoic acid (352 mg) followed by triethylamine (0.720 ml) and water (6.00 ml). The mixture was stirred at room temperature for 18 hours. The mixture was diluted with ethyl acetate and washed with HCl IN, water and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. This provided the desired product (510 mg) as an oil. LRMS (ES+) M/Z (M+H)+ 308.2. Intermediate B12: (2S -cvclopentvirr(r(lig,2i?)-2-(pent-4-vn-l-vncvclopropylloxy}
carbonvDamino] ethanoic acid
Figure imgf000058_0002
Steps 1-2: methyl (2S)-cyclopentyl[({[(lR,2R)-2-(pent-4-yn-l-yl)cyclopropyl]
oxyjcarbonyl) amino Jethanoate
Figure imgf000059_0001
The title compound was prepared using the same method as described for Intermediate BIO, Steps 1 to 2 using methyl (25)-amino(cyclopentyl)ethanoate. Ή NMR (500 MHz, CDC13): δ (ppm) 5.14-5.09 (m, IH), 4.33-4.29 (m, IH), 3.74 (s, 3H), 2.25-2.20 (m, 2H), 1.94-1.93 (m, IH), 1.74-1.49 (m, 9H), 1.44-1.27 (m, 4H), 1.23-1.20 (m, IH), 1.02-0.97 (m, IH), 0.85-0.78 (m, IH), 0.56-0.49 (m, IH).
Step 3 : (28)-€γαΙορεηίγΙ[({[(1 ,2 )-2- βηί-4-γη-1-γ1)€γαΙορΓοργ1]οχγ}οα^οηγΙ)αηιϊηο]
Figure imgf000059_0002
The title compound was prepared using the same method as described for
Intermediate B7, Step 3. LRMS (ES+) M/Z (M+H)+ 294.1.
Intermediates B13-B15
Using the same method as described for either Intermediate Bl 1 (amino acid) or Intermediate B12 (amino ester), the following intermediates were synthesized:
Figure imgf000059_0003
Figure imgf000060_0001
*B14 NMR characterization : Ή NMR (400 MHz, CDC13): δ (ppm) 5.16-5.11 (m, IH), 4.40- 4.33 (m, IH), 3.82-3.79 (m, IH), 2.29-2.23 (m, 3Η), 1.97-1.95 (m, IH), 1.72-1.61 (m, 2H), 1.46- 1.31 (m, 2H), 1.07-0.93 (m, 8H), 0.89-0.83 (m, IH), 0.60-0.52 (m, IH).
Intermediate B16: 15-tert-butyl 14a-ethyl (2S.6Sa2Z.13aSa4aRJ6aSV2-ir(4- bromophenyl sulfonyl1oxy}-6-[(tert-butoxycarbonyl')aminol-5J6-dioxo- 2,3 ,6,7,8,9, 10 , 11 , 13a, 14, 16 , 16a-dodecahydrocyclopropa[elpyrrolo[ 1 ,2- a [1 ,4]diazacyclopentadecine- 14a, 15(1 H,5H -dicarboxylate
Figure imgf000060_0002
Step 1 : (4S)-4-{[(4-bromophenyl)sulfonyl]oxy}-l-(tert-butoxycarbonyl)-L-proline
Figure imgf000061_0001
LiOH (1M in water, 250 ml) was added to the solution of 1-tert-butyl 2-methyl (25,45)-4-{[(4-bromophenyl)sulfonyl]oxy}pyrrolidine-l,2-dicarboxylate (56.37 g) in THF (250 ml). The mixture was stirred at room temperature for 5 hours. The solution was acidified to pH = 1 with HC1 IN and extracted with ethyl acetate (3x). The combined organic fractions were washed with brine, dried over magnesium sulfate, filtered and concentrated. The desired acid was obtained as a white solid (53.4 g). LRMS (ES+) m/z 471.9 (M+Na)+.
Step 2 : tert-butyl (2S,4S)-4-{[(4-bromophenyl)sulfonyl]oxy}-2-{[(lR,2S)-2-ethenyl-l- (ethoxycarbonyl)cyclopropyl]carbamoyl}pyrrolidine-l-carboxylate
Figure imgf000061_0002
HATU (49.6 g) was added to the solution of the acid from Step 1 (53.4 g), (lR,2S)-cyclopropanecarboxylic acid, l-amino-2-ethenyl-, ethyl ester, hydrochloride
(Intermediate A4, 34.1 g) and DIPEA (62.2 ml) in DMF (475 ml). The solution was stirred at room temperature until disappearance of the starting material. HC1 1 N and water were added and the mixture was extracted with ether (3x). The combined organic fractions were washed with brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified on a pad of silica gel (hexanes: ethyl acetate 100:0 to 40:60). The residue was further purified by flash chromatography (ISCO, 0 to 100% ethyl acetate in hexanes) to give the desired product (40 g) as a white solid. LRMS (ES+) m/z 609.0 (M+Na)+.
Step 3: ethyl (lR,2S)-l-{[(4S)-4-{[(4-bromophenyl)sulfonyl]oxy}-L-prolyl]amino}-2- ethenylcyclopropanecarboxylate
Figure imgf000062_0001
HC1 (4M in dioxane, 300 ml) was added to the product of Step 2 (40 g) and the solution was stirred at room temperature for 30 min. The solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate and a saturated sodium bicarbonate solution was added. The phases were separated. The precipitated solid was filtrated from the organic layer to give the desired product (33.8 g) as a white solid. LRMS (ES+) m/z 487.0 (M+H)+. Step 4 : ethyl (lR,2S)-l-{[(4S)-4-{[(4-bromophen l)sidfo^
butox carbonyl)amino]non-8-enoyl}-L-prolyl]amino}
Figure imgf000062_0002
HATU (27.3 g) was added to the solution of (2S)-2-[(tert- butoxycarbonyl)amino]non-8-enoic acid (19.5 g) in DMF (100 ml) and the solution was stirred 15 minutes. The reaction mixture was cooled to 0°C. Then, the amine from Step 3 (31.8 g) in DMF (200 ml) (cooled to 0°C) was added followed by DIPEA (11.40 ml). The solution was stirred at 0°C for 1 hour. Hydrochloric acid (1M) was added and the mixture was extracted with diethyl ether (3x). The combined organic fractions were washed with brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography (ISCO, 0 to 100% ethyl acetate in hexanes) to give the desired product (40.2 g) as a white foam. LRMS (ES+) m/z 762.2 (M+Na)+.
Step 5: ethyl (lR,2S)-l-{[(4S)-4-{[(4-bromophenyl)sulfonyl]oxy}-l-{(2S)-2-[(tert- butoxycarbonyl)amino]non-8-enoyl}-L-prolyl](tert-butoxycarbonyl)amino}-2- ethenylcyclopropanecarboxylate
Figure imgf000063_0001
Di-tert-butyl dicarbonate (17.54 ml) was added at 0°C to the solution of the product of Step 4 (37.3 g) and DMAP (1.85 g) in ethyl acetate (504 ml). The solution was stirred at room temperature for 4 hours. At this point, another 2.5 g of di-tert-butyl dicarbonate was added and the solution was stirred at room temperature for 2 hours. The reaction was quenched with water and the mixture was extracted with ethyl acetate (3x). The combined organic fractions were dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatograph (ISCO, 0 to 40% ethyl acetate in hexanes) to give the desired product (35.8 g) as a white foam. LRMS (ES+) m/z 862.2 (M+Na)+.
Step 6 : 15-tert-butyl 14a-ethyl (2S,6S, 12Z, 13aS, 14aR, 16aS)-2-{[(4-bromophenyl)sulfonyl]oxy}- 6-[ (tert-butoxycarbonyl)amino J-5, 16-dioxo-2, 3, 6, 7, 8, 9, 10,11,13a, 14, 16,16a-dodecahydro c clopropafe Jpyrrolof 1, 2-a][ 1, 4 ]diazacyclopentadecine-14a, 15(1H, 5H)-dicarboxylate
Figure imgf000063_0002
The stirred solution of di-ene from Step 5 (15 g) in dichloroethane (1784 ml) was bubbled with nitrogen for 1 hour. 1 ,4 benzoquinone (0.19 g) and Zhan catalyst 1 B ( 1.31 g) were added and the solution was purged with nitrogen. The solution was then stirred at 75°C for 2 hours under a nitrogen flow. The reaction mixture was cooled to room temperature and ethyl vinyl ether (1.71 ml) was added to quench the catalyst. At this point, the solvent was evaporated under reduced pressure. The residue was purified by flash chromatography (ISCO, 0 to 40% ethyl acetate in hexanes) to give the desired product (12.3 g) as a white solid. LRMS (ES+) m/z 834.2 (M+Na)+.
Synthesis of intermediates C Intermediate CI : 4-methoxy-3-(prop-2-en-l-vDquinolin-2-ol
Figure imgf000064_0001
-(prop-2-en-l-yl)quinoline-2,4-diol
Figure imgf000064_0002
To a degassed solution of 2,4-dihydroxyquinoline (10.0 g) in DMF (100 ml) was added triethylamine (9.51 ml), Pd(Ph3P)4 (2.151 g), followed by allyl acetate (7.43 ml). The mixture was allowed to stir at 60°C under nitrogen for 18 hours. The reaction mixture was cooled to room temperature and quenched into water (600 mL). The pH was adjusted to 12 using a saturated sodium carbonate solution. Dichloromethane was added and the layers were cut. The aqueous layer was extracted with dichloromethane once more. Then, the aqueous layer was cooled with ice and the pH was slowly adjusted to 2.5 with 12N HC1 to give a pink solid. The solids were filtered and washed with water to give 11.5 g (92% yield). LRMS (ES+) M/Z (M+H)+ 202.0.
-methoxy-3-(prop-2-en-l-yl)quinolin-2-ol
Figure imgf000064_0003
Dimethyl sulfate (0.237 ml) was added to a mixture of 3-(prop-2-en-l- yl)quinoline-2,4-diol (1.0 g) and potassium carbonate (1.37 g) in acetone (100 ml) and the mixture was stirred at room temperature for 3 hours then warmed to 40°C for 30 minutes. The reaction mixture was cooled and the solids were removed by filtration. The filtrate was concentrated in vacuo. Purification by flash chromatography (ISCO, 4-10% acetone/DCM) gave the desired product (0.70 g). LRMS (ES+) M/Z (M+H)+ 216.0.
Intermediate C2 : 4-ethoxy-3-(prop-2-en-l-yl quinolin-2-ol
Figure imgf000065_0001
The title compound was prepared using the same method as described for
Intermediate CI using diethyl sulfate. LRMS (ES+) m/z 230.1 (M+H)+. Intermediate C3 : 4-(benzyloxy -3-(prop-2-en-l-vf)quinolin-2-ol
Figure imgf000065_0002
To a mixture of 3-(prop-2-en-l-yl)quinoline-2,4-diol (4.0 g),
triphenylphosphine(6.78 g) and benzyl alcohol (2.27 ml) in THF (240 ml) at 0°C was added dropwise a THF (12 mL) solution of diisopropylazodicarboxylate (5.02 ml). Upon completion of addition, the mixture was allowed to stir at room temperature for 60 minutes. The reaction mixture was concentrated in vacuo to give a thick oil. Oil dissolved in DCM (20 mL) and solids started to precipitate. The solids were filtered and washed with DCM (10 mL). This provided 2.0 g of the desired product. Purification of the mother liquors using flash chromatography (ISCO, 1-8% acetone/DCM) gave an oil that was a mixture of products. This oil was dissolved in 15 mL of diethyl ether and seeded with the desired product. The mixture was stirred overnight and crystallization occurred. The solids were filtered and washed with ether to provide the desired product (1.06 g) as a white solid for a total of 3.06 g of product. LRMS (ES+) M/Z (M+H)+ 292.1. Intermediate C4 : 4-(benzyloxy)-6-bromo-3-(prop-2-en-l-yl)quinolin-2(lH)-one
Figure imgf000065_0003
Step 1: ethyl 3-[(4-bromophenyl)amino]-3-oxopropanoate
Figure imgf000066_0001
4-Bromoaniline (10.0 g) was dissolved in benzene (70 mL) and cooled to 0°C. A solution of ethyl malonyl chloride in benzene (70 mL) was added over 15 minutes. The reaction was allowed to warm to room temperature and was stirred for 1 hour. The reaction mixture was diluted with an aqueous saturated sodium carbonate solution (50 mL) and stirred for 1 hour. The reaction was complete by LCMS. The reaction mixture was diluted with water and the layers were separated. The aqueous layer was re-extracted with diethyl ether. The combined organics were washed with brine, dried over sodium sulfate and concentrated to give 18 g of a cake that was used directly in the next step.
-[(4-bromophenyl)amino]-3-oxopropanoic acid
Figure imgf000066_0002
The product of Step 1 (16.63 g) was dissolved in THF (150 mL) and 2N NaOH
(145 mL) was added over 15 minutes. The reaction was stirred for 24 hours. The reaction mixture was concentrated to remove the THF. Diethyl ether (20 mL) was added and the layers were separated. The aqueous layer was acidified to pH = 2.2 with IN HC1 which resulted in the precipitation of solids. Ethyl acetate was added until the solids were dissolved and the layers were separated. The organic extract was dried with sodium sulfate, filtered and concentrated to give 14.7 g of a cake.
Step 3: 6-bromo-4-hydroxyquinolin-2(lH)-one
Figure imgf000066_0003
The product of Step 2 (14.7 g) was added to polyphosphoric acid (55.3 mL) and mixture was heated to 140°C for 3 hrs. The reaction mixture was cooled slightly and poured into 3N HC1 (168 mL). The pH was adjusted to 4 with 3N NaOH and resulting solid was filtered after cooling the reaction mixture to 10°C. The cake was washed with water and then slurried in 400 mL of 50% isopropanol/water for 18 hours. The solids were filtered, air dried to give a pasty solid which was dried in vacuo at 90°C for 4 hours, ground in mortar/pestle and re-dried at 90°C for another 18 hours to give 15 g of the desired product. Step 4: 6-bromo-4-hydroxy-3-(prop-2-en-l-yl)quinolin-2(lH)-one
Figure imgf000067_0001
The title compound was prepared using the same method as described for Intermediate CI, Step 1 using the product of step 3. LRMS (ES+) m/z 280.0 (M+H)+.
Step 5: 4-(benzyloxy)-6-bromo-3-(prop-2-en-l-yl)quinolin-2(lH)-one
Figure imgf000067_0002
The title compound was prepared using the same method as Intermediate C3, g the product of step 4. LRMS (ES+) m/z 371.9 (M+H)+. Intermediate C5: 7-chloro-4-methoxy-3-(prop-2-en-l-vf)quinolin-2-ol (A and 5-chloro-4- methox -3 -(prop-2-en- 1 -yl)quinolin-2-ol (B
Figure imgf000067_0003
3-chloroaniline (5.01 g) and diethyl malonate (2.51 ml) were combined in a flask and heated to 220°C utilizing a short path condenser with nitrogen bleed over the reaction to remove reaction ethanol. The reaction was stirred for 18 hours and then cooled to room temperature. The solid that had formed in the flask was broken up in diethyl ether 30 mL to give free flowing orange solid upon filtration and washing with ether (3.75 g). LRMS (ES+) m/z (M+H)+ 322.9. -chloroquinoline-2,4-diol and 5-chloroquinoline-2,4-diol
Figure imgf000068_0001
To the product of Step 1 (3.75 g) in a flask was added a solution of methanesulfonic acid (8 ml) containing phosphorus pentoxide (0.8 g) and the mixture was warmed to 170°C for 1 hour. The reaction was cooled and poured into 50 g of ice. The mixture was allowed to stir then it was diluted with water and solids were filtered. The solid was dissolved with 0.5N sodium hydroxide and washed with toluene (2X). The pH was adjusted to 3 with concentrated HCl to give solids which were filtered and washed with water to give 2.1 g of an orange solid. The material was clean but it was a 1 :1 mixture of regioisomers. LRMS (ES+) m/z (M+H)+ 196.1.
Step 3: 7-chloro-3-(prop-2-en-l-yl)quinoline-2,4-diol and 5-chloro-3-(prop-2-en-l-yl)quinoline- 2 4-diol
Figure imgf000068_0002
The title compound was prepared using the same method as described for Intermediate CI, Step 1 using the product of step 2. LRMS (ES+) m/z 236.1 (M+H)+.
Step 4 : 7-chloro-4-methoxy-3-(prop-2-en-l-yl)quinolin-2-ol (A) and 5-chloro-4-methoxy-3- rop-2-en-l-yl)quinolin-2-ol (B)
Figure imgf000068_0003
The title compound was prepared using the same method as described for Intermediate CI, Step 2 using the product of step 3. The separation of isomers was done by flash chromatography (15-60% ethyl acetate/hexanes) to provide product A (570 mg) and B (350 mg). (A) LRMS (ES+) m/z 250.0 (M+H)+. (B) LRMS (ES+) m/z 250.0 (M+H)+. Intermediate C6 : 4-(benzyloxyV3-bromoquinolin-2(lH)-one
Figure imgf000069_0001
Step 1: 3-bromo-4-hydroxyquinolin-2(lH)-one
Figure imgf000069_0002
N-bromosuccinimide (2.21 g) was added to the solution of 2,4- dihydroxyquinoline (2 g) in DCM (50 ml). The mixture was stirred at room temperature for 3 days. The mixture was filtrated and the solid was triturated with isopropanol. After filtration, toluene was added to the solid and the solvent was evaporated under reduced pressure to give the desired product (1.92 g) as a beige solid. LRMS (ES+) m/z 240.1 (M+H)+.
Step 2: 4-(benzyloxy)-3-bromoq inolin-2(lH)-one
Figure imgf000069_0003
To a 0°C solution of PPh3 (1.64 g) in THF (42 mL) was added
diisopropylazodicarboxylate (1.21 mL) dropwise. The mixture was stirred at 0°C for 15 minutes before the addition of benzyl alcohol (0.52 mL) followed by quinoline alcohol from Step 1 (1.0 g). The mixture was stirred 15 minutes at 0°C then 5 hours at room temperature. A suspension had formed at that point. The solid was filtered and washed with cold isopropanol to afford the desired product (0.78 g). LRMS (ES+) m/z 352.1 (M+Na)+.
Intermediate C7: 4-(benzyloxyV3-bromo-8-fluoroquinolin-2(lHVone
Figure imgf000069_0004
Step 1: ethyl 3-[(2-fluorophenyl)amino]-3-oxopropanoate
Figure imgf000070_0001
To a solution of 2-fluoroaniline (8.67 ml) in ethyl acetate (266 ml) was added water (200 ml) and sodium bicarbonate (15.12 g). Ethyl malonyl chloride (13.82 ml) was added and the solution was stirred at room temperature for 1 hour. The two layers were separated and the organic phase was washed with a saturated aqueous solution of sodium bicarbonate, water and brine, dried over sodium sulfate and evaporated to provide a brownish oil. The crude reaction mixture was used directly in the next step. LRMS (ES+) m/z 226.1 (M+H)+.
Step 2 : 8-fluoro-4-hydroxyquinolin-2(lH)-one
Figure imgf000070_0002
A solution of the product from step 1 (20.27 g) in DCM (100 ml) was added to polyphosphoric acid (43.7 ml). Dichloromefhane was distilled from the reaction mixture by increasing the temperature slowly and then the brownish gummy solution was stirred at 120°C for 3 hours and then left at room temperature for 16 hours. The reaction mixture was quenched by adding ice cooled water and the product was filtered. The filter cake was stirred with 500 mL of water and filtered to give the desired product (9.38 g) as a colorless solid. LRMS (ES+) m/z 180.1 (M+H)+.
Step 3: 3-bromo-8-fluoro-4-hydroxyquinolin-2(lH)-one
Figure imgf000070_0003
The title compound was prepared using the same method as described for Intermediate C6, Step 1 using the product of step 2. LRMS (ES+) m/z 257.95 (M+H)+.
Step 4: 4-(benzyloxy)-3-bromo-8-fluoroquinolin-2(lH)-one
Figure imgf000070_0004
The title compound was prepared using the same method as described for Intermediate C6, Step 2 using the product of step 3. LRMS (ES+) m/z 370.15 (M+Na)+.
Intermediate C8 : 4-(benzyloxy -3-bromo-8-methoxyquinolin-2(lH)-one
Figure imgf000071_0001
The title compound was prepared using the same method as described for Intermediate C7 starting with o-anisidine. LRMS (ES+) m/z 382.1 (M+Na)+.
Intermediate C9 : 4-(benzyloxy)-3-bromo-7-(propan-2-yl quinolin-2(lH)-one
Figure imgf000071_0002
The title compound was prepared using the same method as described for Intermediate C7 starting with 3-(propan-2-yl)aniline. LRMS (ES+) m z 372.1 (M+Na)+.
Intermediate CIO : 4-(benzyloxy -3-bromo-7- trifluoromethyl)quinolin-2(lH)-one
Figure imgf000071_0003
methyl 2-amino-4-(trifluoromethyl)benzoate
Figure imgf000071_0004
To a solution of 2-amino-4-(trifluoromethyl)benzoic acid (5 g) in THF (85 ml) was added diazomethane (48.7 ml) in ether until completion of the reaction. Nitrogen was bubbled into the reaction mixture for 15 minutes to remove the excess of diazomethane and the solvent was removed under reduced pressure to provide a light brown solid (5.34 g). The compound was used in the next without purification. LRMS (ES+) m/z 220.1 (M+H)+. Step 2: methyl 2-(acetylamino)-4-(trifluoromethyl)benzoate
Figure imgf000072_0001
To a solution of the product from Step 1 (5.34 g) in dioxane (25 ml) was added acetic anhydride (6 ml) and pyridine (4 ml). After 60 hours of stirring at 80°C, the solution was concentrated under reduced pressure and the residue was dissolved into ethyl acetate. The organic layer was washed with 2M sodium carbonate, 10% aqueous HCl, water and brine, dried over sodium sulfate and evaporated. The product was purified by flash chromatography (ISCO, 5%-20% ethyl acetate in hexanes) to provide a beige solid (5.27 g). LRMS (ES+) m/z 262.0 (M+H)+.
Step 3: 4-hydroxy-7-(trifluoromethyl)quinolin-2(lH)-one
Figure imgf000072_0002
To a solution of the product of step 2 (3.0 g) in THF (60 ml) was added 0.5 M
KHMDS in toluene (108 ml) dropwise at -78°C. After the addition was completed, the mixture was kept at -78°C for 40 minutes, then it was allowed to warm up slowly at room temperature. The mixture was quenched with H20 and the product was extracted twice with water. The combined aqueous layers were washed with ethyl acetate twice and then acidified with 6N HCl. The solid was filtered and the filter cake was washed with water and dried by vacuum aspiration to get a beige solid which was triturated into ethyl acetate to get a white solid (1.7 g). LRMS (ES+) m/z 230.05 (M+H)+.
Step 4: 3-bromo-4-hydroxy-7-(trifluoromethyl)quinolin-2(lH)-one
Figure imgf000072_0003
The title compound was prepared using the same method as described for Intermediate C6, Step 1 using the product of step 3. LRMS (ES+) m/z 308.2 (M+H)+.
Step 5: 4-(benzyloxy)-3-bromo- 7-(trifluoromethyl)quinolin-2(lH)-one
Figure imgf000073_0001
The title compound was prepared using the same method as described for Intermediate C6, Step 2 using the product of step 4. LRMS (ES+) m/z 420.2 (M+Na)+. Intermediate Cl l : 4-(benzyloxyV3-bromo-7-methylquinolin-2(lH)-one
Figure imgf000073_0002
The title compound was prepared using the same method as described for Intermediate CIO starting from 2-amino-4-methylbenzoic acid. LRMS (ES+) m/z 344.05 (M+H)+.
Intermediate C12 : 4-(benzyloxyV3-bromo-7-fluoroquinolin-2(lH -one
Figure imgf000073_0003
The title compound was prepared using the same method as described for Intermediate CIO starting from 2-amino-4-fluorobenzoic acid. LRMS (ES+) m/z 348.0 (Μ+Η)4
Intermediate C13 : 3-bromo-4-[(4-methoxybenzyl oxylquinolin-2(lH -one
Figure imgf000073_0004
The title compound was prepared using the same method as described for Intermediate C6 using (4-methoxyphenyl)methanol. LCMS (ES+) m/z 382.0 (M+Na)+.
Figure imgf000074_0001
A round-bottom flask was charged with (S)-2-(tert-butoxycarbonylamino)-2-(l- methylcyclohexyl)acetic acid (synthesized according to procedures described in Tetrahedron Lett. 2007, 48(36):6343-6347) (10 g, 36.9 mmol) and 4M hydrochloric acid (40 ml, 160 mmol) in dioxane. The mixture was stirred for 1 hour and then concentrated to dryness in rotavap to give intermediate Dl (7.6 g, 36.6 mmol, 99 % yield) as a white powder. No further purification was carried out.
Intermediate D2: (2S,4R)-l-tert-butyl 2-methyl 4-((4-(benzyloxy)-3-bromoquinolin-2- yl)oxy pyrrolidine- 1 ,2-dicarboxylate
Figure imgf000074_0002
A round-bottom flask was charged with triphenylphosphine (3.61 g, 13.77 mmol), L-cis-Boc-4-hydroxyproline methyl ester (BaChem) (3.25 g, 13.26 mmol) and 4-(benzyloxy)-3- bromoquinolin-2-ol (3.37 g, 10.2 mmol). Dry THF (68.0 ml) was added under anhydrous conditions and the resulting slurry was stirred at 0°C. Diisopropyl azodicarboxylate (2.67 ml, 13.77 mmol) was added dropwise and the slurry was stirred for 10 min. The cooling bath was removed and the mixture was stirred for 2 hour (reaction mixture became homogeneous after approximately 30 min). The mixture was diluted with ethyl acetate (500 mL) and washed with aq. 1M HCl (100 mL), aq saturated sodium bicarbonate (2 x 100 mL) and brine (100 mL), dried over magnesium sulfate, filtered and concentrated in rotavap. The residue was purified on RediSep® (330 g; Teledyne Isco, Inc., Lincoln, NE) silica gel column (gradient: 0 to 50 % ethyl acetate in hexanes) to give intermediate D2 (5.42 g, 9.72 mmol, 95 % yield) as a colorless foam. Intermediate D3: 2,5-dioxopyrrolidin-l-yl ((l -(pent-4-vn-l-yl)cyclopropyl carbonate:
Figure imgf000075_0001
A solution of (lR,2R)-2-(pent-4-ynyl)cyclopropanol (8.5 g, 68.4 mmol) in dry acetonitrile (68.4 ml) was treated with pyridine (6.64 ml, 82 mmol) and N,N'-disuccinimidyl carbonate (17.53 g, 68.4 mmol). The slurry was stirred for 10 min at room temp and then heated at 40°C overnight. The mixture was diluted with ethyl acetate (1.2 L) and washed with water (200 mL), aq 1M HC1 (200 mL), aq. saturated sodium bicarbonate (200 mL), and brine (200 mL), dried over magnesium sulfate, filtered and concentrated in rotavap to give intermediate D3 (14.56 g, 54.9 mmol, 80 % yield) as a slightly yellow gum. No further purification was carried out.
Intermediate D4: ( 1 R,2S)- 1 -amino-N-((l -methylcvclopropyl)sulfonyl)-2- vinylcyclopropanecarboxamide hydrochloride
Ste 1: (lR,2S)-l-((tert-butoxycarbonyl)amino)-2-vin lcyclopropanecarboxylic
Figure imgf000075_0002
A round-bottom flask was charged with (lR,2S)-ethyl l-((tert- butoxycarbonyl)amino)-2-vinylcyclopropanecarboxylate (4 g, 15.67 mmol) and lithium hydroxide monohydrate (2.63 g, 62.7 mmol). Methanol (52.2 ml), THF (52.2 ml) and water (52.2 ml) were added. The mixture was heated (oil bath at 45°C) overnight. The reaction mixture was concentrated to half-its volume in rotavap and the pH of the mixture was adjusted to pH = 2-3 with aq 1M HC1. The mixture was extracted with dichloromethane (3 x 150 mL). The combined organic extracts were washed with brine (50 mL), dried over magnesium sulfate, filtered and concentrated in rotavap to give the title compound (3.5 g, 15.40 mmol, 98 % yield) as a white powder. No further purification was carried out.
Step 2: tert-butyl ((lR,2S)-l-(((l-methylcyclopropyl)sulfonyl)carbamoyl)-2- vinylcyclopropyl)carbamate
Figure imgf000076_0001
A round-bottom flask was charged with the carboxylic acid product of step 1 (2 g, 8.80 mmol) and Ι,Γ-carbonyldiimidazole (2.141 g, 13.20 mmol). Dry THF (44.0 ml) was added under anhydrous conditions and the mixture was heated (oil bath at 85°C) for 2 hours with exclusion of moisture. The mixture was cooled to room temp and a solution of 1- methylcyclopropane-1 -sulfonamide (2.379 g, 17.60 mmol) in dry THF (10 mL) was added followed by l,8-diazabicyclo[5.4.0]undec-7-ene (2.63 ml, 17.60 mmol). The mixture was heated (oil bath at 75°C) overnight. The reaction mixture was treated with aq 1M HC1 (20 mL) and water (50 mL). The product was extracted into ethyl acetate (400 mL). Upon separation, the organic layer was washed with aq 1M HCl/water (1 :2, 80 mL), and brine (80 mL), dried over magnesium sulfate, filtered and concentrated in rotavap. The residue was purified on a gold cap RediSep® (120 g) silica gel column (gradient: 0 to 25% ethyl acetate in dichloromethane) to give the the title compound (2.25 g, 6.53 mmol, 74.2 % yield) as a white powder.
Step 3: (lR,2S)-l-amino-N-((l-methylcyclopropyl)sulfonyl)-2-vinylcyclopropanecarboxam hydrochloride
Figure imgf000076_0002
The N-Boc protected amine product of step 2 (2.25 g, 6.53 mmol) was dissolved in 4M hydrochloric acid (20 ml, 80 mmol) in dioxane and stirred for 30 minutes. TLC showed complete reaction. The reaction mixture was concentrated to dryness to afford Intermediate D4 (1.85 g, 6.59 mmol, 101 % yield) as a white powder. No further purification was carried out.
Intermediate D5: (S)-2-amino-2-(2,3-dihydro-lH-inden-2-yl)acetic acid hydrochloride
Figure imgf000076_0003
Boc-L-indanylglycine (Chem-Impex International Inc., Wood Dale, IL) (4.2 g, 14.42 mmol) was treated with 4M hydrochloric acid (80 ml, 320 mmol) in dioxane at room temperature. The resulting slurry was stirred for 2 hours. TLC showed complete reaction and the mixture was concentrated to dryness in rotavap. The residue was dried under vacuum to give the product D5 (3.3 g, 101 %) as a white powder.
NS3 protease enzymatic activity
The HCV NS3 protease inhibitory activity was measured using the protease time- resolved fluorescence (TRF) assay as described below and in International Patent Application Publication No. WO 2006/102087. The assay was performed with HCV genotype lb (BK) NS3 modified enzyme with a R155K mutation and genotype 3a (3A-1).
The assay was performed in a final volume of 50 μΐ in assay buffer containing 50 mM HEPES, pH 7.5, 150 mM NaCl, 15% glycerol, 0.15% TRITON X-100, 10 mM DTT, and 0.1 % PEG 8000. NS3 and NS4A protease is pre-incubated with various concentrations of inhibitors in DMSO for 10 minutes. The reaction was initiated by adding the TRF peptide substrate (final concentration 25 nM) and NS3 mediated hydrolysis of the substrate proceeds for 6 hours at room temperature. Product fluorescence is detected using an Envision plate reader (Perkin Elmer) with excitation at 340 nm and emission at 615 nm with a 400 delay. Testing concentrations of the enzymes were selected to result in a signal to background ratio (S/B) of 5- 20. IC5o values are derived using a standard four-parameter fit to the data.
Alternatively, the Ki values can be obtained using the following protocol:
The assay is performed in a final volume of 100 μΐ in assay buffer containing 50 mM HEPES, pH 7.5, 150 mM NaCl, 15% glycerol, 0.15% TRITON X-100, 10 mM DTT, and 0.1 % PEG 8000. NS3 and NS4A protease is pre-incubated with various concentrations of inhibitors in DMSO for 30 minutes. The reaction is initiated by adding the TRF peptide substrate (final concentration 100 nM). NS3 mediated hydrolysis of the substrate is quenched after 1 hour at room temperature with 100 μΐ of 500 mM MES, pH 5.5. Product fluorescence is detected using either a VICTOR V2 or FUSION fluorophotometer (Perkin Elmer Life and Analytical Sciences) with excitation at 340 nm and emission at 615 nm with a 400 μ8 delay. Testing concentrations of the enzymes are selected to result in a signal to background ratio (S/B) of 8-30. IC50 values are derived using a standard four-parameter fit to the data. Ki values are derived from IC50 values using the following formula, IC50=Ki (l+[S]/KM), Eqn (l), where [S] is the concentration of substrate peptide in the reaction and KM is the Michaelis constant. See Gallinari et al., 1999, Biochem. 38:5620-32; Gallinari et al, 1998, J Virol. 72:6758-69; and Taliani et al, 1996, Anal. Biochem. 240:60-67. ND means not determined.
Figure imgf000078_0001
0.70 35 183 0.070 0.95
0.12 1.4 184 0.057 1.1
1.3 4.9 185 0.032 0.36
4.1 23 186 0.078 1.9
0.54 9.2 187 0.24 6.1
0.32 22 188 0.033 0.85
0.10 1.8 189 0.081 3.4
0.15 2.0 190 0.074 1.5
0.15 3.2 191 0.16 1.5
0.16 6.0 192 0.10 0.71
1.2 94 193 0.16 1.5
0.13 3.5 194 0.032 0.38
1.3 27 195 0.049 0.66
6.6 73 196 0.10 0.85
0.073 1.5 197 0.027 0.31
0.28 9.9 198 0.050 0.77
0.25 7.9 199 0.057 0.74
0.10 0.50 200 0.074 0.96
0.15 4.0 201 0.079 1.3
0.12 2.9 202 0.050 0.95
0.12 0.76 203 0.13 4.9
0.16 1.5 204 0.15 2.4
0.23 6.6 205 0.19 1.9
0.21 1.9 206 0.20 2.6
1.1 10 207 0.11 1.3
0.11 0.55 208 0.11 1.0
0.02 0.45 209 0.056 0.55
0.22 3.9 210 0.046 0.29
0.09 0.95 211 0.033 0.30
0.11 2.3 212 0.22 1.9
0.10 0.57 213 0.36 3.8
0.11 0.45 214 0.021 1.2
0.61 12 215 1.7 55
0.70 20 216 0.24 6.4
1.6 85 217 0.27 7.1
0.35 7.2 218 0.035 2.6 0.43 5.5 219 0.12 1.9
0.56 16 220 0.29 3.9
0.077 25 221 0.050 1.4
0.081 6.6 222 0.045 0.44
0.16 1.6 223 0.055 1.2
<0.016 1.8 224 0.061 0.67
0.066 0.59 225 0.079 0.60
<0.016 0.42 226 0.11 1.6
<0.016 1.1 227 0.095 0.36
0.14 2.5 228 0.11 0.47
0.10 1.3 229 0.034 0.25
0.28 2.3 230 0.065 0.38
0.09 0.71 231 0.13 1.8
0.09 0.72 232 0.020, 0.040 0.275
0.08 0.54 233 0.015, 0.080 4.2
0.06 1.8 234 0.08, 1.38 29.12
0.20 2.4 235 0.53, 4.36 203.15
0.29 4.6 236 0.33, 5.44 109.95
0.18 2.5 237 0.013, 0.098 0.80
1.1 23 238 0.031, 0.047 0.90
0.24 7.2 239 0.016, 0.064 0.278
0.11 0.56 240 0.019, 0.28 2.904
0.23 4.4 241 0.021, 0.162 2.787
0.24 3.2 242 0.013, 0.072 0.935
0.34 4.4 243 0.033, 0.275 3.305
0.07 0.32 244 1.589, 1.653 296.200
0.15 1.6 245 0.546, 1.414 128.100
0.16 1.0 246 1.016, 1.136 211.500
1.6 19 247 ND ND
0.26 2.8 248 0.100, 0.348 40.220
0.093 0.59 249 0.026, 0.500 7.550
0.18 1.0 250 0.024, 0.160 4.450
0.15 0.78 251 0.015, 0.051 1.150
0.08 073 252 0.009, 0.022 0.088
0.18 2.9 253 0.026, 0.265 11.000
0.28 2.8 254 0.116, 2.304 47.531 100 0.24 2.0 255 0.120, 2.206 59.112
101 0.090 0.96 256 0.021, 0.122 5.450
102 0.21 3.2 257 0.032, 0.230 3.900
103 0.77 8.5 258 0.012, 0.079 2.750
104 1.3 26 259 0.030, 0.350 7.400
105 0.43 14 260 0.019, 0.093 2.400
106 0.78 17 261 0.026, 0.155 3.450
107 0.74 23 262 0.018, 0.120 1.200
108 0.93 23 263 0.006, 0.011 0.041
109 4.1 122 264 0.037, 1.400 7.700
110 14 488 265 0.016, 0.110 1.150
111 11 272 266 0.020, 0.044 7.500
112 24 620 267 0.114, 4.600 56.000
113 0.090 1.6 268 0.012, 0.034 0.200
114 0.051 0.25
115 0.057 0.25 270 0.021, 0.180 1.400
116 0.17 1.6 271 0.023, 0.215 5.200
117 0.080 0.93 272 0.015, 0.128 2.120
118 0.066 0.89 273 0.100, 1.850 68.000
119 0.12 3.2 274 0.015, 0.015 0.094
120 0.062 1.1 275 0.110, 1.150 16.000
121 0.38 12 276 0.013, 0.019 0.140
122 0.33 8.8 277 0.008, 0.013 0.078
123 0.49 6.1 278 0.860, 20.000 740.000
124 0.79 10 279 0.012, 0.145 2.600
125 4.1 114 280 0.024, 0.280 4.650
126 0.40 7.7 281 0.016, 0.125 1.245
127 0.11 2.1 282 0.140, 5.300 140.000
128 0.41 13 283 0.014, 0.022 0.108
129 0.51 8.7 284 0.023, 0.053 0.280
130 2.2 18 285 0.042, 0.104 0.410
131 0.11 1.3 286 0.022, 0.094 0.515
132 0.39 6.8 287 0.092, 2.550 58.000
133 0.11 1.0 288 0.018, 0.050 0.224
134 0.56 6.1 289 0.030, 0.197 3.275
135 0.20 1.8 290 0.012, 0.125 1.144 136 0.58 5.1 291 0.010, 0.085 0.774
137 0.14 1.2 292 0.120, 0.733 49.400
138 0.63 7.0 293 0.029, 0.138 1.300
139 0.10 0.38 294 0.015, 0.046 2.270
140 0.26 3.0 295 0.082 1.070
141 0.066 0.33 296 0.27 6.0
142 0.70 15 297 0.27 4.3
143 0.059 0.64 298 0.49 4.0
144 0.61 6.2 299 0.19 3.8
145 0.079 1.2 300 0.23 7.1
146 0.054 0.68 301 0.35 5.9
147 0.26 2.2 302 0.16 2.0
148 0.065 0.74 303 0.28 3.6
149 0.041 0.74 304 0.078 1.2
150 0.12 1.3 305 0.066 2.0
151 0.074 0.62 306 0.083 0.72
152 0.25 1.5
153 0.059 0.61
154 0.11 1.5
155 0.11 1.4
Example 1 : (3a ?JS,10S.12i?.21E.24aS)-7-cvclopentyl-N-irii?,2S)-l- (cvclopropylsulfonyl carbamoyll-2-ethenylcvclopropy -19-ethoxy-5,8-dioxo- 1.2.3.3a.5.6.7.8.11.12,20,23,24,24a-tetradecahvdro-10H-9.12-methanocvclo
penta l 8 Λ 91 Γ 1 0,3,61dioxadiazacyclononadecino l 1 , 12-61quinoline- 10-carboxamide
Figure imgf000082_0001
Step 1 : 1-tert-butyl 2 -methyl (2S,4R)-4-{[4-ethoxy-3-(prop-2-en-l-yl)quinolin-2- yl]oxy}pyrrolidine-l,2-dicarboxylate
Figure imgf000083_0001
To a mixture of 1 -tert-butyl 2-methyl (2S,4S)-4-{[(4- bromophenyl)sulfonyl]oxy}pyrrolidine-l,2-dicarboxylate (1337 mg) and Intermediate C2 (600 mg) in N-methyl-2-pyrrolidinone (12 ml) was added cesium carbonate (2558 mg) and the mixture was stirred at 60°C for 1 hour. The reaction was not complete and additional brosylate (250 mg) and cesium carbonate (450 mg) were added. The mixture was stirred at 60°C for 1 more hour. The reaction mixture was then cooled before quenching into water (150 mL) and aqueous KHS04 (pH = 3.5). The product was extracted into ethyl acetate (150 mL). The organic layer was washed with aq. NaHC03 and brine, dried over sodium sulfate, filtered and concentrated. The material was dissolved in ACN and purified by reverse phase HPLC. After extractive workup (aq. NaHC03) with ethyl acetate, the desired product was obtained (1.0 g). LRMS (ES+) M/Z (M+H)+ 457.0.
-ethoxy-3-(prop-2-en-l-yl)quinolin-2-yl]oxy}-L-prolinate
Figure imgf000083_0002
To a 0°C solution of the product of Step 1 (500 mg) in dichoromefhane (10 ml) was added TFA (10 ml) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo. The residue was dissolved in dichloromethane and the organic was washed with aq. NaHC03 then brine, dried over sodium sulfate, filtered and concentrated to give the desired product (0.39 g). LRMS (ES+) M/Z(M+H)+ 357.0. Step 3: methyl (4R)-l-{(2S)-2-[({[(lR,2S)-2-(but-3-en-l-yl)cyclopentyl]oxy} carbonyl) cyclopentylacetyl}-4-{[4-ethoxy-3-(prop-2-en-l-yl)quinolin-2-yl]oxy}-L-prolinate
Figure imgf000084_0001
The product of Step 2 (390 mg), DMAP (66.8 mg), DIPEA (0.573 ml) and Intermediate B2 (406 mg) were combined in DMF (10 mL) and stirred 5 minutes before adding HATU (541 mg). The reaction was stirred for 1 hour before quenching with aq. KHS04 and water (60 mL). The product was extracted into ethyl acetate (70 mL). The organic layer was washed with 10% aq. NaHC03 then brine. The aqueous extracts were re-extracted with ethyl acetate. The combined organics were dried over sodium sulfate, filtered and concentrated. Purification by flash chromatography (ISCO, 10-50% ethyl acetate/hexanes) gave the desired product as a foam (0.662 g). LRMS (ES+) M/Z( +H)+ 648.2.
Step 4 : methyl (3aR, 7S,10S,12R,21Z,24aS)-7-cyclopentyl-19-ethoxy-5,8-dioxo- 1, 2, 3, 3a, 5, 6, 7, 8, 11,12, 20, 23, 24, 24a-tetradecahydro-l OH-9, 12-methanocyclopenta
[18, 19] [1 , 10,3,6]dioxadiazacyclononadecino[l 1 ,12-bJquinoline-l 0-carboxylate (A) and methyl (3aR, 7S, 1 OS, 12R, 2 IE, 24aS)-7-cyclopentyl-19-ethoxy-5, 8-dioxo-l, 2, 3, 3a, 5, 6, 7, 8, 11, 12,
20,23, 24, 24a-tetradecahydro-10H-9, 12-methanocyclopenta[ 18,19] [1, 10,3,6]
dioxadiazacyclononadecinof 11, 12-b ]quinoline-l 0-carboxylate (B)
Figure imgf000085_0001
To degassed solution of the product of Step 3 (660 mg) in dichloroethane (150 ml) was added -benzoquinone (44.1 mg) followed by Zhan IB (150 mg). The mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated in vacuo. Purification by flash chromatography (ISCO, 1-8 % acetone/DCM) provided 60 mg of a hi-RF product (cis, A) and 440 mg of a low-RF product (trans,B). LRMS (ES+) M/Z (M+H)+ 620.1. Step 5 : (3aR, 7S, 1 OS, 12R,21E, 24aS)- 7-cyclopentyl-19-ethoxy-5, 8-dioxo-l, 2, 3, 3a, 5, 6, 7, 8, 11, 12,20, 23, 24, 24a-tetradecahydro-l OH-9, 12-methanocyclopenta[18,19][l,10, 3, 6]
dioxadiazacyclononadecinof 11, 12-b Jquinol ine-10-carboxylic acid
Figure imgf000085_0002
To a solution of the ester from Step 4 (100 mg) in THF (4 ml) was added 1 M NaOH (1.291 ml) and the mixture was stirred 18 hours at room temperature. The reaction mixture was diluted with IN HC1 (1.35 mL) and 10% aq. KHS04. The product was extracted into ethyl acetate. The combined organics were dried over sodium sulfate, filtered and concentrated to give the desired acid as a foam (98 mg). LRMS (ES+) M/Z (M+H)+ 606.1. Step 6 : (3aR, 7S,10S,12R,21E,24aS)-7-cyclopentyl-N-{(lR,2S)-l-[(cyclopropyl
sulfonyl)carbamoyl]-2-ethenylcyclopropyl}-19-ethoxy-5, 8-dioxo-l, 2, 3, 3 a, 5, 6, 7, 8, 11, 12,20, 23, 24, 24a-tetradecahydro-l OH-9, 12-methanocyclopenta[18, 19] [1,10, 3, 6]
ne-l O-carboxamide
Figure imgf000086_0001
The acid from Step 5 (0.040 g), DMAP (4.03 mg), DIPEA (0.035 ml) and Intermediate Al (0.040 g) were combined in DMF (2 mL) and stirred 5 minutes before adding HATU (33 mg). The reaction was stirred for 2 hours. The reaction mixture was purified by reverse phase HPLC to provide the desired product as a foam (40 mg). LRMS (ES+) M/Z (M+H)+ 818.2. Examples 2-16
By following the procedures outlined in Example 1 and using the appropriate A, B and C intermediates and indicated reaction schemes (depicted below the structure as Int. and Rx., respectively), the following compounds were prepared.
Figure imgf000086_0002
Figure imgf000087_0001
l,2,3,3a,5,6,7,8,l 1,12, 20,23, 24,24a-tetradecahydro- Int. A1, B6, CI 1 OH-9, 12-methanocyclopenta[l 8, 19][1 , 10,3,6]dioxa
diazacyclononadecino [11,12-6] quinoline- 10- carboxamide
(3ai?,7S, 1 OS, 127?,2 lE,24aS 19-(benzyloxy)-7-cyclo 880.3 pentyl-N- { ( 1 R,2S)- 1 - [(cyclopropylsulfonyl)
carbamoyl] -2-ethenylcyclopropyl } -5 ,8-dioxo- 1 ,2,3 , 3a,5,6,7,8,l 1,12,20,23,24, 24a-tetradecahydro-10H-
° 6 } 9, 12-methanocyclopenta[ 18, 19] [ 1 , 10,3 ,6]dioxa
Int. A1,B2, C3 diazacyclononadecino [11 ,12-6]quinoline-10- carboxamide
(3ai?,7S, 1 OS, 12i?,2 lE,24aS)- 16-chloro-7- 838.3
XX cyclopentyl-N- {( li?,2S)- 1 - [(cyclopropylsulfonyl)
carbamoyl] -2-ethenylcyclopropyl } - 19-methoxy- 5,8-dioxo-l,2,3,3a,5,6,7,8,l l, 12,20,23,24,24a-
° 6 /} tetradecahydro- 1 OH-9, 12-methanocyclopenta
Int. Al, B2, C5 [ 18, 19] [ 1 , 10,3 ,6]dioxadiazacyclononadecino
Rx. A [11,12-b] quinoline- 10-carboxamide
(3 ai?,7S, 1 OS, 12i?,21 E,24aS)- 18-chloro-7- 838.3 cyclopentyl-N- {(1 R,2S)- 1 -[(cyclopropylsulfonyl) carbamoyl] -2-ethenylcyclopropyl } - 19-methoxy- 5,8-dioxo-l,2,3,3a,5,6,7,8,l 1, 12,20,23,24,24a-
° 6 /} tetradecahydro- 1 OH-9, 12-methanocyclopenta
Int. Al, B2, C5 [ 18, 19] [ 1 , 10,3 ,6]dioxadiazacyclononadecino
Rx. B [11,12-b] quinoline- 10-carboxamide
(1 ai?,5S,8S, 1 OR, 19E,22ai?)-5-cyclo pentyl-N- 776.8 { ( 1 R,2S)- 1 - [(cyclopropylsulfonyl) carbamoyl]-2- ethenylcyclo propyl } - 17-methoxy-3 ,6-dioxo- 1,1a,
3,4,5,6,9,10,18, 21,22,22a-dodeca hydro-8H-7,10- methanocyclopropa[l 8,19] [1 , 10,3,6]dioxadiaza
Int. Al, Bl, CI cyclononadecino[l 1,12-6] quinoline-8-carboxamide
Figure imgf000089_0001
quinoline- 10-carboxamide
Figure imgf000090_0001
Example 17: (3&R SA0SA2R2lE24aS)-7-CYc\opentyl-N-UlR2S)-l-\(cYcloOropyl
sulfonvncarbamoyl -2-ethenylcyclopropyl|-19-hvdroxy-5,8-dioxo-L2,3,3a,5,6,7,8, 11,12, 20,23 ,24.24a-tetradecahvdro- 1 OH-9, 12-methanocvclopentar 18, 191 Γ 1.10.3.61dioxadiaza
Figure imgf000090_0002
Example 8 (19 mg) was treated with TFA (1 ml) in a sealed tube and warmed to 55°C. After 30 minutes, the reaction was concentrated and the residue was dissolved in ACN and purified by reverse phase HPLC to provide the desired product as a white foam (13 mg). LRMS (ES+) m/z (M+H)+ 790.2.
Example 18: (3ai?.7S.10S.12i?.21E,25aj? -7-cvclopentyl-N-(aj?,25)-l-r(cvclopropyl sulfonvncarbamoyll^-ethenylcvclopro yU-ig-hvdroxy-S.S-dioxo^.S a.S.ej.S.l l. .
20.23.24.25 ,25a-tetradecahvdro- 1 H.1 OH-9.12-methanocvclopentar 19,201 Γ 1 ,10,3 ,61dioxa diazacvcloicosino [11,12- >lquinoline- 10-carboxamide
Figure imgf000091_0001
QaR S, 1 OS, 12R,2 \E,25&R)- 19-(benzyloxy)-7-cyclopentyl-N- { (\R,2S)- 1 - [(cyclopropylsulfonyl)carbamoyl]-2-ethenylcyclopropyl}-5,8-dioxo-2,3,3a,5,6,7,8, 11,12, 20,23 ,24,25 ,25a-tetradecahydro- 1H, 1 OH-9, 12-methanocyclopenta[ 19,20] [ 1 , 10,3 ,6]dioxa diazacycloicosino[ 11 , 12-6]quinoline- 10-carboxamide prepared by the method described for Example 1 using intermediates Al, B4, and C3 was deprotected using the method described for Example 17. HRMS (ES+) m/z 804.3639 (M+H)+.
Example 19 : riai?.5^8 .10i?J9E,22ai?V5-cvclopentyl-N-{(lj?.2S)-l-r(cvclopropyl sulfonyl)carbamoyl]-2-ethenylcyclopropyl } - 17-hydroxy- 1 a-methyl-3 ,6-dioxo-
1.1 a.3.4.5.6.9.10.18,21.22.22a-dodecahydro-8H-7, 10-methanocyclopropar 18.191
Figure imgf000091_0002
(1 aR,5S,8S, 1 OR, 19E,22ai?)- 17-(benzyloxy)-5-cyclopentyl-N- {(IR,2S)- 1 - [(cyclopropylsulfonyl)carbamoyl]-2-ethenylcyclopropyl} -1 a-methyl-3, 6-dioxo- 1 , 1 a,3 ,4,5 ,6,9, 10, 18 ,21 ,22,22a-dodecahydro-8H-7, 10-methanocyclopropa[ 18,19]
[l,10,3,6]dioxadiazacyclononadecino[l l,12-6]quinoline-8-carboxamide prepared by the method described for Example 1 using intermediates Al, B7, and C3 (with separation of isomers after ring closing metathesis) was deprotected using the method described for Example 17. HRMS (ES+) m/z 776.3309 (M+H)+. Example 20 : (la ,5^8^.10j?.19E.22a )-5-cvclopentyl-N-{f l^S l-ITcyclopropyl
sulfonyl')carbamoyl]-2-ethenylcvclopropyl } - 17-hydroxy- 1 a-methyl-3.6-dioxo- 1.1 a.3.4.5.6.9.10,18.21.22.22a-dodecahydro-8H-7, 10-methanocvclopropar 18, 191
Figure imgf000092_0001
( 1 aS,5S,8S, 1 OR, 19£,22aS)- 17-(benzyloxy)-5-cyclopentyl-N- { (1 R,2S)- 1 -
[(cyclopropylsulfonyl)carbamoyl]-2-ethenylcyclopropyl}-la-methyl-3,6-dioxo-
I , 1 a,3 ,4,5,6,9, 10, 18,21 ,22,22a-dodecahydro-8H-7, 10-methanocyclopropa[ 18,19]
[l,10,3,6]dioxadiazacyclononadecino[l l,12-6]quinoline-8-carboxamide prepared by the method described for Example 1 using intermediates A1,B7,C3 (with separation of isomers after ring closing metathesis) was deprotected using the method described for Example 17. LRMS (ES+) m/z 776.7 (M+H)+. )+.
Example 21 : (3ai?.7lSl,10S.12i?.21E.24a^-7-cvclopentyl-N-r(lS.2igV2- (cvclopropyl sulfonyDcarbamoyl -l.r-bi cyclopropyD^-yll-^-hvdroxy-S^-dioxo- 1.2.3 ,3a.5.6.7.8.11.12.20.23.24.24a-tetradecahvdro- 1 OH-9.12-methanocyclopentar 18, 191
II.10.3.61dioxadiazacyclononadecinor 11.12-fcl quinoline- 10-carboxamide
Figure imgf000093_0001
(3a^,75,105,12i?,21E,24aS)-19-(benzyloxy)-7-cyclopentyl-N-[(15,2i?)-2- [(cyclopropylsulfonyl)carbamoyl]-l,r-bi(cyclopropyl)-2-yl]-5,8-dioxo-l,2,3,3a,5,6,7,8,
11,12,20,23 ,24,24a-tetradecahydro- 1 OH-9, 12-methanocyclopenta[ 18, 19] [ 1 , 10,3 ,6]
dioxadiazacyclononadecino [ 11 , 12-b] quinoline- 10-carboxamide prepared by the method described for Example 1 using intermediates A3, B2, and C3 was deprotected using the method described for Example 17. LRMS (ES+) m/z 804.8 (M+H)+.
Example 22 : (3ai?JSq0Sa2i?,21E,24aS)-17-bromo-7-cvclopentyl-N-i('li?,2S)-l- (cyclopropylsulfonvncarbamovn-2-ethenylcyclopropyl}-19-hydroxy-5,8-dioxo- l,2,3,3a,5,6J.8Jia2.20,23,24.24a-tetradecahvdro-10H-9,12-methanocvclopentari8J91 Γ ΙΛ 03 ,6]dioxadiazacvclononadecino 11 , 12-b] quinoline- 10-carboxamide
Figure imgf000093_0002
(3ai?,7S, 1 OS, 12i?,2 lE,24aS> 19-(benzyloxy)- 17-bromo-7-cyclopentyl-N- {( IR,2S)- 1 - [(cyclopropylsulfonyl)carbamoyl]-2-ethenylcyclopropyl } -5 ,8-dioxo-
1 ,2,3 ,3a,5 ,6,7, 8, 11 , 12,20,23 ,24,24a-tetradecahydro- 1 OH-9, 12-methanocyclopenta[ 18,19] [l,10,3,6]dioxadiazacyclononadecino[l l,12-Z>]quinoline-l 0-carboxamide prepared by the method described for Example 1 using intermediates Al, B2, and C4 was deprotected using method described for Example 17. LRMS (ES+) m/z 868.2602 (M+H)+.
Example 23 : (3ai?JSJ0SJ2i?.21E.24ay)-7-cvclopentyl-N-r(li?,2^-2-ethenyl-l-{r(l- methylcvclopropyl)sulfonyl1carbamoyl>cvclopropyl]-19-hvdroxy-5,8-dioxo-L2,3, 3a.5.6.7.8.11.12,20,23, 24.24a-tetradecahvdro- 10H-9.12-methanocvclopentar 18.191
[1,10,3 ,61dioxadiazacyclononadecino [ 11 , 12-61 quinoline- 10-carboxamide
Figure imgf000094_0001
The title compound was prepared using the same method as described for
Example 17 using Example 15. HRMS (ES+) m/z 804.3642 (M+H)+.
Example 24 : r3aj?.7^.10S.12i?,24ai?)-7-cvclopentyl-N-(ni?,2^-l-r(cvclopropyl sulfonvDcarbarnoyll-2-ethenylcyclopropyU - 19-ethoxy-5,8-dioxo- 1 ,2,3 ,3a,5,6,7,8, 1 1,12, 20,21 ,22.23 ,24.24a-hexadecahvdro- 1 OH-9.12-methanocvclopentar 18, 191 Γ 1 , 10.3.61dioxa diazacyclononadecino Γ 11 , 12-61quinoline- 10-carboxamide
Figure imgf000094_0002
Step 1 : methyl (3aR, 7S,10S,12R,24aR)-7-cyclopentyl-19-ethoxy-5,8-dioxo-
1, 2, 3, 3a, 5, 6, 7, 8, 11,12, 20,21, 22, 23, 24, 24a-hexadecahydro-10H-9, 12-methanocyclo
diazacyclononadecino[ 11, 12-b Jquinoline-10-carboxylate
Figure imgf000095_0001
To a solution of methyl (3ai?,7S,10S,12i?,21E,24aS)-7-cyclopentyl-19-ethoxy-5,8- dioxo-l,2,3,3a,5,6,7,8,l l,12,20,23,24,24a-tetradecahydro-10H-9,12- methanocyclopenta[ 18, 19] [1,10,3 ,6]dioxadiazacyclononadecino[ 11 , 12-Z>]quinoline- 10- carboxylate (Example 1, Step 4) (100 mg) in ethyl acetate (20 ml) and methanol (20 ml) was added 5% Rh/C (20 mg) and the mixture was stirred for 18 hours under hydrogen atmosphere. After exchanging the atmosphere for nitrogen, the reaction mixture was filtered and concentrated to give the desired product as a foam (100 mg). LRMS (ES+) M/Z (M+H)+ 622.1.
Step 2 : (3aR, 7S,10S,12R,24aR)-7-cyclopentyl-19-ethoxy-5,8-dioxo-l,2,3,3a,5,6, 7,8, 11,
12, 20, 21, 22, 23, 24, 24a-hexadecahydro-l OH-9, 12-methanocyclopenta[18, 19] [1, 10, 3, 6] dioxadiazacyclononadecinofl 1, 12-b Jquinoline-10-carboxylic acid
Figure imgf000095_0002
Using the product from Step 1, the title compound was prepared according to the procedure in Example 1, Step 5. LRMS (ES+) m/z 608.2 (M+H)+. Step 3 : (3aR, 7S, 10S,12R,24aR)-7-cyclopentyl-N-{(lR,2S)-l-[(cyclopropylsulfonyl) carbamoyl] - 2-ethenylcyclopropyl}-19-ethoxy-5, 8-dioxo-l, 2, 3, 3a, 5, 6, 7, 8, 11,12, 20, 21, 22, 23, 24, 24a-hexadeca hydro-10H-9, 12-methanocyclopenta[18, 19] [1, 10,3, 6] dioxadiazacyclononadecinofl 1, 12-b] quinoline-10-carboxamide
Figure imgf000096_0001
Using the product from Step 2, the title compound was prepared according to the procedure in Example 1, Step 6. LRMS (ES+) m/z 820.3 (M+H)+.
Examples 25-28
By following the procedures outlined in Example 24 and using the appropriate A,
B and C intermediates (depicted below the structure as Int.), the following compounds were prepared.
Figure imgf000096_0002
Figure imgf000097_0001
Example 29 : (3aig.7S.10S.12i?.24ai?V7-cvclopentyl-N-(rii?.2S)-l-rrcvclopropylsulfonvn carbamoyl]-2-ethenylcvclopropyl}-19-hvdroxy-3a-methyl-5,8-dioxo-l,2,3,3a,5,6,7,8J l, 12,20,21 ,22,23 ,24,24a-hexadecahydro- lQH-9,12-methano cvclopentai 18,191 Γ 1.10.3 ,6] dioxadiazacyclononadecino [11,12-b] quinoline- 10-carboxamide
Figure imgf000098_0001
Step 1 : (3aR, 7S, 10S, 12R,24aR)-7-cyclopentyl-19-hydroxy-3a-methyl-5,8-dioxo-
1, 2, 3, 3a, 5, 6, 7, 8, 11, 12, 20, 21, 22, 23, 24, 24a-hexadecahydro-10H-9, 12-methanocyclopenta
cyclononadecino[l 1 , 12-b]quinoline-l O-carboxylic acid
Figure imgf000098_0002
To a solution of (3ai?,75',105',12i?,21E,24aS)-19-(benzyloxy)-7-cyclopentyl-3a- methyl-5,8-dioxo-l,2,3,3a,5,6,7,8,l l ,12,20,23,24,24a-tetradecahydro-10H-9,12-methano cyclopenta[l 8, 19] [ 1 , 10,3,6]dioxadiazacyclononadecino[ 1 1 , 12-b]quinoline- 1 O-carboxylic acid (synthesized as described in Example 1 with intermediates B7 and C3) (1 13 mg) in ethyl acetate (5 ml) was added 10% Pd/C (20 mg) and the mixture was stirred for 18 hours under hydrogen atmosphere. After exchanging the atmosphere for nitrogen, the reaction mixture was filtered and concentrated to give the desired product (93 mg). LRMS (ES+) M/Z (M+H)+ 594.7.
Step 2 : (3aR, 7S, 10S, 12R,24aR)-7-cydopentyl~N-{(lR,2S)-l-[(cyclopropylsulfonyl) carbamoyl]- 2-ethenylcyclopropyl}-19-hydroxy-3a-methyl-5, 8-dioxo-l, 2, 3, 3a, 5, 6, 7, 8, 11,
12,20,21, 22, 23, 24, 24a-hexadecahydro-l OH-9, 12-methanocyclopenta [ 18, 19] [1, 10,3, 6] dioxadiazacyclononadecino[l 1, 12-b Jquinoline-10-carboxamide
Figure imgf000099_0001
Using the product from Step 1, the title compound was prepared according to the procedure in Example 1 Step 6 using Intermediate Al . The two diastereoisomers were separated by reverse phase HPLC (40%-100% ACN/water/0.15%TFA) to provide the desired product (38 mg) HRMS (ES+) m/z 806.3802 (M+H)+.
Examples 30-34
By following the procedures outlined in Example 29 and using the appropriate A,
B and C intermediates (depicted below the structure as Int.), the following compounds were prepared.
Figure imgf000099_0002
quinoline- 10-carboxamide
32 QaR S, 105, 12i?,24ai?)-7-cyclo pentyl-N- 808.4
{(li?,2i?)-l-[(cyclopropyl sulfonyl) carbamoyl]-2-
X H YW ethylcyclopropyl } - 19-hy droxy-3 a-methyl-5 , 8 - dioxo- 1 ,2,3 ,3a,5,6, 7,8, 11 , 12,20,21 ,22,23,24,24a-
° 0 hexadeca hydro- 1 OH-9, 12-methanocyclopenta
Int. A5, B7, C3
[ 18, 19] [ 1 , 10,3 ,6]dioxadiazacyclononadecino
[11,12-6] quinoline- 10-carboxamide
33 (2R,4S,7S, 135)-7-cyclopentyl-N- { ( 1 R,2S)- 1 - 835.8
rV [(cyclopropylsulfonyl) carbamoyl] -2-ethenyl
cyclopropyl}-21-ethoxy-6,9-dioxo-3,4,6,7, 8,9,12,
13,15,16,17,18,19,20-tetradecahydro-2H, 11 H- Q 2,5: 10,13 -dimethano [ 1 , 14,5 ,7, 10]dioxatriazacyclo
Int. Al, B3, C2 docosino [ 15 , 16-b] quinoline-4-carboxamide
34 (3aR,7S, 1 OS, 12 ,24aK)-7-cyclo pentyl-N- 792.3
{(li?,2S)-l -[(cyclopropyl sulfonyl) carbamoyl]-2-
/— °- ethenylcyclopropyl}-19-hydroxy-5,8-dioxo- 1 ,2,3,3a,5,6,7,8,l 1,12, 20,21 ,22,23,24,24a- ° 6 /} hexadecahydro- 1 OH-9, 12-methanocyclopenta
Int. Al, B2, C3
[18, 19] [1,10,3,6] dioxadiazacyclononadecino
[11,12-6]quinoline- 10-carboxamide
Examples 35-37
By following the procedures outlined in Example 29 and using the appropriate A, B and C intermediates (depicted below the structure as Int.), the following compounds were prepared.
Figure imgf000100_0001
Figure imgf000101_0001
Example 38 : (-3ai?.7S.10SJ2^,21E.24aS)-7-cvclopentyl-10-ridj?.2S)-l- [(cvclopropylsulfonyl carbamoyl]-2-ethenylcvclopropyl|carbamoyl)-5,8-dioxo- 1.2.3.3a.5.6.7.8.11.12,20,23,24,24a-tetradecahvdro-10H-9,12-methanocvclopentari8J91 [l,10,3,6]dioxadiazacyclononadecino[l 1 2-6]quinorin-19-yl diethyl phosphate
To a solution of (3ai?,7S',10S,12i?,21E,24aS)-7-cyclopentyl-N-{(li?,2S)-l-
[(cyclopropylsulfonyl)carbamoyl]-2-ethenylcyclopropyl}-19-hydroxy-5,8-dioxo- l,2,3,3a,5,6,7,8,l l,12,20,23,24,24a-tetradecahydro-10H-9,12-methanocyclopenta
[18,19][l,10,3,6]dioxadiazacyclononadecino[l l,12-i>]quinoline-10-carboxamide (Example 17) (35 mg) in dichloromethane (0.44 mL) was added triethylamine (123 μΐ) followed by diethyl chlorophosphate (64 μΐ). The reaction mixture was stirred at room temperature until disappearance of the starting material. The reaction was quenched with water and extracted with ethyl acetate (3x). The combined organic fractions were dried over magnesium sulfate, filtered and concentrated. Purification by reverse phase HPLC (40-100% ACN/0.015% TFA-water) afforded the desired product (20 mg). LRMS (ES+) m/z 926.4 (M+H)+.
Example 39 : r3ai?.7S.10S.12i?.21E,24aS)-7-cvclopentyl-10-('i(1^.2S -l-r('cvclopropyl sulfonyl)carbamoyl1-2-ethenylcvclopropyl|carbamoyl)-5,8-dioxo-l,2,3,3a,5,6,7,8J l,12,
20.23.24.24a-tetradecahvdro- 1 OH-9.12-methanocvclopentar 18.191 IT .10.3.61
dioxadiazacyclononadecinofl l,12-61quinolin-19-yl acetate
Figure imgf000102_0001
To a solution of (3ai?,7S,10S,12i?,21E,24aS)-7-cyclopentyl-N-{(li?,2S)-l-
[(cyclopropylsulfonyl)carbamoyl]-2-ethenylcyclopropyl}-19-hydroxy-5,8-dioxo- l,2,3,3a,5,6,7,8,l l,12,20,23,24,24a-tetradecahydro-10H-9,12-methanocyclopenta[18,19]
[l,10,3,6]dioxadiazacyclononadecino[l l,12- >]quinoline-10-carboxamide (Example 17) (35 mg) in pyridine (0.44 mL) was added acetic anhydride (42 μΐ). The reaction mixture was stirred at room temperature until disappearance of the starting material. The reaction was quenched with water and extracted with ethyl acetate (3x). The combined organic fractions were dried over magnesium sulfate, filtered and concentrated. Purification by reverse phase HPLC (40% ACN/0.05%TFA water to 100%) afforded the desired product (26 mg) after workup with NaHC03 and ethyl acetate. LRMS (ES+) m/z 832.8 (M+H)+.
Example 40 : r3a ? J^10lS.12i?.21E.24a^-7-cvclopentyl-10-r{nig.2(^-l-r(cvclopropyl sulfonyf)carbamoyll-2-ethenylcyclopropyl}carbamoyl')-5,8-dioxo-L2,3,3a,5,6,7,8,l l,
12.20.23.24.24a-tetradecahvdro- 1 OH-9.12-methanocvclopentar 18.191 \ 1.10.3.61
Figure imgf000103_0001
The title compound was prepared using the same method as described in Example 39, using isobutyric anhydride. HRMS (ES+) m/z 860.3863 (M+H)+.
Example 41 : r3ai?.7S.10S.12j?.21E.24aS -7-cvclopentyl-10-(((lj?.2S)-l-r('cvclopropyl sulfonyl)carbamoyll-2-ethenylcvclopropyl}carbamoylV5.8-dioxo-1.2.3.3a.5.6.7.8.11.
12.20.23.24.24a-tetradecahvdro- 1 OH-9.12-methanocvclopentar 18.191Π.10.3.61
dioxadiazacvclononadecino [ 11.12-6]quinolin- 19-yl 3-methylbutanoate
Figure imgf000103_0002
The title compound was prepared using the same method as described for Example 39, using isovaleric anhydride. HRMS (ES+) m/z 874.4027 (M+H)+. Example 42 : r3a ?.7S.10S.12i;.21E,24aS)-7-cvclopentyl-N-{rii?.2S)-l-rrcvclopropyl sulfonyl)carbamoyll-2-ethenylcvclopropyl}-5,8-dioxo-19- 2-(2-oxo-l,3-oxazolidin-3- vnethoxyl-1.2 .3a.5.6.7.8.11.12,20,23,24,24a-tetradecahvdro-10H-9,12-methanocvclo
Figure imgf000104_0001
To a solution of (3aR,7S,10S,\2R,2\E,24aS)-7-cyclopentyl-N-{(lR,2S)-\-
[(cyclopropylsulfonyl)carbamoyl]-2-ethenylcyclopropyl}-19-hydroxy-5,8-dioxo- l,2,3,3a,5,6,7,8,l l,12,20,23,24,24a-tetradecahydro-10H-9,12-methanocyclopenta[18,19]
[l,10,3,6]dioxadiazacyclononadecino[l l,12-0]quinoline-l 0-carboxamide (Example 17) (40 mg) in DMF (0.75 mL) under nitrogen was added cesium carbonate (495 mg) followed by 2-(2-oxo- l,3-oxazolidin-3-yl)ethyl 4-methylbenzenesulfonate (144 mg). The reaction mixture was stirred at room temperature for 30 minutes and at 50°C for 3 hours. After cooling back to room temperature, the reaction was quenched with water and extracted with ethyl acetate (3x). The combined organic fractions were dried over magnesium sulfate, filtered and concentrated.
Purification by reverse phase HPLC (40%-100% ACN/0.15% TFA-water) afforded the desired product (39 mg) after workup with NaHC03 and ethyl acetate. HRMS (ES+) m/z 903.3933 (M+H)+.
Examples 43-60
By following the procedures outlined in Example 42 and using the appropriate A, B and C intermediates and reagent (depicted below the structure as Int. and Rg., respectively), the following compounds were prepared.
Figure imgf000105_0001
carboxamide
Figure imgf000106_0001
benzenesulfonate 1 nonadecino [11,12-6] quinoline- 10-carboxamide
Figure imgf000107_0001
benzene sulfonate (All) 10-carboxamide
Figure imgf000108_0001
carboxamide
Figure imgf000109_0001
Example 61 : (3ai?JSJ0S.12i?.24ai? -7-tert-butyl-N-r('li?.2S)-2-ethenyl-l-('{ ri-(methoxy methvDcvclopropyll sulfonyl } carbamo vDcyclopropyl] - 19- [2-(morpholin-4-yl')ethoxyl -5 ,8-dioxo- 1.2.3.3 a.5.6.7,8, 11 , 12,20.21.22.23 ,24.24a-hexadecahvdro- 1 OH-9.12-methano
cyclopenta[ 18, 191 [ 1 , 10,3.61dioxadiazacyclononadecino [11.12- >lquinoline- 10-carboxamide
Figure imgf000110_0001
The title compound was prepared using the same method as described for Example 42 using 4-(2-bromoethyl)morpholine and (3ai?,7S,10S,12i?,24ai?)-7-tert-butyl-N- [( 1 i?,25)-2-ethenyl- 1 -( { [ 1 -(methoxymethyl)cyclopropyl] sulfonyl } carbamoyl) cyclopropyl] -19- hydroxy-5,8-dioxo-l,2,3,3a,5,6,7,8,l l,12,20,21,22,23,24,24a-hexadecahydro-10H-9,12- methanocyclopenta[l 8,19][l,10,3,6]dioxadiazacyclo nonadecino[l l,12-£]quinoline-10- carboxamide (Example 35). Purification by flash chromatography (ISCO) afforded the desired product (21.5 mg). LRMS (ES+) m/z 937.3 (M+H)+. Examples 62-65
By following the procedures outlined in Example 61 and using the appropriate A, B and C intermediates and reagent (depicted below the structure as Int. and Rg., respectively), the following compounds were prepared.
Figure imgf000110_0002
Figure imgf000111_0001
Example 66 : (r(3aj?.7S.10S.12i?.21E.24aS -7-cvclopentyl-10-({(lj?.2S)-l-r(cvclor>ropyl sulfonyl carbamoyl]-2-ethenylcvclopropyl|carbamoylV5.8-dioxo-l,2.3,3a.5.6.7.8.11,12. 20,23 ,24,24a-tetradecahvdro- 1 OH-9.12-methanocyclopentar 18.191Π.10.3.61
dioxadiazacyclononadecinor 11 , 12-6]quinolin- 19-ylloxy) acetic acid
Figure imgf000112_0001
Step 1 : methyl {[(3aR,7S,10S,12R,21E,24aS)-7-cyclopentyl-10-({(lR,2S)-l- [(cyclopropylsulfonyl)carbamoyl]-2-ethenylcyclopropyl}carbamoyl)-5,8-dioxo- 1 ,2,3 ,3a,5,6,7,8, 11 , 12,20,23 ,24,24a-tetradecahydro- 1 OH-9, 12-methanocyclopenta
[ 18, 19] [ 1 , 10,3 ,6]dioxadiazacyclononadecino [11, 12-b]quinolin- 19-yl]oxy } acetate
Figure imgf000112_0002
The title compound was prepared using the same method as described in Example 42, using methyl bromoacetate. LRMS (ES+) m/z 862.6 (M+H)+.
Step 2 : {[(3aR, 7S, 10S, 12R,21E,24aS)-7-cyclopentyl-10-({(lR,2S)-l- [( cyclopropylsulfonyl)carbamoyl ]-2-ethenylcyclopropyl}carbamoyl)-5, 8-dioxo- 1, 2, 3, 3a, 5, 6, 7, 8, 11,12, 20, 23, 24, 24a-tetradecahydro-l OH-9, 12-methanocyclopenta
[18,19][1, 10, 3, 6]dioxadiazacyclononadecino[ll, 12-b]quinolin-19-yl]oxy}acetic acid
Figure imgf000113_0001
The product of Step 1 (43 mg) was dissolved in THF (1 ml) and methanol (0.2 ml). Water (0.5 ml) and LiOH (11.95 mg) were added and the reaction was stirred until complete conversion. The reaction was quenched with IN HC1 (0.4 mL) and 5% KHS04 was added until the pH was 3. The mixture was extracted with ether then ethyl acetate. The combined organics were washed with water (5x) then brine, dried over magnesium sulfate, filtered and concentrated to yield 42 mg of pure product. HRMS (ES+) m/z 848.3522 (M+H)+.
Example 67 : (3ai?,7S,10SJ2i?,21E,24aS)-7-cvclopentyl-N-{(l ?,2S)-l-r(cvclopropyl sulfonyl)carbamoyll-2-ethenylcvclopropyU-5,8-dioxo-19- 2-oxo-2-(pyrrolidin-l-yl)ethoxyl- 1 ,2.3.3a.5.6,7,8, 11.12.20,23 ,24.24a-tetradecahvdro- 1 OH-9.12-methanocvclopenta
Γ 18, 19] [ 1.10,3 ,6]dioxadiazacyclononadecino Γ 11.12-61 quinoline- 10-carboxamide
Figure imgf000113_0002
To a solution of {[(3aR,7S,10S,12R,21E,24aS)-7-cyclopentyl-10-({(lR,2S)-l- [(cyclopropy lsulfonyl)carbamoyl] -2-ethenylcyclopropyl } carbamoyl)- 5 , 8-dioxo- l,2,3,3a,5,6,7,8,l l,12,20,23,24,24a-tetradecahydro-10H-9,12-methano
cyclopenta[ 18, 19] [ 1 , 10,3 ,6]dioxadiazacyclononadecino [11,12-b]quinolin- 19-yl]oxy } acetic acid (Example 66) (27 mg) in DMF (0.5 mL) was added pyrrolidine (5.27 μΐ), DIPEA (0.028 mL)
- Ill - and HATU (14.53 mg). The reaction mixture was stirred at room temperature for 15 minutes. The reaction was quenched with water and 5% KHS04 until pH = 3. More water was added and the mixture was stirred 5 minutes. The white solid was filtered (washed with water). This solid was dissolved in ethyl acetate and the mixture was dried over magnesium sulfate, filtered and concentrated to afford the desired product (26 mg). HRMS (ES+) m/z 901.4109 (M+H)+.
Example 68 : (,3ai?JS,10^12i?,21E,24aS -7-cyclopentyl-N-{(li?,2.S)-l-r('cvclopropyl
sulfonyl)carbamoyl1-2-ethenylcvclopropyl}-19-(4-hydroxybutoxy)-5,8-dioxo- l,2,3,3a,5,6,7,8,l l,12,20,23,24,24a-tetradecahvdro-10H-9J2-methanocyclopenta
Figure imgf000114_0001
Step 1 : (SaR, 7S,10S,12R,21E,24aS)-19-(4-{[tert-butyl(dimethyl)silyl]oxy}butoxy)-7-cyclopentyl- N-{(lR,2S)-l-[(cyclopropylsulfonyl)carbamoyl]-2-ethenylcyclopropyl}-5,8-dioxo- 1, 2, 3, 3a, 5, 6, 7, 8, 11,12, 20, 23, 24, 24a-tetradecahydro-l OH-9, 12-methanocyclo
12-b]quinoline-l 0-carboxamide
Figure imgf000114_0002
The title compound was prepared using the same method as described in Example
42, using 3-chlorobutanol-TBS ether and heating to 100°C for 8 hours. LRMS (ES+) m/z 976.9 (M+H)+.
Step 2 : (3aR, 7S,10S,12R,21E,24aS)-7-cyclopentyl-N-{(lR,2S)-l-[(cyclopropyl
sulfonyl)carbamoyl]-2-ethenylcyclopropyl}-19-(4-hydroxybutoxy)-5,8-dioxo-
1, 2, 3, 3a, 5, 6, 7, 8, 11,12, 20, 23, 24, 24a-tetradecahydro-10H-9, 12-methanocyclopenta
[18, 19] [1, 10, 3, 6]dioxadiazacyclononadecino[l 1, 12-bJquinoline-l 0-carboxamide
Figure imgf000115_0001
To a solution of the product of Step 1 (50 mg) in THF (0.5 mL) was added HF- TEA (0.334 mL) at room temperature. The solution was heated to 50°C for 30 minutes. The reaction mixture was concentrated to remove THF and then diluted with EtOAc (10 mL) and water was added (10 mL). To that mixture was added Na2C03 (353 mg) portion wise at 0°C. When the quench was complete, the layers were separated. The organic layer was washed with 10% Na2C03, water and brine. The aqueous layer was re-extracted with ethyl acetate (2x). The combined organics were dried over magnesium sulfate, filtered and concentrated. Purification by reverse phase HPLC (40-100% ACN/water with 0.15% TFA) afforded the desired product (7.2 mg) after workup with NaHC03 and ethyl acetate. HRMS (ES+) m/z 862.4073 (M+H)+.
Example 69 : r3ai?.7^10 ,12i?.21E.24aS,)-7-cvclopentyl-N-i(Ti?,2 -l-rfcvclopropyl sulfonyl)carbamoyll-2-ethenylcvclopropyl|-19-(2-hydroxyethoxy -5,8-dioxo-
1 ,2,3 ,3a,5 ,6,7,8, 11 , 12,20,23 ,24,24a-tetradecahvdro- 1 OH-9, 12-methanocyclopenta
Γ 18, 19] 1 , 10,3 ,61dioxadiazacyclononadecino l 1 , 12- ?lquinoline- 10-carboxamide
Figure imgf000116_0001
The title compound was prepared using the same method as described in Example 68, using the (2-bromoethoxy)-tert-butyldimethylsilane (See Zink et al., 2006, J Org. Chem. 71 :202). LRMS (ES+) m/z 834.6 (M+H)+.
Example 70 : (Z^R SSQSA2R \E2^aS)-l-tert^uty\-N-U\R2S) - ( c\o )roO \
sulfonyl carbamoyl]-2-ethenylcvclopropyl>-19-(3-hydroxypropoxy')-5.8-dioxo- l,2,3,3a.5.6,7,8,l 1,12,20,23 ,24,24a-tetradecahydro- 1 OH-9, 12-methanocyclopenta
[11, 12-&lquinoline- 10-carboxamide
Figure imgf000116_0002
The title compound was prepared using the same method as Example 70, using 3- bromopropanol-TBS ether and (3ai?,7S,105,12^,21E,24aS)-7-tert-butyl-N-{(lJ?,2S)-l- [(cyclopropylsulfonyl)carbamoyl]-2-ethenylcyclopropyl}-19-hydroxy-5,8-dioxo- l,2,3,3a,5,6,7,8,l l ,12,20,23,24,24a-tetradecahydro-10H-9,12-methanocyclo
penta[18,19][l,10,3,6]dioxadiazacyclononadecino[l l,12-£]quinoline-l 0-carboxamide that was synthesized by the method described in Example 17 with intermediates Al, B6, and C3. HRMS (ES+) m/z 836.3922 (M+H)+. Example 71 : (3aR SA0SA2R21E24aS)-7-tert-butyl-N-\(lR2S)-2-et enylA-m^ methylcvclopropyDsulfonyllcarbamoyllcvclopropy^-ig-O-hvdroxypropoxy^-S^-dioxo-
1.2.3.3a.5.6.7.8.11.12.20.23.24,24a-tetradecahvdro-10H-9.12-methanocvclo
~ldioxadiazacyclononadecino[ 11 , 12- >lquinoline- 10-carboxamide
Figure imgf000117_0001
The title compound was prepared using the same method as Example 68, using 3- bromopropanol-TBS ether and (3a ?,7S,10S,12i?,21J£:,24aS)-7-tert-butyl-N-[(li?,2S)-2-ethenyl-l- { [( 1 -methylcyclopropyl)sulfonyl] carbamoyl } cyclopropyl] - 19-hydroxy-5 ,8-dioxo- 1 ,2,3 ,3a,5 ,6,7,8, 11 , 12,20,23 ,24,24a-tetradecahydro- 1 OH-9, 12- methanocyclopenta[ 18, 19] [ 1 , 10,3 ,6]dioxadiazacyclononadecino[ 11 , 12-6]quinoline- 10- carboxamide that was synthesized by the method described in Example 17 with intermediates A2, B6, and C3. HRMS (ES+) m/z 850.5 (M+H)+.
Example 72 : r3aig.7SJ0S,12i?.21E,24aS)-7-cvclopentyl-N-(rii?,2^)-l-rrcvclopropyl sulfonvDcarbamoyll -2-ethenylcyclopropyl } - 19-(3-hydroxypropoxy)-5 , 8-dioxo- L2,3 a,5.6.7,8,lia2.20.23.24.24a-tetradecahvdro-10H-9J2-methanocyclo
pentaf 18, 19] [1 , 10,3,61dioxadiazacyclononadecino[ 11 , 12-¾]quinoline- 10-carboxamide
Figure imgf000117_0002
The title compound was prepared using the same method as described in Example
68 using 3-bromopropanol-TBS ether. HRMS (ES+) m/z 848.3923 (M+H) .
Example 73 : (3sLR SA0SA2R2lE,24aS)-7-cYc\omn yl-N-UlR2S)-l-\(cYcloOrom\
sulfonyl')carbamoyl]-2-ethenylcvclopropyl>-19-(2,2-difluoro-3-hvdroxypropoxyV5,8-dioxo- L2,33a,5,6,7,8J lJ2,20,23,24,24a-tetradecahvdro-10H-9.12-methanocvclo
penta[l 8, 191 [1 , 10,3 ,6]dioxadiazacyclononadecino[ 11 , 12- >]quinoline- 10-carboxamide
Figure imgf000118_0001
The title compound was prepared using the same method as described in Example 68 using 3-{[tert-butyl(dimethyl)silyl]oxy}-2,2-difluoropropyltrifluoro methanesulfonate (See International Patent Application Publication No. WO 2009/101917). HRMS (ES+) m/z
884.3722 (M+H)+.
Example 74 : 3-t\(3aR SA0SA2R2\E24aS)-7-CYc\opentyl-l0-(UlR2S)-l- lYcyclopropyl sulfonvDcarbamoyll -2-ethenylcvclopropyl } carbamoyl)-5 , 8-dioxo- 1.2.3.3 a.5.6.7.8.11.12,20.23.24,24a-tetradecahydro- 1 OH-9.12-methanocvclo
pentaf 18.19] [1,10,3 ,6]dioxadiazacvclononadecino [11,12-^1quinolin- 19-yl"|oxy } propyl N,N- dimethylglycinate
Figure imgf000119_0001
To a solution of Example 72 (31 mg) in dichloromethane (0.5 mL) was added Ν,Ν-dimethylglycine (11.3 mg) then triethylamine (0.015 ml), A N'-dicyclo hexylcarbodiimide (18.9 mg) and DMAP (1.1 mg). The solution was stirred at room temperature for 3 days. The mixture was diluted with ether and the solids that were formed were filtered off. The filtrate was concentrated in vacuo. Purification by reverse phase HPLC (30-100% ACN/water w/ 0.15% TFA) yielded 21 mg of the desired product after workup with NaHC03 and ethyl acetate.
HRMS (ES+) m/z 933.4454 (M+H)+. Example 75 : (3aR SA0SA2R2lE24s )-7-tert-but\\-N-UlR2S)-U(c\cloOrop\l
sulfonyl carbamoyll-2-ethenylcvclopropyl>-5,8-dioxo-19-[2-(piperidin-l-yl)ethoxy]- 12 a,5 ,6 J,8 Λ 1 Λ 2,20,23 ,24,24a-tetradecahydro- 1 OH-9, 12-methanocvclo
vclononadecino [11,12-b] quinoline- 10-carboxamide
Figure imgf000119_0002
To a solution of (3aR,7S, 105,12i?,21E,24a5)-7-tert-butyl-N-{(li?,2S)-l-
[(cyclopropylsulfonyl)carbamoyl] -2-ethenylcyclopropyl } - 19-hydroxy-5 , 8 -dioxo- 1 ,2,3 ,3 a,5 ,6,7,8, 11 , 12,20,23 ,24,24a-tetradecahydro- 10H-9, 12-niethanocyclopenta
[18,19][l,10,3,6]dioxadiazacyclononadecino[l l,12-Z)]quinoline-10-carboxamide (synthesized by the method described in Example 17 with intermediates Al, B6, C3) (40 mg) in THF (0.8 mL) under nitrogen was added 2-(piperidin-l-yl)ethanol (0.137 niL), trimethylphosphine (1.028 mL) and diisopropylazodicarboxylate (0.200 mL). After stirring for 18 hours, the mixture was diluted with ethyl acetate and water was added. The mixture was extracted with ethyl acetate (3x). The combined organics were dried over magnesium sulfate, filtered and concentrated. Purification by reverse phase HPLC (30%-100% ACN/0.015% TFA-water) yielded 13.2 mg of the desired product. HRMS (ES+) m/z 889.4523 (M+H)+.
Examples 76-92
By following the procedures outlined in Example 75 and using the appropriate A, B and C intermediates and reagent (depicted below the structure as Int. and Rg., respectively), the following compounds were prepared.
Figure imgf000120_0001
Figure imgf000121_0001
carboxamide
Figure imgf000122_0001
10-carboxamide
Figure imgf000123_0001
carboxamide
Figure imgf000124_0001
2 See US Pat. No. 2,794,806
Example 93 : (,3ai?.7S,10Sa2i?,21E,24aS)-7-cvclopentyl-10- rii?.2S -l-r('cvclo propylsulfonvDcarbamoyl] -2-ethenylcyclopropyl } carbamovD-5 ,8-dioxo- 1 ,2 ,3 ,3a, 5,6,7,8,1 l,12,20,23.24.24a-tetradecahvdro-10H-9,12-methanocvclopentari8.191 Γ 1 , 10,3 ,6]dioxadiazacyclononadecino [11,12-6]quinolin- 19-yl propan-2-ylcarbamate
Figure imgf000125_0001
To a solution of (3a ?,7S,105,12i?,21E,24a5)-7-cyclopentyl-N-{(li?,2,S)-l- [(cyclopropylsulfonyl)carbamoyl]-2-ethenylcyclopropyl}-19-hydroxy-5,8-dioxo- 1 ,2,3 ,3a,5,6,7,8, 11 , 12,20,23,24,24a-tetradecahydro- 1 OH-9, 12-methanocyclo
enta[18,19][l ,10,3,6]dioxadiazacyclononadecino[l l,12- )]quinoline-10-carboxamide (Example 17) (30 mg) in dichloroethane (0.6 mL) was added isopropylisocyanate (0.037 mL) then DMAP (4.6 mg). The reaction mixture was heated to 50°C for 1 hour. After cooling back to room temperature, the mixture was diluted with ethyl acetate and water was added. The mixture was extracted with ethyl acetate (3x). The combined organics were dried over magnesium sulfate, filtered and concentrated. Purification by reverse phase HPLC (40% ACN- 100% ACN/0.05% TF A/water) yielded 27 mg of the desired product after workup with NaHC03 and ethyl acetate. HRMS (ES+) m/z 875.3981 (M+H)+.
Example 94 : (3ai?JS,10^,12ig.21E,24ay)-19-(3-aminopropoxyV7-cvclopentyl-N-{(li?,25f)-l- [(cvclopropylsulfonyl)carbamoyll -2-ethenylcyclopropyl > -5 , 8 -dioxo-
1 ,2,3 ,3a,5,6,7,8, 11,12,20,23 ,24,24a-tetradecahydro- 1 OH-9, 12-methanocyclopenta
1 , 12-6]quinoline- 10-carboxamide
Figure imgf000125_0002
(3-{[(3ai?,7S,10S,12i?,21E,24a5)-7-cyclopentyl-10-({(li?,2S)-l- [(cyclopropylsulfonyl)carbamoyl]-2-ethenylcyclopropyl}carbamoyl)-5,8-dioxo- 1, 2,3, 3a,5,6,7,8, 11,12,20,23 ,24,24a-tetradecahydro-10H-9,12-methanocyclopenta[ 18, 19] 1 , 10,3 ,6]dioxadiazacyclononadecino[l 1 , 12-b]quinolin- 19-yl]oxy}propyl)carbamate (Example 84) (21 mg) was dissolved in HC1 (4M in dioxane) (277 μΐ) and the resulting mixture was stirred for 30 minutes. The solvent was removed in vacuo. The crude product was dissolved in ethyl acetate and a saturated solution of sodium bicarbonate was added. The mixture was extracted with ethyl acetate (3x). The combined organics were dried over magnesium sulfate, filtered and concentrated to give 17 mg of the desired product. HRMS (ES+) m/z 847.4097 (M+H)+.
Example 95 : 3-i\(3aR SA0SA2RaiE24aS)-7-cyclopentYl-l0-(UlR2S)-l-\(c\cloproOyl sulfonvDcarbamoyll^-ethenylcvclopropyllcarbamovD-S^-dioxo-l^J a^^ ^, 11,12,20, 23 ,24,24a-tetradecahydro- 1 OH-9, 12-methanocyclopental 8, 19] [1 , 10,3 ,6]dioxadiazacvclo nonadecino|T l,12-blquinolin-19-ylloxy}propyl dihydrogen phosphate
Figure imgf000126_0001
Step 1 : diethyl (3-{[(3aR,7S,10S,12R,21E,24aS)-7-cyclopentyl-10-({(lR,2S)-l- [(cyclopropylsulfonyl)carbamoyl]-2-ethenylcyclopropyl}carbamoyl)-5,8-dioxo- 1, 2,3,3a,5, 6,7,8, 11, 12,20,23,24 ,24a-tetradecahydro-10H-9,12-methanocyclopenta
[ 18, 19] [ 1 , 10,3 ,6]dioxadiazacyclononadecino [11, 12-b]quinolin- 19-yl]oxy} propyl) phosphonate
Figure imgf000127_0001
The title compound was prepared using the same method as Example 42, using diethyl (3-bromopropyl)phosphonate and stirring at room temperature. HRMS (ES+) m/z 968.4214 (M+H)+.
Step 2 : 3-{[(3aR, 7S,10S,12R,21E,24aS)-7-cyclopentyl-10-({(lR,2S)-l-[(cyclopropyl
sulfonyl)carbamoyl]-2-ethenylcyclopropyl}carbamoyl)-5, 8-dioxo-l, 2, 3, 3 a, 5, 6, 7, 8, 11,
12,20,23,24,24a-tetradecahydro-10H-9, 12-methanocyclopenta[18, 19] [1,10,3, 6]
opyl dihydrogen phosphate
Figure imgf000127_0002
To a solution of the product of Step 1 (43 mg) in dichloromethane (1 mL) was added trimethylsilyl bromide (0.115 mL). After 1 hour at room temperature, another 0.115 mL of trimethylsilyl bromide was added and the mixture was stirred for 2 hours. The reaction was quenched with 0.1 mL water and 1.5 mL ethanol. The solvents were removed in vacuo. The crude product was dissolved in dichloromethane and ether was added to precipitate a white solid. The solid was filtered and washed with ether to yield 36 mg of the desired product. HRMS (ES+) m/z 912.3603 (M+H)+. Example 96 : (3siR SA0SA2R24aR)-7-tert-butYl-N- (lR2S)-2-et enyl- {\l- CmethoxymethyDcvclopropyll sulfonyl ) carbamoyl cyclopropyll -5 ,8-dioxo- 19-Γ3 -(piperidin- 1 - ynpropoxyl-1.2,3,3a,5,6J,8.11.12.20,21,22,23,24.24a-hexadecahydro-10H-9,12- methanocyclopentaf 18 , 19] [ 1J 0,3 ,61dioxadiazacyclononadecino|T 1 , 12-Z>lquinoline- 10- carboxamide
Figure imgf000128_0001
Step 1 : methyl (3aR, 7S,10S,12R,24aR)-7-tert-butyl-19-hydroxy-5,8-dioxo-l,2,3,3a,5,
6, 7, 8, 11,12, 20, 21, 22, 23, 24, 24a-hexadecahydro-l OH-9, 12-methanocyclopenta[18,19]
[1, 10,3,6 Jdioxadiazacyclononadecinof 11, 12-b Jq inoline-10-carboxylate
Figure imgf000128_0002
To a solution of methyl (3 aR S, 1 OS, 12^,21 E,24aS 19-(benzyloxy)-7-tert-butyl- 5,8-dioxo-l,2,3,3a,5,6,7,8,l l,12,20,23,24,24a-tetradecahydro-10H-9,12- methanocyclopenta[ 18, 19] [ 1 , 10,3 ,6]dioxadiazacyclononadecino[ 11 , 12-6]quinoline- 10- carboxylate (synthesized as in Example 1 with intermediates B6 and C3) (1.16 g) in THF (8.7 ml) and methanol (8.7 mL) was added 10% Pd/C (92 mg) and the mixture was stirred for 18 hours under hydrogen atmosphere. The atmosphere was changed to nitrogen and the reaction was carefully filtered through celite to give 0.88 g of the desired product. LRMS (ES+) m/z 582.40 (M+H)+. Step 2 : methyl (3aR, 7S 0S, 12R,24aR)-7-tert-butyl-5,8-dioxo-19-[3-(piperidin-l-yl)propoxy]- 1, 2, 3, 3a, 5, 6, 7, 8, 11,12, 20, 21, 22, 23, 24, 24a-hexadecahydro-l OH-9, 12- methanocyclopentafl 8,19][1,10,3,6 Jdioxadiazacyclononadecinof 11,12-b Jq inoline-10- carboxylate
Figure imgf000129_0001
The title compound was prepared using the same method as described in Example 42 using l-(3-chloropropyl)piperidine hydrochloride as the alkylating agent with the product of Step 1. LRMS (ES+) m/z 707.5 (M+H)+.
Step 3 : (3aR, 7S,10S,12R,24aR)-7-tert-butyl-5,8-dioxo-i9-[3-(piperidin-l-yl)propoxy]- 1,2, 3, 3a, 5, 6, 7, 8, 11,12, 20, 21, 22, 23, 24, 24a-hexadecahydro-l OH-9, 12-methanocyclo
lononadecino[l 1, 12-b ]quinoline-l 0-carboxylic acid
Figure imgf000129_0002
To a solution of the ester from Step 2 (55.8 mg) in THF (0.8 mL) and ethanol (0.2 mL) was added 2M LiOH (0.4 mL). After 1 hour at room temperature, the reaction was done. The mixture was diluted with ethyl acetate and water. Then, acetic acid was added until pH = 5. The mixture was extracted with ethyl acetate (3x). The combined organics were dried over sodium sulfate, filtered and concentrated. LRMS (ES-) m/z 691.3 (M-H)".
Step 4 : (3aR, 7S,10S,12R,24aR)-7-tert-butyl-N-[(lR,2S)-2-ethenyl-l-({[l- (methoxymethyl)cyclopropyl ]sulfonyl}carbamoyl)cyclopropyl]-5, 8-dioxo-19-[3-(piperidin-l- yl)propoxy]-l, 2, 3, 3a, 5, 6, 7, 8, 11,12, 20, 21, 22, 23, 24, 24a-hexadecahydro-l 0H-9, 12- methanocyclopentafl 8, 19] [1, 10, 3, 6]dioxadiazacyclononadecino[ 11, 12-b ]quinoline-l 0- carboxamide
Figure imgf000130_0001
1, Step 6 with intermediate A6. Purification by flash chromatography (ISCO, 0 to 10% methanol in DCM) afforded the desired product (44.6 mg). LRMS (ES+) m/z 949.5 (M+H)+.
Examples 97-105
By following the procedures outlined in Example 96 and using the appropriate A,
B and C intermediates and reagent (depicted below the structure as Int. and Rg., respectively), the following compounds were prepared.
Figure imgf000130_0002
Figure imgf000131_0001
carboxamide
Figure imgf000132_0001
Example 106 : naj?JSJ0Sa2i?,24a ?V7-tert-butyl-N- li?.2^-l-rrdimethylsulfamoyl) carbamoyl]-2-ethenylcvclopropyl}-19- 2-(,mo holin-4-yl)ethoxyl-5,8-dioxo-l,2,33a,5, 6.7.8.11.12.20.21.22.23.24.24a-hexadecahvdro- 1 OH-9.12-methanocyclopentar 18.191
[1,10,3 ,6]dioxadiazacvclononadecino[ 11.12-&lquinoline- 10-carboxamide
Figure imgf000133_0001
Step 1: ethyl (lR,2S)-l-[({(3aR S 0S 2R,24aR)-7-tert-butyl-19-[2-(morphoto
5, 8-dioxo-l, 2, 3, 3a, 5, 6, 7, 8, 11,12, 20, 21, 22, 23, 24, 24a-hexadecahydro-l OH-9, 12- methanocyclopentafl 8,19 ][1, 10,3,6 ]dioxadiazacyclononadecino[ 11,12-b Jquinolin-10- yl}carbonyl)amino]-2-ethenylcyclopropanecarboxylate
Figure imgf000133_0002
The title compound was prepared using the same method as described in Example
1, Step 6 with intermediate A4 and (3a7^,7S,10S,12 ^,24a ^)-7-tgrt-butyl-19-[2-(moφholin-4- yl)ethoxy]-5,8-dioxo-l,2,3,3a,5,6,7,8,l l,12,20,21,22,23,24,24a-hexadecahydro-10H-9,12- methanocyclopenta[ 18, 19] [ 1 , 10,3 ,6] dioxadiazacyclononadecino [11,12- >]quinoline- 10- carboxylic acid (Synthesized by the method described for Example 96, Steps 1-3 with 4-(2- bromoethyl)morpholine)). LRMS (ES+) m/z 818.5 (M+H)+.
Step 2 : (lR,2S)-l-[({(3aR, 7S,10S,12R,24aR)-7-tert-butyl-19-[2-(morpholin-4-yl)ethoxy]-5,8- dioxo-1, 2, 3, 3 a, 5, 6, 7, 8,11,12, 20,21, 22, 23, 24, 24a-hexadecahydro-l OH-9, 12- methanocyclopenta[18, 19] [1,10,3, 6]dioxadiazacyclononadecino[ll, 12-b]quinol
boxylic acid
Figure imgf000134_0001
The title compound was prepared using the same method as Example 96, Step 3 but the reaction was stirred for 18 hours. LRMS (ES+) m/z 790.60 (M+H)+.
Step 3: (3aR, 7S,10S,12R,24aR)-7-tert-butyl-N-{(lR,2S)-l-[(dimethylsulfamoyl) carbamoyl]-2- ethenylcyclopropyl}-19-[2-(morpholin-4-yl)ethoxy]-5,8-dioxo-
1, 2, 3, 3a, 5, 6, 7, 8, 11,12, 20, 21, 22, 23, 24, 24a-hexadecahydro-10H-9, 12-methanocyclo
penta[18, 19] [1,10,3, 6]dioxadiazacyclononadecino[l 1 , 12-b]quinoline-l 0-carboxamide
Figure imgf000134_0002
To a solution of the acid from Step 2 (46.6 mg) and Ν,Ν-dimethylsulfuric diamide (29.3 mg) in DMF (lmL) was added DIPEA (52 μΐ), DMAP (28.8 mg) and DBU (40 μΐ,). The reaction mixture was stirred 5 minutes before adding HATU (26.9 mg). The mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with Et20 and ethyl acetate and quenched with water and acetic acid (pH = 4). The mixture was extracted with diethyl ether (3x). The combined organic phases were washed with water (3x), dried over magnesium sulfate, filtered and concentrated. Purification by flash chromatography (ISCO, 0 to 10 % methanol in dichloromethane) afforded the desired product (34.2 mg). LRMS (ES+) m/z 896.50 (M+H)+. By following the procedures outlined in Example 106 and using the appropriate reagent (depicted below the structure as Rg.), the following compounds were prepared.
Figure imgf000135_0001
Figure imgf000136_0001
International Patent Application Publication No.: WO2003/029226)
Example 113 : aai?,5S,8SJ0i?,22aj?V5-fert-butyl-N-ra^.2S)-2-ethenyl-l-{rri-methyl cyclopropyPsulfonyl] carbamoyl } cyclopropyl] - 17- [2-(morpholin-4-yl)ethoxy| -3 ,6-dioxo- 1.1 a.3.4.5.6.9, 10,18.19.20,21.22.22a-tetradecahydro-8H-7.10-methanocyclopropar 18.19] [1,10.3.6]dioxadiazacyclononadecino[l 1 , 12-Z?]quinoline-8-carboxamide
Figure imgf000137_0001
Step 1: 1-tert-butyl 2-methyl (2S,4R)-4-{[4- enzyloxy)-3-bromoquinolin-2-yl]oxy}pyrrolidine- 1, 2-dicarboxylate
Figure imgf000137_0002
To a 0°C solution of triphenylphosphine (2.54 g) in THF (75 ml) was added dropwise diisopyl azodicarboxylate (1.820 ml). The resulting mixture was stirred at 0 °C for 10 minutes then 1-tert-butyl 2-methyl (2S,4S)-4-hydroxypyrrolidine-l, 2-dicarboxylate (2.01g) followed by intermediate C6 (2.06 g) were added to the mixture. The mixture was stirred another 15 minutes at 0°C then allowed to reach room temperature and stirred for 2 hours. Silica gel was added and the adsorbed product was purified by flash chromatography (ISCO) to provide the desired product (2.88 g). LRMS (ES+) m/z 557.0 (M+H)+.
Step 2 : N-({[(lR )-2-{5-[4-(benzyloxy)-2-{[(3R,5S)-l-(tert-butoxycarbonyl)-5- (methoxycarbonyl)pyrrolidin-3-yl]oxy}quinolin-3-ylJpent-4-yn-l-yl}cyclopropylJ oxyjcarbonyl)- 3-methyl-L-valine
C02Me
Figure imgf000138_0001
PdCl2(MeCN)2 (51 mg), tri-t-butylphosphonium tetrafluoroborate (170
K2C03 (1.35 g) and intermediate BIO (2.43 g) were added to a reaction flask. The reaction mixture was degassed and refilled with nitrogen (3x). In another flask, bromide from step 1 (2.18 g) was dissolved in 33 mL acetonitrile. This solution was degassed and refilled with nitrogen (3x). Then, this solution was added to the reaction mixture. The complete reaction mixture was degassed and refilled with nitrogen (3x) and stirred at 75°C for 18 hours. After the reaction mixture was cooled back to room temperature, the acetonitrile was removed in vacuo. The crude reaction mixture was dissolved in ethyl acetate and IN HC1 was slowly added. The reaction mixture was extracted 3x with ethyl acetate. The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude mixture was used directly in the next step. LRMS (ES+) m/z 758.3 (M+H)+.
Step 3 : N-({[(lR,2R)-2-{5-[4-(benzyloxy)-2-{[(3R,5S)-5-(methoxycarbonyl) pyrrolidinium-3- cyclopropyl]oxy}carbonyl)-3-methyl-L-valine chloride
Figure imgf000138_0002
The product from step 2 was dissolved in HC1 in dioxanes (4M, 9.78 mL). The reaction mixture was stirred at room temperature for 1 hour. The solvent was removed in vacuo. The crude product was used directly in the next step. LRMS (ES+) m/z 658.5 (M+H)+.
Step 4 : methyl (laR,5S,8S,10R,22aR)-17-(benzyloxy)-5-tert-butyl-3,6-dioxo-18,19-didehydro- 1,1a, 3, 4, 5, 6, 9, 10, 20, 21, 22, 22a-dodecahydro-8H- 7, 10-methanocyclopropa
lononadecino[ll, 12-b]quinoline-8-carboxylate
Figure imgf000139_0001
To a solution of the product of step 3 in DMF (52 mL) at 0°C was added DIPEA
(3.1 mL) and HATU (1.64 g). The mixture was stirred at room temperature for 2 hours until disappearance of the starting material. The reaction mixture was diluted with Et20 and quenched with water and HC1 (IN). The mixture was extracted (3x) with ether. The combined organic phases were washed with water then brine, dried over sodium sulfate, filtered and concentrated.
Purification by flash chromatography (ISCO, 0 to 100% ethyl acetate in hexanes) afforded the desired product (1.3 g). LRMS (ES+) m/z 640.45 (M+H)+.
Step 5 : methyl (laR, 5S, 8S, 1 OR, 22aR)-5-tert-butyl-l 7-hydroxy-3, 6-dioxo-
1, la, 3, 4, 5, 6, 9, 10,18,19, 20, 21, 22, 22a-tetradecahydro-8H- 7, 10-methanocyclopropa
cyclononadecino[ 11,12-b ]quinoline-8-carboxylate
The title compound was prepared using the same method as Example 96, Step 1.
The reaction was stirred for 4 days at room temperature and additional Pd/C (1 mol %) was added after the third day. LRMS (ES+) m/z 554.35 (M+H)+.
Step 6 : methyl (laR,5S,8S,10R,22aR)-5-tert-butyl-17-[2-(morpholin-4-yl)ethoxy]-3,6-dioxo- 1,1a, 3, 4, 5, 6, 9, 10,18,19, 20, 21, 22, 22a-tetradecahydro-8H-7, 10-methanocyclopropa
[18, 19] [1,10, 3, 6]dioxadiazacyclononadecino[ll, 12-b]quinoline-8-carboxylate
Figure imgf000140_0001
The title compound was prepared using the same method as described in Example
42. LRMS (ES+) m/z 667.45 (M+H)+.
Step 7 : (laR, 5S, 8S, 1 OR, 22aR)-5-tert-butyl-l 7-[2-(morpholin-4-yl)ethoxy]-3, 6-dioxo- 1,1 a, 3, 4, 5, 6,9, 10, 18, 19,20,21, 22, 22a-tetradecahydro-8H- 7, 10-methanocyclopropa
[18,19] [1,10,3,6 ]dioxadiazacyclononadecino[ 11,12-b [quinol ine-8-carboxylic acid
Figure imgf000140_0002
The title compound was prepared using the same method as described in Example 96, Step 3. LRMS (ES+) m/z 653.50 (M+H)+.
Step 8 : (laR, 5S, 8S, 1 OR, 22aR)-5-tert-butyl-N-[(lR, 2S)-2-ethenyl-l-{[(l- methylcyclopropyl)sulfonyl ]carbamoyl}cyclopropyl]-l 7-[2-(morpholin-4-yl)ethoxy]-3, 6-dioxo- 1,1 a, 3, 4, 5,6,9, 10, 18, 19,20,21, 22, 22a-tetradecahydro-8H- 7, 10-methanocyclopropa[l 8,19]
[1,10,3,6 Jdioxadiazacyclononadecinofl 1,12-b ]quinoline-8-carboxamide
Figure imgf000141_0001
The title compound was prepared using the same method as Example 1 , Step 6 with intermediate A2. Purification by flash chromatography (ISCO, 0 to 10% methanol in DCM) afforded the desired product. LRMS (ES+) m/z 879.40 (M+H)+.
Examples 114-130
By following the procedures outlined in Example 113 and using the appropriate A, B and C intermediates and reagent (depicted below the structure as Int. and Rg., respectively), the following compounds were prepared.
Figure imgf000141_0002
Figure imgf000142_0001
one
Figure imgf000143_0001
morpholine [11,12-Z>]quinoline-8-carboxamide
Figure imgf000144_0001
morpholine cyclononadecino[l 1 ,12-&]quinoline-8-carboxamide
Figure imgf000145_0001
nonadecino [ 11 , 12-b] quinoline-8-carboxamide
Example 131 : (lai?.5S.8S.10i?,22ai?V5-tgrt-butyl-N-r(li?,2S)-2-ethenyl-l-ira-methyl cvclopropyl sulfonyl]carbamoyUcyclopropyl1-17- 3-(4-methylpiperazin-l-yl)propoxy]-3,6- dioxo- 1.1 a,3.4.5.6.9.10.18.19.20.21.22,22a-tetradecahvdro-8H-7, 10-methano
cyclopropa|T 8, 191 Γ 1.10.3,6]dioxadiazacvclononadecinof 11 , 12-&1quinoline-8-carboxamide
Figure imgf000146_0001
The title compound was prepared using the same method as described in Example 42, using the l-(3-bromopropyl)-4-methylpiperazine and (la/?,5S,8S,10/?, 22ai?)-5-tert-butyl-N- [( 1 J?,25)-2-ethenyl- 1 - { [( 1 -methylcyclopropyl)sulfonyl] carbamoyl } cyclopropyl] - 17-hydroxy- 3 ,6-dioxo-l , 1 a,3,4,5,6,9, 10,18,19,20,21 ,22,22a-tetradecahydro-8H-7, 10- methanocyclopropa[l 8, 19] [1 , 10,3,6]dioxadiazacyclononadecino[l 1 , 12-&]quinoline-8- carboxamide (Example 120). LRMS (ES+) m/z 906.40 (M+H)+.
Example 132 : naj?.5S.8S.10i?.22ai?V5-tert-butyl-N-r(lj?.25' -2-ethenyl-l-{r(l-methyl cvclopropyl)sulfonyl]carbamovUcvclopropyl]-17- 2-(morpholin-4-yl ethoxy]-3,6-dioxo-14- rpropan-2-ylVl.la.3.4.5.6.9.10.18.19.20.21.22,22a-tetradecahvdro-8H-7.10-methano
Figure imgf000146_0002
The title compound was prepared using the same method as described in Example 42, using the 4-(2-bromoethyl)morpholine and (UR,5S,SS,\0R,22aR)-5-tert-bnty\-N-[(lR,2S)-2- ethenyl- 1 - { [( 1 -methylcyclopropyl)sulfonyl]carbamoyl} cyclopropyl] - 17-hydroxy-3 ,6-dioxo- 14- (propan-2-yl)- 1 , 1 a,3 ,4,5 ,6,9, 10, 18, 19,20,21 ,22,22a-tetradecahydro-8H-7, 10- methanocyclopropa[ 18, 19] [ 1 , 10,3,6]dioxadiazacyclononadecino [11,12-6]quinoline-8- carboxamide (synthesized in the same way as Example 120 but using intermediates A2, BIO and C9). LRMS (ES+) m/z 921.55 (M+H)+.
Figure imgf000147_0001
ethenyl- !-{[(! -methylcyclopropyDsulfonyl] carbamoyl} cyclopropyl]-3,6-dioxo-
1 , 1 a,3 ,4.5 ,6.9, 10, 18, 19,20.21 ,22.22a-tetradecahydro-8H-7, 10-methano
Figure imgf000147_0002
The title compound was prepared using the same method as described in Example
75, using the 3-(azetidin-l-yl)propan-l-ol and (la/?,55,81S,10i?,22ai?)-5-tert-butyl-iV-[(li?,2S)-2- ethenyl-l-{[(l-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-17-hydroxy-3,6-dioxo- 1 , 1 a,3 ,4,5 ,6,9, 10, 18, 19,20,21 ,22,22a-tetradecahydro-8H-7, 10-methanocyclopropa[ 18,19]
[l,10,3,6]dioxadiazacyclononadecino[l l,12-b]quinoline-8-carboxamide (Example 120). LRMS (ES+) m/z 863.50 (M+H)+.
Examples 134-136
By following the procedures outlined in Example 133 and using the appropriate reagent (depicted below the structure as Rg.), the following compounds were prepared.
Figure imgf000147_0003
Figure imgf000148_0001
Example 137 : tert-butyl (3S -3-(,{[riai?,5^8^10i?,22a^ -5-tert-butyl-8-{[('lj;,2S -2-ethenyl-l- {[(l-methylcyclopropyl)sulfonyl]carbamoyl}cvclopropyl]carbamoyll-3,6-dioxo- 1.1 a.3.4.5.6.9.10.18.19.20.21.22.22a-tetradecahydro-8H-7.10-methanocvclo
propa[ 18, 19] [ 1 , 10.3 ,6]dioxadiazacyclononadecino [11.12-6]quinolin- 17-ylloxy}
methyDpyrrolidine- 1 -carboxylate
Figure imgf000149_0001
The title compound was prepared using the same method as described in Example 75, using the tert-butyl (3S)-3-(hydroxymethyl)pyrrolidine-l -carboxylate and
(1 aR,5S,8S, 10i?,22ai?)-5-tert-butyl-N-[(li?,25)-2-ethenyl-l -{ [(1 -methylcyclopropyl)
sulfonyl] carbamoyl } cyclopropyl] - 17-hydroxy-3 ,6-dioxo- 1 , 1 a,3 ,4,5 ,6,9, 10, 18, 19,20,21 , 22,22a- tetradecahydro-8H-7, 10-methanocyclopropa[ 18, 19] [ 1 , 10,3 ,6]dioxadiazacyclononadecino [11,12- b]quinoline-8-carboxamide (Example 120). The method was slightly modified as
triphenylphosphine was used instead of trimethylphosphine and the reaction was done at a 0.3 M concentration LRMS (ES+) m/z 949.5 (M+H)+.
Examples 138-142
By following the procedures outlined in Example 137 and using the appropriate reagent (depicted below the structure as Rg.), the following compounds were prepared.
Figure imgf000149_0002
Figure imgf000150_0001
azetidine- 1 -carboxylate Example 143 : riaJ?.5 .8^J0jg,22ai?V5-fert-butyl-N- ri^.2,$l)-2-ethenyl-l-ira-methyl cyclopropyPsulfonyllcarbamoyl } cyclopropyll- 13 -methoxy-3 ,6-dioxo- 17- [3 -(pyrrolidin- 1 - vnpropoxyl - 1.1 a.3.4.5.6,9.10.18.19.20,21.22.22a-tetradecahvdro-8H-7.10-methano
cvclopropaf 18.19] [ 1.10.3.61dioxadiazacyclononadecino [ 11.12-b] quinoline-8-carboxamide
Figure imgf000151_0001
Step 1 : methyl (laR,5S,8S,10R,22aR)-17-(3-bromopropoxy)-5-tert-butyl-13-methoxy-3,6-dioxo-
1, la, 3, 4, 5, 6, 9, 10,18,19, 20, 21, 22, 22a-tetradecahydro-8H- 7, 10-methano
cyclopropafl 8, 19] [1,10,3, 6]dioxadiazacyclononadecino[ll, 12-b]quinoline-8-carboxylate
Figure imgf000151_0002
To a solution of methyl (lai?,55,85',10i?,22a ?)-5-tert-butyl-17-hydroxy-13- methoxy-3, 6-dioxo-l , 1 a,3,4,5,6,9, 10, 18, 19,20,21 ,22,22a-tetradecahydro-8H-7, 10-methano cyclopropafl 8,19][l,10,3,6]dioxadiazacyclononadecino[l l,12-Z>]quinoline-8-carboxylate (253 mg) (prepared by the same method as Example 113, Steps 1-5 with intermediates B10 and C8) and 1,3-dibromopropane (500 μΐ) in DMF (5 ml) was added cesium carbonate (700 mg). After 90 minutes of stirring at room temperature, the reaction mixture was partitioned between water/brine 1 : 1 and ethyl acetate. The product was extracted twice with ethyl acetate and the combined organic phases were washed with water and brine, dried over sodium sulfate and evaporated. The crude residue was purified by flash chromatography (ISCO 10%-50% ethyl acetate in hexanes) to afford a white solid (231 mg). LRMS (ES+) m/z 704.30 (M+H)+. Step 2 : methyl (laR,5S,8S,10R,22aR)-5-tert-butyl-13-methoxy-3,6-dioxo-17-[3-(pyrrolidin-l- yl)propoxy]-l, la, 3, 4, 5, 6, 9, 10,18,19, 20, 21, 22, 22a-tetradecahydro-8H- 7, 10-methano
nonadecino[l 1 , 12-b]quinoline-8-carboxylate
Figure imgf000152_0001
To a solution of the product resulting from step 1 (72 mg) in DMSO (1.5 ml) were added pyrrolidine (85 μΐ) and DIPEA (25 μΐ). After 2 hours of stirring at 50°C, the reaction mixture was poured into water and the product was extracted twice with ethyl acetate. The combined organic phases were washed with water and brine, dried over sodium sulfate and evaporated. The crude product was used as such for the next step. LRMS (ES+) m/z 695.50 (M+H)+.
Step 3 : (laR,5S,8S,10R,22aR)-5-tert-butyl-13-methoxy-3,6-dioxo-17-[3-(pyrrolidin-l-yl) propoxyj-l, la, 3, 4, 5, 6, 9,10,18,19, 20,21, 22, 22a-tetradecahydro-8H- 7, 10-methano
cyclopropaf 18, 19] [1, 10,3,6 ]dioxadiazacyclononadecino[l 1, 12-b ]quinoline-8-carboxylic acid
Figure imgf000152_0002
The title compound was prepared using the same method as described in Example
113, Step 7. LRMS (ES+) m/z 681.40 (M+H)+.
Step 4 : (laR,5S,8S,10R,22aR)-5-tert-butyl-N-[(lR,2S)-2-ethenyl-l-{[(l-methylcycl^
propyl)sulfonyl]carbamoyl}cyclopropyl]-13-methoxy-3,6-dioxo-17-[3-(pyrrolidin-l-yl) propoxy J-l, 1 a, 3, 4, 5, 6, 9,10,18, 19,20,21, 22, 22a-tetradecahydro-8H- 7, 10-methanocyclo
[ 11, 12-b ]quinoline-8-carboxamide
Figure imgf000153_0001
The title compound was prepared using the same method as described in Example 113, Step 8. Purification by flash chromatography (ISCO reverse phase, 15%-70% ACN in water (0.1% TFA buffer)) afforded the desired product (40.5 mg). LRMS (ES+) m/z 907.30 (M+H)+.
Example 144 : (laig.5S.8S.10i?.22a^ -5-tgrt-butyl-N-rn ?.2S -2-ethenyl-l-( ri-methyl cycloprop vDsulfonyll carbamoyl } cycloprop yl] - 17- [3 -d H-imidazol- 1 - vDpropoxy] - 13 -methoxy- 3 ,6-dioxo- 1.1 a.3 A5.6.9.10.18.19.20.21.22.22a-tetradecahvdro-8H-7.10-methano
cyclopropafl 8.19][1.10,3,61dioxadiazacyclononadecino[l 1.12-6]quinoline-8-carboxamide
Figure imgf000153_0002
The title compound was prepared using the same method as described in Example 143 using imidazole. LRMS (ES+) m/z 904.45 (M+H)+.
Example 145 : (lai?.5S.8^.10i?.22ai?)-5-tgrt-butyl-17-r3-(cvclopropylamino propoxyl-N-
[Y li?,2S)-2-ethenyl- 1 - { [Y 1 -methylcyclopropyDsulfonyllcarbamoyl } cyclopropyl]- 14-methyl-3.6- dioxo- 1.1 a.3.4.5.6.9.10,18.19.20.21.22.22a-tetradecahvdro-8H-7, 10-methano
Figure imgf000154_0001
Step 1 : (laR,5S,8S,10R,22aR) 7-(3-bromopropoxy)-5-tert-butyl-N-[(lR,2S)-2-ethenyl-l-{[(l- methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-14-methyl-3,6-dioxo-
1, la, 3, 4, 5, 6, 9, 10,18,19, 20,21, 22, 22a-tetradecahydro-8H- 7, 10-methanocyclopropa
[18,19 ][ 1, 10, 3, 6]dioxadiazacyclononadecino[ 11, 12-b Jquinoline-8-carboxamide
Figure imgf000154_0002
(lai?,5S,85,10i?,22ai?)-5-rert-butyl-iV-[(li?,25)-2-ethenyl-l-{[(l- methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-17-hydroxy-14-methyl-3,6-dioxo- 1 , 1 a,3 ,4,5,6,9, 10,18,19,20,21 ,22,22a-tetradecahydro-8H-7, 10-methanocyclopropa[ 18,19]
[l,10,3,6]dioxadiazacyclononadecino[l l,12-6]qmnoline-8-carboxamide (synthesized by the method described for Example 120 using intermediates A2,B10,C11) was alkylated using the method for example 143, step 1. LRMS (ES+) m/z 900.30 (M+H)+.
Step 2 : (laR,5S,8S,10R,22aR)-5-tert-butyl-17-[3-(cyclopropylamino)propoxy]-N-[(lR,2S)^ ethenyl-l-{[(l-methylcyclopropyl)s lfonyl]carbamoyl}cyclopropylJ-14-methyl-3,6-dioxo- 1,1 a, 3, 4,5, 6,9,10,18,19,20,21, 22, 22a-tetradecahydro-8H- 7, 10-methano
cyclopropa[18, 19] [1,10,3, 6]dioxadiazacyclononadecino[ll,12-b]quinoline-8-carboxamide
Figure imgf000155_0001
The title compound was prepared using the same method as described in Example 143, Step 2 using cyclopropyl amine. Purification by flash chromatography (ISCO reverse phase, 20%-80% ACN in water (0.1% TFA buffer)) afforded the desired product (40.5 mg). LRMS (ES+) m/z 877.30 (M+H)+.
Examples 146-209
By following the procedures outlined in Example 145 and using the appropriate
A, B and C intermediates and reagent (depicted below the structure as Int. and Rg., respectively), the following compounds were prepared.
Figure imgf000155_0002
Figure imgf000156_0001
[11,12-&]quinoline-8-carboxamide
Figure imgf000157_0001
[11,12-b]quinoline-8-carboxamide
Figure imgf000158_0001
hydrochloride decino [ 11 , 12-b] quinoline- 8 -carboxamide
Figure imgf000159_0001
quinoline- 8-carboxamide
Figure imgf000160_0001
sulfonyl) pyrrolidine cyclononadecino[ 11,12-b]quinoline-8-carboxamide
Figure imgf000161_0001
hydrochloride
Figure imgf000162_0001
cyclononadecino[l 1 ,12-Z>]quinoline-8-carboxamide
Figure imgf000163_0001
[11,12-£]quinoline-8-carboxamide
Figure imgf000164_0001
[ 11 , 12-b] quinoline-8-carboxamide
Figure imgf000165_0001
[11 , 12-0]quinoline-8-carboxamide
Figure imgf000166_0001
quinoline-8-carboxamide
Figure imgf000167_0001
cyclononadecino[ 11,12-b]quinoline-8-carboxamide
Figure imgf000168_0001
nonadecino[l 1 ,12-Z>]quinoline-8-carboxamide
Figure imgf000169_0001
quinoline- 8 -carboxamide
Figure imgf000170_0001
carboxamide
Figure imgf000171_0001
carboxamide
Figure imgf000171_0002
cyclopropyDsulfonyl] carbamoyl } cyclopropyl] - 17- [Yl -methylpiperidin-4- vDoxy] -3.6-dioxo- 1.1 a.3.4.5.6.9.10, 18, 19,20.21.22.22a-tetradecahydro-8H-7, 10-methanocvclopropa
Figure imgf000172_0001
Step 1 : methyl (laR,5S,8S,10R,22aR)-5-tert-butyl-17-[(l-methylpiperidin-4-yl)oxy]-3,6-dioxo- l,la,3,4,5,6,9,10,18,19,20,21, 22, 22a-tetradecahydro-8H- 7, 10-methanocyclopropa
[18, 19] [1,10, 3, 6]dioxadiazacyclononadecino[ll, 12-b]quinoline-8-carboxylate
Figure imgf000172_0002
Methyl (la/?,55,85,10i?,22ai?)-5-tert-butyl-17-hydroxy-3,6-dioxo- l,la,3,4,5,6,9,10,18,19,20,21 ,22,22a-tetradecahydro-8H-7, 10-methanocyclopropa
[18,19][l,10,3,6]dioxadiazacyclononadecino[l l,12-£]quinoline-8-carboxylate synthesized in example 113, step 5 was reacted with l-methylpiperidin-4-ol using the procedure described for Example 137 (heating was required: 40°C for 18 hours). LRMS (ES+) m/z 651.55 (M+H)+. Step 2 : (1 aR, 5S,8S, 1 OR, 22aR)-5-tert-butyl-l 7-[(l -methylpiperidin-4-yl)oxy] -3,6-dioxo- 1, la, 3, 4, 5, 6, 9, 10,18,19, 20, 21, 22, 22a-tetradecahydro-8H-7, 10-methanocyclopropa
[18,19] [1,10, 3, 6]dioxadiazacyclononadecino[l l,12-b]quinoline-8-carboxylic acid
Figure imgf000173_0001
The title compound was prepared using the same method as described for
Example 96, Step 3. LRMS (ES+) m/z 637.45 (M+H)+.
Step 3 : (laR,5S,8S,10R,22 R)-5-tert-butyl-N-[(lR,2S)-2-ethenyl-l-{[(l-methyl
cyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-l 7-[(l-methylpiperidin-4-yl)oxy]-3, 6-dioxo- 1, la, 3, 4, 5, 6, 9, 10,18,19, 20, 21, 22, 22a-tetradecahydro-8H- 7, 10-methanocyclo
ino[ll, 12-b]quinoline-8-carboxamide
Figure imgf000173_0002
The title compound was prepared using the same method as described in Example 1, Step 6 with intermediate A2. Purification by flash chromatography (ISCO, 0 to 10% methanol in DCM, loading with 0.5% acetic acid in DCM) afforded the desired product. LRMS (ES+) m/z 863.50 (M+H)+.
Examples 211-220
By following the procedures outlined in Example 210 and using the appropriate
A, B and C intermediates and reagent (depicted below the structure as Int. and Rg., respectively), the following compounds were prepared.
Figure imgf000174_0001
cyclononadecino[ 11,12-Z>]quinoline-8-carboxamide
Figure imgf000175_0001
[11,12-b]quinoline-8-carboxamide
Figure imgf000176_0001
Example 221 : (lai?.51y,85,a0i?,22ai?V5-tgrt-butyl-N-[rii?,2S)-2-ethenyl-l-{[(,l-methyl cvclopropyl)sulfonyl]carbamoyl|cvclopropyl1-17-[(2i?')-morpholin-2-ylmethoxy1-3,6-dioxo- 1,1 a,3 ,4,5,6,9, 10,18,19,20,21 ,22,22a-tetradecahydro-8H-7, 10-methanocvclopropa
11 , 12-b]quinoline-8-carboxamide
Figure imgf000176_0002
Step 1 : tert-butyl (2R)-2-({[(laR,5S,8S, 10R,22aR)-5-tert-butyl-8-{[(lR,2S)-2-ethenyl-l-{[(l- methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]carbamoyl}-3, 6-dioxo-l, la, 3, 4, 5, 6, 9, 10, 18,19, 20, 21, 22, 22a-tetradecahydro-8H- 7, 10-methanocyclopropa [18,19] [1, 10,3, 6]dioxadiaza cyclononadecino [11, 12-b]quinolin-l 7 -yl] oxy [methyl) morpholine-4-carboxylate
Figure imgf000177_0001
The title compound was prepared using the same method as described in Example 210, Step 1-3 with tert-butyl (2i?)-2-(hydroxymethyl)morpholine-4-carboxylate as the reagent for the Mitsunobu reaction. LRMS (ES+) m/z 965.50 (M+H)+.
Step 2 : (laR,5S,8S,10R,22aR)-5-tert-butyl-N-[(lR,2S)-2-ethenyl-l-{[(l-methylcyclo propyl sulfonyl] carbamoyl}cyclopropyl] -17 -[(2R)-morpholin-2-ylmethoxy] -3 ,6-dioxo- 1, la, 3, 4, 5, 6, 9, 10,18,19, 20, 21, 22, 22a-tetradecahydro-8H- 7, 1 O-methanocyclopropa
[18,19][1,10, 3, 6]dioxadiazacyclononadecino[ll, 12-b]quinoline-8-carboxamide
Figure imgf000177_0002
To a solution of the product from step 1 (92 mg) in dichloromethane (0.5 mL) was added trifluoroacetic acid (0.5 mL). The resulting solution was stirred for 3 hours at room temperature until disappearance of the starting material. The solvent was removed in vacuo. The reaction mixture was dissolved in ethyl acetate and a saturated solution of sodium
bicarbonate was added slowly. After extracting 3x with ethyl acetate, the combined organics were dried with sodium sulfate, filtered and concentrated to afford the desired product (77.9 mg). LRMS (ES+) m/z 865.45 (M+H)+.
Example 222 : (laig.5^8^J0ig,22ai? -17-(azetidin-3-yloxyV5-fert-butyl-N-r(li?.2S)-2-ethenyl-l- { Γ( 1 -methylcvclopropyl sulfonyl]carbamoyl } cvclopropyl] -3 ,6-dioxo- 1.1 a.3.4.5.6.9, 10.18,19,20,21 ,22,22a-tetradecahydro-8H-7.1 O-methanocvclopropa
"| [ 1 , 10.3 ,6]dioxadiazacvclononadecino [11, 12-&lquinoline-8-carboxamide
Figure imgf000178_0001
The title compound was prepared using the same method as described in Example 221 using ter -butyl 3 -hydroxyazetidine-l-carboxylate for the Mitsunobu reaction. Purification by flash chromatography (ISCO reverse phase, 25 to 70% ACN in water (0.1% TFA buffer)) afforded the desired product LRMS (ES+) m/z 821.50 (M+H)+.
Example 223 : nai?,5S,8S,10i?,22ai? -5-tgrt-butyl-17-(ri-rcvclopropylmethyl azetidin-3- ylloxy}-N-[(lj?,2S)-2-ethenyl-l-{[(l-methylcvclopropyl)sulfonyl]carbamoyl> cyclopropyl]-3,6- dioxo- 1 , 1 a,3 ,4,5 ,6,9, 10, 18, 19,20,21 ,22.22a-tetradecahvdro-8H-7.10- methanocyclopropa[ 18, 19] [ 1 , 10,3 ,61dioxadiazacvclononadecino[l 1 , 12-6]quinoline-8- carboxamide
Figure imgf000178_0002
To a solution of Example 222 (100 mg) in DMF (0.5 ml) were added cyclopropyl methyl bromide (28.9 mg) and DIPEA (100 μΐ). After 18 hours of stirring at 50°C, the reaction mixture was diluted in DMSO (1.5 mL) and it was loaded over a CI 8 column and purified by flash chromatography (ISCO, 10%-70% ACN in water (0.1% TFA buffer)) to afford a white solid (44 mg of TFA salt). LRMS (ES+) m/z 875.35 (M+H)+. Example 224 : (laR.5S.8S,10R,22aR)-5-tert-butyl-N-rriR.2SV2-ethenyl-l-ira- methylcyclopropyDsulfonyl]carbamoyl) cyclopropyl] - 17- [( 1 -methylazetidin-3 -yl) methoxy] -3,6- dioxo- 1.1 a.3.4.5.6.9, 10, 18, 19,20,21 ,22,22a-tetradecahydro-8H-7, 10- methanocyclopropaf 18, 19] Γ 1 , 10,3 ,6]dioxadiazacyclononadecinof 11 , 12-b]quinoline-8- carboxamide
Figure imgf000179_0001
Step 1 : (laR,5S,8S 0R,22aR)-17-(azetidin-3-ylmethoxy)-5-tert-butyl-N-^
{[(l-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-3,6-dioxo- 1, 1 a, 3, 4, 5, 6,9, 10, 18, 19,20,21, 22, 22a-tetradecahydro-8H- 7, 10-methanocyclopropa
1, 12-b]quinoline-8-carboxamide
Figure imgf000179_0002
The title compound was prepared using the same method as described in Example
221, Step 2 with Example 142. LRMS (ES+) m/z 835.45 (M+H)+.
Step 2 .■ (laR,5S,8S 0R,22aR)-5-tert-butyl-N-[(lR,2S)-2-ethenyl-l-{[(l-methyl
cydopropyl)sulfonyl]carbamoyl}cyclopropyl]-17-[(l-methylazetidin-3-yl)meth^
1, la, 3, 4, 5, 6, 9, 10, 18,19, 20, 21, 22, 22a-tetradecahydro-8H-7, 10-methanocyclopropa
[18, 19] [1, 10, 3,6]dioxadiazacyclononadecino[ll, 12-b]quinoline-8-carboxamide
Figure imgf000180_0001
To a suspension of the amine from Step 1 (20.6 mg) in methanol (1 mL) was added formaldehyde (10 μΐ). Sodium borohydride (5.6 mg) was added slowly. The clear reaction mixture was stirred overnight at room temperature. The solvent was removed in vacuo and the product was dissolved in ethyl acetate and water (with acetic acid to a pH=5). The mixture was extracted (3x) with ethyl acetate. The combined organics were dried with sodium sulfate, filtered and concentrated. Purification by flash chromatography (ISCO reverse phase, 0 to 95 % water in acetonitrile followed by ISCO : 0 to 20 % methanol in DCM) gave the desired product (1.4 mg). LRMS (ES+) m/z 849.55 (M+H)+.
Example 225 : (lai?,5S,8SJ0i?,22a^ -5-tgrt-butyl-N-rni?,2^-2-ethenyl-l-{r(l-methyl cvclopropyDsulfonyllcarbamoyl } cyclopropyll - 17- { |Ί -(2-methoxyethyl piperidin-4- yl]oxy } -3,6- dioxo- 1 , 1 a,3 A5 ,6,9, 10.18 , 19.20.21.22.22a-tetradecahvdro-8H-7, 10-methano
cyclopropaf 18, 19] [ 1.10.3,6]dioxadiazacvclononadecino[ 11 , 12-Z>1quinoline-8-carboxamide
Figure imgf000180_0002
Step 1 : methyl (laR,5S,8S,10R,22aR)-17-{[l-(tert-butoxycarbonyl)piperidin-4-yl]oxy}-5-tert- butyl-3, 6-dioxo-l, la, 3, 4, 5, 6, 9,10,18,19, 20,21, 22, 22a-tetradecahydro-8H- 7, 10- methanocyclopropa[18, 19] [1, 10, 3, 6]dioxadiazacyclononadecino[ 11, 12-b Jquinoline-8- carboxylate
Figure imgf000181_0001
The title compound was prepared using the same method as described in Example 210, Step 1 with methyl ( 1 ai?,5S,8S, 10i?,22ai?)-5-tert-butyl- 17-hydroxy-3 ,6-dioxo- 1 , 1 a,3 , 4,5,6,9,10,18, 19,20,21 ,22,22a-tetradecahydro-8H-7, 10-methanocyclopropa
[18,19][l,10,3,6]dioxadiazacyclononadecino[l l,12-b]quinoline-8-carboxylate (Example 113, Step 5) and l-Boc-4-hydroxypiperidine. LRMS (ES+) m/z 737.5 (M+H)+.
Step 2 : methyl (laR,5S,8S,10R,22aR)-5-tert-butyl-3,6-dioxo-17-(piperidin-4-yloxy)- 1, 1 a, 3, 4, 5, 6, 9, 10, 18, 19, 20, 21, 22, 22a-tetradecahydro-8H- 7, 10-methanocyclopropa
[18,19 ][1, 10,3,6 Jdioxadiazacyclononadecinofl 1,12-b Jquinoline-8-carboxylate trifluoroacetate
Figure imgf000181_0002
To a solution of the product from step 1 in dichloromethane (2 mL) was added trifluoroacetic acid (2 mL). The resulting solution was stirred for 1 hour at room temperature until disappearance of the starting material. The solvent was removed in vacuo. Purification of the residue by flash chromatography (ISCO reverse phase, 5 to 95 % acetonitrile in water (0.5% TFA buffer)) gave the desired product (170 mg). LRMS (ES+) m/z 637.5 (M+H)+. Step 3 : methyl (laR,5S,8S,10R,22aR)-5-tert-butyl-17-{[l-(2-methoxyethyl)piperidin-4-yl]oxy}- 3, 6-dioxo-l,l , 3, 4, 5, 6, 9, 10,18,19, 20, 21, 22, 22a-tetradecahydro-8H- 7, 10-methano
cyclopropafl 8,19 ][1, 10,3,6 ]dioxadiazacyclononadecino[ 11,12-b Jquinol ine-8-carboxylate
Figure imgf000182_0001
The amine from Step 2 (70.9 mg) was dissolved in DMF (0.3 mL) and triethylamine (53 μΐ), potassium iodide (1.6 mg) and 2-bromoethyl methyl ether (20 μΐ) were added sequentially. The reaction mixture was stirred at 60°C for 24 hours. The reaction mixture was then cooled to room temperature and quenched with a saturated solution of sodium bicarbonate. The mixture was extracted (3x) with ethyl acetate and the combined organics were dried with sodium sulfate, filtered and concentrated. Purification of the residue by flash chromatography (ISCO, 0 to 10% methanol in DCM) gave the desired product (50.6 mg).
LRMS (ES+) m/z 695.5 (M+H)+.
Step 4 : (laR,5S,8S,10R,22aR)-5-tert-butyl-17-{[l-(2-methoxyethyl)piperidin-4-yl]oxy dioxo-1, la, 3, 4, 5, 6, 9,10,18,19, 20, 21, 22, 22a-tetradecahydro-8H- 7, 10-methanocyclo
propa[l 8, 19] [1 , 10,3,6]dioxadiazacyclononadecino[l 1 , 12-b]quinoline-8-carboxylic acid
Figure imgf000182_0002
The title compound was prepared using the same method as Example 96, Step 3. LRMS (ES+) m/z 681.5 (M+H)+. Step 5 : (laR,5S,8S 0R R)-5-tert-butyl-N-[(lR,2S)-2-ethenyl-l-{[(l-methylcyclo propyl)sulfonyl]c rbamoyl}cyclopropyl]-17-{[l-(2-methoxyethyl)piperidin-4-ylJox
1, la,3,4,5,6,9, 10, 18, 19,20,21, 22,22a-tetradecahydro-8H-7, 10-methanocyclo
2-b]quinoline-8-carboxamide
Figure imgf000183_0001
The title compound was prepared using the same method as described in Example 1, Step 6 with intermediate A2. Purification of the residue by flash chromatography (ISCO reverse phase, 5 to 95% acetonitrile in water (0.5% TFA buffer)) gave the desired product. LRMS (ES+) m/z 907.45 (M+H)+.
Examples 226
By following the procedures outlined in Example 225 and using the appropriate reagent (depicted below the structure as Rg.), the following compounds were prepared.
Figure imgf000183_0002
Figure imgf000184_0001
ethyliodide
Figure imgf000185_0001
Example 232 : (1 aR,5S,8S, 10i?,22ai? -N-[(lig,2S)-2-ethenyl- !-{[(! -methylcyclopropyn sulfonyl] carbamoyl } cyclopropyl] -5-( 1 -methylcyclohexyD- 17- [(1 -methylpiperidin-4-yDoxy] - 3 ,6-dioxo- 1.1 a,3 ,4.5.6,9,10,18,19,20,21 ,22,22a-tetradecahydro-8H-7, 10-methanocyclopropa [18, 19][1, 10,3,6] dioxadiazacyclononadecino [ 11 , 12-b] quinoline-8-carboxamide
Figure imgf000185_0002
Step 1: (S)-2-(l-methylcyclohexyl)-2-((((lR,2R)-2-(pent-4-yn-l-yl)cyclopropoxy)
aminojacetic acid
Figure imgf000186_0001
A solution of intermediate D3 (4.3 g, 16.21 mmol) in acetohitrile (81 ml) was treated with intermediate Dl (3.37 g, 16.21 mmol) and triethylamine (9.04 ml, 64.8 mmol). Water (81 ml) was added to facilitate dissolution. The mixture was stirred at room temperature for 4 hours. The mixture was concentrated to half its volume and then diluted with ethyl acetate (500 mL), washed with aq 1M HCI (2 x 100 mL) and brine (100 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in the rotavap to give the title compound as a crude product (5.3 g, 16.49 mmol, 102 % yield) as a slightly yellow oil.
Step 2: (S)-2-((((lR, 2R)-2-(5-(4-(benzyloxy)-2-(((3R, 5S)-l-(tert-butoxycarbonyl)-5- (methoxycarbonyl)pyrrolidin-3-yl)oxy)quinolin-3-yl)pent-4-yn-l-yl)cycloprop
carbonyl)amino)-2-(l-methylcyclohexyl)acetic acid
Figure imgf000186_0002
A reaction vessel was charged with the product of step 1, (643 mg, 2 mmol), cesium carbonate (1629 mg, 5.00 mmol), bis(acetonitrile)dichloropalladium(II) (51.9 mg, 0.200 mmol) and tri-tert-butylphosphonium tetrafluoroborate (174 mg, 0.600 mmol). Acetonitrile (5000 μΐ) was added followed by dibenzylamine (387 μΐ, 2.000 mmol). The reaction mixture was purged with argon followed by addition of a solution of intermediate D2 (1115 mg, 2.000 mmol) in acetonitrile (5000 μΐ). The reaction mixture was purged with argon and the tube was sealed. The reaction was heated in an oil bath (80°C) overnight. Ethyl acetate was added (150 mL) and the mixture was washed with aq 1M HC1 (2 x 50 mL) and brine (50 mL), dried over magnesium sulfate, filtered and concentrated in rotavap to give the crude product. The crude product was purified on a gold cap Redisep (220 g) silica gel column (gradient: 0 to 30% solvent B in dichloromethane (solvent B: 20% methanol in ethyl acetate)) to give the title compound (840 mg, 1.053 mmol, 52.6 % yield) as a slighlty yellow foam.
Step 3: (S)-2-((((lR,2R)-2-(5-(4-(benzyloxy)-2-(((3R,5S)-5-(methoxycarbonyl) pyrrolidin-3-yl)
Figure imgf000187_0001
The N-Boc protected product from Step 2 (1.8 g, 2.256 mmol) was dissolved in dichloromethane (15.04 ml) and treated with TFA (7.52 ml). The mixture was stirred at room temp and monitored by LCMS. Reaction was completed after 45 min. The mixture was concentrated to dryness in rotavap. The residual TFA was azeotropically removed with toluene and the title compound (1.83 g, 2.254 mmol, 100 % yield) was dried under vacuum. No further purification was carried out.
Step 4: Methyl (laR,5S,8S,10R,22aR)-17-(benzyloxy)-5-(l-methylcyclohexyl)-3,6-dioxo-18,19- didehydro-l, la, 3, 4, 5, 6, 9, 10, 20, 21, 22, 22a-dodecahydro-8H- 7, 10-methanocyclopropa
[18, 19] [1, 10, 3,6]dioxadiazacyclononadecino[ll, 12-b]quinoline-8-carboxylate
Figure imgf000188_0001
A round-bottom flask was charged with HATU (1711 mg, 4.50 mmol) and dry DMF (2.25E+04 μΐ) at 0 °C. N,N-diisopropylethylamine (1531 μΐ, 9.00 mmol) was added followed by addition of a solution of the product of step 3 (1827 mg, 2.25 mmol) in dry DMF (2.25E+04 μΐ) via syringe pump over 1 hour. After addition was complete the reaction was stirred at room temperature for 2 hours. LCMS and MS analyses showed a complete reaction. The reaction mixture was concentrated to almost dryness in rotavap (high vacuum) and the residue was diluted with ethyl acetate (200 mL). The mixture was washed with water (50 mL), aq. 1M HC1 (50 mL), half-saturated sodium bicarbonate (50 mL) and brine (50 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in rotavap. The residue was purified on a Redisep (120 g) silica gel column (gradient: 0 to 40 % ethyl acetate in hexanes) to give the title compound (900 mg, 1.324 mmol, 58.8 % yield) as a white powder. Step 5: Methyl (laR,5S,8S,10R,22aR)-5-(l-methylcyclohexyl)-17-hydroxy-3,6-dioxo- 1, la, 3, 4, 5, 6, 9, 10,18,19, 20, 21, 22, 22a-tetradecahydro-8H- 7, 10-methanocyclopropa
[18, 19] [1, 10, 3, 6]dioxadiazacyclononadecino[ 11, 12-b ]quinoline-8-carboxylate
Figure imgf000188_0002
A solution of the product of step 4 (870 mg, 1.280 mmol) in MeOH (8532 μΐ) and THF (4266 μΐ) was treated with a catalytic amount of 10% palladium on carbon (68 mg). The mixture was hydrogenated at 30 psi. After 6 hours LCMS showed complete reaction. The mixture was diluted with dichloromethane (50 mL) and the solids were removed by filtration. The filtrate was concentrated in rotavap and the residue was purified on a gold cap RediSep® (80 g) silica gel column (gradient: 0 to 40 % ethyl acetate in hexanes) to give the title compound (710 mg, 1.196 mmol, 93 % yield) as a white powder.
Step 6: Methyl (laR, 5S, 8S, 1 OR, 22aR)-5-(l-methylcyclohexyl)-l 7-[ (l-methylpiperidin-4-yl)oxy]- 3, 6-dioxo-l,la,3,4,5, 6,9, 10, 18, 19,20,21, 22, 22a-tetradecahydro-8H-7, 10-methano
cyclopropaf 18, 19] [1, 10, 3, 6]dioxadiazacyclononadecino[ 11, 12-b ]quinoline-8-carboxylate
Figure imgf000189_0001
A reaction tube was charged with the product of step 5 (400 mg, 0.674 mmol) and triphenylphosphine (1414 mg, 5.39 mmol). The tube was sealed and THF (6737 μΐ) was added via syringe at 0°C. 4-hydroxy-l-methylpiperidine (633 μΐ, 5.39 mmol) was added followed by slow addition of diisopropyl azodicarboxylate (1044 μΐ, 5.39 mmol). After 5 min, the cooling bath was removed and the mixture was allowed to reach room temperature and stirred for 10 minutes. The reaction tube was heated at 40°C. LCMS showed complete reaction after 2 hours. The reaction mixture was concentrated to dryness in rotavap and the residue was purified on a gold cap silica gel (120 g) column (gradient: 0 to 50% solvent B in dichloromethane (solvent B: 20%) methanol in ethyl acetate)) to give the title compound (450 mg, 0.651 mmol, 97 %> yield) as a white powder.
Step 7: (laR, 5S, 8S, 1 OR, 22aR)-5-(l-methylcyclohexyl)-l 7-[(l-methylpiperidin-4-yl)oxy]-3, 6- dioxo-1, la, 3, 4, 5, 6, 9,10,18,19, 20,21, 22, 22a-tetradecahydro-8H- 7, 10-methanocyclo
propaf 18,19 ][1, 10,3,6 Jdioxadiazacyclononadecinof 11, 12-b Jquinoline-8-carboxylic acid
Figure imgf000190_0001
A round-bottom flask was charged with the product of step 6 (450 mg, 0.651 mmol) and lithium hydroxide monohydrate (137 mg, 3.26 mmol). MeOH (2171 μΐ), THF (2171 μΐ) and water (2171 μΐ) were successively added and the mixture was stirred at room temperature LCMS showed complete reaction after 2 hours. The reaction was quenched by addition of acetic acid (373 μΐ, 6.51 mmol). Water was added (20 mL) and the mixture was extracted with dichloromethane (2 x 20 mL) and ethyl acetate (20 mL). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated in rotavap. Residual acetic acid was azeotropically removed with toluene to give the title compound as a crude product (450 mg, 0.665 mmol, 102 % yield) as a white powder. No further purification was carried out.
Step 8: (laR,5S,8S,10R,22aR)-N-[(lR,2S)-2-ethenyl-l-{[(l-methylcyclopropyl)su^
carbamoyl) cyclopropyl] -5 -(1 -methylcyclohexyl)-! 7-[(l -methylpiperidin-4-yl)oxy]-3,6-dioxo- 1,1 a, 3, 4, 5,6,9,10,18, 19,20,21, 22, 22a-tetradecahydro-8H- 7, 10-methanocyclopropa[ 18,19]
[1,10, 3, 6]dioxadiazacyclononadecino[l 1, 12-b ]quinoline-8-carboxamide
Figure imgf000190_0002
A round-bottom flask was charged with the product of step 7 (1.1 g, 1.625 mmol), intermediate D4 (0.684 g, 2.438 mmol) and HATU (0.927 g, 2.438 mmol). Dry DMF (16.25 ml) was added by syringe at 0°C followed by N,N-diisopropylethylamine (1.106 ml, 6.50 mmol). The cooling bath was removed after 10 minutes and the reaction mixture was stirred overnight. The mixture was concentrated to one third of its volume in rotavap and the residue was diluted with ethyl acetate (200 mL). The organic layer was washed with water (2 x 25 mL) and brine (25 mL), dried over magnesium sulfate, filtered and concentrated in rotavap. The residue was purified on a gold cap RediSep® (220 g) silica gel column (gradient: 0 to 50 % solvent B in dichloromethane (solvent B: 20% MeOH in ethyl acetate)) to give the title compound (810 mg, 0.897 mmol, 55.2 % yield) as a white powder. LRMS (ESI) Calcd for C48H67N609S [M + H]+ 903.46; found 902.8
Example 233 : (lai?,5S,8S.10i?.22ai? -5-(23-dihvdro-lH-inden-2-yl)-17-r3-(dimethylamino propoxy|-N-|Y 1 R.2S)-2-ethenyl- 1 - { \( 1 -methylcyclopropyl) sulfonyl] carbamoyl } cvclopropyl] - 3 ,6-dioxo- 1.1 a.3.4.5.6.9.10.18.19.20.21.22.22a-tetradecahvdro-8H-7.10-methano
Figure imgf000191_0001
Step l: (S)-2-(2,3-dihydro-lH-inden-2-yl)-2-((((lR,2R)-2-(pent-4- l)cyclopropoxy)carbonyl)amino)acetic acid
Figure imgf000191_0002
A solution of intermediate D3 (3.54 g, 12.0 mmol) in MeCN (30.0 ml) was treated with intermediate D5 (3.28 g, 14.40 mmol) and triethylamine (6.70 ml, 48.0 mmol). The slurry was vigorously stirred while water (30.0 ml) was added. The resulting mixture was stirred overnight. The mixture was diluted with ethyl acetate (400 mL) and washed with aq. 1M HCl (2 x 100 mL) and brine (100 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated to half its volume in the rotavap. The solids were recovered by filtration and dried under vacuum to give the first batch of the title compound (2.0 g, 48%). The filtrate was concentrated to dryness in rotavap to give the second batch of the title compound (2.3 g, 56%). Step 2: (S)-2-((((lR, 2R)-2-(5-(4-(benzyloxy)-2-(((3R, 5S)-l-(tert-butoxycarbonyl)-5- (methoxycarbonyl)pyrrolidin-3-yl)oxy)quinolin-3-yl)pent-4-yn-l-yl)cycloprop
Figure imgf000192_0001
A reaction vessel was charged with the product of step 1 (1990 mg, 5.83 mmol), potassium carbonate (1831 mg, 13.25 mmol), bis(acetonitrile)dichloro palladium(II) (68.7 mg, 0.265 mmol), and tri-tert-butylphosphonium tetrafluoroborate (231 mg, 0.795 mmol).
Acetonitrile (1.77E+04 μΐ) was added followed by dibenzylamine (1017 μΐ, 5.30 mmol). The reaction mixture was purged with argon followed by addition of a solution of intermediate D2 (2954 mg, 5.3 mmol) in acetonitrile (8833 μΐ). The reaction mixture was purged with argon and the tube was sealed. The reaction was heated in an oil bath (80°C) overnight. Ethyl acetate was added (300 mL) and the mixture was washed with aq. 1M HCl (2 x 50 mL) and brine (50 mL), dried over magnesium sulfate, filtered and concentrated in rotavap. The crude product was purified on a gold cap ediSep® (220 g) silica gel column (gradient: 0 to 30% solvent B in dichloromethane (solvent B: 20% methanol in ethyl acetate)). The fractions containing the product were combined and fractions containing impure product were combined, evaporated and purified again under the same conditions (120 g column) to give a second batch of product. The purified products were combined to give the title compound (950 mg, 22%) as a colorless foam. Step 3: (S)-2-((((lR, 2R)-2-(5-(4-(benzyloxy)-2-(((3R, 5S)-5-(methoxycarbonyl)pyrrolidin-3- yl)oxy)quinolin-3-yl)pent-4-yn-l-yl)cyclopropoxy)carbonyl)amino)-2
yl)acetic acid
Figure imgf000193_0001
A solution of the product of step 2 (750 mg, 0.917 mmol) in CH2C12 (4.58 ml) was treated with trifiuoroacetic acid (4.5 ml, 58.8 mmol) and stirred at room temperature.
LCMS showed complete reaction after 30 minutes. The mixture was concentrated to dryness in rotavap and residual TFA was azeotropically removed with toluene. The title compound as crude product (760 mg, 100%) was dried under vacuum and used without further purification. Step 4: Methyl (laR,5S,8S,10R,22aR)-17^enzyloxy)-5-(2,3-dihydro-lH^nden-2-yl)-3,6-dioxo- 18,19-didehydro-l, 1 a, 3, 4, 5,6,9,10,20,21, 22, 22a-dodecahydro-8H- 7, 1 -methano
cyclopropafl 8, 19] [ 1, 10, 3, 6]dioxadiazacyclononadecino[ 11, 12-b Jquinoline-8-carboxylate
Figure imgf000194_0001
A round-bottom flask was charged with HATU (695 mg, 1.828 mmol) and dry DMF (9140 μΐ) at 0°C. N,N-diisopropylethylamine (637 μΐ, 3.66 mmol) was added followed by addition of a solution of the product of step 3 (760 mg, 0.914 mmol) in dry DMF (9140 μΐ) via syringe pump over 1 hour. After addition was complete the reaction was stirred at room temperature for 1 hour. LCMS and MS analyses showed a complete reaction. The reaction mixture was concentrated to almost dryness in rotavap (high vacuum) and the residue was diluted with ethyl acetate (100 mL). The mixture was washed with water (40 mL), aq. 1M HCl (40 mL), half-saturated sodium bicarbonate (30 mL) and brine (30 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in rotavap. The residue was purified on a RediSep® (80 g) silica gel column (gradient: 0 to 50 % ethyl acetate in hexanes) to give the title compound (510 mg, 0.729 mmol, 80 % yield) as a white powder.
Step 5: Methyl (laR,5S,8S, 10R,22aR)-5-(2, 3-dihydro-lH-inden-2-yl)-17-hydroxy-3, 6-dioxo- 1, 1 a, 3, 4,5, 6,9, 10, 18, 19,20,21, 22, 22a-tetradecahydro-8H- 7, 1 -methanocyclopropa[l 8, 19]
[1, 10, 3, 6]dioxadiazacyclononadecino[l 1, 12-b Jquinoline-8-carboxylate
Figure imgf000195_0001
A solution of the product of step 4 (480 mg, 0.686 mmol) in MeOH (9146 μΐ) and THF (4573 μΐ) was treated with a catalytic amount of 10% palladium on carbon (36 mg). The mixture was hydrogenated at 20 psi. After 2 hours LCMS showed >70% conversion.
Hydrogenation was continued for another 2 h. LCMS showed >90% conversion. The mixture was diluted with ethyl acetate (50 mL) and the solids were removed by filtration. The filtrate was concentrated in rotavap and the residue was purified on a RediSep® (80 g) silica gel column (gradient: 0 to 50 % ethyl acetate in hexanes) to give the title compound (420 mg, 0.684 mmol, 100 % yield) as a white powder.
Step 6: Methyl (laR, 5S, 8S, 1 OR, 22aR)-5-(2, 3-dihydro-l H-inden-2-yl)-l 7-[ 3-(dimethylamino) propoxy]-3, 6-dioxo-l, la, 3, 4, 5, 6, 9, 10,18,19, 20, 21, 22, 22a-tetradecahydro-8H- 7, 10-methano cyclopropafl 8,19 ][1, 10,3,6] dioxadiazacyclononadecinof 11,12-b ]quinoline-8-carboxylate
Figure imgf000195_0002
A reaction tube was charged with the product of step 5 (200 mg, 0.326 mmol) and triphenylphosphine (855 mg, 3.26 mmol). The tube was sealed and THF (3259 μΐ) was added via syringe at 0°C. 3-dimethylamino-l-propanol (381 μΐ, 3.26 mmol) was added followed by slow addition of diisopropyl azodicarboxylate (631 μΐ, 3.26 mmol). After 5 minutes the cooling bath was removed and the mixture was allowed to reach room temperature and stirred for 10 minutes. The reaction tube was heated at 40°C for 3 hours. The reaction mixture was concentrated to dryness in rotavap and the residue was purified on a gold cap silica gel (80 g) column (gradient: 0 to 60% solvent B in dichloromethane (solvent B: 20% methanol in ethyl acetate)) to give the title compound (210 mg, 0.300 mmol, 92 % yield) as a white powder. Step 7: (laR, 5S, 8S, 1 OR, 22aR)-5-(2, 3-dihydro-l H-inden-2-yl)-l 7-[3-(dimethylamino)propoxy]- 3, 6-dioxo-l, la, 3, 4, 5, 6, 9, 10,18,19, 20, 21, 22, 22a-tetradecahydro-8H- 7, 10-methano
boxylic acid
Figure imgf000196_0001
A solution of the product of step 6 (210 mg, 0.300 mmol) in MeOH (3005 μΐ), THF (1502 μΐ) and eater (1502 μΐ) was treated with lithium hydroxide monohydrate (63.0 mg, 1.502 mmol). The reaction mixture was stirred at room temperature. After 5 hour the reaction was quenched by addition of acetic acid (172 μΐ, 3.00 mmol) and water (10 mL). The mixture was extracted into dichloromethane (2 x 10 mL) and ethyl acetate (10 mL). The combined organic extracts were dried over magnesium sulfate filtered and concentrated in rotavap to give the title compound (215 mg, 0.314 mmol, 104 % yield) as a white powder. No further purification was carried out for the product.
Step 8: (laR, 5S, 8S, 1 OR, 22aR)-5-(2, 3-dihydro-l H-inden-2-yl)-l 7-[3-(dimethylamino)propoxy]- N-[ (lR,2S)-2-ethenyl-l-{[ (l-methylcyclopropyl)sulfonyl] carbamoyl} cyclopropyl] -3, 6-dioxo- 1, la, 3, 4, 5, 6, 9, 10,18,19, 20, 21, 22, 22a-tetradecahydro-8H-7, 10-methanocyclopropa
[18,19] [1, 10,3, 6]dioxadiazacyclononadecino[ll,12-b]quinoline-8-carboxamide
Figure imgf000197_0001
A round-bottom flask was charged with the product of step 7 (105 mg, 0.153 mmol), intermediate D4 (53.8 mg, 0.192 mmol) and HATU (72.9 mg, 0.192 mmol). Dry DMF (3066 μΐ) was added by syringe followed by 4-methylmorpholine (67.4 μΐ, 0.613 mmol). The reaction mixture was stirred for 22 hours. Ethyl acetate was added (20 mL) and the mixture was washed with water (2 x mL), brine (5 mL), dried over magnesium sulfate, filtered and concentrated in rotavap. The residue was purified on a gold cap RediSep® (12 g) silica gel column (gradient: 0 to 60 % solvent B in dichloromethane (solvent B: 20% MeOH in ethyl acetate)) to give the title compound (52 mg, 0.057 mmol, 37.2 % yield) as a white powder. LRMS (ESI) Calculated for C49H63N609S [M + H]+ 911.4; found 911.2
Example 234 : ( 1 aR,5S,8S.10R.22aR)-5-tert-butyl-N-r( 1 R.2S)-2-ethenyl- 1 - ( Γ( 1 -methyl cyclopropyl sulfonyl]carbamov cyclopropyll-3 ,6-dioxo- 17- ( [ 1 -(2.2.2-trifluoroethyl)piperidin- 4-ylloxy } - 1 , 1 a ,3 Λ5.6,9.10.18.19.20.21.22.22a-tetradecahvdro-8H-7.10-methano
cyclopropa|T 8.19] 1.10.3.61dioxadiazacyclononadecinor 11 , 12-b]quinoline-8-carboxamide
Figure imgf000197_0002
Step 1: methyl (laR,5S,8S,10R,22aR)-5-tert-butyl-17-{[l-(2,2,2-trifluoroethyl)piperidin-4- yl Joxy}-3, 6-dioxo-l, la, 3, 4, 5, 6, 9,10,18,19, 20,21, 22, 22a-tetradecahydro-8H- 7, 10-methano cyclopropa [18, 19] [1,10,3, 6]dioxadiazacyclononadecino[ll, 12-b]quinoline-8-carboxylate
Figure imgf000198_0001
To a solution of the product from Example 225 Step 2 (90 mg, 0.141 mmol) in 2 mL acetonitrile were added cesium carbonate (92 mg, 0.283 mmol) followed by 2,2,2- trifluoroethyl trifluoromethanesulfonate (65.6 mg, 0.283 mmol). The reaction was stirred at room temperature for 2 hours at which stage it was judged to be complete by LCMS. The reaction mixture was filtered through celite, washed with EtOAc, concentrated and purified by PTLC (40% EtOAc/Hexane) to give the title compound (75 mg, 0.104 mmol, 73.8 % yield). Step 2: (laR, 5S, 8S, 1 OR, 22aR)-5-tert-butyl-N-[ (1R, 2S)-2-ethenyl-l-{[ (1 -methyl
cyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-3, 6-dioxo-l 7-{[l-(2, 2, 2-trifluoroethyl)piperidin-4- yl]oxy}-l, 1 a, 3, 4, 5, 6, 9,10,18, 19,20,21, 22, 22a-tetradecahydro-8H- 7, 10-methanocyclopropa
[18, 19] [1,10, 3, 6]dioxadiazacyclononadecino[l 1, 12-b]quinoline-8-carboxamide
The product from Step 1 was converted to Example 234 using the previously described procedures for the synthesis of Example 225. The title compound was purified by PTLC (3% MeOH in CH2C12). LRMS m/z 931.4 (M+H)+
Example 235: tert-butyl 4-{rriaR,5S,8S,10R.22aRV5-cvclohexyl-8-{r(TR.2S)-2-ethenyl-l-irri- methylcvclopropyl)sulfonyl1carbamoyl}cvclopropyllcarbamoyll-3,6-dioxo-l,la,3,4,5,6,9,10, 18.19,20.21 ,22.22a-tetradecahvdro-8H-7, 10-methanocvclopropar 18,191 [ 1 , 10 ,3 ,61
dioxadiazacyclononadecino[ 11 , 12-blquinolin-l 7-yl] oxylpiperidine-1 -carboxylate
Figure imgf000199_0001
Example 235 was prepared by utilizing the procedures described for the synthesis of Example 211. Tert-butyl 4-hydroxypiperidine-l -carboxylate was used instead of 1 - methylpiperidine-4-ol for the Mitsunobu reaction. LRMS m/z 975.4 (M+H)+
Example 236: 4-(rflaR.5S,8Sa0R.22aRV5-cvclohexyl-8-(r(lR.2SV2-ethenyl-l-{r(l- methylcvclopropyl)sulfonyll carbamoyl 1 cyclopropyll carbamoyl} -3,6-dioxo- 1 , 1 a,3,4,5,6,9, 10, 18,19,20,21 ,22,22a-tetradecahydro-8H-7, 10-methanocyclopropa[ 18, 19"] [ 1 , 10,3 ,61dioxadiaza cyclononadecino [11,12-b]quinolin- 17-yl] oxyj - 1 -(2,2,2-trifluoroethvDpiperidinium formate
Figure imgf000199_0002
Step 1 : 4-{[ (laR, 5S, 8S, 1 OR, 22aR)-5-cyclohexyl-8-{[(lR, 2S)-2-ethenyl-l-{[(l -methylcyclopropyl) sulfonyl ]carbamoyl}cyclopropyl]carbamoyl}-3, 6-dioxo-l, la, 3, 4, 5, 6, 9, 10,18,19, 20, 21, 22, 22a- tetradecahydroSH- 7, 10-methanocyclopropaf 18,19][1,10,3, 6Jdioxadiazacyclononadecino
[11, 12-bJquinolin-l 7-yl]oxy}-piperidinium trifluoroacetate
Figure imgf000200_0001
To a solution of Example 235 (100 mg, 0.103 mmol) in dichloromethane (5 ml) was added trifluoroacetic acid (1.025 ml, 0.103 mmol). The reaction was stirred at room temperature for 2 hours at which stage LCMS indidcated complete hydrolysis of the NBoc group. The volatiles were evaporated under reduced pressure and the residue was diluted with DCM and azeotroped twice with toluene. The resulting residue (-101 mg) was dried under vacuum and used for the next step without purification.
Step 2: 4-{[(laR, 5S, 8S, 1 OR, 22aR)-5-cyclohexyl-8-{[ (1R, 2S)-2-ethenyl-l-{[ (1-methylcyclopropyl) sulfonyl]carbamoyl}cyclopropyl]carbamoyl}-3, 6-dioxo-l, la, 3, 4, 5, 6, 9,10,18, 19, 20,21, 22, 22a- tetradecahydro-8H- 7, 10-methanocyclopropaf 18,19] [1,10,3,6 ] dioxadiazacyclononadecino
[11, 12-bJquinolin-l 7-yl]oxy}-l-(2,2,2-trifluoroethyl)piperidinium formate
To a solution of the product from Step 1 (101 mg, 0.102 mmol) in acetonitrile (5 mL) was added Hunig's base (0.089 mL, 0.511 mmol) followed by 2,2,2 -trifluoroethyl trifluoromethanesulfonate (71.1 mg, 0.306 mmol). The reaction was stirred at 55°C for 3 hours after which it was quenched with water and extracted with EtOAc. Purification by PTLC (3%
MeOH in CH2C12) followed by reverse phase HPLC (0 to 90% acetonitrile in water; with 0.1%
HCOOH) provided the title compound.
Example 237: 4- { ΓΓ1 aR,5S,8S, 10R,22aR -5-cyclohexyl-8-{ r(lR,2SV2-ethenyl-l -{ ΓΠ -methyl cyclopropyl)sulfonyllcarbamoyl}cyclopropyllcarbamoyl}-3,6-dioxo-lJa,3,4,5,6,9J0,18, 19,20,21 , 22,22a-tetradecahydro-8H-7, 10-methanocvclopropa[ 18 Λ 9} \ 1 0,3,6]dioxadiaza cyclononadecino[ 11 , 12-blquinolin- 17-yl]oxy } - 1 -(2-methoxyethyl piperidinium formate
Figure imgf000201_0001
To a solution of the product from Step 1, Example 236 (100 mg, 0.101 mmol) in DMF (3 mL) was added triethylamine (0.070 mL, 0.506 mmol), potassium iodide (3.36 mg, 0.020 mmol) and 2-bromoethylmethylether (42.2 mg, 0.303 mmol). The reaction was heated to 55°C and stirred for 4 hours at which stage LCMS indicated no starting material. After cooling to room temperature, water was added and the reaction was extracted with ethyl acetate. The combined organic fractions were washed with brine, dried (Na2S04) arid concentrated to give an oily residue, which was purified by HPLC (0 to 90% acetonitrile in water; with 0.1 % HCOOH) to furnish the title compound.
Example 238: 4-i r(laR.5S.8S.10R.22aRV5-cvclohexyl-8-( r(lR.2SV2-ethenyl-l-{ r(l-methyl cyclopropyDsulfonyl"]carbamovU cyclopropyll carbamoyl} -3,6-dioxo- 1 , 1 a,3 ,4,5,6,9, 10, 18, 19, 20,21 ,22,22a-tetradecahydro-8H-7, 10-methanocyclopropa[ 18,191 IT, 10,3,61dioxadiaza
Figure imgf000201_0002
Example 238 was prepared by utilizing procedures described for the synthesis of Example 237. (Bromomethyl)cyclopropane was used instead of l-bromo-2-methoxyethane in the last step to furnish the title compound.
Example 239: 4-U(laR.5S.8S.10R.22aRV5-cvclohexyl-8-U(lR.2SV2-ethenyl-l-(r(l- methylcyclopropyDsulfonyllcarbamoyl } cyclopropyllcarbamoyl } -3.6-dioxo- 1,1 a.3 ,4,5 ,6.9, 10. 18,19,20,21 ,22.22a-tetradecahvdro-8H-7.1 O-methanocvclopropar 18.191 Γ 1.10,3,61
dioxadiazacyclononadecino[l 1 , 12-blquinolin- 17-ylloxy} - 1 -ethylpiperidinium formate
Figure imgf000202_0001
Example 23 was prepared by utilizing procedures described for the synthesis of Example 237. lodoethane was used instead of l-bromo-2-methoxyethane and potassium iodide was not utilized in the last step to furnish the title compound.
Example 240: 4-(3-{raaR,5S,8S.10R.22aRV5-cyclohexyl-8-{rriR.2SV2-ethenyl-l-(rri- methylcvclopropyDsulfonyll carbamoyl } cyclopropyll carbamoyl) -3 ,6-dioxo- 1 , 1 a,3 ,4,5.6,9. 10,18.19.20.21.22.22a-tetradecahvdro-8H-7.10-methanocvclopropar 18.191Π ,10.3.61dioxadiaza cyclononadecino [11.12-bl quinolin- 17-yll oxy} propyl)morpholin-4-ium formate
Figure imgf000202_0002
Step 1: (laR,5S,8S,10R,22aR)-5-cyclohexyl-l 7-[3-bromopropoxy]-N-[(lR,2S)-2-ethenyl-l-{[(l- methylcyclopropyl)sulfonyl ] carbamoyl } cyclopropyl J -3, 6-dioxo-l, 1 a, 3, 4, 5, 6, 9,10,18,
19,20,21, 22, 22a-tetradecahydro-8H- 7, 10-methanocyclopropa[ 18,19] [1,10,3, 6 Jdioxadiaza cyclononadecinof 11, 12-b ]quinoline-8-carboxamide
Figure imgf000203_0001
The title compound in step 1 was prepared by utilizing procedures similar to that described for the synthesis of the intermediate obtained in Example 145, Step 1.
Step 2: 4-(3-{[(laR,5S,8S,10R,22aR)-5-cyclohexyl-8-{[(lR,2S)-2-ethenyl-l-{[(l-methyl cyclopropyl)sulfonyl]carbamoyl}cyclopropyl]carbamoyl}-3, 6-dioxo-l, la, 3, 4, 5, 6, 9, 10, 18, 19, 20,21, 22, 22a-tetradecahydro-8H- 7, 10-methanocyclopropa[ 18,19] [1,10, 3, 6]dioxadiaza cyclononadecino[l 1 , 12-b]quinolin-l 7-yl]oxy}propyl)morpholin-4-ium formate
A solution of the intermediate from Step 1 (60 mg, 0.066 mmol), morpholine (28.6 mg, 0.329 mmol), triethylamine (0.046 mL, 0.329 mmol) and potassium iodide (21.82 mg, 0.131 mmol) in DMF (2 mL) was stirred at 55 °C for 4 hours at which stage LCMS indicated complete conversion to the desired product. After cooling the reaction to room temperature, water was added the reaction was extracted with ethyl acetate. The combined organic fractions were dried over Na2S04 and concentrated under reduced pressure. Purification by HPLC (0 to 90% acetonitrile in water; with 0.1% HCOOH) provided the title compound. LRMS m/z 919.4 (M+H)+.
Example 241 : N-(3-{ r(laR,5S,8S,10R,22aRV5-cvclohexyl-8-{ r(lR.2SV2-ethenyl-l-i Γ(1- memylcyclopropyl)sulfonyllcarbamoyl>cvclopropyl1carbarnoyl}-3,6-dioxo-
1.1 a.3.4.5.6.9.10.18.19.20.21 ,22,22a-tetradecahydro-8H-7.10- methanocyclopropa[ 18, 19] [ 1 , 10.3 ,61dioxadiazacvclononadecino [11,12-blquinolin- 17- "|oxy|propyDcvclopropanaminium formate
Figure imgf000204_0001
A solution of the intermediate from Example 240, Step 1 (85 mg, 0.093 mmol) and cyclopropyl amine (80 mg, 1.401 mmol) in DMF (2 mL) was stirred at 50°C for 3 hours; LCMS indicated complete conversion. After cooling the reaction to room temperature, water was added the reaction was extracted with ethyl acetate. The combined organic fractions were dried over Na2S04 and concentrated under reduced pressure. Purification by HPLC (0 to 90% acetonitrile in water; with 0.1% HCOOH) furnished the title compound. LRMS m/z 889.4 (M+H)+.
Example 242: N-(3-ir(laR.5S,8SJ0R,22aRV5-cvclohexyl-8-(r(lR.2SV2-ethenyl-l-{r(l- methylcvclopropyl)sulfonyl]carbamoyl| cvclopropyl]carbamoyl) -3 ,6-dioxo- 1.1 a.3.4.5,6,9, 10.18.19.20.21 ,22.22a-tetradecahvdro-8H-7, 10-methano
cyclopropaf 18,191 [1,10,3,6] dioxadiazacyclononadecino [ 11 , 12-b] quinolin- 17-
Figure imgf000204_0002
Example 242 was prepared by utilizing procedures similar to that described for the synthesis of Example 241. LRMS m/z 903.4 (M+H)+
Example 243: riaR.5S.8S.10R.22aRV5-cvclohexyl-17-{3-r(,3.3-difluorocvclobutvnaminol propoxy}-N- (lR,2S)-2-ethenyl-l-{ (l-methylcyclopropyl sulfonyllcarbamoyl|cyclopropyll- 3.6-dioxo- 1.1 a.3.4.5.6.9.10.18.19.20.21.22.22a-tetradecahydro-8H-7.10-methanocvclopropa
, 12-b] quinoline-8-carboxamide
Figure imgf000205_0001
A solution of the intermediate from Example 240, Step 1 (50 mg, 0.055 mmol), 3,3-difluorocyclobutanamine (46.9 mg, 0.438 mmol), triethylamine (0.076 mL, 0.548 mmol) and potassium iodide (91 mg, 0.548 mmol) was stirred at 55 °C for 4h at which stage LCMS indicated complete conversion to the desired product. After cooling the reaction to room temperature, water was added the reaction was extracted with ethyl acetate. The combined organic fractions were dried over Na2S04 and concentrated under reduced pressure. Purification by PTLC (5% MeOH in CH2C12) furnished the title compound. LRMS m/z 939.4 (M+H)+.
Example 244 : (laR.5S.8S.10R.22aR>5-tert-butyl-N-ri 1 R.2S >2-ethenyl- 1 - { Γ(1 - methylcvclopropyl)sulfonyl1carbamoyl}cvclopropyl1-3,6-dioxo-17-(pyridin-4-yl)- 1.1 a.3.4.5.6.9.10.18.19.20.21.22.22a-tetradecahydro-8H-7.10-methano
cyclopropaf 18.19] [ 1.10.3.61dioxadiazacvclononadecino [11.12-b]quinoline-8-carboxamide
Figure imgf000206_0001
Step 1: methyl (laR,5S,8S,10R,22aR)-5-tert-butyl-17-{[(trifluoromethyl)sulfonyl]oxy}-3,6-dioxo- 1, la, 3, 4, 5, 6, 9, 10,18,19, 20, 21, 22, 22a-tetradecahydro-8H-7, 10-methanocyclopropa
cyclononadecino[l 1, 12-b ]quinoline-8-carboxylate
Figure imgf000206_0002
To a solution of the intermediate from Example 113, step 5 (200 mg, 0.361 mmol) in pyridine (2 ml) was added triflic anhydride (0.305 ml, 1.806 mmol) at 0°C. The reaction was stirred at 0°C for 15 minutes and then at room temperature for 15 minutes after which water was added and an extraction was performed with EtOAc. The combined organics were washed with saturated aq. NH4C1 and then with 10% aq. KHS04 solution followed by brine. Purification by PTLC (30% EtOAc/hexanes) provided the title compound.
Step 2: methyl (laR,5S,8S,10R,22aR)-5-tert-butyl-17-(pyridin-4-yl)-3,6-dioxo- 1, la, 3, 4, 5, 6, 9, 10,18,19, 20, 21, 22, 22a-tetradecahydro-8H- 7, 10-methanocyclopropa
[18, 19] [1,10, 3, 6]dioxadiazacyclononadecino[l 1 , 12-b]quinoline-8-carboxylate
Figure imgf000207_0001
To a solution of the product from step 1 (50 mg, 0.073 mmol) in dioxane (5 ml) was added pyridine-4-boronic acid, (35.9 mg, 0.292 mmol), potassium phosphate tribasic (38.7 mg, 0.182 mmol) and tetrakis (16.85 mg, 0.015 mmol). After purging with N2 for 5 min, the reaction was stirred at 80°C for 16 hours. After cooling to room temperature, water was added and the reaction was extracted with ethyl acetate, washed with brine, dried (Na2S04) and concentrated. Purification by PTLC (40% EtOAc hexane) provided the desired compound. Step 3: (laR, 5S, 8S, 1 OR, 22aR)-5-tert-butyl-N-[ (1R, 2S)-2-ethenyl-l-{[ (1 -methyl
cyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-3, 6-dioxo-l 7 -(pyridin-4-yl)-l , la, 3, 4, 5, 6, 9, 10,18,19, 20, 21, 22, 22a-tetradecahydro-8H- 7, 10-methanocyclopropa[18, 19 ][1, 10,3,6]
noline-8-carboxamide
Figure imgf000207_0002
The product from step 2 was converted to Example 244 using the procedures described for the synthesis of Example 113, steps 7 and 8. LRMS m/z 827.2 (M+H)+.
Example 245 : ( 1 aR,5 S,8S, 10R.22aRV5-tert-butyl-N-r(l R.2SV2-ethenyl- 1 - { Γ(Τ - methylcyclopropyDsulfonyl] carbamoyl} cyclopropyl] -3 ,6-dioxo- 17-(pyridin-2-yl - 1,1 a,3 , 4,5,6,9,10,18, 19,20,21 ,22,22a-tetradecahydro-8H-7, 10-methanocyclopropa
[ 18, 19] [ 1 , 10,3 ,6] dioxadiazacvclononadecino Γ 11 , 12-blquinoline-8-carboxamide
Figure imgf000208_0001
To a solution of the product from Example 244 step 1 (50 mg, 0.073 mmol) in dioxane (3 ml) was added 2-(tributylstannyl)pyridine (53.7 mg, 0.146 mmol), copper(I)iodide (2.78 mg, 0.015 mmol) and tetrakis (16.85 mg, 0.015 mmol). After purging with N2 for 5 minutes, the reaction was stirred at 80°C for 16 hours. After cooling to room temperature, water was added and the reaction was extracted with ethyl acetate, washed with brine, dried (Na2S04) and concentrated. Purification by PTLC (40% EtOAc/hexane) provided the desired compound, which was converted to Example 245 using the procedures described for the synthesis of Example 244. LRMS m/z 827.2 (M+H)+.
Example 246: (1 aR,5S.8S, 10R.22aRV 5-tert-butyl-N-rq R.2S -2-ethenyl- 1 - { Γ( 1 - methylcvclopropyl)sulfonyl]carbamoyl|cvclopropyl]-3,6-dioxo-17-(pyridin-3-yl)- 1.1 a.3.4.5.6.9.10.18.19.20.21.22.22a-tetradecahvdro-8H-7.10-methanocvclo
propa|" 18.19] [ 1.10.3 ,6 dioxadiazacyclononadecino[ 11.12-b]quinoline-8-carboxamide
Figure imgf000208_0002
Example 246 was prepared using the procedures described for the synthesis of Example 244. Pyridin-3-ylboronic acid was used instead of pyridin-4-ylboronic acid in the coupling step. LRMS m/z 827.2 (M+H)+. Example 247 : Π aR.5S.8S.10R.22aRV5-tert-butyl-N-r( 1 R.2S V2-ethenyl- 1 - { \(\ - methylcyclopropyDsulfonyl] carbamoyl } cyclopropyl] -3.6-dioxo- 17-( 1 ,3 -thiazol-2-ylV
1.1 a.3.4.5.6.9.10.18.19.20.21.22.22a-tetradecahydro-8H-7.1 O-methanocvclopropa
[18, 19] [ 1.10.3.61dioxadiazacyclononadecino[ 11.12-blquinoline-8-carboxamide
Figure imgf000209_0001
Example 247 was prepared using the procedures described for the synthesis of Example 245. 2-(Tributylstannyl)thiazole was used instead of 2-(tributylstannyl)pyridine. LRMS m/z 833.2 (M+H)+ Example 248: potassium (r(lR.2S -l-riraaR.5S.8S.10R.22aRV5-tert-butyl-17-(morpholin-4- ylmethvn-3.6-dioxo- 1.1 a.3.4.5.6.9.10.18.19.20.21.22.22a-tetradecahydro-8H-7.10- methanocyclopropafl 8, 19] [ 1 , 10,3,6]dioxadiazacyclononadecino 11 , 12-b]quinolin-8- yl] carbonyl } amino -2-ethenylcyclopropyl1 carbonyl } [( 1 -methylcyclopropyDsulfonyl] azanide
Figure imgf000209_0002
Step 1 : methyl (laR, 5S, 8S, 1 OR, 22aR)-5-tert-butyl-l 7-vinyl-3, 6-dioxo-
1, la, 3, 4, 5,6,9,10,18,19,20,21, 22, 22a-tetradecahydro-8H- 7, 10-methanocyclopropa
[18,19] [1, 10, 3, 6]dioxadiazacyclononadecino[ll,12-b]quinoline-8-carboxylate
Figure imgf000210_0001
To a solution of the product from Example 244 step 1 (100 mg, 0.146 mmol) in dioxane (3 ml) was added tributyl(vinyl)stannane (92 mg, 0.292 mmol), copper (I) iodide (5.55 mg, 0.029 mmol) and tetrakis (33.7 mg, 0.029 mmol). After purging with N for 5 min, the reaction was stirred at 80°C for 16 hours. After cooling to room temperature, water was added and the reaction was extracted with ethyl acetate, washed with brine, dried (Na2S04) and concentrated. Purification by PTLC (30% EtOAc/hexane) provided the desired compound. Step 2: methyl (laR,5S,8S,10R,22aR)-5-tert-butyl-17-formyl-3,6-dioxo- 1, la, 3, 4, 5, 6, 9, 10,18,19, 20, 21, 22, 22a-tetradecahydro-8H- 7, 10-methanocyclopropa
cyclononadecino[l 1, 12-b]quinoline-8-carboxylate
Figure imgf000210_0002
To a solution of the product from Step 1 (30 mg, 0.053 mmol) in acetone (1 ml) and water (ImL) was added potassium osmate dehydrate (19.61 mg, 0.053 mmol). The reaction was stirred at room temperature for 10 minutes after which sodium periodate (114 mg, 0.532 mmol) was added. After stirring for 2 hours, an additional ~15 mg of potassium osmate and 115 mg of sodium periodate were added. After stirring 16 hours, the reaction was filtered and the solid was washed with acetone. The filtrate was concentrated, diluted with EtOAc and washed with Na2S203 and NaHC03 aq. soln. Purification by PTLC (30% EtOAc-hexane) provided the desired aldehyde. Step 3: methyl (laR,5S,8S,10R,22aR)-5-tert-butyl-17-(morpholinomethyl)-3,6-dioxo- 1,1 a, 3, 4, 5, 6, 9,10,18,19, 20, 21, 22, 22a-tetradecahydro-8H- 7, 10-methanocyclopropa
clononadecino[ll, 12-b]quinoline-8-carboxylate
Figure imgf000211_0001
To a solution of the product from Step 2 (34 mg, 0.060 mmol) in CH2C12 (3 ml) was added morpholine (0.016 ml, 0.180 mmol) and acetic acid (10.32 μΐ, 0.180 mmol) followed by sodium triacetoxyborohydride (38.2 mg, 0.180 mmol). The reaction was complete in 30 minutes at which stage it was quenched with water and extracted with dichloromethane.
Purification by PTLC (40% EtOAc/hexane) provided the desired compound.
Step 4: potassium {[ (1R, 2S)-l-({[ (laR, 5S, 8S, 1 OR, 22aR)-5-tert-butyl-l 7-(morpholin-4-ylmethyl)- 3, 6-dioxo-l,la, 3, 4, 5, 6, 9, 10,18,19, 20, 21, 22, 22a-tetradecahydro-8H- 7, 10- methanocyclopropa[18, 19] [1, 10, 3, 6]dioxadiazacyclononadecino[l 1, 12-b ]quinolin-8- onyl}[(l-methylcyclopropyl)sulfony
Figure imgf000211_0002
Steps 7 and 8 described for the synthesis of Example 113 were performed on the product from step 3 and the resulting compound was converted to Example 248 after treatment with 1 equivalent of 0.1N aqueous KOH solution. LRMS m/z 849.2 (M+H)+. Example 249: daR.5S,8S.10R.22aRV5-cvclohexyl-17-r3-(,3,3-difluoroazetidin-l-vnpropoxyl- N- [d R.2 S)-2 -ethenyl- 1 - { [Y 1 -methylcyclopropyDsulfonyl] carbamoyl I cvclopropyl] -3.6-dioxo- 1, 1 a.3 ,4,5,6.9.10.18.19.20.21.22.22a-tetradecahvdro-8H-7.10-methanocvclopropa
18.191 1.10.3.61dioxadiazacyclononadecino l l,12-b1quinoline-8-carboxamide
Figure imgf000212_0001
Example 249 was prepared using the procedures described for the synthesis of Example 243. 3,3-Difluoroazetidine hydrochloride was used instead of 3,3- difluorocyclobutanamine in the final alkylation step to provide the title compound. LRMS m/z 925.6 (M+H)+
Example 250: aaR.5S.8S.10R.22aRV5-cvclohexyl-N-r(lR.2SV2-ethenyl-l-(ra -methyl cyclopropyDsulfonyl] carbamoyl } cvclopropyl] - 17- [3 -(3 -fluoroazetidin- 1 - vDpropoxy] -3.6-dioxo- 1.1 a.3.4.5.6.9.10.18.19.20.21 ,22,22a-tetradecahvdro-8H-7.10-methanocvclopropa
18, 19] [ 1 , 10,3 ,6]dioxadiazacyclononadecino Γ 11 , 12-b] quinoline-8-carboxamide
Figure imgf000212_0002
Example 250 was prepared using the procedures described for the synthesis of Example 243. 3-fluoroazetidine hydrochloride was used instead of 3,3-difluorocyclobutanamine in the final alkylation step to provide the title compound. LRMS m/z 907.6 (M+H)+
Example 251 : (laR,5S,8S J0R,22aRV5-cvclohexyl-N-r(lR,2SV2-ethenyl-l-{rn -methyl cyclopropyDsulfonyl] carbamoyl } cyclopropyl] - 17- [3 -(4-methylpiperazin- 1 - yDpropoxy] -3,6- dioxo- 1,1 a,3 ,4,5,6,9, 10, 18, 19,20,21 ,22,22a-tetradecahydro-8H-7, 10-methanocyclo
propafl 8, 19] [1 , 10,3,6]dioxadiazacyclononadecino[l 1 , 12-blquinoline-8-carboxamide
Figure imgf000213_0001
Example 251 was prepared using the procedures described for the synthesis of Example 243. N-methylpiperazine was used instead of 3,3-difluorocyclobutanamine in the final alkylation step to provide the title compound. LRMS m/z 932.6 (M+H)+
Example 252: potassium {[qR.2SV2-ethenyl-l-((r(laR,5S.8S.10R.22aRV17-r(l-methyl piperidin-4-vnoxyl -3.6-dioxo-5-(tetrahydro-2H-pyran-4-vn- 1.1 a.3 ,4.5.6.9.10.18.19.20,21.22. 22a-tetradecahydro-8H-7, 10-methanocyclopropan 8.19] [1.10.3.61dioxadiazacyclo
nonadecino Γ 11.12-b] quinolin- 8 - yll carbonyl } amino'jcvclopropyl] carbonyl } [( 1 - methylcvclopropyPsulfonyllazanide
Figure imgf000214_0001
Step 1: (S)-methyl 2-((((lR,2R)-2^ent-4-yn-l-yl)cyclopropoxy)carbonyl)amino)-2-(tetrahydro- -pyran-4-yl)acetate
Figure imgf000214_0002
The title compound was prepared using the procedures described for Intermediate
Bl 1, Step 2. (S)-methyl 2-amino-2-(tetrahydro-2H-pyran-4-yl)acetate was reacted with the product obtained after Step 1 in the preparation of Intermediate Bl 1.
Step 2: (S)-2-(( ((1R, 2R)-2-(pent-4-yn-l-yl)cyclopropoxy)carbonyl)amino)-2-(tetrahydro-2H- pyran-4-yl)acetic acid
Figure imgf000214_0003
To a solution of the product from Step 1 (1.88 g, 5.81 mmol) in THF (20 ml) and
MeOH (10 mL) was added an aq. 2M solution of lithium hydroxide monohydrate (14.53 ml, 29.1 mmol). The reaction was stirred at 50°C for 20 hours at which stage TLC indicated no more starting material. The reaction was treated with 10% aq. KHS04 and extracted with EtOAc. The organic fractions were washed with brine, dried over sodium sulfate, evaporated and dried to provide the desired compound, which was used for the next step without purification. Step 3: potassium {[(1R, 2S)-2-ethenyl-l-({[ (laR, 5S, 8S, 1 OR, 22aR)-l 7-[ (l-methylpiperidin-4- yl)oxy]-3, 6-dioxo-5-(tetrahydro-2H-pyran-4-yl)-l, la, 3, 4, 5, 6, 9, 10,18,19, 20, 21, 22, 22a- tetradecahydroSH- 7, 10-methanocyclopropa[ 18, 19] [1,10,3, 6Jdioxadiazacyclo
nonadecino[ll,12-b]quinolin-8-yl]carbonyl}amino)cyclopropyl]carbonyl}[(l-
Figure imgf000215_0001
The product from Step 2 was converted to Example 252 using the procedures described for the synthesis of Example 210; the potassium salt was prepared upon treatment of the parent compound with 1 equivalent of 0.1N aqueous KOH solution. LRMS m/z 891.2
(M+H)+
Example 253: (1 aR,5S,8S, 10R,22aRV5-cvclohexyl-N-r(l R.2S V2-ethenyl- 1 - { Γ(1 -methyl cyclopropyDsulfonyllcarbamoyl|cyclopropyll-3,6-dioxo-17-('tetrahvdro-2H-pyran-4-yloxy)- 1 , 1 a,3 ,4,5 ,6,9, 10, 18, 19,20,21 ,22,22a-tetradecahydro-8H-7, 10-methanocyclopropa
[ 18 J 9] [ 1 , 10,3 ,61dioxadiazacyclononadecino [11,12-blquinoline-8-carboxamide
Figure imgf000215_0002
Example 253 was prepared by utilizing the procedures described for the synthesis of Example 211. Tetrahydro-2H-pyran-4-ol was used instead of l-methylpiperidine-4-ol for the Mitsunobu reaction. LRMS m/z 876.6 (M+H)+
Example 254: tert-butyl 9-(r(laR,5S.8SJ0 ,22aRV5-tert-butyl-8-l|'flR.2SV2-etfaenyl-l-ir(l- memylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl carbamoy -3,6-dioxo-
1 , 1 a,3 ,4,5 ,6.9.10.18.19.20,21.22,22a-tetradecahvdro-8H-7, 10- methanocyclopropa 18, 19] (T , 10,3 ,6]dioxadiazacyclononadecino[ 11 , 12-b]quinolin- 17-yl]oxy} -3- oxa-7-azabicyclo 3.3.1 lnonane-7-carboxylate
Figure imgf000216_0001
Step 1: methyl (1 aR,5S,8S, 10R,22aR)-5-tert-butyl-l 7-{syn-[7-(tert-butoxycarbonyl)-S-oxa-7- azabicyclof 3.3.1 ]non-9-yl]-oxy}-3, 6-dioxo-l, la, 3, 4, 5, 6, 9, 10,18,19, 20, 21, 22, 22a-tetradecahydro- 8H- 7, 10-methanocyclopropa [18, 19] [1, 10, 3, 6]dioxadiazacyclononadecino[l 1, 12-b ]quinoline-8- carboxylate
Figure imgf000216_0002
The title compound was prepared using the procedure described for the synthesis of Example 210, Step 1. (lR,5S)-tert-butyl 9-hydroxy-3-oxa-7-azabicyclo[3.3.1]nonane-7- carboxylate (1:2 mixture of anti:syn alcohols; prepared as described in International Patent Publication No. WO2009055331) was used instead of l-methylpiperidin-4-ol. The title compound (syn isomer) was separated from the anti isomer by column chromatography (0-40% EtOAc in hexane); the syn isomer eluted first and was collected as the minor isomer.
Step 2: tert-butyl 9-{[(laR,5S,8S,10R,22aR)-5-tert-butyl-8-{[(lR,2S)-2-ethenyl-l-{[(l- methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]carbamoyl}-3,6-dioxo- 1,1a, 3, 4, 5, 6, 9, 10,18,19, 20, 21, 22, 22a-tetradecahydro-8H- 7, 10- methanocyclopropa[18, 19] [1,10,3, 6]dioxadiazacyclononadecino[ll, 12-b]quinolin-l 7-yl]oxy}- -oxa- 7-azabicyclo[3.3.1 Jnonane- 7-carboxylate
Figure imgf000217_0001
Example 254 was prepared from the product of Step 1 by utilizing the procedi described for the synthesis of Example 210. LRMS m/z 991.2 (M+H)+
Example 255: tert-butyl 9-{raaR,5S,8S,10R,22aRV5-tert-butyl-8-{rnR,2SV2-ethenyl-l-{r(l- methylcvclopropyl sulfonyl]carbamoyl}cyclopropyl1carbamoyl|-3,6-dioxo-lJa,3,4,5,6,9J0, 18, 19.20.21.22.22a-tetradecahydro-8H-7.10-methanocyclopropaf 18.191 Γ 1.10.3 ,61
dioxadiazac yclononadecino 11 , 12-b] quinolin- 17-yl] oxy } -3 -oxa-7-azabicyclo [3.3.1 ]nonane-7- carboxylate
Figure imgf000217_0002
Step 1: methyl (laR,5S,8S,10R,22aR)-5-tert-butyl-17-{anti-[7-(tert-butoxycarbonyl)-3-oxa-7- azabicyclo[3.3.1 ]non-9-yl]-oxy}-3, 6-dioxo-l, la, 3, 4, 5, 6, 9, 10,18,19, 20, 21, 22, 22a-tetradecahydro- 8H- 7, 10-methanocyclopropa [18, 19] [1, 10,3,6 ]dioxadiazacyclononadecino[ 11, 12-b ] quinoline-8- carboxylate
Figure imgf000218_0001
The title compound was prepared using the procedure described for the synthesis of Example 210, Step 1. (lR,5S)-tert-butyl 9-hydroxy-3-oxa-7-azabicyclo[3.3.1]nonane-7- carboxylate (1:2 mixture of anti:syn alcohols; prepared as described in International Patent Publication No. WO2009055331) was used instead of l-methylpiperidin-4-ol. The title compound (anti isomer) was separated from the syn isomer by column chromatography (0-40% EtOAc in hexane); the anti isomer eluted after the syn isomer and was collected as the major isomer.
Step 2: tert-butyl 9-{[(laR,5S,8S 0R,22aR)-5-tert-butyl-8-{[(lR,2S)-2-ethenyl-l-{[(l- methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl ]carbamoyl}-3, 6-dioxo- 1, 1 a, 3, 4, 5, 6, 9,10,18, 19, 20, 21, 22, 22a-tetradecahydro-8H- 7, 10- methanocyclopropafl 8, 19] [1,10,3, 6] dioxadiazacyclononadecino [11 , 12-bJquinolin-l 7-ylJoxy}- -oxa-7-azabicyclo[3.3.1 Jnonane-7-carboxylate
Figure imgf000218_0002
Example 255 was prepared from the product of Step 1 by utilizing the procedures described for the synthesis of Example 210. LRMS m/z 991.2 (M+H)+
Example 256: 9-i r(laR,5S,8SJ0R,22aR)-5-tert-butyl-8-irriR,2S)-2-ethenyl-l-{ r(l- methylcvclopropyl sulfonyllcarbamoyl|cvclopropyl]carbamovU-3,6-dioxo- 1 , 1 a,3 A5 ,6,9 , 10.18.19,20,21 ,22.22a-tetradecahvdro-8H-7.10- methanocyclopropa[ 18, 19] [ 1,10,3 ,6]dioxadiazacyclononadecino [11,12-b]quinolin- 17-νΠοχν} -7-
Figure imgf000219_0001
Example 256 was prepared from Example 255 by utilizing the procedures described for the synthesis of Example 238. LRMS m/z 945.2 (M+H)+
Example 257: 9-{r(laR.5S.8S.10R.22aRV5-tert-butyl-8-(rflR.2SV2-ethenyl-l-{r(l- methylcyclopropyDsulfonyllcarbamoyl} cyclopropyl] carbamoyl} -3 ,6-dioxo- 1 , 1 a.3.4.5.6.9.10.18.19,20,21 ,22,22a-tetradecahydro-8H-7.10- methanocyclopropa[ 18 , 19] [ 1 , 10,3,6] dioxadiazacyclononadecino [ 11 , 12-b] quinolin- 17-yl] oxy ) -7- 2-methoxyethyl)-3-oxa-7-azoniabicyclo[3.3.nnonane formate
Figure imgf000219_0002
Example 257 was prepared from Example 255 by utilizing the procedures described for the synthesis of Example 237. LRMS m/z 949.2 (M+H)+
Example 258: 9-(rriaR.5S.8S.10R.22aRV5-tert-butyl-8-(rflR.2SV2-ethenyl-l-{r(l- methylcyclopropyl)sulfonyllcarbamovUcvclopropyl]carbarnoyl}-3,6-dioxo-
1.1 a.3.4.5.6.9.10.18.19,20,21 ,22.22a-tetradecahydro-8H-7.10- methanocyclopropa[18,191[l,10,3,61dioxadiazacvclononadecino[l l,12-blquinolin-17-ylloxy}-3- oxa-7-azoniabicyclo [3.3.1 ]nonane trifluoroacetate
Figure imgf000220_0001
Example 258 was prepared from Example 255 by utilizing the procedure described for the synthesis of Example 236, Step 1. LRMS m/z 891.2 (M+H)+. Example 259: 9-{rriaR.5S.8S.10R.22aR)-5-tert-butyl-8-{rriR.2SV2-ethenyl-l-irri-methyl cyclopropyl)sulfonyl1carbamoyl)cvclopropyl carbamovU-3,6-dioxo-l , 1 a,3,4,5,6,9, 10, 18, 19,20.21 ,22,22a-tetradecahydro-8H-7, 10-methanocyclopropa[ 18, 19] [ 1.10,3 ,6]dioxadiaza cyclononadecino [11,12-b] quinolin- 17-yl]oxy) -3-oxa-7-azoniabicyclo [3.3.1 ]nonane trifluoroacetate
Figure imgf000220_0002
Example 259 was prepared from Example 254 by utilizing the procedure described for the synthesis of Example 236, Step 1. LRMS m/z 891.2 (M+H)+
Example 260: (laR.5S.8S, 10R,22aRV5-tert-butyl-N-r(lR.2SV2-ethenyl-l - ( ΓΠ -methyl cvclopropyDsulfonyl]carbamovU cyclopropyl]- 17-[(7-ethyl-3 -oxa-7-azabicyclo[3.3.1 ]non-9-yl oxy|-3 ,6-dioxo- 1 , 1 a,3.4,5.6,9, 10.18.19.20.21 ,22,22a-tetradecahydro-8H-7.10-methano cyclopropa[ 18, 191 [ 1.10,3.6] dioxadiazacyclononadecino [ 11.12-b] quinoline- 8 -carboxamide
Figure imgf000221_0001
Example 260 was prepared from Example 254 by utilizing the procedure described for the synthesis of Example 239. LRMS m/z 919.2 (M+H)+. Example 261 : (laR.5S.8S.10R.22aRV5-tert-butyl-N-rriR.2SV2-ethenyl-l-(r(l-methyl cvclopropyl sulfonyllcarbamoyl>cvclopropyn-17-([7-('2-methoxyethyl -3-oxa-7-azabicvclo Γ3.3.11non-9-yll oxyl -3.6-dioxo- 1.1 a.3.4.5.6.9.10.18.19.20.21.22.22a-tetradecahydro-8H-7, 10- methanocyclopropa[ 18, 19] [ 1 , 10.3,61dioxadiazacyclononadecino[ 11.12-b1quinoline-8- carboxamide
Figure imgf000221_0002
Example 261 was prepared from Example 254 by utilizing the procedures described for the synthesis of Example 237. LRMS m z 949.2 (M+H)+.
Example 262: potassium {rriR.2SVl-({r(laR.5S.8S.10R.22aRV5-cyclohexyl-3.6-dioxo-17-r(l- r2-(trifluoromethoxy ethyllpiperidin-4-yl } oxy )- 1.1 a.3.4.5.6.9.10.18.19.20,21.22.22a- tetradecahydro-8H-7, 10-methanocyclopropa 18, 191 [1 , 10.3 ,61dioxadiazacyclononadecino l 1,12- blquinolin-S-yllcarbonyllamino'l^-ethenylcvclopropyncarbonyll d- methylcyclopropyDsulfonyllazanide
Figure imgf000222_0001
Example 262 was prepared by utilizing the procedures described for the synthesis of Example 236. 2-(Trifluoromethoxy)ethyl trifluoromethanesulfonate was used instead of 2,2,2-trifluoroethyl trifluoromethanesulfonate in the final alkylation step. LRMS m/z 987.2 (M+H)+.
Example 263: (laR.5S.8S.10R.22aRVN-r(,lR.2SV2-ethenyl-l-ira-methylcvclopropyn sulfonyl]carbamoyl}cvclopropyl]-17- (8-methyl-8-azabicvclo[3.2.1]oct-3-yl)oxy]-5-(l-methyl cyclohexylV3.6-dioxo- 1.1 a.3.4.5.6.9.10.18, 19,20,21.22.22a-tetradecahydro-8H-7.10-methano cyclopropaf 18, 19] [ 1 , 10,3,6]dioxadiazacyclononadecino|"l 1.12-b]quinoline-8-carboxamide
Figure imgf000222_0002
Example 263 was prepared by utilizing the procedures described for the synthesis of Example 232; tropine was used instead of l-methylpiperidin-4-ol. LRMS m/z 929.2 (M+H)+. Example 264: tert-butyl 4-(3-{rdaR.5S.8S.10R.22aRV5-cvclohexyl-8-{rriR.2SV2-ethenyl-l- { [(1 -methylcy clopropyf)sulfonyll carbamoyl } cyclopropyl] carbamoyl } -3 ,6-dioxo- 1.1 a.3.4.5.6.9.10.18,19,20.21.22.22a-tetradecahydro-8H-7.10-methanocyclopropa
[18, 19] [1,10,3,6] dioxadiazacyclononadecino [ 11 , 12-b] quinolin- 17- yl] oxy } propy Dpiperazine- 1 - carboxylate
Figure imgf000223_0001
Example 264 was prepared by utilizing the procedures described for the synthesis of Example 251; NBoc-piperazine was used instead of N-methylpiperazine. LRMS m/z 1019.2 (M+H)+.
Example 265: potassium ({(lR,2SVl-r(((laR,5S,8S.10R.22aRV5-cvclohexyl-3.6-dioxo-17-r3- (piperazin- 1 -vflpropoxyl -1,1 a,3,4,5,6,9, 10,18,19.20.21.22.22a-tetradecahvdro-8H-7.10- methanocyclopropa 18, 19] [ 1 , 10,3 ,6] dioxadiazacyclononadecino [11,12-blquinolin-8- yl } carbonvDamino] -2-ethenylcyclopropyl } carbonyl) Γ( 1 -methylcyclopropyDsulfonyl] azanide
Figure imgf000223_0002
Example 265 was prepared from Example 262 by utilizing the procedure described for the synthesis of Example 236, Step 1; the potassium salt was prepared upon treatment of the parent compound with 0.1N aqueous KOH solution. LRMS m/z 918.4 (M+H)+. Example 266: potassium fi(lR,2S -l-rr{naR.5S,8S.10R.22aRV5-cvclohexyl-17-rf4- methylpiperazin- 1 -vDmethyll -3 ,6-dioxo- 1.1 a.3.4.5.6.9.10.18.19.20.21.22.22a-tetradecahydro- 8H-7, 10-methanocyclopropa[l 8, 191 Π , 10,3 ,61dioxadiazacyclononadecinoi 11 , 12-blquinolin-8- yl|carbonvnamino1-2-ethenylcvclopropyl}carbonyl) (l-methylcyclopropynsulfonyl1azanide
Figure imgf000224_0001
Example 266 was prepared by utilizing the procedures described for the synthesis of Example 248. LRMS m/z 888.3 (M+H)+.
Example 267: tert-butyl 4-{r(laR,5S,8SJ0R.22aRV8-{r(lR.2SV2-ethenyl-l-{rri- methylcvclopropyDsulfonyll carbamoyl } cyclopropyl] carbamoyl} -5 -( 1 -methylcvclohexyiy 3 ,6- dioxo- 1.1 a.3 ,4,5,6,9, 10,18.19.20.21.22,22a-tetradecahvdro-8H-7, 10- methanocyclopropal" 18.19] 1 , 10,3 ,61dioxadiazacyclononadecino [11,12-b]quinolin- 17- yl1oxy}piperidine- 1 -carboxylate
Figure imgf000224_0002
Example 267 was prepared by utilizing the procedures described for Example 263; NBoc-piperidine was used instead of tropine. LRMS m/z 989.2 (M+H)+.
Example 268 : ( 1 aR.5S.8S, 10R.22aRVN-r(l R,2SV2-ethenyl- 1 - { \( 1 -methylcyclopropyD sulfonyl1carbamoyl}cvclopropyll-5-(l-methylcyclohexyl)-3,6-dioxo-17-(piperidin-4-yloxyV 1.1 a.3 ,4.5.6.9, 10,18.19,20.21.22,22a-tetradecahydro-8H-7.10-methanocvclopropar 18.191
[l,10.3,6]dioxadiazacvclononadecino l l,12-b1quinoline-8-carboxamide
Figure imgf000225_0001
Example 268 was prepared from Example 267 by utilizing the procedure described for the synthesis of Example 236, Step 1. LRMS m/z 889.2 (M+H)+. Example 270: (1 aR,5 S.8S, 10R.22aRVN-f(l R,2SV2-ethenyl- 1 - i Γ(Ί -methylcyclopropyn sulfonyl] carbamoyl } cyclopropyll -5-d -methylcyclohexyl)- 17- [3 -(1 ,4-oxazepan-4-vDpropoxy1 - 3,6-dioxo- 1 , 1 a,3,4,5,6,9, 10,18,19,20,21 ,22,22a-tetradecahydro-8H-7, 10-methanocyclopropa [ 18, 19] [ 1 , 10,3 ,61dioxadiazacyclononadecino [11, 12-blquinoline-8-carboxamide
Figure imgf000225_0002
Example 270 was prepared by utilizing the procedures described for the synthesis of Example 240. LRMS m/z 947.2 (M+H)+.
Example 271 : riaR.5S,8S,10R,22aRV5-cvclohexyl-N-rriR.2S -2-ethenyl-l-{ rri-methyl cvclopropyDsulfonyl]carbamoyUcvclopropyll-17-({l-[2-(methylsulfonyl)ethyl piperidin-4- yl I oxy)-3 ,6-dioxo- 1 , 1 a.3 ,4,5 ,6,9, 10, 18 J 9,20.21 ,22,22a-tetradecahydro-8H-7.10-methano cyclopropa[ 18,19"||"1,10,3.6 dioxadiazacyclononadecino [ 11.12-b] quinoline- 8 -carboxamide
Figure imgf000226_0001
To a solution of the product from Step 1, Example 236 (50 mg, 0.057 mmol) in CH2C12 (3 ml) was added DIPEA (0.030 ml, 0.171 mmol) followed by methyl vinyl sulfone (12.10 mg, 0.114 mmol). The reaction was stirred in a sealed vial for 16h at which stage LCMS indicated complete conversion to one peak corresponding to a product with desired mass. After removing the solvent the crude mixture was purified by PTLC (5% MeOH in CH2CI2) and then repurified by PTLC using 40% acetone in hexane to furnish the title compound. LRMS m/z 981.6 (M+H)+. Example 272: 4-ir(laR,5S,8SJ0R,22aRV5-cyclohexyl-8-{ (lR.2SV2-ethenyl-l-(r(l- methylcyclopropyl)sulfonyllcarbamoyl}cvclopropyl]carbamoyl}-3,6-dioxo- 1 , 1 a,3 ,4,5 ,6,9.10, 18, 19.20,21 ,22,22a-tetradecahydro-8H-7.10-methanocyclopropa
[18, 19] [1 , 10,3 ,61dioxadiazacyclononadecino|~ 11 , 12-b]quinolin- 17-ν1]οχνΙ - 1 -(2- fluoroethvDpiperidinium formate
Figure imgf000226_0002
The product from Step 1, Example 236 was reacted with l-bromo-2-fluoro ethane as described for the synthesis of Example 237 to give Example 272. LRMS m/z 921.2 (M+H)+.
Example 273: tert-butyl 3-{rriaR.5S.8S.10R.22aR -5-tert-butyl-8-(r(lR.2S -2- ethenyl- 1 - ( |Y 1 -methylcyclopropyPsulfonyl] carbamoyl ) cyclopropyll carbamoyl } -3 ,6-dioxo- 1 , 1 a,3.4,5,6.9,10,18, 19.20.21 ,22,22a-tetradecahydro-8H-7.10- methanocyclopropa[ 18, 19] [1,103.6] dioxadiazacyclononadecino f 11 , 12-b]quinolin- 17-yl]oxy| -8- azabicyclo [3.2.1] octane-8-carboxylate
Figure imgf000227_0001
Example 273 was prepared using the procedures described for the synthesis of Example 210. The endo isomer of tert-butyl 3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate (as prepared in International Patent Application No. WO2009055331) was used instead of 1- methylpiperidin-4-ol. LRMS m/z 975.4 (M+H)+.
Example 274: 3-( Γ(Ί aR.5S.8S, 10R,22aRV5-tert-butyl-8-{ [(lR.2S -2-ethenyl-l -{ [(1 - methylcyclopropyl sulfonyl]carbamoyl} cyclopropyl] carbamoyl} -3 ,6-dioxo- 1.1 a.3.4.5.6.9, 10.18.19.20.21.22.22a-tetradecahydro-8H-7.10- methanocyclopropa[ 18.19] [1.10,3.6] dioxadiazacyclononadecino [11.12-b]quinolin- 17-yl]oxy} -8- azoniabicyclo [3.2.1] octane trifluoroacetate
Figure imgf000227_0002
Example 274 was prepared from Example 273 by utilizing the procedure described for the synthesis of Example 236, Step 1. LRMS m/z 875.4 (M+H)+
Example 275: potassium iraR^SVl-rirdaR.SS^S.lOR^aR S-tert-butyl-S.e-dio o-n-irS- (2,2,2-trifluoroethvn-8-azabicvclo[3.2.11oct-3-yl1oxy}-l.la,3,4,5,6,9,10,18,19,20,21.22,22a- tetradecahydro-8H-7, 10-methanocyclopropa[ 18 , 19] [ 1.10.3.6]dioxadiazacyclononadecino [11.12- b] quinolin- 8 -yl] carbonyl } amino)-2-ethenylcvclopropyl] carbonyl } [( 1 - methylcvclopropyl)sulfonyl]azanide
Figure imgf000228_0001
Example 274 was converted into Example 275 by utilizing the procedures described for the synthesis of Example 236; the potassium salt was prepared upon treatment of the free base with 0. IN aqueous KOH solution. LRMS m/z 957.4 (M+H)+.
Example 276: potassium ir(lR.2S)-l-rir(laR,5S,8SJ0R.22aRV5-tert-butyl-17-ir8-(2- methoxyethylV8-azabicvclor3.2.11oct-3-yl1oxy>-3.6-dioxo-l.la.3A5.6.9.10.18.19.20.2L22.22a- tetradecahydro-8H-7, 10-methanocyclopropa[ 18, 19] [ 1 , 10,3 ,6]dioxadiazacyclononadecino [11,12- b] quinolin- 8 - yl] carbonyl 1 amino)-2-ethenylcyclopropyl] carbonyl } [( 1 - methylcyclopropyDsulfonyllazanide
Figure imgf000228_0002
Example 274 was converted into Example 276 by utilizing the procedures described for the synthesis of Example 237; the potassium salt was prepared upon treatment of the free base with 0. IN aqueous KOH solution. LRMS m/z 933.4 (M+H)+.
Example 277: potassium ({(lR.2SVl-r((riaR.5S.8S.10R,22aRV5-tert-butyl-17-r(8-ethyl-8- azabicvclor3.2.11oct-3-vnoxyl-3.6-dioxo-lJa,3.4.5.6,9,10.18a9,20.21,22.22a-tetradecahvdro- 8H-7, 10-methanocyclopropa[l 8, 19] [ 1 , 10,3,61dioxadiazacyclononadecino[ 11 , 12-blquinolin-8- yl } carbony amino] -2-ethenylcvclopropyl) carbonyD ( 1 -methylcyclopropynsulfonyllazanide
Figure imgf000229_0001
Example 274 was converted into Example 277 by utilizing the procedures described for the synthesis of Example 238; the potassium salt was prepared upon treatment of the free base with 0. IN aqueous KOH solution. LRMS m/z 903.4 (M+H)+.
Example 278: tert-butyl 3-iff laR.5S.8S 0R.22aRV5-1^-b ityl-8-(r(lR^SV2-ethenyl-l-{rf 1- methylcvclopropyDsulfonyllcarbamoyl) cyclopropyl] carbamoyl > -3 ,6-dioxo- 1 , 1 a.3.4.5.6.9.10, 18, 19.20,21.22.22a-tetradecahvdro-8H-7.10- methanocyclopropa[ 18.191 |T .10,3 ,61dioxadiazacyclononadecino|T 1 , 12-blquinolin- 17-yl]oxy> -8- azabicyclo[3.2.1 ]octane-8-carboxylate
Figure imgf000229_0002
Example 210. The exo isomer of tert-butyl 3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate (as prepared in International Patent Publication No. WO2009055331) was used instead of 1- methylpiperidin-4-ol. LRMS m/z 975.4 (M+H)+.
Example 279: 3-{ (laR.5S.8S.10R.22aRV5-tert-butyl-8-(rriR.2SV2-ethenyl-l-i[n- methylcvclopropyl)sulfonyllcarbamoyl}cvclopropyllcarbamoyl}-3,6-dioxo- 1.1 a.3.4.5.6.9.10.18.19,20,21 ,22,22a-tetradecahydro-8H-7.10- methanocyclopropa 18, 19] [ 1 , 10.3.6]dioxadiazacyclononadecino [11.12-blquinolin- 17-ν1]οχν> -8- azoniabicyclor3.2.1 ]octane trifluoroacetate
Figure imgf000230_0001
Example 279 was prepared from Example 278 by utilizing the procedure described for the synthesis of Example 236, Step 1. LRMS m/z 875.4 (M+H)+. Example 280: potassium i r(lR.2SVl-({rdaR,5S,8S.10R.22aRV5-tert-butyl-17-( r8-r2- methoxyethylV8-azabicvclor3.2.noct-3-yl1oxyl-3.6-dioxo-l,la.3,4,5,6,9,10a8,19,20,21,22,22a- tetradecahydro-8H-7, 10-methanocyclopropari 8, 19] [1 , 10,3 ,61dioxadiazacyclononadecino[ 11,12- b]quinolin-8-yllcarbonyl } aminoV 2-ethenylcyclopropyllcarbonyll |Y 1 - methylcyclopropyDsulfonyl azanide
MeQ
Figure imgf000230_0002
Example 279 was converted into Example 280 by utilizing the procedures described for the synthesis of Example 237; the potassium salt was prepared upon treatment of the free base with 0. IN aqueous KOH solution. LRMS m/z 933.5 (M+H)+. Example 281 : potassium (((lR.2SVl-r((flaR.5S.8S.10R.22aRV5-tert-butyl-17-r(8-etfayl-8- azabicvclon .2.11οοτ-3-νΓ)οχν1-3 ,6-dioxo- 1.1 a,3 ,4.5.6.9, 10.18.19,20.21 ,22.22a-tetradecahvdro- 8H-7, 10-methanocyclopropa[ 18 , 191 [ 1 , 10,3 ,61dioxadiazacyclononadecino [1 1,12-blquinolin-8- yl } carbonvDaminol -2-ethenylcyclopropyl 1 carbonyl') [( 1 -methylcyclopropyDsulfonyllazanide
Figure imgf000231_0001
Example 279 was converted into Example 281 by utilizing the procedures described for the synthesis of Example 238; the potassium salt was prepared upon treatment of the free base with 0. IN aqueous KOH solution. LRMS m/z 903.4 (M+H)+.
Example 282: tert-butyl 3-i r(,laR.5S,8Sa0R,22aRV5-cvclohexyl-8-ir(lR,2SV2-ethenyl-l-(r(l- methylcvclopropyl)sulfonyllcarbamoyl)cvclopropyl1carbamov -3,6-dioxo- l.la.3.4,5,6,9a0.18a9,20,21,22,22a-tetradecahvdro-8H-7.10- methanocyclopropaf 18, 19] [ 1.10,3,61dioxadiazacyclononadecino[ 1 1 , 12-b]quinolin- 17-yl]oxyl -8- azabic clo[3.2.11octane-8-carboxylate
Figure imgf000231_0002
Example 282 was prepared by utilizing the procedure described for the synthesis of Example 273. LRMS m/z 945.3 (M+H-tBu)+. Example 283: potassium ( rfl R.2SVl-f(rflaR.5S.8S.10R.22aRV17-f8-azabicvclor3.2.noct-3- yloxy>5-cvclohexyl-3.6-dioxo- 1.1 a .3.4.5,6,9.10.18.19.20.21 ,22.22a-tetradecahvdro-8H-7.10- methanocyclopropa[ 18.19] [ 1 , 10,3 ,61dioxadiazacyclononadecinor 11 , 12-blquinolin-8- yl]carbonvUaminoV2-ethenylcvclopropyl]carbonyl| [(l-methylcyclopropynsulfonyl1azanide
Figure imgf000232_0001
Example 283 was prepared from Example 282 by utilizing the procedure described for the synthesis of Example 274; the potassium salt was prepared upon treatment of the free base with 0. IN aqueous KOH solution. LRMS m/z 901.2 (M+H)+.
Example 284 : (1 aR.5 S.8S.10R,22aRV5-cvclohexyl-N-i( 1 R.2S V2-ethenyl- 1 - { Γ(1 -methyl cvclopropyl)sulfonyl]carbamoyllcyclopropyl]-17-{[8-(2-methoxyethylV8-azabicyclo[3.2.1]oct- 3 -ylloxyl -3.6-dioxo- 1.1 a,3 ,4.5 ,6,9.10.18.19.20.21.22.22a-tetradecahvdro-8H-7, 10-methano cyclopropa l 8, 19] [ 1 , 10,3,61dioxadiazacyclononadecinof 11 , 12-blquinoline-8-carboxamide
Figure imgf000232_0002
Example 284 was prepared from Example 283 by utilizing the procedure described for the synthesis of Example 276. LRMS m/z 959.4 (M+H)+.
Example 285 : flaR.5S.8S.10R.22aRV5-cyclohexyl-N-r(lR.2SV2-ethenyl-l -{ Γίΐ -methyl cvclopropyf)sulfonyllcarbamoyl}cyclopropyll-17-r(8-methyl-8-azabicyclor3.2.11oct-3-yl)oxyl- 3 ,6-dioxo- 1 , 1 a.3.4,5.6.9, 10, 18, 19,20.21 ,22.22a-tetradecahydro-8H-7.10-methano
cyclopropa 18, 19] 1.10,3,6] dioxadiazacyclononadecino 11 , 12-b] quinoline-8 -carboxamide
Figure imgf000233_0001
Example 285 was prepared by utilizing the procedures described for the synthesis of Example 211; tropine was used instead of 1 -methylpiperidin-4-ol. LRMS m/z 915.2 (M+H)+. Example 286: daR.5S.8S.10R,22aR -5-cvclohexyl-N-[aR.2SV2-ethenyl-l-ira -methyl cyclopropyDsulfonyl] carbamoyl > cycloprop yl] - 13 -fluoro- 17- |Y 1 -methylpiperidin-4-yl)oxy] -3,6- dioxo- 1 , 1 a,3 ,4,5 ,6,9, 10, 18, 19,20,21 ,22,22a-tetradecahydro-8H-7, 10-methanocyclopropa
Figure imgf000233_0002
Example 286 was prepared by utilizing the procedures described for the synthesis of Example 211. LRMS m/z 907.6 (M+H)+.
Example 287: tert-butyl 7-(rnaR.5S,8S,10R,22aRV5-cvclohexyl-8-{r(lR.2SV2-ethenyl-l-{r(l- methylcvclopropyPsulfonyllcarbamoyl } cyclopropyl] carbamoyl } -3 ,6-dioxo- 1 , 1 a.3 ,4.5.6.9, 10,18,19.20,21 ,22,22a-tetradecahydro-8H-7.10- methanocyclopropaf 18,19] [1,10,3,6] dioxadiazacyclononadecino 11 , 12-b] quinolin- 17-yl] oxy> -3 - oxa-9-azabicyclo [3.3.1 lnonane-9-carboxylate
Figure imgf000234_0001
The syn isomer of tert-butyl 7-hydroxy-3-oxa-9-azabicyclo[3.3.1]nonane-9- carboxylate (as prepared in International Patent Publication No. WO2009055331) was converted into Example 287 by utilizing the procedures described for the synthesis of Example 282.
LRMS m/z 961.2 (M+H-tBu)+.
Example 288: (laR,5S.8S.10R.22aRV5-cvclohexyl-N-r(lR.2SV2-ethenyl-l-{rq- methylcyclopropyDsulfonyll carbamoyl } cyclopropyl]- 17-(3-oxa-9-azabicvclo[3.3.1 ]non-7- yloxy V 3.6-dioxo- 1 , 1 a,3 ,4,5.6,9, 10,18,19,20,21 ,22,22a-tetradecahydro-8H-7, 10- methanocyclopropa 18, 19] [" 1 , 10,3 ,61dioxadiazacyclononadecinor 11 , 12-b]quinoline-8- carboxamide
Figure imgf000234_0002
Example 288 was prepared by utilizing the procedure described for the synthesis of Example 274. LRMS m/z 917.2 (M+H)+.
Example 289: (laR.5S.8S.10R.22aR)-5-cyclohexyl-N-r(lR.2SV2-ethenyl-l-i (,l-methyl cyclopropyl)sulfonyllcarbamoyl>cyclopropyn-17-([9-(2-methoxyethylV3-oxa-9-azabicyclo Γ3.3.1 lnon-7-yll oxyl -3 ,6-dioxo- 1.1 a.3 ,4.5 ,6.9, 10, 18, 19,20.21 ,22.22a-tetradecahydro-8H-7, 10- methanocyclopropaf 18, 19] [ 1 , 10,3,61dioxadiazacyclononadecino l 1.12-blquinoline-8- carboxamide
Figure imgf000235_0001
Example 288 was converted into Example 289 by utilizing the procedures described for the synthesis of Example 47. LRMS m/z 975.2 (M+H)+. Example 290: 7-(r(laR.5S.8S.10R.22aRV5-cvclohexyl-8-irriR,2SV2-ethenyl-l-{ra- methylcvclopropyDsulfonyl] carbamoyl ) cyclopropyl] carbamoyl } -3 ,6-dioxo- 1.1 a.3.4.5.6.9.10,18,19,20.21.22.22a-tetradecahydro-8H-7.10- methanocyclopropa[ 18, 19 [1 , 10,3 ,61dioxadiazacyclononadecino[ 11 , 12-blquinolin- 17-yl"|oxy} -9-
Figure imgf000235_0002
Example 288 was converted into Example 290 by utilizing the procedures described for the synthesis of Example 48. LRMS m/z 945.2 (M+H)+.
Example 291 : 3-i [flaR,5S,8S,10R.22aRV5-cyclohexyl-8-{rqR,2SV2-ethenyl-l-{[ri- methylcyclopropyl)sulfonyl]carbamoyl } cyclopropyl] carbamoyl } -3 ,6-dioxo- 1.1 a.3.4.5.6.9.10.18.19.20.21.22.22a-tetradecahvdro-8H-7.10- methanocyclopropa[ 18, 19] [ 1 , 10,3 ,6 dioxadiazacyclononadecino [11,12-blquinolin- 17-yl]oxyl - 1 - methylpiperidinium formate
Figure imgf000236_0001
Example 291 was prepared by utilizing the procedures described for the synthesis of Example 211; l-methylpiperidin-3-ol was used instead of l-methylpiperidin-4-ol. LRMS m/z 889.2 (M+H)+.
Example 292: tert-butyl (3S.4RV4-irriaR.5S.8S.10R.22aRV5-cvclohexyl-8-{r(lR.2S)-2- ethenyl- 1 - { [Y 1 -methylcyclopropyDsulfonyl] carbamoyl } cyclopropyl] carbamoyl } -3 ,6-dioxo- 1 , 1 a ,3 ,4,5,6,9, 10,18,19,20,21.22.22a-tetradecahvdro-8H-7.10- methanocyclopropa 18, 19] [ 1,10,3,61dioxadiazacyclononadecino|T 1 , 12-b]quinolin- 17-yl]oxy} -3- fluoropiperidine- 1 -carboxylate
Figure imgf000236_0002
The trans isomer of tert-butyl 3 -fluoro-4-hydroxypiperidine-l -carboxylate (as prepared in International Patent Publication No. WO 2011036576) was converted into Example 292 by utilizing the procedures described for the synthesis of Example 282. The substituents at the 3 and 4 position of the piperidine group in the title compound are in cis orientation; only relative stereochemistry is shown. Example 292 is a diastereomeric mixture. LRMS m/z 993.2 (M+H-fBu)+. Example 293: r3S,4RV4-{raaR,5S,8S.10R.22aRV5-cvclohexyl-8-{rdR.2SV2-ethenyl-l-ir(l- methylcvclopropyl sulfonyl1carbamoyl}cvclopropyllcarbamoyl}-3,6-dioxo-
1.1 a.3.4.5.6.9.10, 18, 19,20.21 ,22.22a-tetradecahydro-8H-7.10- methanocyclopropa[ 18, 19] [ 1.10,3 ,61dioxadiazacyclononadecino[ 11 , 12-b]quinolin- 17-yl]oxy} -3- fluoropiperidinium chloride
Figure imgf000237_0001
Example 292 was converted into Example 293 by utilizing the procedure described for the synthesis of Example 236, Step 1. LRMS m/z 893.2 (M+H)+. Example 294: potassium (r(lR.2SVl-((rriaR.5S,8S.10R.22aRV5-cyclohexyl-17-ir(3S.4RV3- fluoro- 1 -methylpiperidin-4- yl"|oxy} -3 ,6-dioxo- 1 , 1 a.3.4.5.6.9.10.18.19.20.21 ,22,22a- tetradecahydro-8H-7, 10-methanocyclopropa 18, 19] 1 , 10,3,6]dioxadiazacyclononadecino[ 11,12- blquinolin-8-yl1carbonyl}aminoV2-ethenylcyclopropyllcarbonyl}[(l-
Figure imgf000237_0002
Step 1: methyl (1 aR,5S,8S 0R,22aR)-5-cyclohexyl-l 7-[(cis-3-fluoropiperidin-4-yl)oxy]-3,6- dioxo-1, la, 3, 4, 5, 6, 9, 10,18,19, 20, 21, 22, 22a-tetradecahydro-8H- 7, 10-methanocyclopropa
[18,19] '[1, 10, 3, 6]dioxadiazacyclononadecino[l 1, 12-b Jq inoline-8-carboxylate
Figure imgf000238_0001
The trans isomer of tert-butyl 3-fluoro-4-hydroxypiperidine-l-carboxylate (as prepared in International Patent Publication No. WO 2011036576) was converted into the title compound by utilizing the procedures described in Example 225, steps 1 and 2.
Step 2: methyl (laR, 5S, 8S, 1 OR, 22aR)-5-cyclohexyl-l 7-[(cis-3-fluoro-l-methylpiperidin-4- yl)oxy]-3, 6-dioxo-l, la, 3, 4, 5, 6, 9, 10,18,19, 20, 21, 22, 22a-tetradecahydro-8H- 7, 10- methanocyclopropa [18,19][1,10,3, 6]dioxadiazacyclononadecino[ll, 12-b]quinoline-8- carboxylate
Figure imgf000238_0002
The product from step 1 (90 mg, 0.132 mmol), formaldehye (0.107 ml, 1.322 mmol), and acetic acid (11.91 mg, 0.198 mmol) were dissolved in dichloromethane (1.322 ml) and allowed to stir for 30 minutes. Sodium triacetoxyborohydride (84 mg, 0.397 mmol) was added and the reaction was stirred overnight at room temperature, after which it was quenched with water and extracted (x3) with ethyl acetate. The combined organics were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. Purification by PTLC (25% acetone in hexane) provided the title compound.
Step 3: potassium {[(1R, 2S)-l-({[ (laR, 5S, 8S, 1 OR, 22aR)-5-cyclohexyl-l 7-{[(3S, 4R)-3-fluoro-l- methylpiperidin-4-yl ]oxy}-3, 6-dioxo-l, la, 3, 4, 5, 6, 9,10,18,19, 20, 21, 22, 22a-tetradecahydro-8H- 7, 10-methanocyclopropa[ 18, 19] [1, 10,3,6 Jdioxadiazacyclononadecinof 11, 12-b ]quinolin-8- yl ] carbonyl}amino)-2-ethenylcyclopropyl] carbonyl} [ ( I -methylcyclopropyl)sulfonyl Jazanide
Figure imgf000239_0001
The product from Step 2 was converted into Example 294 by utilizing the procedures described for the synthesis of Example 225, steps 4 and 5.
Example 295: riaS.5S.8S.10R,22aSV5-tert-butyl-N-iriR.2SV2-ethenyl-l-r(l- methylcyclopropanesulfonamido carbonyllcyclopropyl 1 - 17- |Y 1 -methylpiperidin-4-v oxy] -3,6- dioxo- Ua.3.4.5.6.9.10.18.19,20,21 ,22.22a-tetradecahvdro-8H-7.10- methanocyclopropa[ 18, 19] [ 1 , 10,3 ,6]dioxadiazacyclononadecino [ 11 , 12-b] [ 1 ,61naphthyridine-8- carboxamide
Figure imgf000239_0002
Metallic sodium l.OOg (43 mmol) was dissolved in 30 mL of ethanol at room temperature to form sodium ethoxide. 25 mL of this solution was added to a mixture of la (5.00 g, 32.9 mmol) and diethyl malonate (5.26 g, 32.9 mmol) and heated at 150°C for 20 hours. The reaction mixture was allowed to cool to room temperature and diluted with ether. The solid separating out was filtered and used as it is in next step as it is without any further purification. Step 2: 4-hydroxy-2,6-naphthyridin-l(2H)-one hydrobromide
Figure imgf000240_0001
The sodium salt lc from previous step was dissolved in hydrobromic acid (100 mL) and heated at reflux for 12 hours. The reaction mixture was concentrated in vacuo and the solid Id was used as it is in next step.
Step 3: 3-bromo-4-hydroxy-2,6-naphthyridin-l(2H)-one hydrobromide
Figure imgf000240_0002
A solution of naphtyridinone Id (241 mg, 1.49 mmol) in acetic acid (3.00 mL) was treated with bromine (77 micro liters, 1.49 mmol) and stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo, triturated with ether and filtered. The filtered solid le (1.25 g, 84%) was used as it is in the next step.
Step 4: 4-(benzyloxy)-3-bromo-2,6-naphthyridin-l(2H)-one
Figure imgf000240_0003
A suspension of le (2.75 g, 6.83 mmol) in THF (20 mL) was treated with potassium tert-butoxide (2.30 g, 20.48 mmol), benzyl bromide (1.17 g, 6.83 mmol) and stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and treated with water. The solid separating out was filtered and dried in vacuo. The residue If (1.25, 55.3%) was used as it is in next step.
Step 5: (2S,4R)-l-tert-butyl 2-methyl 4-((4-(benzyloxy)-3-bromo-l,6-naphthyridin-2- yl)oxy)p rrolidine-l,2-dicarboxylate
Figure imgf000241_0001
A solution of naphtyridine If (1.25 g, 3.77 mmol), triphenylphosphine (1.98 g,
7.55 mmol), and cis-4-hydroxyproline lg (1.29 g) in CH2CI2 (40 mL) was cooled to 0°C and treated with a solution of DIAD (1.145 g) in CH2C12 (10 mL). The reaction mixture was stirred at room temperature for overnight concentrated in vacuo and purified by silica gel
chromatography using Acetone/Hexanes to yield product lh (610 mg, 29%) as a yellow solid. Step 6: (S)-tert-butyl 3,3-dimethyl-2-((((lR,2R)-2-(pent-4-yn-l- yl)cyclopropoxy)carbonyl)amino)butanoate
Figure imgf000241_0002
A solution of succinyl carbonate li (5.42 g, 20.43 mmol) in dry acetonitrile (50 mL) was treated with tert-butylglycine ferr-butyl ester (4.57 g, 20.43 mmol) and cooled to 0°C. The reaction mixture was treated with triethyl amine (2.95 mL, 20.43 mmol) and stirred at room temperature for 36 hours. The reaction mixture was concentrated in vacuo and extracted into EtOAc (300 mL). The combined organic layers were dried (MgS04), filtered, concentrated in vacuo and purified by silica gel chromatography to yield product lj (4.2 g, 61%).
Step 7: (S)-tert-butyl 3,3-dimethyl-2-((((lR,2R)-2-((E)-5-(tributylstannyl)pent-4^
yl)cyclopropoxy)carbonyl)amino)butanoate and (S)-tert-butyl 3,3-dimethyl-2-((((lR,2R)-2-(4- (tributylstannyl)pent-4-en-l-yl)cyclopropoxy)carbonyl)amino)butanoate
Figure imgf000242_0001
A solution of alkyne lj (2.00 g, 5.93 mmol) in THF (50 mL) was cooled to 0°C and treated with Pd(PPh3)2Cl2 and tributyltin hydride (1.73 g, 5.93 mmol). The reaction mixture was stirred at room temperature for 0.5 hours and concentrated in vacuo. The residue was taken in hexane and filtered through a plug of celite. The filtrate was concentrated in vacuo and purified by silica gel chromatography to yield stannanes lk and 11 as a inseparable mixture (1.99 g, 53%).
Step 8: (2S,4R)-l-tert-butyl 2-methyl 4-((4-(benzyloxy)-3-((E)-5-((lR,2R)-2-((((S)-l-(tert- butoxy)-3,3-dimethyl-l-oxobutan-2-yl)carbamoyl)oxy)cyclopropyl)pent-l-en-l-yl)-l,6- naphthyridin-2-yl)oxy)pyrrolidine-l,2-dicarboxylate and (2S,4R)-l-tert-butyl 2-methyl 4-((4- (benzyloxy)-3-(5-((lR,2R)-2-((((S)-l-(tert-butoxy)-3,3-dimethyl-l-oxobutan-2-yl)
carbamoyl)oxy)cyclopropyl)pent-l-en-2-yl)-l,6-naphthyridin-2-yl)oxy)pyrrolidine-l,2- dicarboxylate
Figure imgf000242_0002
A solution of stannanes lk & 11 (225 mg, 0.358 mmol), bromide lh (100 mg, 0.179 mmol) and Pd(PPh3)2Cl2 (20.7 mg) in dioxane (3.0 mL) was degassed and heated at 115°C for 14 hours. The reaction mixture was cooled and taken in EtOAc, filtered through a plug of celite. The filtrate was concentrated in vacuo and purified by silica gel chromatography to yield coupled product lm (60 mg).
Step 9: (2S,4R)-l-tert~butyl 2-methyl 4-((3-(5-((lR,2R)-2-((((S)-l-(tert-butoxy)-3,3-dimethyl-l- oxobutan-2-yl)carbamoyl)oxy)cyclopropyl)pentyl)-4-hydroxy-l,6-naphthyridin-2- yl)oxy)pyrrolidine-l,2-dicarboxylate
Figure imgf000243_0001
A solution of benzylated derivative lm (130 mg, 0.159 mmol) in methanol was treated with palladium hydroxide on carbon (10%, 130 mg) and hydrogenated with hydrogen in a balloon for 12 hours. The reaction mixture was filtered through a plug of celite, concentrated in vacuo and purified by silica gel chromatography (Acetone, Hexanes) to yield reduced product lo.
Step 10: (2S,4R)-l-tert-butyl 2-methyl 4-((3-(5-((lR,2R)-2-((((S)-l-(tert-butoxy)-3,3-dimethyl-l- oxobutan-2-yl)carbamoyl)oxy)cyclopropyl)pentyl)-4-((l-methylpiperidin-4-yl)oxy)-l,6- naphthyridin-2-yl)oxy)pyrrolidine-l,2-dicarboxylate
Figure imgf000244_0001
A solution of lo (60 mg, 0.082 mmol), triphenylphosphine (216 mg, 0.823 mmol), 4-hydroxy-N-methylpiperidine (95 mg, 0.823 mmol) in THF (3.00 mL) in a two necked flask was filled with nitrogen and treated drop wise with DIAD (166 mg, 0.823 mmol). The reaction mixture was stirred at 40°C for 3 hours. The reaction mixture was concentrated in vacuo and purified by silica gel chromatorgraphy to yield lp. After first purification, the product co-eluted with N-methylpiperidinol. It was therefore subjected to second purification using methylene chloride and ammoniacal methanol, to yield product still containing some N- methylpiperidinol (162 mg).
Step 11: Methyl-(laS,5S,8S,10R,22aS)-5-tert-butyl- 17-[(l-methylpiperidin-4-yl)oxy]-3,6-dioxo- 1, 1 a, 3, 4, 5,6,9,10,18,19,20,21, 22, 22a-tetradecahydro-8H- 7, 10-methanocyclopropa
[18, 19] [1, 10,3,6 ]dioxadiazacyclononadecino[l 1, 12-b ][ 1, 6]naphthyridine-8-carboxylate
Figure imgf000245_0001
A solution of lp (85 mg, 0.103 mmol) dissolved in CH2C12 (2.0 mL) and TFA (2.0 mL) and stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo and used as it is in next step. The crude mixture was dried in vacuo for 48 hours, dissolved in DMF (2.00 mL) and cooled to 0°C. It was treated with NMM (41.6 mg, 0.412 mmol) and HATU (117 mg, 0.31 mmol) and stirred at 0°C for 0.5 hours and room temperature for 1 hour. The reaction mixture was diluted with 30 mL aqueous sodium bicarbonate solution and extracted into EtOAc (90 mL). The combined organic layers were dried (MgS04), filtered, concentrated in vacuo, and purified by silica gel chromatography using (CH2C12, and 10% methanol in CH2CI2) to yield cyclized product l as colorless solid (30 mg).
Step 12: Methyl-(laS,5S,8S, 10R,22aS)-5-tert-butyl- 17-[(l-methylpiperidin-4-yl)oxy]-3,6-dioxo-
1, 1 a, 3, 4, 5,6,9,10, 18, 19,20,21, 22, 22a-tetradecahydro-8H- 7, 10-methanocyclopropa
[18, 19 ][1, 10,3, 6 Jdioxadiazacyclononadecinof 11,12-b Jfl, 6]naphthyridine-8-carboxylic acid
Figure imgf000246_0001
A solution of lq (30.0 mg, 0.046 mmol) in water, methanol THF (0.6 mL each) was treated with aqueous solution of lithium hydroxide (0.5 M, 0.276 mL) and stirred overnight. The reaction mixture was quenched with acetic acid (30 μΐ) and extracted into CH2C12 (7x20 mL) and EtOAc (2x20 mL). The combined organic layers were dried (MgS04), filtered, concentrated in vacuo and used as it is in next step.
Step 13: (laS,5S,8S,10R,22aS)-5-tert-butyl-N-{(lR,2S)-2-ethenyl-l-[(l-methyl
cyclopropanesulfonamido)carbonyl]cyclopropyl}-l 7-[(l-methylpiperidin-4-yl)oxy]-3, 6-dioxo- l,la,3,4,5,6,9,10,18,19,20,21, 22, 22a-tetradecahydro-8H- 7, 10-methanocyclo
ide
Figure imgf000246_0002
A solution of lr (22 mg, 0.034 mmol), amine Is (12.6 mg, 0.052 mmol) and HATU (26.2 mg, 0.069 mmol) in DMF (0.6 mL) and CH2C12 (0.6 mL) was stirred at room temperature for 10 minutes and treated with 4-methyl morpholine (20 μΐ). The reaction mixture was stirred at room temperature overnight and quenched with 20 μΐ of acetic acid. The reaction mixture was extracted with methylene chloride and the combined organic layers were dried (MgS04), filtered, concentrated in vacuo and purified by silica gel chromatography (CH2C12, ethanol) to yield 1 (13 mg, 44%) as a colorless solid. LR-MS (ESI) Calculated for C44H62N709S (M+H)+ 864.43; Found 864.45.
Example 296: (laR.5£l lZJ2aS.13aj?a6Sa9i?,27E31aj?VN-r(l-methylcvclopropyl)sulfonvn- 3 J5 3-trioxo-26-r2-(piperidin-l-yl ethoxy1-l.la.3.4.5.6.7.8.9.10,12a.l3.15.16.18.19,29, 30.31.31a-icosahvdro-5.17:16.19-dimethanodicvclopropari2.13:28.29iri.20.3.14.171
Figure imgf000247_0001
Step 1 : 15-tert-butyl 14a-ethyl (2R,6S, 12Z,13aS,14aR,16aS)-2-{[4-(ben∑yloxy)-3- bromoquinolin-2-yl]oxy}-6-[(tert-butoxycarbonyl)amino J -5, 16-dioxo- 2, 3, 6, 7, 8, 9, 10,11,13 a, 14,16, 16a-dodecahydrocyclopropa[e Jpyrrolof 1, 2- a][l,4 Jdiazacyc pentadecine-l 4a, 15(lH, 5H)-dicarboxylate
Figure imgf000247_0002
To a solution of Intermediate C6 (1.48 g) and Intermediate B16 (2.03 g) in DMA (12.5 mL) was added cesium carbonate (1.02 g). The reaction mixture was heated to 60°C for 5 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and water. The mixture was extracted (3x) with ethyl acetate. The combined organic layers were washed with water, then brine, dried over magnesium sulfate, filtered and concentrated. The residue was suspended in dichloromethane and filtered to remove the insoluble Intermediate C6. The mother liquors were concentrated and the residue was purified by flash chromatography (ISCO, 0 to 100% ethyl acetate in hexanes) to give the title compound (2.06 g). LRMS (ES+) m/z 905.0 (M+H)+.
Step 2 : ethyl (2R,6S, 12Z,13aS, 14aR,16aS)-6-amino-2-[(3-bromo-4-hydroxyquinolin-2-yl)oxy]- 5, 16-dioxo-l, 2, 3, 6, 7, 8, 9, 10,11,13 a, 14, 15,16, 16a-tetradecahydrocyclopropa[ Jpyrrolof 1, 2- [1 ,4]diazacyclopentadecine-14a(5H)-carboxylate
Figure imgf000248_0001
The product of Step 1 (2.06 g) was dissolved in TFA (22.7 mL) and the reaction was stirred for 5 hours at room temperature. The solvent was removed in vacuo. The residue was dissolved in ethyl acetate and a saturated solution of sodium bicarbonate was added slowly. The layers were separated and the organic layer was washed again with a saturated solution of sodium bicarbonate then with brine, dried over magnesium sulfate, filtered and concentrated.
The product was used without further purification. LRMS (ES+) m/z 615.2 (M+H)+.
Step 3 : ethyl (2R,6S, 12Z, 13aS, 14aR, 16aS)-2-[(3-bromo-4-hydroxyquinolin-2-yl)oxy]-5,16- dioxo-6-{[( {(1R, 2R)-2-[ (4E)-5-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)pent-4-en-l- yl]cyclopropyl}oxy)carbonyl Jamino -1, 2, 3, 6, 7, 8, 9, 10, 11,13a, 14, 15,16,16a- tetradecahydrocyclopropaf e Jpyrrolofl, 2-a][l, 4]diazacyclopentadecine-14a(5H)-carboxylate
Figure imgf000248_0002
To a solution of the amine from Step 2 (1.58 g) and Intermediate A14 (1.11 g) in acetonitrile (12.8 mL) was added triethylamine (1.78 mL). The reaction mixture was stirred overnight at room temperature. The solvent was removed in vacuo. The residue was dissolved in ethyl acetate and water was added. The mixture was extracted (3x) with ethyl acetate. The combined organics were dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (ISCO, 0 to 10% methanol in dichloromethane) to give the title compound (1.53 g) as a white solid. LRMS (ES+) m/z 893.3 (M+H)+.
Step 4 : ethyl (2R,6S,12Z,13aS,l 4aR,l 6aS)-2-({3-bromo-4-[2-(piperidin-l -yl)ethoxy]quinolin-2- yl}oxy)-5, 16-dioxo-6-{[ ({(1R, 2R)-2-[(4E)-5-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)pent-4- en-l-yl ]cyclopropyl}oxy)carbonyl]amino}-l, 2, 3, 6, 7, 8, 9,10,11, 13a, 14, 15,16,16a- tetradecahydrocyclopropaf e Jpyrrolof 1, 2-a][ 1, 4]diazacyclopentadecine-14a(5H)-carboxylate
Figure imgf000249_0001
To a solution of phenol from Step 3 (0.513 g) in DMF (5.7 mL) was added l-(2- bromoethyl)piperidine (0.39 g) and cesium carbonate (1.5 g). The reaction mixture was stirred at room temperature for 18 hours. The reaction was quenched with water and the reaction mixture was diluted with ethyl acetate. The mixture was extracted (3x) with ethyl acetate. The combined organics were washed with water (2x), then brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography (ISCO, 0 to 10% methanol in dichloromethane) to give the title compound (456 mg) as a colorless oil. LRMS (ES+) m/z 1004.4 (M+H)+.
Step 5 : ethyl (laR,5S,HZ,12aS,13aR,16S,19R,27E,31aR)-3,15,33-trioxo-26-[2-(piperidin-l- yl)ethoxy]-l, la, 3, 4, 5, 6, 7, 8, 9, 10, 12a, 13, 15,16,18,19, 29, 30,31, 31a-icosahydro-5, 17: 16,19- dimethanodicyclopropa[12, 13:28,29J[1,20,3, 14,17]dioxatriazacyclononacosino[21,22- b ]quinoline-13a( 14H)-carboxylate
Figure imgf000250_0001
In a reaction flask, boronate from Step 4 (456 mg), Catacxium A (35.4 mg), cesium carbonate (483 mg) were dissolved in 10.3 mL of dioxane and 2.1 mL of water. The reaction mixture was degassed with nitrogen (3 cycles) before the addition of palladium acetate (11.1 mg). The reaction mixture was once again degassed with nitrogen (3 cycles) and heated to 100°C for 1 hour. After cooling to room temperature, the reaction was quenched with a saturated solution of ammonium chloride. The mixture was extracted (3x) with ethyl acetate. The combined organics were dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography (ISCO, 0 to 10% methanol in dichloromethane) to give the title compound (232 mg) as a yellow foam. LRMS (ES+) m/z 798.35 (M+H)+.
Step 6 : (laR,5S,llZ,12aS,13aR,16S,19R,27E,31aR)-3,15,33-trioxo-26-[2-(piperidin-l- yl)ethoxy]-l, la, 3, 4, 5, 6, 7, 8, 9, 10, 12a, 13, 15,16,18,19, 29, 30,31, 31a-icosahydro-5, 17: 16,19- dimethanodicyclopropafl 2, 13:28, 29] [1, 20, 3,14,17]dioxatriazacyclononacosino[21, 22-b ] quinoline-13a(14H)-carboxylic acid
Figure imgf000250_0002
Ester from step 5 (231 mg) was dissolved in THF (1.4 mL) and methanol (0.7 mL). LiOH (121 mg) in 0.7 mL of water was then added to the reaction mixture. The reaction was stirred overnight at room temperature. The reaction mixture was acidified to pH = 4 with acetic acid. The mixture was extracted (3x) with ethyl acetate. The combined organics were dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography (ISCO reverse phase, 5 to 95% acetonitrile in water) to give the desired product (87.3 mg). LRMS (ES+) m/z 770.60 (M+H)+.
Step 7 : (laR,5S,l lZ,12aS,13aR,16S,19R,27E,31aR)-N-[(l-methylcyclopropyl)sulfonyl]-3, 15,33- trioxo-26-[2-(piperidin-l -yl)ethoxy]-l, la, 3, 4, 5, 6, 7, 8, 9, 10, 12a, 13, 15,16,18,19, 29, 30,31,3 la- icosahydro-5, 17:16, 19-dimethanodicyclopropa[12, 13:28, 29] [1, 20,3, 14, 17]
3a(14H)-carboxamide
Figure imgf000251_0001
To a solution of acid from Step 6 (87.3 mg) in THF (0.6 mL) was added 1,1'- carbonyldiimidazole (28 mg) and the reaction mixture was heated to 40°C for 1 hour. The reaction mixture was cooled to room temperature. At this point, 1- methylcyclopropanesulfonamide (61 mg) and DBU (85 μΐ) were added. The reaction mixture was heated to 40°C for 18 hours. Once the mixture cooled to room temperature, it was diluted with ethyl acetate. Water was added and the mixture was acidified to pH = 4. The mixture was extracted (3x) with ethyl acetate. The combined organics were dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography (ISCO reverse phase, 5 to 95% acetonitrile in water) to give the desired product (40.8 mg). LRMS (ES+) m/z 887.40 (M+H)+.
Examples 297-299
By following the procedures outlined in Example 296 and using the appropriate reagents (depicted below the structure as Rg.), the following compounds were prepared.
Figure imgf000251_0002
Figure imgf000252_0001
Example 300 : aai?.5S.l lZa2aS.13ai?.16S.19i?.27E.31ai?V26-methoxy-N-rri-methyl cvclopropynsulfonyll-3.15.33-trioxo-l.la.3.4.5.6J.8.9.10.12a. 13.15.16.18.19.29.30,31.31a- icosahvdro-5.17:16.19-dimethanodicvclopropa Γ 12.13 :28.29Ί Γ 1.20.3.14.1 1
dioxatriazacyclononacosino \21.22-Z?lquinoline- 13a( 14H)-carboxamide
Figure imgf000253_0001
Step 1 : ethyl (2R,6S, 12Z, 13aS, 14aR, 16aS)-2-[(3-bromo-4-methoxyquinolin-2-yl)oxyJ-5, 16- dioxo-6-{[({ (1R, 2R)-2-[ (4E)-5-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)pent-4-en-l- yl ]cyclopropyl}oxy)carbonyl] amino}- 1, 2, 3, 6, 7, 8, 9, 10,11,13a, 14, 15,16, 16a- tetradecahydrocyclopropa[e]pyrrolo[l,2-a] [1 ,4] diazacyclopentadecine-14a(5H)-carboxylate
Figure imgf000253_0002
To a solution of phenol from Example 296, Step 3 (402 mg) in DMF (2.2 mL) was added methyl iodide (84 μΐ) and DIPEA (314 μΐ). The reaction mixture was stirred at room temperature for 18 hours. The reaction was quenched with water and the reaction mixture was diluted with ethyl acetate. The mixture was extracted (3x) with ethyl acetate. The combined organics were washed with brine (2x), dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography (ISCO, 0 to 10% methanol in
dichloromethane) to give the title compound (403 mg, 99%) as a yellow foam. LRMS (ES+) m/z 907.3 (M+H)+.
Steps 2 to 4 : (laR,5S, llZ, 12aS, 13aR,16S, 19R,27E,31aR)-26-methoxy-N-[(l-methyl cyclopropyl)sulfonyl]-3, 15, 33-trioxo-l, la, 3, 4, 5, 6, 7, 8, 9, 10, 12a, 13, 15, 16, 18, 19, 29, 30,31, 31a- icosahydro-5, 17: 16, 19-dimethanodicyclopropafl 2, 13 : 28,29] [1 ,20,3, 14, 17]dioxatriaza cyclononacosino[21, 22-b ]quinoline-13a(14H)-carboxamide
Figure imgf000254_0001
The title compound was prepared using the same method as Example 296, Steps 5-7 using the product of step 1. LCMS (ES+) m/z 790.25 (M+H)+. Example 301 : riaR.5S.l lZ.12aS.13aR.16S.19R.31aRVN-rri-methylcvclopropynsulfonyll-26- r2-rmon?holin-4-vnethoxy1-3J533-trioxo-lJa3A5.6.7.8.9,10.12a,13.15J6,18,19,27,28, 29.30,31.31 a-docosahvdro-5, 17:16.19-dimethanodicvclopropa[ 12.13:28.29"|[1.20.3.14.17]
Figure imgf000254_0002
Step 1 : 15-tert-butyl 14a-ethyl (2R, 6S, 12Z, 13aS,14aR,16aS)-2-({3-bromo-4-[(4- methoxybenzyl)oxy]quinolin-2-yl}oxy)-6-[(tert-butoxycarbonyl)amino]-5,16-dioxo- 2, 3,6, 7,8,9,10,11,13a, 14, 16,16a-dodecahydrocyclopropa[e ]pyrrolo[ 1,2- a][l,4 Jdiazacyclopentadecine-14a, 15(1H, 5H) -dicarboxylate
Figure imgf000255_0001
The title compound was prepared using the same method as Example 296, Step 1 using Intermediate CI 3. LCMS (ES+) m/z 957.4 (M+Na)+.
Step 2 : 15-tert-butyl 14a-ethyl (2R,6S, 12Z, 13aS, 14aR, 16aS)-6-amino-2-({3-bromo-4-[(4- methoxybenzyl)oxy]quinolin-2-yl } oxy)-5, 16-dioxo-2, 3, 6, 7, 8, 9, 10,11,13a, 14, 16,16a- dodecahydrocyclopropafe ]pyrrolo[ 1, 2-a][ 1, 4]diazacyclopentadecine-14a, 15(1H, 5H)- dicarboxylate
Figure imgf000255_0002
Tert-butyldimethylsilyl trifluoromethanesulfonate (0.655 mL) was added to the solution of 2,6-lutidine (0.31 mL) and the product from Step 1 (1.91 g) in DCM (40 mL). The solution was stirred at room temperature for 1 hour. Tetra-butyl ammonium fluoride (1.0M in THF, 3.06 mL) was added and the solution was stirred at room temperature for 30 minutes. A saturated solution of ammonium chloride was added and the mixture was extracted with dichloromethane (3x). The combined organic fractions were washed with saturated solution of sodium bicarbonate, dried over magnesium sulfate, filtered and concentrated. The crude product was used directly in the next step. LCMS (ES+) m/z 835.3 (M+H)+.
Step 3 : 15-tert-butyl 14a-ethyl (2R,6S, 12Z, 13aS, 14aR, 16aS)-2-({3-bromo-4-[(4-methoxy benzyl)oxy]quinolin-2-yl}oxy)-5, 16-dioxo-6-{[({(lR, 2R)-2-[5-(4, 4, 5, 5-tetramethyl-l, 3, 2- dioxaborolan-2-yl)pentyl ]cyclopropyl}oxy)carbonyl ]amino}-2, 3, 6, 7, 8, 9,10,11,13a, 14,16,16a- dodecahydrocyclopropa[e]pyrrolo[ 1, 2-a][l, 4]diazacyclopentadecine-14a, 15(1H, 5H)- dicarboxylate
Figure imgf000256_0001
The title compound was prepared using the same method as described in Example 296, Step 3 using intermediate A15.
Step 4 : 14-tert-butyl lSa-ethyl (laR,5S,llZ,12aS,13aR,19R,31aR)-26-[(4-methoxybenzyl)oxy]- 3, 15, 33-trioxo-l, la, 3, 4, 5, 6, 7, 8, 9, 10, 12a, 13,15,16,18,19,27, 28, 29, 30,31, 31a-docosahydro- 5, 17: 16,19-dimethanodicyclopropa[ 12, 13:28,29] [1,20,3,14,17]dioxatriazacyclononacosino [21 ,22-b]quinoline-l 3a, 14-dicarboxylate
Figure imgf000256_0002
The title compound was prepared using the same method as described in Example
296, Step 5 except that cataxium A and palladium acetate were pre-mixed before addition to the reaction mixture. The reaction mixture was heated at 100°C for 9 hours. LCMS (ES+) m/z 909.45 (M+H)+.
Step 5 : ethyl (laR, 5S, 11Z, 12aS, 13aR, 19R, 31aR)-26-hydroxy-3, 15, 33-trioxo-
1, la, 3, 4, 5, 6, 7, 8, 9,10, 12a, 13,15,16, 18,19,27, 28,29, 30, 31, 31a-docosahydro-5, 17:16, 19- dimethanodicyclopropa[12, 13:28,29] [1,20, 3,14, 17]dioxatriazacyclononacosino[21,22- b]quinoline-13a(14H)-carboxylate
Figure imgf000257_0001
TFA (1.51 ml) was added to the solution of bis-macrocycle from Step 4 (0.412 g) in DCM (3.0 ml) at room temperature. The solution was stirred for 3 hours. The solvent was evaporated under reduced pressure and the residue was purified by flash chromatography (ISCO, reverse phase) to afford the desired product (0.122 g) as a white solid. LCMS (ES+) m/z 689.5 (M+H)+.
Step 6 : ethyl (laR,5S,llZ,12aS,13aR,16S,19R,31aR)-26-[2-(morpholin-4-yl)ethoxy]-3, 15,33- trioxo-1, la, 3, 4, 5, 6, 7, 8, 9, 10, 12a, 13,15,16,18, 19,27, 28, 29,30, 31, 31a-docosahydro-5, 17: 16,19- dimethanodicyclopropaf 12,13: 28, 29 ][1, 20,3,14,17]dioxatriazacyclononacosino[21, 22- b]quinoline-13a(14H)-carboxylate
Figure imgf000257_0002
4-(2-Bromoethyl)morpholine (0.069 g) was added to the mixture of phenol from
Step 5 (0.122 g) and cesium carbonate (0.462 g) in DMF (1.77 ml). The mixture was stirred at room temperature for 1 hour 30 minutes. At this point, water was added and the mixture was extracted with ethyl acetate (3x). The combined organic fractions were dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography (ISCO reverse phase) to give the undesired epimer (19 mg) as a white powder and the desired product (12.9 mg) as a white powder. LCMS (ES+) m/z 802.45 (M+H)+.
Step 7-8 : (laR,5S,llZ,12aS,13aR,16S,19R,31aR)-N-[(l-methylcyclopropyl)sulfonyl]-26-[2- (morpholin-4-yl)ethoxy]-3,15, 33-trioxo-l, la, 3, 4, 5, 6, 7, 8, 9, 10, 12a, 13,15,16,18,19,27, 28,29,30, 31,31a-docosahydro-5, 17 : 16, 19-dimethanodicyclopropa[12, 13:28,29] [1,20,3, 14, 17] dioxatriazacyclononacosino[21,22-b]quinoline-13a(14H)-carboxamide
Figure imgf000258_0001
The title compound was prepared using the same method as Example 296, Steps 6-7. LCMS (ES+) m/z 891.40 (M+H)+.
Example 302: aaj?.5S.l lZ.12aS.13aiU6S.19i?.27£.31^
3,15,33-trioxo-26-[3-(piperidin-l-vnpropoxy1-l,la.3.4.5,6.7,8.9,10,12a,13,15,16.
18.19.29.30.31.31 a-icosahvdro-5.17:16.19-dimethanodicvclopropar 12.13 :28.291 Γ 1.20.3.14.171 dioxatriazacyclononacosino \21.22- >lquinoline- 13aC 14H)-carboxamide
Figure imgf000258_0002
Step 1 : ethyl (2R,6S,12Z,13aS,14aR 6aS)-2-{[3-bromo-4-(3-bromopropoxy)quinolin-2-yl]oxy}- 5, 16-dioxo-6-{[ ({ (1R, 2R)-2-[ (4E)-5-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)pent-4-en-l- yl] cyclopropyl}oxy)carbonyl] amino}- 1, 2, 3, 6, 7, 8, 9,10,11,13a, 14, 15,16,16a- tetradecahydrocyclopropa[e]pyrrolo[l ,2-a] [1 , 4]diazacyclopentadecine-14a(5H)-carboxylate
Figure imgf000259_0001
To a 0°C solution of phenol from Example 296, Step 3 (868 mg) in DMF (6 mL) was added sodium hydride (38 mg). The mixture was stirred 10 minutes and 1,3- dibromopropane (1.98 mL) was added. The reaction mixture was stirred at the same temperature for 30 minutes and then it was warmed up to room temperature and stirred for 18 hours. The reaction was quenched with a saturated solution of ammonium chloride and extracted with ethyl acetate (3x). The combined organic fractions were dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography (ISCO, 0 to 10 % methanol in dichloromethane) to give the title compound (602 mg) as a white foam.
Step 2 : ethyl (2R,6S,12Z,13aS,l 4aR,l 6aS)-2-({3-bromo-4-[3-(piperidin-l -yl)propoxy] quinolin- 2-yl}oxy)-5,16-dioxo-6-{[({(lR,2R)-2-[(4E)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pent- 4-en-l-yl]cyclopropyl}oxy)carbonyl] amino}- 1, 2, 3, 6, 7,8,9,10,11, 13a, 14,15,16,16a- ntadecine-14a(5H)-carboxylate
Figure imgf000259_0002
Piperidine (317 μΐ) was added to a solution of bromide from Step 1 (326 mg) in DMSO (2 mL) and the resulting mixture was stirred for 2 hours at room temperature. The reaction was quenched with water and extracted with ethyl acetate (3x). The combined organic fractions were washed with water then brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography (ISCO reverse phase, 0 to 95 % acetonitrile in water) to give the title compound (262 mg) as a mixture with the boronic acid. Step 3-5 : (laR,5S lZ 2aS,13aR,16S,19R,27E,31aR)-N-[(l-methylcyclopropyl)sulfonyl]- 3, 15, 33-trioxo-26-[3-(piperidin-l-yl)propoxy]-l, la, 3, 4, 5, 6, 7, 8, 9,10, 12a, 13, 15,16,18,
19, 29, 30, 31, 31a-icosahydro-5, 17:16, 19-dimethanodicyclopropa[l 2,13:28, 29] [1, 20, 3, 14, 17]
4H)-carboxamide
Figure imgf000260_0001
The title compound was prepared using the same method as Example 296, Steps 5-7. LCMS (ES+) m/z 901.20 (M+H)+.
Examples 303-304
By following the procedures outlined in Example 7 and using the appropriate reagents (depicted below the structure as Rg.), the following compounds were prepared.
Figure imgf000260_0002
304 (1 ai?,5S, 11Z, 12aS, 13aR, 165, 19i?,27E,31 aR)-N- 916.50
[(1 -methylcyclopropyl) sulfonyl]-26-[3-(4-methyl
piperazin- 1 -yl)propoxy] -3 ,15,33 -trioxo- 1 , 1 a,3 ,4,
Rg. 1 -methyl 5,6,7,8,9,10,12a,13, 15,16,18,19,29,30,31,31a- piperazine icosahydro-5, 17:16,19-dimethanodicyclopropa
[ 12, 13 :28,29] [ 1 ,20,3 , 14, 17]dioxatriazacyclonona
cosino[21 ,22-b quinoline- 13 a( 14H)-carboxamide
Example 305 : (laj?,5SJ lZ,12aSJ3ai?,16S,19i?,31ai?V26-methoxy-iV-ra- methylcvclopropynsulfonyll-3.15.33-trioxo-l,la,3,4.5.6.7.8.9.10J2a,13J5.16.18.19,
27,28,29,30,31 1a-docosahvdro-5.17:16,19-dimethanodicvclopropan2.13:28.29in.20 J4J71 dioxatriazacvclononacosino 21,22- ?1quinoline-13a(14H)-carboxamide
Figure imgf000261_0001
Bismuth trichloride (91 mg) was added to a solution of Example 300 (22.8 mg) in ethanol (2.9 mL) and cooled to 0°C. Then, potassium borohydride (156 mg) was added in small portions. The mixture was stirred at 0°C for 45 minutes then at room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate and acidified with 4N HC1 until pH = 3. The mixture was filtered over celite, rinsing with ethyl acetate. The solvent was removed in vacuo. The residue was purified by flash chromatography (ISCO, 0 to 10% methanol in
dichloromethane) to give the title compound (5.3 mg) as a white solid. LRMS (ES+) m/z 792.25 (M+H)+.
Example 306 : (laj?.5Sa iZ.12aSa3a^J6Sa9ig31a^VN-r(l-methylcvclopropynsulfonyll- 3.15.33-trioxo-26-r2-(pyrrolidin-l-vnethoxyl-l,la.3A5,6,7.8.9.10.12a.l3.15.16.18.
19.27,28.29.30,31 ,31 a-docosahvdro-5.17: 16, 19-dimethanodicvclopropar 12.13 :28.291
Γ 1 ,20.3.14.17]dioxatriazacyclononacosino [21.22-^lquinoline- 13 a( 14H)-carboxamide
Figure imgf000262_0001
The title compound was prepared using the same method as Example 305 with Example 299 except that 200 equivalents of potassium borohydride and 20 equivalents of bismuth trichloride were used. LRMS (ES+) m/z 875.50 (M+H)+.
It will be appreciated that various of the above-discussed and other features and functions, or alternatives thereof, may be desirably combined into many other different systems or applications. Also that various presently unforeseen or unanticipated alternatives, modifications, variations or improvements therein may be subsequently made by those skilled in the art which are also intended to be encompassed by the following claims.

Claims

WHAT IS CLAIMED IS:
1. A compound of formula (I) or a pharmaceutically acceptable salt thereof:
Figure imgf000263_0001
Y is CH or N;
R1 is:
-OH,
-OCrealkyl,
-OCrealkyl-heth
-Od-ealkyl-OH,
-Od-6alkyl-NRaRb,
-O-heti,
-OCr6alkylC02H,
-Od-ealkylC^-het
-0(CH2)1-6OC(=0)CH2NRaRb,
-OC i -6alkyl-C i -6alkoxy,
-OC i -6alkyl-C i -6alkoxy-C i - alkoxy,
-OC(0)Ci-6alkyl,
-OC(0)NRaRb,
-Od-ealkyl-S-heti,
-OC i -6alkyl-phosphate,
a phosphate group,
-(CH^-het!, pyridinyl, or
thiazolyl;
wherein
said alkyl is optionally substituted with 1 or 2 fluoro substituents, said phosphate group is optionally substituted with 1, 2 or 3 C1-6alkyl; said hett is:
a) aryl selected from phenyl or napthyl optionally substituted with 1 or 2 substituents selected from -OH, C!-6alkyl, or halo;
b) heteroaryl selected from 5- and 6-membered aromatic rings having 1, 2 or 3 heteroatoms independently selected from N, O and S, wherein said heteroaryl is attached through a ring atom selected from C or N and optionally substituted with 1 or 2 substituents independently selected from d-6alkyl and -OH; or c) heterocycle selected from 4-7 membered monocyclic or 6-10 membered polycyclic bridged, linearly fused or spirocyclic saturated or unsaturated non-aromatic rings having 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, wherein said heterocycle is attached through a ring atom selected from C or N and optionally substituted with 1 or 2 substituents independently selected from C1-6alkyl, oxo, -(CH2)mF, Boc,
-(CH2)mCF3, -(CH2)mOCF3, -OH, -NRaRb, -C1-6alkoxy,
-(CH2)mS02CH3, aryl, -C1-6alkoxy-C1-6alkyl, -C1-6alkyl-d- 6alkoxy optionally substituted with CF3, cyano, C(=0)NH2,
C3-6cycloalkyl, -C1-6alkyl-C3-6cycloalkyl, -COOC1-6alkyl, -Ci- 6alkyl-S02C1-6alkyl, and benzimidazolyl wherein the benzimidazolyl is optionally substituted with F;
Ra and Rb are independently selected from H; d-6 alkyl; t-Boc; aryl; C3-6cycloalkyl optionally substituted with 1 or 2 fluoro; d-6alkoxy- d-6alkyl; tetrahydropyranyl; d-6alkyl-OH; d-6alkyl-arylA; d-6 alkyl- C(OH)-arylA; d-ealkyl-imidazolyl optionally substituted with methyl, d-6alkyl-benzimidazolyl optionally substituted with methyl; d-6alkyl- pyrazolyl; C ealkyl-dihydrotriazole optionally substituted with oxo; or
Q-ealkyl-pyrrolidinyl optionally substituted with oxo;
wherein
m is 0 or 1 to 4;
said arylA is phenyl, naphthalenyl, tetrahydronapthalenyl, or 7-10 membered fused bicyclic ring structure wherein at least one of the rings is aromatic and is optionally substituted with 2 -OH;
said tetrahydropyranyl is optionally substituted with 1 oxo;
R2 is C 6alkyl, C2-6alkenyl, C3-C6cycloalkyl or NRcRd;
wherein
the C3-6cycloalkyl is optionally substituted with C1-6alkyl optionally substituted with -OH, morpholinyl, C1-6alkoxy, Ci-ealkoxy-C^alkoxy, C1-6alkoxy-phenyl, or Ci^alkenyl;
R° and Rd are independently H or C1-6alkyl, or may be taken together, with the N to which they are attached, to form a 4-7-membered monocyclic ring;
R3 is Ci-6alkyl, C2-6alkenyl, C3-C6cycloalkyl, CF2 or CF3;
R4 is C s alkyl, C3-8 cycloalkyl, Ci-g alkyl-C3-8 cycloalkyl, adamantyl, dihydroindenyl, or a 4-8 membered heterocycloalkyl having 1 or 2 heteroatoms selected from N, O, or S, wherein R4 is optionally substituted with one or two substituents independently selected from (Q- C6)alkyl, halo, and -0(C1-C6)alkyl; or
R3 and R4 together form heptene;
Z is C or N;
R5 is H or C!-6alkyl; or R5 is absent when Z is N;
W is a bond, O or NR;
R is H or C ealkyl;
X is absent or is halo, CF3, -OCHF2, -OCH2F, -OCD2F, -OCDF2, d-Qalkyl, Cj-6alkoxy, aryl, heteroaryl, or -0(CH2)1-6NRaRb;
A is absent, O or N;
B is (CH2)m; and
n is 1-4.
2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof having a formula of
Figure imgf000266_0001
3. The compound according to claims 1 or 2, or a pharmaceutically acceptable salt thereof, wherein Z is C.
4. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, having a formula of
Figure imgf000267_0001
5. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, having a formula of
Figure imgf000267_0002
6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R5 is H or CH3.
7. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R3 is ethyl, ethylene, or cyclopropyl.
8. The compound according to claims 7, or a pharmaceutically acceptable salt thereof, wherein R3 is ethylene.
9. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R4 is propyl, t-butyl, cyclopentyl, cyclohexyl optionally substituted with 1 or 2 F, cyclohexylmethyl, methylcyclohexyl, methylcyclopentyl, dihydroindenyl, or tetrahydro-2H-pyranyl.
10. The compound according to claim 9, or a pharmaceutically acceptable salt thereof, wherein R4 is t-butyl, cyclopentyl, or cyclohexyl, 1-methylcyclohexyl, propan-2-yl, 2,3- dihydroindenyl, tetrahydro-2H-pyranyl, or cyclohexylmethyl.
11. The compound according to claim 9, or a pharmaceutically acceptable salt thereof, wherein R4 is t-butyl, cyclopentyl, or cyclohexyl, 1-methylcyclohexyl, 2,3- dihydroindenyl, or tetrahydro-2H-pyranyl.
12. The compound according to any one of claims 1 to 11 , or a pharmaceutically acceptable salt thereof, wherein n is 1 to 3.
13. The compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein R is cyclopropyl, N(CH3)2, or azetidinyl, wherein the cyclopropyl is optionally substituted with methyl, CH(CH3)2, C(CH3)=CH2;
C(CH3)2OH, CH2CH2-morpholinyl, CH2OCH3, CH2OCH2CH2OCH3, or CH2OCH2-phenyl.
14. The compound according to claim 13, of a pharmaceutically acceptable salt thereof, wherein R2 is cyclopropyl, N(CH3)2, (methyl)cyclopropyl,
(methoxymethyl)cyclopropyl, [(benzyloxy)methyl] cyclopropyl, l-(prop-l-en-2-yl)cyclopropyl, or 1 -[2-^ο ηο1ΐη-4^1)6ΐ1^1^ο1ορπ^1.
15. The compound according to claim 13, or a pharmaceutically acceptable salt thereof, wherein R is cyclopropyl, N(CH3)2, (methyl)cyclopropyl, or 1- (methoxymethyl)cyclopropyl.
16. The compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein R1 is -OH; -0-C1-6alkyl; -OC(0)C1-6alkyl;
-OC l -ealkyl-hett ; -OC \ -6alkyl-C \ -6alkoxy ; -OC t-ealkyl-C i -6alkoxy-C i -6alkoxy ;
-OCH2C(=0)-het1; -0(CH2)1-6 OC(=0)CH2NRaRb; -OC(0)NRaRb; -Od-ealkyl-phosphate;
-OC ealkyl-S-heti; -O-heti; -0-C1-6alkyl-OH optionally substituted with 1 or 2 fluoro substituents; or -OC1-6alkyl-NRaRb
wherein Ra and Rb are independently
H,
Ci-6 alkyl,
t-Boc, C3-6cycloalkyl optionally substituted with 1 or 2 fluoro substituents,
C 6 alkyl-Ci-6alkoxy,
Ci-6alkyl-OH, phenyl,
C i -6alkyl-pheny 1 ,
tetrahydropyranyl,
C1-6alkyl-C(OH)-phenyl,
naphthalenyl,
C t -6alkyl-naphthalenyl,
C i -6alkyl-dihydrooxopyrrolidinyl,
Crealkyl-benzimidazolyl optionally substituted with methyl, C i -6alkyl-pyrazolyl,
Crealkyl-triazole optionally substituted with oxo, or
Ci-ealkyl-imidazolyl optionally substituted with methyl.
17. The compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein the heti is: phenyl; oxazepanyl;
oxooxazolidinyl; pyridinyl; pyrazolyl; pyrrolyl; tetrahydropyranyl, triazolyl optionally substituted with C1-6alkyl; dioxolanyl; oxoimidazolidinyl; morpholinyl optionally substituted with dimethyl or ethyl; pyrrolidinyl optionally substituted with 1 or 2 substituents independently selected from oxo, Boc, Ci-6alkyl, OH, C(0)NH2, dimethylamino, and methylsulfornyl;
piperidinyl optionally substituted with 1 or 2 substituents independently selected from C1-6alkyl, C1-6alkoxy, C1-6alkoxy-C1-6alkyl optionally substituted with CF3, cyclopropyl-C1-6alkyl, cyclopropyl, -(CH2)mF, OH, -Ci-6alkyl-S02C1-6alkyl, -(CH2)mCF3, -COOC1-6alkyl, Boc, and benzimidazol; imidizolyl; thiazolyl optionally substituted with methyl; azabicycloheptyl;
azaspiroheptyl; azaspirononyl; oxaazabiocycloheptyl; oxaazaspiroheptyl optionally substituted with methoxyethyl; azetidinyl optionally substituted with 1 or 2 substituents independently selected from C1-6alkyl, Ci-6alkoxy, cyano, fluoro, OH, phenyl and Boc; dioxidothiomorpholinyl; piperazinyl optionally substituted with 1 or 2 substituents independently selected from C1-6alkyl, C1-6alkyl-cyclopropyl, CF3, methylsulfonyl , Boc, and oxo; azabicyclooctyl substituted with Q. 6alkyl, C^ealkoxy-C^alkyl, -COOC1-6alkyl, or -(CH2)mCF3; oxaazabicyclononyl optionally substituted with Boc, C1-6alkyl, -COOC1-6alkyl, C1- alkoxy-C1-6alkyl or cyclopropylC1-6alkyl; or azabicyclooctanyl optionally substituted with C1-6alkyl.
18. The compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein X is absent or selected from -Br, -CI, -F, methoxy, methyl, propanyl and CF3.
A compound according to claim 1 selected from:
Figure imgf000270_0001
Figure imgf000271_0001
Figure imgf000272_0001
Figure imgf000273_0001
Figure imgf000274_0001
, or a pharmaceutically acceptable salt thereof.
20. A compound according to claim 1 selected from:
( 1 aR,5 S, 11 Z, 12aS, 13aR, 16S, 19R,27E,31 aR)-N-[(l -methylcyclopropyl)sulfonyl]- 3,15,33-trioxo-26-[2-(piperidin-l-yl)ethoxy]-l,la,3,4,5,6,7,8,9,10,12a,13,^
31 a-icosahydro-5 , 17:16,19-dimethanodicyclopropa[ 12,13 :28,29] [ 1 ,20,3 , 14, 17]
dioxatriazacyclononacosino [21 ,22-b]quinoline- 13a(l 4H)-carboxamide;
(lai?,5S,l lZ,12aS,13a£,16S,19i?,27E,31aR^
26-[2-(moφholin-4-yl)ethoxy]-3,15,33-trioxo-l,la,3,4,5,6,7,8,9,10,12a,13,15,16,18,19,29^ 31 a- icosahydro-5, 17: 16, 19-dimethanodicyclopropa[12, 13 :28,29] [1 ,20,3, 14, 17]
dioxatriazacyclononacosino [21 ,22-b]quinoline- 13a( 14H)-carboxamide;
( 1 ai?,5S, 11 Z, 12aS, 13afl, 16S, 19i?,27£,31 aR)-N-[( 1 -methylcyclopropyl)sulfonyl] - 26-[3-(mo holin-4-yl)propoxy]-3,15,33-trioxo-l,la,3,4,5,6,7,8,9,10,12a,13, 15,16,18,19,29,30, 31,31 a-icosahydro-5 , 17: 16,19-dimethanodicyclopropa[ 12,13 :28,29] [ 1 ,20,3 , 14, 17]
dioxatriazacyclononacosino [21 ,22-b] quinoline- 13a( 14H)-carboxamide; ( 1 aR,5S, 11 Z, 12aS, 13 aR, 16S, 19i?,27£,31 aR)-N- [( 1 -methylcyclopropyl)sulfonyl]-
3,15,33-trioxo-26-[2-^yrrolidin-l-yl)ethoxy]-l,la,3,4,5,6,7,8,9,10,12a,13,15,16,18,19,29,30,31^ 31 a-icosahydro-5 , 17:16,19-dimethanodicyclopropa[ 12,13 :28,29] [ 1 ,20,3 ,14,17]
dioxatriazacyclononacosino [21 ,22-6]quinoline- 13a( 14H)-carboxamide;
(1 ai?,5S, 11 Z, 12aS 13a^, 16S, 19i?,27E,31 ai?)-26-methoxy-N-[( 1 - methylcyclopropyl)sulfonyl]-3,15,33-trioxo-l,la,3,4,5,6,7,8,9,10,12a,13,15,16,18,19,29,30,31, 31 a-icosahydro-5 , 17:16,19-dimethanodicyclopropa[ 12,13 :28,29] [ 1 ,20,3 , 14, 17]
dioxatriazacyclononacosino[21,22-6]quinoline-13a(14H)-carboxamide;
" (laR,5S,l lZ,12aS,13aR,16S,19R,31aR)-N-[(l-methylcyclopropyl)sulfonyl]-26- [2-(morpholin-4-yl)ethoxy]-3,15,33-trioxo-l,la,3,4,5,6,7,8,9,10,12a,13,15,16,18,19,2
31,31 a-docosahydro-5, 17:16,19-dimethanodicyclopropa[ 12, 13 :28,29] [ 1 ,20,3 , 14, 17] dioxatriazacyclononacosino [21 ,22-b]quinoline- 13a( 14H)-carboxamide;
(laR,5S, 11Z, 12aS,l 3aR, 16S, 19i?,27E,31 aR)-N-[(\ -methylcyclopropyl)sulfonyl]- 3,15,33-trioxo-26-[3-(piperidin-l-yl)propoxy]-l,la,3,4,5,6,7,8,9,10,12a,13,15,16,18,l^ 31 a-icosahydro-5, 17:16,19-dimethanodicyclopropa[l 2, 13 :28,29] [1 ,20,3, 14, 17]
dioxatriazacyclononacosino [21 ,22-&]quinoline- 13a( 14H)-carboxamide;
( 1 aR,5S, 11 Z, 12aS, 13aR, 16S, 19i?,27E,31 aR)-N- [( 1 -methylcyclopropyl)sulfonyl]- 3,15,33 -trioxo-26-[3 -(pyrrolidin- 1 -yl)propoxy] - l,la,3,4,5,6,7,8,9,10,12a,13,15,16,18,19,29,30,31,31a-icosahydro-5,17:16,19- dimethanodicyclopropa[ 12,13 :28,29] [1 ,20,3 , 14, 17]dioxatriazacyclononacosino[21 ,22- 0]quinoline-13a(14H)-carboxamide; or
(1 aR,5S, 11Z,12aS,l 3ai?, 16S, 19i?,27E,31 aR)-N-[(l -methylcyclopropyl)sulfonyl]- 26-[3-(4-methylpiperazin-l-yl)propoxy]-3,15,33-trioxo-l,la,3,4,5,6,7,8,9,10,12a,13,15,16,18, 19,29,30,31,31a-icosahydro-5,17:16,19-dimethanodicyclopropa[12,13:28,29][l,20,3, 14,17] dioxatriazacyclononacosino [21 ,22-Z>]quinoline- 13a( 14H)-carboxamide,
or a pharmaceutically acceptable salt thereof.
21. A pharmaceutical composition comprising an effective amount of the compound according to any one of claims 1 to 20, and a pharmaceutically acceptable carrier.
22. The pharmaceutical composition according to claim 21, further comprising a second therapeutic agent selected from the group consisting of HCV antiviral agents, immunomodulators, and anti-infective agents.
23. The pharmaceutical composition according to claim 22, further comprising a second therapeutic agent selected from the group consisting of HCV protease inhibitors, HCV NS5B polymerase inhibitors, HCV NS5A and NS4B inhibitors, ribavarin and pegylated interferon.
24. The pharmaceutical composition according to claim 22, wherein the second therapeutic agent is ribavirin.
25. Use of the compound according to any one of claims 1 to 20 for inhibiting HCV NS3 protease activity in a subject in need thereof.
26. Use of the compound according to any one of claims 1 to 20 for preventing or treating infection by HCV in a subject in need thereof.
27. The use of claim 25 or 26 wherein the use is with interferon and ribavirin.
28. The pharmaceutical composition of any one of claims 21 to 24 for inhibiting HCV NS3 protease activity in a subject in need thereof.
29. The pharmaceutical composition of any one of claims 21 to 24 for preventing of treating infection by HCV in a subject in need thereof.
30. The pharmaceutical composition of any one of claims 21 to 24 for use as a medicament.
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