WO2000040561A1 - Quinolinecarboxamides as antiviral agents - Google Patents

Quinolinecarboxamides as antiviral agents Download PDF

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Publication number
WO2000040561A1
WO2000040561A1 PCT/US1999/027960 US9927960W WO0040561A1 WO 2000040561 A1 WO2000040561 A1 WO 2000040561A1 US 9927960 W US9927960 W US 9927960W WO 0040561 A1 WO0040561 A1 WO 0040561A1
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WO
WIPO (PCT)
Prior art keywords
oxo
chlorobenzyl
dihydro
methyl
hydroxy
Prior art date
Application number
PCT/US1999/027960
Other languages
French (fr)
Inventor
Steven Ronald Turner
Joseph Walter Strohbach
Suvit Thaisrivongs
Valerie A. Vaillancourt
Mark E. Schnute
John Alan Tucker
Original Assignee
Pharmacia & Upjohn Company
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to SK830-2001A priority Critical patent/SK8302001A3/en
Application filed by Pharmacia & Upjohn Company filed Critical Pharmacia & Upjohn Company
Priority to BR9916772-7A priority patent/BR9916772A/en
Priority to KR1020017008629A priority patent/KR20010101421A/en
Priority to JP2000592270A priority patent/JP2002534416A/en
Priority to EP99967145A priority patent/EP1140850A1/en
Priority to EA200100757A priority patent/EA003945B1/en
Priority to AU23486/00A priority patent/AU760207B2/en
Priority to IL14417199A priority patent/IL144171A0/en
Priority to NZ512824A priority patent/NZ512824A/en
Priority to CA002353636A priority patent/CA2353636A1/en
Publication of WO2000040561A1 publication Critical patent/WO2000040561A1/en
Priority to NO20013383A priority patent/NO20013383L/en
Priority to HK02103396.2A priority patent/HK1041699A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
    • 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
    • A61P31/20—Antivirals for DNA viruses
    • A61P31/22—Antivirals for DNA viruses for herpes viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/24—Oxygen atoms attached in position 8
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/36—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
    • C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/58—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems with hetero atoms directly attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/08—Bridged systems

Definitions

  • the present invention provides 4-oxo- 1 ,4-dihydro-3-quinolinecarboxamide derivatives. These compounds are useful as antiviral agents, in particular, as agents against viruses of the herpes family.
  • herpesviruses comprise a large family of double stranded DNA viruses. They are also a source of the most common viral illnesses in man. Eight of the herpes viruses, herpes simplex virus types 1 and 2 (HSV-1 and HSV-2), varicella zoster virus (VZV), human cytomegalovirus (HCMV), epstein-Barr virus (EBV), and human herpes viruses 6, 7, and 8 (HHV-6, HHV-7, and (HHV-8), have been shown to infect humans. HSV-1 and HSV-2 cause herpetic lesions on the lips and genitals, respectively. They also occasionally cause infections of the eye and encephalitis.
  • HSV-1 and HSV-2 cause herpetic lesions on the lips and genitals, respectively. They also occasionally cause infections of the eye and encephalitis.
  • HCMV causes birth defects in infants and a variety of diseases in immunocompromised patients such as retinitis, pneumonia, and gastrointestinal disease.
  • VZV is the causitive agent of chicken pox and shingles.
  • EBV causes infectious mononucleosis. It can also cause lymphomas in immunocompromised patients and has been associated with Burkitt's lymphoma, nasopharyngeal carcinoma, and Hodgkins disease.
  • HHV-6 is the causitive agent of roseola and may be associated with multiple sclerosis and chronic fatigue syndrome.
  • HHV-7 disease association is unclear, but it may be involved in some cases of roseola.
  • HHV-8 has been associated with Karposi s sarcoma, body cavity based lymphomas, and multiple myeloma.
  • Compounds of the present invention are distinct from other hydro xyquinoline antiviral agents in that the 4-substituent on the benzyl amide of the present invention (i.e. the chloro, bromo, cyano, or nitro substituent) provides significantly improved antiviral activity.
  • Certain compounds of formula (I) also possess unique substituents R 4 that provide improved antiviral activity.
  • U.S. Patent 3,960,868 discloses derivatives of 6, 7. or 8 cycloalkyl-4-oxoquinoline- 3-carboxylic acid that are reported to possess analgesic, anti- inflammatory, anti- micro bial. and histamine liberating properties.
  • the structure of these compounds differs from the structure of the compounds of formula I by requiring a cycloalkyl substituent at the 6, 7. or 8 position of the quinoline ring.
  • U.S. Patent 4,959,363 discloses quinolonecarboxamide compounds that are reported to possess antiviral activity. The structure of these compounds differs from the structure of the compounds of formula I disclosed herein at the 3-position by not including a 4-substitutedbenzamide, and at the 6-position by requiring a hydrogen or fluoro substituent.
  • U.S. Patent 5,175,151. discloses quinolone compounds that are reported to possess antihypertensive and antiviral activity. The structure of these compounds differs from the structure of the compounds of formula I disclosed herein at the 3-position by not including a 4-substitutedbenzamide, and at the 2-position by requiring an oxygen linked substituent.
  • U.K. Patent Application 1,191,443 discloses quinoline derivatives that are reported to possess antiviral activity.
  • the structure of these compounds differs from the structure of the compounds of formula I disclosed herein by not including a 4-substitutedbenzamide at the 3-position. and by requiring a fused furan heterocyclic ring at the 5,6-, 6.7-. or 7,8- position of the quinolone.
  • WO 97/14682 discloses quinoline derivatives that are reported to be useful to treat specific hormone dependent diseases.
  • the structure of these compounds differs from the structure of the compounds of formula I disclosed herein at the 3-position by not including a 4-substitutedbenzamide. at the 1 -position, by requiring a halogenoaralkyl. and at the 7- position by requiring an acylaminoaryl group.
  • U.S. Patent 4,786,644 discloses 1 -aryl-3-quinolinecarboxamides that are reported to be useful to treat pain and inflammation.
  • the structure of these compounds differs from the structure of the compounds of formula I disclosed herein at the 3-position by not including a 4-substitutedbenzamide, and at the 1 -position by requiring an optionally substituted phenyl substituent.
  • U.S. Patent 4,835,163 discloses N-alkoxyalkyl derivatives of quinolone carboxamides that are reported to possess anticonvulsive and psychotonic activity. The structure of these compounds differs from the structure of the compounds of formula I disclosed herein at the 3-position by not including a 4-substitutedbenzamide substituent.
  • JP 02124871 discloses quinolone compounds that are reported to possess 5- lipoxygenase activity.
  • the structure of these compounds differs from the structure of the compounds of formula I disclosed herein at the 3-position by not including a 4- substitutedbenzamide substituent.
  • EP 0 332 930A2 discloses quinolone compounds that are reported to possess antibacterial antiviral activity.
  • the structure of these compounds differs from the structure of the compounds of formula I disclosed herein at the 3-position by not including a 4- substitutedbenzamide, and at the 6-position by requiring a hydrogen, halo, or nitro substituent.
  • U.S. Patents 5,051,418 and 4,908,366, disclose 8-cyano-quinolone compounds that are reported to possess antibacterial activity.
  • the structure of these compounds differs from the structure of the compounds of formula I disclosed herein at the 3-position by not including a 4-substitutedbenzamide, and at the 8-position by requiring a cyano substituent.
  • EP 0 370 686 discloses a process for preparing quinolone carboxylic acid intermediates.
  • the structure of the disclosed compounds differs from the structure of the compounds of formula I disclosed herein at the 3-position by not including a 4- substitutedbenzamide, and at the 6-position by requiring a fluoro substituent.
  • U.S. Patent 4,621,088, discloses quinolone amino acid derivatives that are reported to possess antiallergic activity, central nervous system activity and cardiovascular activity. The structure of these compounds differs from the structure of the compounds of formula I disclosed herein at the 3-position by not including a 4-substitutedbenzamide.
  • U.S. Patent 5,328,887 discloses an array of compounds including numerous quinolone compounds that are reported to be useful as fluorescent donor elements for use in a thermal transfer possess. The single specific 4-quinolone compound prepared and tested in the application differs from the compounds of formula I disclosed herein at the 3-position by not including a 4-substitutedbenzamide, at the 2-position by having a phenyl substituent. at the 6-position by having a hydrogen, and at the 1 -position by being unsubstituted.
  • U.S. Patent 4,855,291 discloses quinolone compounds that are reported to possess antihypertensive activity. The structure of these compounds differs from the structure of the compounds of formula I disclosed herein at the 3-position by not including a 4- substitutedbenzamide.
  • U.S. Patent 3,524,858 discloses quinolone compounds that are reported to possess anti-microbial activity. The structure of these compounds differs from the structure of the compounds of formula I disclosed herein at the 3-position by not including a 4- substitutedbenzamide, and at the 6J-positions by requiring a methylenedioxy substituent.
  • WO 98/23608 discloses quinolone compounds that are reported to possess integrin antagonist activity. The structure of these compounds differs from the structure of the compounds of formula I disclosed herein at the 3-position by not including a 4- substitutedbenzamide.
  • U.S. Patent 5,026,856 discloses isoindoline compounds that are reported to possess antibacterial activity.
  • the structure of these compounds differs from the structure of the compounds of formula I disclosed herein at the 3-position by not including a 4- substitutedbenzamide, and at the 6-position by requiring a halo, hydroxy. or loweralkoxy substituent.
  • U.S. Patent 5,563,141 discloses an array of compounds that are reported to inhibit cell adhesion. Although the disclosed genus of compounds may include 3aminocarbonyl-4- quinolones, these compounds do not comprise a 4-substituted-benzamide at the 3-position. All of final compounds specifically prepared in the patent comprise a 4-pyridyl(piperazin- 1 - yl) ring system.
  • WO 9932450 discloses compounds of the following generic formula which are useful for the treatment of herpesvirus infections.
  • EP 343560 discloses antibacterial agents having the following structure.
  • JP 02040379 discloses compounds useful as antibacterials having generic structure.
  • US 5,412,104 discloses the following generic structure as being useful as antiviral agents against DNA containing viruses such as herpes group viruses.
  • the present invention provides a compound of formula I.
  • X is a) O, or b) S; W is a) R 2 ; b) NR 7 R 8 , c) OR 9 , or d) SO,R 9 ;
  • ' is a) Cl, b) F, c) Br, d) CN, or e) NO 2 ;
  • R 3 is a) H, b) halo, or c) C ⁇ -4 alkyl, optionaUy substituted by one to three halo:
  • R 4 is a) H, b) aryl, c) het, d) SO 2 NHR 12 , e) CONHR 12 ,
  • Ciching 8 alkyl which may be partiaUy unsaturated and is optionaUy substituted by one or more substituents selected from a group consisting of N , OR 10 , NR 7 R 8 .
  • R 5 is a) H, b) halo, c) C ⁇ CR 14 , d) NR 7 R 8 , e) SO 2 NHR 12 , t) het, or g) Cj_7 alkyl, optionaUy substituted by OH;
  • R 6 is a) H, b) halo, c) SC ⁇ -7 alkyl, d) C1-7 alkoxy, optionaUy substituted by one or more halo or OH, or e) C1-7 alkyl. which may be partiaUy unsaturated and is optionaUy substituted by halo.
  • NR 10 R 10 (CH 2 )
  • R 11 . OC ,. 7 alkyl which is further substituted with het, NR 7 R 8 . or SO.R 9 :
  • R 7 and R 8 are independently a) H, b) aryl, c) C ⁇ _ 7 alkyl which may be partiaUy unsaturated and is optionally substituted by one or more substituents selected from a group consisting of NR 10 R 10 . CONR 10 R 10 . R 11 , SO,R 9 . halo: or d) R 7 and R 8 together with the nitrogen to which they are attached to form a het;
  • R 9 is a) aryl, b) het, c) C 3 _ 8 cycloalkyl. or d) C ⁇ _ 7 alkyl which may be partiaUy unsaturated and optionaUy substituted by one or more OR 10 , Oaryl, het, aryl, NR 10 R 10 , CN.
  • R 10 is a) H, or b) Ci-7 alkyl, optionaUy substituted by OH;
  • R n is a) OR 10 , b) Ohet, c) Oaryl, d) CO 2 R 10 , e) het, f) aryl, or g) CN;
  • R 12 is a) H, b) het, c) aryl, d) C 3- 8 cycloalkyl, or e) Ci-7 alkyl optional > 7r > 8 i l l .
  • R I4 is a) het, b) (CH 2 ) n OR 13 , or c) Ci- alkyl substituted by one or more substituents selected from a group consisting of R 11 , OC ⁇ -7 alkyl which is further substituted with het, NR 7 R 8 , or SO,R 9 ;
  • aryl is a phenyl radical or an ortho-fused bicyclic carbocychc radical wherein at least one ring is aromatic: het is a four- (4), five- (5), six- (6), or seven- (7) membered saturated or unsaturated heterocycUc ring having 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, suttur, and nitrogen, which is optionaUy fused to a benzene ring, or any bicycUc heterocycle group; wherein any aryl is optionaUy substituted with one or more substituents selected from the group consisting of halo, OH
  • NR l ⁇ R 10 , OR 10 , or CO 2 R 10 wherein any het is optionaUy substituted with one or more substituents selected from the group consisting of halo, OH, CF 3 , C ⁇ . 6 alkoxy, oxo, oxine, and C ⁇ _6 alkyl which maybe further substituted by one to three SR 10 , NR 10 R !0 , OR 10 , or CO 2 R 10 ; i is 0. 1. or 2: m is 1. 2. or 3: n is 1, 2. 3, 4, 5, or 6: and
  • M is sodium, potassium, or Uthium:
  • R 1 is not Cl, Br, F. or CN
  • R 2 is C ? alkyl optionaUy substituted by R 15 :
  • R 3 is H. methyl, or halo;
  • R 4 is H. CONH(C ⁇ -7 alkyl), NR 16 R 17 , or C,. 7 alkyl optionaUy substituted by OR 10 . CN.
  • R 5 is H. halo, SO 2 NHR 10 , NR 16 R 17 , or C, -7 alkyl optionaUy substituted by OR 10 :
  • R 6 is H. halo, C ⁇ -7 alkoxy, or C ⁇ - alkyl optionaUy substituted by halo, OR 10 , CO 2 R 10 or NR 16 R 17 :
  • R 15 is NR 16 R 17 , OR 10 , CN, or CO 2 R 10 ;
  • R 16 and R 17 are independently H or d -7 alkyl; or NR 16 R 17 together with the nitrogen to which they are attached form a 5- or 6-membered ring such as pyrroUdine. piperidine. morpholine. or piperazine.
  • the present invention also provides: a pharmaceutical composition comprising a compound of formula I.
  • a method of treating or preventing a herpesviral infection comprising administering to a mammal in need of such treatment, a compound of formula (I) or a pharmaceuticaUy acceptable salt thereof, a compound of formula (I) or a pharmaceuticaUy acceptable salt thereof for use in medical treatment or prevention of a herpesviral infection.
  • the use of a compound of formula (I) or a pharmaceuticaUy acceptable salt thereof to prepare a medicament for treating or preventing a herpesviral infection in a mammal, and a method for inhibiting a viral DNA polymerase. comprising contacting (in vitro or in vivo) the polymerase with an effective inhibitory amount of a compound of formula I. or a pharmaceuticaUy acceptable salt thereof.
  • the invention also provides novel intermediates and processes disclosed herein that are useful for preparing compounds of formula I.
  • alkyl, alkoxy, etc. denote both straight and branched groups; but reference to an individual radical such as "propyl "" embraces only the straight chain radical, a branched chain isomer such as "'isopropyl" being specificaUy referred to.
  • alkyl can be partiaUy unsaturated.
  • the alkyl chain may comprise one or more (e.g. 1 , 2, 3. or 4) double or triple bonds in the chain.
  • Aryl denotes a phenyl radical or an ortho-fused bicycUc carbocycUc radical wherein at least one ring is aromatic.
  • Aryl is optionaUy substituted with one or more substituents selected from the group consisting of halo, OH, CF , Cj. 6 alkoxy. and C ⁇ -6 alkyl which maybe further substituted by one to three SR 10 , NR 10 R 10 , OR 10 , or CO 2 R'°:
  • Het denotes a four- (4), live- (5), six- (6). or seven- (7) membered saturated or unsaturated heterocychc ring having 1 , 2, or 3 heteroatoms selected from the group consisting of oxygen, sutfur.
  • Het is optionaUy substituted with one or more substituents selected from the group consisting of halo, OH, CF 3 , Ci- ⁇ alkoxy. oxo. oxine. and C ⁇ -6 alkyl which maybe further substituted by one to three SR 10 .
  • amino acid includes a residue of natural amino acid (e.g. Ala. Arg. Asn. Asp, Cys, Glu, Gin. Gly, His, Hyl, Hyp, He, Leu, Lys, Met, Phe, Pro. Ser. Thr. Trp, Tyr, and Val) in D or L form, as weU as unnatural amino acids (e.g. phosphoserine.
  • natural amino acid e.g. Ala. Arg. Asn. Asp, Cys, Glu, Gin. Gly, His, Hyl, Hyp, He, Leu, Lys, Met, Phe, Pro. Ser. Thr. Trp, Tyr, and Val
  • unnatural amino acids e.g. phosphoserine.
  • an amino acid can conveniently be linked to the remainder of a compound of formula I through the carboxy terminus, the amino terminus, or through any other convenient point of attachment, such as. for example, through the suUur of cysteine.
  • an amino acid can conveniently be linked to the remainder of a compound of formula I through the carboxy terminus.
  • Mammal denotes human and animals. It wUl be appreciated by those skiUed in the art that compounds of the invention having a chiral center may exist in and be isolated in optically active and racemic forms. Some compounds may exhibit polymorphism. It is to be understood that the present invention encompasses any racemic, opticaUy-active, polymorphic, tautomeric.
  • opticaUy active forms for example, by resolution of the racemic form by recrystaUization techniques, by synthesis from opticaUy- active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase
  • opticaUy active forms for example, by resolution of the racemic form by recrystaUization techniques, by synthesis from opticaUy- active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase
  • the carbon atom content of various hydrocarbon-containing moieties is indicated by a prefix designating the minimum and maximum number of carbon atoms in the moiety, i.e.. the prefix C ,_, indicates a moiety of the integer to the integer *' j " carbon atoms, inclusive.
  • C ⁇ _ 7 alkyl refers to alkyl of one to seven carbon atoms, inclusive.
  • alkyl can be methyl, ethyl, propyl, isopropyl. butyl, iso-butyl, sec-butyl, pentyl, 3-pentyl, hexyl, heptyl, etc.;
  • C 3 - 8 cyclo alkyl can be cyclopropyl. cyclobutyl, cyclopentyl, cyclohexyl. cycloheptyl, or cyclooctyl;
  • alkoxy can be methoxy, ethoxy, propoxy, isopropoxy. butoxy, iso-butoxy, sec-butoxy, pentoxy, 3-pentoxy. hexyloxy.
  • heteroaryl can be furyl. imidazolyl. triazolyl, triazinyl, oxazoyl, isoxazoyl, thiazolyl, isothiazoyl, pyrazolyl, pyrrolyl. pyrazinyl, tetrazolyl, pyridyl, (or its N-oxide). thienyl, pyrimidinyl (or its N-oxide). indolyl, isoquinolyl (or its N-oxide) or quinolyl (or its N-oxide).
  • R 1 A specific value for R 1 is Cl.
  • a specific value for R 1 is F.
  • a specific value for R 1 is CN, or NO?.
  • R 2 is (CH 2 CH 2 O) m H. or (CH 2 CH 2 O) m C ⁇ _ 4 alkyl, wherein m is 2. or 3.
  • R 2 is Cv 8 cycloalkyl optionaUy substituted by R 11 .
  • R 2 is cyclopropyl
  • R 2 A specific value for R 2 is het wherein said het is bonded via a carbon atom and is the same as defined above.
  • R 2 is tetrahydro-2H-pyranyl, piperdinyl, 1 -methyl-piperidinyl, or 1 J -dioxo-tetrahydro-2H-thiopyran.
  • R 2 is C,_ 7 alkyl substituted by NR 7 R 8 .
  • R 2 is C ⁇ _ 7 alkyl substituted by SO,R 9 wherein R 9 and i are the same as defined above.
  • a specific value for R 2 is C 1-7 alkyl substituted by SO,R 9 ; wherein R 9 is C,. 4 alkyl, optionaUy substituted by OH, or R 9 is phenyl. optionaUy substituted by Cl; wherein i is 0. 1. or 2.
  • a specific value for R 2 is methyl.
  • a specific value for W is NR 7 R 8 , wherein R 7 and R 8 are the same as defined above.
  • a specific value for W is NR 7 R 8 . wherein R 7 and R 8 together with the nitrogen to which they are attached to form a het wherein said het is the same as defined above.
  • a specific value for W is morpholine. piperidine. pyrroUdine, piperazine, or 4- methyl-piperazine.
  • a specific value for W is NR 7 R 8 , wherein R 7 and R 8 are independently H or C ⁇ alkyl optionaUy substituted by OH.
  • a specific value for W is morpholine.
  • a specific value for W is OR 9 , or SO,R 9 wherein R 9 is C ⁇ . 6 alkyl which may be partiaUy unsaturated and optionaUy substituted by OR 10 .
  • a specific value for R 3 is H.
  • a specific value for is CF , or halo.
  • R 4 is aryl or het.
  • R 4 is SO 2 NHR 12 . CONHR 12 , NHCOR 12 . or NHSO 2 R 12 . wherein R 12 is the same as defined above.
  • a specUic value for R 4 is C? fashion 8 alkyl which is partiaUy unsaturated and optionaUy substituted by OR 10 .
  • R 7 . R 8 , R 9 . R 10 , R 11 and R 13 are the same as defined above.
  • R 4 is C ⁇ -8 alkyl substituted by SO,R 9 . wherein R 9 is the same as defined above.
  • R 4 is NR 7 R 8 , wherein R 7 and R 8 are the same as defined above.
  • a specific value for R 4 is d -8 alkyl substituted by NR 7 R 8 . wherein R 7 and R 8 are the same as defined above.
  • a specific value for R 4 is C ⁇ . 8 alkyl substituted by NR 7 R 8 , wherein R 7 and R 8 together with the nitrogen to which they are attached to form a het. wherein het is the same as defined above.
  • R 4 A specific value for R 4 is d_ 8 alkyl substituted by NR 7 R 8 , wherein R 7 and R 8 are independently C ⁇ _ 6 alkyl, optionaUy substituted by one or more substituents selected from a group consisting of OH, aryl, or CN wherein aryl is the same as defined above.
  • R 4 is C ⁇ -8 alkyl substituted by N 3 .
  • a specific value for R 4 is C ⁇ _ 8 alkyl substituted by het wherein het is the same as defined above.
  • a specific value for R 4 is 4-morpholine methyl.
  • R 4 is C ⁇ -7 alkyl substituted by R 11 .
  • R ! l is the same as defined above.
  • R ⁇ is H or C ⁇ . 7 alkyl optionaUy substituted by OH.
  • a specific value for R 6 is OC 1 . 7 alkyl optionally substituted by one or more OH.
  • a specific value for R 6 is halo.
  • R 6 is C ⁇ CC ⁇ - 7 alkyl substituted by one or more OH. or C 2- 7 alkoxy substituted by one or more OH.
  • R 6 is H or d. 7 alkyl. optionally substituted by halo.
  • a specific value for M is sodium, potassium, or Uthium.
  • R 1 . R 2 , R 3 . R 4 . R ⁇ R 6 are the same as defined above.
  • a specific value is where X is O; R 1 , R 3 . R 4 , R ⁇ R 6 are the same as defined above, W is NR 7 R 8 , OR 9 . SO,R 9 or R 2 ; wherein R 2 is: a) (CH?CH 2 O) n R 10 . b) het, wherein said het is bonded via a carbon atom. c) C ⁇ _ 7 alkyl which is partiaUy unsaturated and optionaUy substituted by OH, d) - 8 cycloalkyl. or e) C1-7 alkyl which is optionaUy substituted by one or more substituents selected from a group consisting of Ohet, Oaryl.
  • R 9 is phenyl optionaUy substituted by Cl, or R 9 is Ci- ⁇ alkyl optionaUy substituted by OH.
  • a specific value is where X is O or S: R 1 is Cl; R 3 is H: R' is H: R 6 is C ⁇ CC ⁇ -4 alkyl optionaUy substituted by OH; R 4 is H or which may be partially unsaturated and optionaUy substituted by OH, and W is C ⁇ - 4 alkyl optionaUy substituted by OH.
  • alkyl When alkyl is partiaUy unsaturated . it can be vinyl, aUyl. 1 -propenyl, 2-propenyl. 1 - butenyl, 2-butenyl. 3-butenyl, 1 J-butadienyl, 1-pentenyl. 2-pentenyl. 3-pentenyl. 4-pentenyl, 1-hexenyl, 2-hexenyl. 3-hexenyl, 4-hexenyl. 5-hexenyl. ethynyl, 1-propynyl. 2-propynyl, 1- butynyl, 2-butynyl. 3-butynyl.
  • Examples of the present invention are (1) N-(4-chlorobenzyl)-6-(3-hydroxy-l-propynyl)- l-isopropyl-4-oxo- 1.4-dihydro-3- quinolinecarboxamide; (2) 1 -(sec-butyl)-N-(4-chlorobenzyl)-6-(3-hydroxy- 1 -propynyl)-4-oxo- 1 ,4-dihydro-3- quino linec arbo xamid :
  • Charts A - AA describe the preparation of the compounds of the present invention.
  • AU of the starting materials are prepared by procedures described in these charts or by procedures analogous thereto, which would be weU known to one of ordinary skiU in organic chemistry.
  • All of the final compounds of the present invention are prepared by procedures described in these charts or by procedures analogous thereto, which would be weU known to one of ordinary skill in organic chemistry. All of the variables used in the charts are as defined below or as in the claims. Chart A.
  • the ethyl ester of Formula A- 1 which is ethyl 4-hydroxy-6-iodo-3- quinolinecarboxylate, is prepared by heating 4-iodoaniline with diethyl ethoxymethylene malonate, first at about 150°C. then in refluxing diphenyl ether. Aminolysis of compound A- 1 with 4-substituted-benzylamine at about 160°C provides amide A-2. Palladium and copper mediated coupling of A-2 with propargyl alcohol leads to compound A-3. Alkylation of the pyridone nitrogen is accompUshed with potassium carbonate and an optionaUy substituted alkyl haUde, affording the compound of Formula A-4.
  • compound A-3 is partiaUy hydrogenated to the alkenyl derivative, compound A-5 (E or Z).
  • 4-quinolone structures of Formula A-4 are partiaUy hydrogenated to afford alkenyl derivatives of Formula A-6 (E or Z).
  • Alkylation of compound A-5 with optionaUy substituted alkyl haUdes and potassium carbonate also provides compounds of Formula A-6.
  • the compound of Formula B-l which is 2-fluoro-5-iodobenzoic acid, is prepared by carbonation of the anion of 4-fluoroiodobenzene, which is prepared by deprotonation of 4- fluoroiodobenzene with LDA.
  • the ketoester is converted to quinoUnones B-3 by sequential treatment with triethyl orthoformate, an amine, and potassium tert-butoxide.
  • PaUadium catalyzed carbonylation of the 6-iodo-4-hydroxyquinoline-3-carboxamide A-2 affords the corresponding ester C-l which is then reduced with LAH to afford the alcohol C-2.
  • Compounds of Formula D-l are phosphitylated with di-tert-butyl diethyl phosphoramidite to give an intermediate phosphite, which is oxidized in situ with m- chloroperbenzoic acid to provide di-tert-butyl phosphates of Formula D-2.
  • Treatment of the phosphates with trifluoroacetic acid cleaves the tert-butyl groups, providing phosphoric acids of Formula D-3.
  • Alcohols of Formula D- 1 are coupled with suleptanic acid triethylammonium salt, which is triethylammonium 2-[(7-carboxyheptanoyl)(methyl)amino]-l-ethanesuU " onate, using dusopropylcarbodiimide and 4- dimethylamino yridine, to provide the corresponding esters.
  • suleptanic acid triethylammonium salt which is triethylammonium 2-[(7-carboxyheptanoyl)(methyl)amino]-l-ethanesuU " onate, using dusopropylcarbodiimide and 4- dimethylamino yridine, to provide the corresponding esters.
  • Exchanse of the triethvlammonium salt with sodium ion affords sodium salts E-l.
  • H-1 Alkylation of N-(4-chlorobenzyl)-6-iodo-4-oxo- 1 ,4-dihydro-3-quinolinecarboxamide with potassium carbonate and tert-butylbromoacetate affords H-1.
  • PaUadium catalyzed coupling of the iodide with propargyl alcohol affords H-2.
  • Reaction with platinum and hydrogen gas affords the saturated propyl alcohol (H-3).
  • Treatment with tritluoroactic acid affords the free acid (H-4).
  • H-2 is treated with trifluoroacetic acid to give H-5.
  • 2-Fluoro-6-iodoaniline is condensed with diethyl ethoxymethylenemalonate and then heated in diphenyl ether to afford the 4-hydroxyquinoline ethyl ester (J-1).
  • Aminolysis of compound J- 1 with 4-chlorobenzylamine affords the corresponding amide (J-2).
  • Compound J-2 is heated in the presence of an alkoxide to afford compound J-3.
  • PaUadium catalyzed coupling of the resulting quinoUne with propargyl alcohol affords alkyne J-4.
  • the pyridone nitrogen of J-4 is then N-alkylated with an alkyl haUde and potassium carbonate to afford 4- quinolones of Formula J-5.
  • Hydrogenation of compound J-5 affords the hydroxypropyl derivate of Formula J-6.
  • the resulting 6-iodo-4-quinolones are coupled with trialkyl alkenyl stannanes (e.g. tributyl vinyl stannane) catalyzed by PdCl 2 (PPh 3 ) 2 to afford compounds such as those described by formula P-2
  • Alkyl chloride N- 1 is treated with the sodium salt of an alkyl thiol to afford suUides of the general formula Q-l (wherein R 2 and R 9 is the same as defined above).
  • W-2 O, NMe, NBoc
  • W-3 O, ⁇ Me, ⁇ Boc
  • Reductive animation of 3-bromo-4-fluorobenzaldehyde with morpholine and sodium triacetoxyborohydride affords aryl bromide X-l.
  • Halogen-kthium exchange foUowed by acetylation with a N-methoxy-N-methylacetamide gives methyl ketone X-2.
  • the resulting ketone is then converted to ⁇ -keto ester X-3 with diethyl carbonate under basic conditions.
  • Refluxing ⁇ -keto ester X-3 in triethylorthoformate and acetic anhydride produces an intermediate enol ether which is then reacted with a selected hydrazide.
  • Butyl acetate sUyl ketene acetal is reacted with 2-chloro-5-iodobenzoylchloride to afford ⁇ -ketoester Y- l .
  • Refluxing Y-l in triethylorthoformate and acetic anhydride produces an intermediate enol ether which is then reacted with a selected hydrazide.
  • the resulting enamine Y-2 (wherein R 7 and R 8 are the same as defined above) is then cycUzed by heating with sodium hydride to afford the corresponding quinolone-3-ester Y-3.
  • Direct thermolysis of the ester with 4-chlorobenzylamine affords amides of the general formula Y- 4.
  • PaUadium catalyzed coupling of Y-4 with propargyl alcohol affords compounds of general formula Y-5.
  • Subsequent catalytic hydrogenation of the alkyne provides hydroxypropyl
  • N-(4-chlorobenzyl)-4-hydroxy-6- iodo-3-quinolinecarboxamide (A-2) is treated with O-(mesitylsuU nyl)hydroxylamine to afford 1-amino-quinolone Z- 1.
  • Compound Z-1 may then be transformed in a simUar fashion to that described for general intermediate Y-4 above.
  • Ethyl 3-(2-fluorophenyl)-3-oxopropanoate (AA-1) is refluxed in triethylorthoformate and acetic anhydride to afford an intermediate enol ether which is then reacted with a selected N-alkoxyamine.
  • the resulting enamine AA-2 is then cycUzed by heating with sodium hydride to afford the corresponding quinolone-3-ester AA-3.
  • Direct thermolysis of the ester with 4-chlorobenzylamine affords amides of the general formula AA-4.
  • pharmaceuticaUy acceptable salts are organic acid addition salts formed with acids which form a physiological acceptable anion. for example, tosylate. methanesuU ' onate, acetate, citrate, malonate. tartarate, succinate. benzoate. ascorbate, etoglutarate, and glycerophosphate.
  • Suitable inorganic salts may also be formed, including hydrochloride. sulfate, nitrate, bicarbonate, and carbonate salts.
  • PharmaceuticaUy acceptable salts may be obtained using standard procedures weU known in the art, for example by reacting a sufficiently basic compound such as an amine with a suitable acid affording a physiologicaUy acceptable anion.
  • a sufficiently basic compound such as an amine
  • a suitable acid affording a physiologicaUy acceptable anion.
  • AlkaU metal for example, sodium, potassium or hthium
  • alkaline earth metal for example calcium
  • Compounds of the present invention can conveniently be administered in a pharmaceutical composition containing the compound in combination with a suitable excipient.
  • the composition being useful in combating viral infections.
  • Pharmaceutical compositions containing a compound appropriate for antiviral use are prepared by methods and contain excipients which are weU known in the art. A generally recognized compendium of such methods and ingredients is Remington's Pharmaceutical Sciences by E.W. Martin (Mark Publ. Co., 15th Ed.. 1975).
  • the compounds and compositions of the present invention can be administered parenteraUy (for example, by intravenous, intraperitoneal or intramuscular injection), topicaUy. oraUy. or rectally. depending on whether the preparation is used to treat internal or external viral infections.
  • the active compound may be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
  • Such compositions and preparations should contain at least 0.1 % of active compound.
  • the percentage of the compositions and preparations may. of course, be varied and may conveniently be between about 2 to about 60% of the weight of a given unit dosage form.
  • the amount of active compound in such therapeuticaUy useful compositions is such that an effective dosage level wiU be obtained.
  • the tablets, troches, piUs, capsules, and the like may also contain the foUowing: binders such as gum tragacanth, acacia, corn starch or gelatin: excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate: and a sweetening agent such as sucrose, fructose, lactose or aspartame or a flavoring agent such as peppermint, oU of wintergreen, or cherry flavoring may be added.
  • binders such as gum tragacanth, acacia, corn starch or gelatin: excipients such as dicalcium phosphate
  • a disintegrating agent such as corn starch, potato starch, alginic acid and the like
  • a lubricant such as magnesium stearate
  • a sweetening agent such as sucrose, fructose, lactose or as
  • the unit dosage form When the unit dosage form is a capsule, it may contain, in addition to materials of the above type, a Uquid carrier, such as a vegetable oU or a polyethylene glycol. Various other materials may be present as coatings or to otherwise modU ' y the physical form of the soUd unit dosage form. For instance, tablets, pills, or capsules may be coated with gelatin, wax, sheUac or sugar and the like.
  • a syrup or elixir may contain the active compound, sucrose or fructose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor.
  • any material used in preparing any unit dosage form should be pharmaceuticaUy acceptable and substantiaUy non-toxic in the amounts employed.
  • the active compound may be incorporated into sustained-release preparations and devices.
  • the compounds or compositions can also be administered intravenously or intraperitoneally by infusion or injection.
  • Solutions of "the active compound or its salts can be prepared in water, optionaUy mixed with a nontoxic surfactant.
  • Dispersions can also be prepared in glycerol, Uquid polyethylene glycols, triacetin, and mixtures thereof and in oUs. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • compositions suitable for injection or infusion can include sterUe aqueous solutions or dispersions or sterUe powders comprising the active ingredient which are adapted for the extemporaneous preparation of sterUe injectable or infusible solutions or dispersions, optionaUy encapsulated in Uposomes.
  • the ultimate dosage form should be sterUe, fluid and stable under the conditions of manufacture and storage.
  • the Uquid carrier or vehicle can be a solvent or Uquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof.
  • the proper fluidity can be maintained, for example, by the formation of Uposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants.
  • the prevention of the action of microorganisms can be brought about by various antibacterial and antif ' ungal agents, for example, parabens. chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it wiU be preferable to include isotonic agents, for example, sugars, buffers or sodium chloride.
  • Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.
  • SterUe injectable solutions can be prepared by incorporating the active compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, foUowed by filter sterilization.
  • the preferred methods of preparation are vacuum drying and the freeze drying techniques, which yield a powder of the active ingredient plus any additional desired ingredient present in the previously sterile-filtered solutions.
  • the present compounds may be appUed in pure form, i.e.. when they are Uquids. However, it will generaUy be desirable to administer them to the skin as compositions or formulations, in combination with a dermatologically acceptable carrier, which may be a soUd or a Uquid.
  • Useful soUd carriers include finely divided solids such as talc. clay, microcrystalline ceUulose, siUca. alumina and the like.
  • Useful Uquid carriers include water, alcohols or glycols or water-alcohol/glycol blends, in which the present compounds can be dissolved or dispersed at effective levels, optionaUy with the aid of non-toxic surfactants.
  • Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize the properties for a given use.
  • the resultant Uquid compositions can be appUed from absorbent pads, used to impregnate bandages and other dressings, or sprayed onto the affected area using pump-type or aerosol sprayers.
  • Thickeners such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols. modUied ceUuloses or modified mineral materials can also be employed with Uquid carriers to form spreadable pastes, gels, ointments, soaps, and the like, for appUcation directly to the skin of the user.
  • Examples of useful dermatological compositions which can be used to deUver the compounds of formula I to the skin are known to the art: for example, see Jacquet et al. (U.S. Pat. No. 4.608392), Geria (U.S. Pat. No. 4.992,478). Smith et al. (U.S. Pat. No. 4,559,157) and Wortzman (U.S. Pat. No. 4.820.508).
  • Useful dosages of the compounds of formula I can be determined by comparing their in vitro activity, and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to the art: for example, see U.S. Pat. No. 4,938,949.
  • the compound is conveniently administered in unit dosage form; for example, containing 5 to 1000 mg, conveniently 10 to 750 mg, most conveniently, 50 to 500 mg of active ingredient per unit dosage form.
  • the desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day.
  • the sub-dose itseU ' may be further divided, e.g., into a number of discrete loosely spaced administrations: such as multiple inhalations from an insufflator or by appUcation of a pluraUty of drops into the eye.
  • compositions can be administered oraUy or parenteraUy at dose levels, calculated as the free base, of " about 0.1 to 300 mg/kg, preferably 1.0 to 30 mg/kg of mammal body weight, and can be used in man in a unit dosage form, administered one to four times daUy in the amount of 1 to 1000 mg per unit dose.
  • the compounds are presented in aqueous solution in a concentration of from about 0.1 to about 10%, more preferably about 0J to about 1%.
  • the solution may contain other ingredients, such as emulsUiers, antioxidants or buffers.
  • the concentration of " the compound(s) of " formula I in a Uquid composition, such as a lotion, wUl be from about 0J-25 wt-%, preferably from about 0.5-10 wt-%.
  • the concentration in a semi-soUd or soUd composition such as a gel or a powder wiU be about 0J-5 wt-%, preferably about 0.5-2.5 wt-%.
  • the antiviral activity of " a compound of the invention can be determined using pharmacological models which are weU known to the art, or using Test A described below.
  • the compounds of formula (I) and pharmaceuticaUy acceptable salts thereof " are useful as antiviral agents. Thus, they are useful to combat viral infections in animals, including man.
  • the compounds are generaUy active against herpes viruses, and are particularly useful against the variceUa zoster virus, the Epstein-Barr virus, the herpes simplex virus, the human herpes virus type 8 (HHV-8) and the cytomegalovirus (CMV).
  • the HCMV polymerase assay is performed using a scintillation proximity assay (SPA) as described in several references, such as N.D. Cook, et al., Pharmaceutical Manufacturing International, pages 49-53 (1992); K. Takeuchi, Laboratory Practice, September issue (1992); US Patent No. 4,568,649 (1986); which are incorporated by reference herein. Reactions are performed in 96-weU plates. The assay is conducted in 100 ⁇ l volume with 5.4 mM HEPES (pH 7.5), 1 1.7 mM KCI, 4.5 mM MgCl 2 , 0.36 mg/ml BSA, and 90 nM 3 H-dTTP.
  • SPA scintillation proximity assay
  • HCMV polymerase is dUuted in enzyme dUution buffer containing 50% glycerol, 250 mM NaCl, 10 mM HEPES (pH 7.5), 100 ⁇ g/ml BSA, and 0.01 % sodium azide. The HCMV polymerase.
  • Plates are incubated in a 25 C or 37 C H?O bath and terminated via the addition of 40 ⁇ l/reaction of 0.5 M EDTA (pH 8) per well. Reactions are terminated within the time-frame during which substrate incorporation is linear and varied depending upon the enzyme and conditions used, i.e., 30 min. for HCMV polymerase. Ten ⁇ l of streptavidin-SPA beads (20 mg/ml in PBS/10% glycerol) are added foUowing termination of the reaction. Plates are incubated 10 min. at 37 C, then equUibrated to room temperature, and counted on a Packard Topcount. Linear regressions are performed and IC 50 's are calculated using computer software.
  • a mixture of 11.85 g of 2-fluoro-4-iodoaniline and 10.81 g of diethylethoxy- methylene malonate is heated to 130 °C in a flask equipped with a Dean-Stark trap to coUect formed ethanol.
  • the mixture is then cooled to 75 °C and dUuted with hexanes.
  • the resulting soUd is coUected and dried.
  • the soUd is then dissolved in 60 mL diphenyl ether and heated to 250 °C for 3 h in a flask equipped with a Dean- Stark trap to coUect the ethanol.
  • N-(4-Chlorobenzyl)-8-tluoro-4-hydroxy-6-iodo-3-quinoUnecarboxamide (2.95 g) from Preparation No. 1 and sodium hydride (60% dispersion, 520 mg) is suspended in DMF (60 mL) and to the mixture is added methanol (288 ⁇ L). After being heated for 1 h at 135 °C, additional sodium hydride (200 mg) is added, and the mixture is heated for an additional 1 h. The reaction mixture is aUowed to cool to rt and then is poured into saturated aqueous ammonium chloride (200 mL). The resulting precipitate is filtered and washed with water (20 mL).
  • a brown soUd precipitated from the CH?C1 2 layer is filtered and coUected to obtain pure product as indicated by NMR.
  • the organic layers are combined, dried over Na 2 SO , and concentrateed to obtain a brown residue.
  • the residue is placed under high vac to remove residual DMF.
  • the residue is adsorbed onto sUica and chromatographed eluting with 2% MeOH in CH?C1? and 3% MeOH in CH 2 Ck Fractions homogenous by TLC are combined, condensed and recrystaUized with EtOAc/hexanes to obtain a creme soUd.
  • the two crops yielded 325.4 mg (79%) of the desired product as a tan soUd.
  • the reaction mixture was filtered to get rid of the aluminum salt that had precipitated..
  • the filtrate was condensed to obtain a green residue.
  • the green residue was adsorbed onto sUica and chromatographed eluting with 2% MeOH in CH 2 C1? and 3% MeOH in CH 2 C1 2 . Fractions homogenous by TLC were condensed to yield 76.8 mg (55%) of the desired product as a white sokd.
  • the reaction is quenched by adding 2 mL H?O, 2 mL 15% NaOH, and 2 mL H O to the reaction mixture.
  • the reaction mixture is filtered to remove the aluminum salt that had precipitated.
  • the filtrate is condensed to obtain a yeUow-green residue.
  • the residue is adsorbed onto siUca and chromatographed eluting with 2% MeOH in CH 2 C1? ( IL), 3% MeOH in CH 2 C1? (2L), 4% MeOH in CH?_C1 2 (2L), 5% MeOH in CH 2 C1 2 (IL), 6% MeOH in CH?_C1? (IL), and 7% MeOH in CH 2 C1 2 (2L).
  • the desired product elutes with 4-7% MeOH in CH 2 C1 2 . Fractions homogenous by TLC are condensed to yield 1.85 g (67%) of the title compound as yeUow crystals.
  • Ethyl 8-fluoro-4-hydroxy-6-iodo-3-quinolinecarboxylate (18J g ) prepared as an intermediate in Preparation No. 1 is dissolved in DMF (430 mL). and K 2 CO 3 (36J g, 261 mmol) and methyl iodide (3.25 mL, 52.3 mmol) are added.
  • the reaction mixture is heated to 95 °C for 6 h, then aUowed to stir at room temperature overnight.
  • the mixture is spUt into two parts. The first part is poured into H?O and extracted with five 100-mL portions of CH?C1?.
  • the residue is azeotroped three times with toluene to remove residual pyridine.
  • the residue is adsorbed onto sUica and chromatographed on sUica eluting with 50% ethyl acetate in heptane.
  • the product-containing fractions are evaporated to give 4.9 g ol " 2-(ethyl-4- nitro anilino) ethyl acetate as a yeUow oU.
  • aqueous is back-extracted once with ethyl acetate and the combined organic layers are washed with brine, dried over sodium suUate, and concentarted under reduced pressure.
  • the residue is adsorbed onto sUica and chromatographed on siUca eluting with 3% to 9% ethyl acetate in heptane.
  • the product- containing fractions are combined and evaporated to afford 1.85 g of the title compound as a tan oU.
  • N-((4-Chlorobenzyl)-4-hydroxy-6-(3-hydroxy- l-propynyl)-3-quinofinecarboxamide (366 mg) from Preparation No. 5 and potassium carbonate (276 mg) are dissolved in DMF (5 mL).
  • 2-Bromopropane (470 ⁇ L) is added and the mixture is heated to 100 °C for 1 h.
  • the reaction mixture is aUowed to cool to rt, poured into water (25 mL) and extracted with ethyl acetate (2 x 50 mL).
  • the organic layer is washed with sat. aqueous brine (10 mL).
  • the aqueous layer is back-extracted with ethyl acetate (20 mL).
  • N-((4-Chlorobenzy])-4-hydroxy-6-(3-hydroxy- l-propynyl)-8-methoxy-3-quinoline- carboxamide 300 mg from Preparation No. 3 and potassium carbonate (310 mg) are dissolved in DMF (5 mL).
  • 2-Iodobutane (345 ⁇ L) is added and the mixture is heated to 120 °C for 4 h.
  • Additional 2-Iodobutane (200 ⁇ L) and potassium carbonate (100 mg) is added and the mixture is heated for 16 h.
  • the reaction mixture is aUowed to cool to rt, poured into water (75 mL) and extracted with ethyl acetate (3 x 50 mL).
  • the reaction mixture is filtered through a CeUte pad, and the filtrate is concentrated in vacuo.
  • the resulting yeUow oU is dissolved in methanol (60 mL) and hydrogenated over Pd Black (35 mg) for 4 h.
  • the reaction mixture is filtered through a CeUte pad, and the filtrate is concentrated in vacuo.
  • the resulting yeUow oU is purified by column chromatography (dichloromethane/methanol, 98/2: 95/5).
  • the resulting brown oU is purified by column chromatography (dichloromethane / methanol, 98/2). Mixed fractions are combined and re-purified (ethyl acetate/heptane, 1/1). Fractions homogeneous by TLC are combined and concentrated in vacuo to yield a yeUow soUd which is recrystaUized from ethyl acetate to yield 1.701 g (48%) of the intermediate amide as a pale yeUow soUd.
  • soUd is dissolved in CHC1 and filtered to remove 0.045 g of a precipitate.
  • the filtrate is concentrated in vacuo and crystaUized from ethyl acetate to give 0.065 g of the title compound as a soUd.
  • EXAMPLE 28 tert-Butyl 2-[3- ⁇ [(4-chlorobenzyl)amino]carbonyl ⁇ -6-(3-hydroxy- 1 -pro pynyl)-4-oxo-l(4H)-quinolinyl] acetate
  • the reaction is concentrated under reduced pressure, dUuted with dichloromethane containing a small amount of methanol, and partioned against water.
  • the organic layer is washed with brine, dried and concentrated under reduced pressure.
  • the residue is adsorbed onto sUica and chromatographed on sUica eluting with 2% to 4% methanol in dichloromethane .
  • the product-containing fractions are combined and concentrated under reduced pressure to afford 0J3 g of " the title compound as a soUd.
  • EXAMPLE 36 Sodium 2-[ ⁇ 8-[3-(3- ⁇ [(4-chlorobenzyl)am ⁇ no]carbonyl ⁇ -l- cyclopropyl-4-oxo- 1.4-dihydro-6-quinolinyl)propoxy]-8-oxooctanoyl ⁇ (methyl)amino]- 1 - ethanesuU ' onate
  • EXAMPLE 38 Sodium 2-[(8- ⁇ [3-(3- ⁇ [(4-chlorobenzyl)amino]carbonyl ⁇ - l- cyclopropyl-4-oxo- l,4-dihydro-6-quinolinyl)-2-propynyl]oxy ⁇ -8- oxooctanoyl)(methyl)amino]- 1 -ethanesulfonate
  • the aqueous phase is chiUed in ice and acidUied with 40 mL of 6N HCl.
  • the precipitate is extracted with two portions of ether, and the organic phase dried (MgSO 4 ) and concentrated under reduced pressure. RecrystaUization of the residue with ethyl acetate- hexane provides 19.57 g of " the title compound as white needles.
  • a second crop of 3.78 g is obtained by recrystaUization of the mother Uquor residue.
  • EXAMPLE 40 Sodium 2-[ ⁇ 8-[3-(l-(tert-butyl)-3- ⁇ [(4-chlorobenzyl)amino]- carbonyl ⁇ -4-oxo- l,4-dihydro-6-quinolinyl)propoxy]-8-oxooctanoyl ⁇ (methyl)aminol-l- ethanesuUonate
  • Ethyl 4-hydroxy-6-iodo-3-quinoUnecarboxylate prepared as an intermediate in Preparation No. 4 (5.0 g) , potassium carbonate (10.4 g) and methyl iodide (0.94 mL) are suspended in DMF (100 mL) and heated to 95°C under a nitrogen atmosphere for 6.5 hrs. After the mixture is brought to room temperature potassium carbonate is filtered off. and the solvent is evaporated under reduced pressure untU a white soUd precipitates out of solution. This white soUd is fUtered, washed with water and dried in a stream of air. A sample of this soUd (2.0 g) is suspended in ethanol (12 mL) and sodium hydroxide (8 mL.
  • This soUd is fUtered and then dissolved in hot acetic acid.
  • the insoluble impurities are fUtered from the solution whUe still hot, and the product precipitates as the solution cools.
  • the soUd is fUtered, washed with 3 x 25 mL water and dried in a stream of air on a fritted funnel. The procedure affords 0.31 g of the title compound as an off-white soUd.
  • EXAMPLE 44 6-((Bis(2-hydroxyethyl)amino)methyl)-N-(4-chlorobenzyl)-l- methyl-4-oxo- 1.4-dihydro-3-quinolinecarboxamide.
  • MethanesuU ' onyl chloride (0.048 mL) is added to a cold (0 °C) solution of N-(4- chlorobenzyl)-6-(hydroxymethyl)- 1 -methyl-4-oxo- 1 ,4-dihydro-3-quinolinecarboxamide (200 mg) from Preparation No. 10, DMAP (11.5 mg), and 2,4,6-coUidine (0.087 mL) in anhydrous DMF (9.5 mL).
  • the mixture is stirred at room temperature untU starting material is consumed and diethanolamine (0.54 mL) is added.
  • the reaction mixture is heated to 56 °C for 1.5 h.
  • the reaction mixture is cooled to room temperature and partitioned between CH 2 C1 2 and water.
  • MethanesuU ' onyl chloride (0.065 mL) is added to a cold (0 °C) solution of N-(4- chlorobenzyl)-6-(hydroxymethyl)- 1 -methyl-4-oxo- 1 ,4-dihydro-3-quinolinecarboxamide (0.27 g) from Preparation No. 10, DMAP (0.017 g). and 2,4.6-coUidine (0J2 mL) in anhydrous DMF ( 14 mL). The mixture is stirred at room temperature overnight and 2- (methylamino)ethanol (0.61 mL) is added. The reaction mixture is stirred at room temperature for 2 h, poured into water, and extracted with CH 2 Ch (3x).
  • MethanesuU ' onyl chloride (0.080 mL) is added to a cold (0 °C) solution of N-(4- chlorobenzyl)-6-(hydroxymethyl)- 1 -methyl-4-oxo- 1.4-dihydro-3-quinolinecarboxam ⁇ de (330 mg) from Preparation No. 10, DMAP (19J mg). and 2,4,6-coUidine (0J4 mL) in anhydrous DMF (15.7 mL). The mixture is stirred at room temperature until the starting material is consumed and a solution of 1.4-oxepane (0.963 g) from Preparation No. 33 in anhydrous DMF (3 mL) is added. The reaction mixture is heated to 56 °C for 1.5 h.
  • MethanesuU ' onyl chloride (0.096 mL) is added to a cold (0 °C) solution of N-(4- chlorobenzyl)-6-(hydroxymethyl)-l-methyl-4-oxo-l ,4-dUiydro-3-quinolinecarboxamide (400 mg) from Preparation No. 10, DMAP (23 mg). and 2.4.6-coUidine (0J7 mL) in anhydrous DMF (19 mL). The mixture is stirred at room temperature until the starting material is consumed and 1.4 thiazepane (1 J3 g) from Preparation No. 34 is added. The reaction mixture is heated to 65 °C for 1.5 h.
  • MethanesuU ' onyl chloride (0.06 mL) is added to a cold (0 °C) solution of N-(4- chlorobenzyl)-6-(hydroxymethyl)-l-methyl-4-oxo-1.4-dihydro-3-quinohnecarboxamide (250 mg) from Preparation No. 10, DMAP (14.4 mg), and 2.4,6-coUidine (0.1 1 mL) in anhydrous DMF (12 mL). The mixture is stirred at room temperature untU the starting material is consumed. (15, 45)-(+)-2-Aza-5-oxabicyclo[2JJ]heptane hydrochloride (475.9 mg) and Et 3 N (0.49 mL) are added to the solution.
  • the reaction mixture is heated to 65 °C overnight.
  • the mixture is cooled to room temperature and filtered to remove the salt that had precipitated out of solution.
  • the filtrate is diluted with water (125 mL) to precipitate the product.
  • the soUd is adsorbed onto sUica and purified by column chromatography (eluent 1% MeOH in CH 2 Ch (IL), 2% MeOH in CH 2 Ch (IL), 3% MeOH in CH?C1?
  • MethanesuU ' onyl chloride (0J0 mL) is added to a cold (0 °C) solution of N-(4- chlorobenzyl)-6-(hydroxymethyl)- 1 -methyl-4-oxo- 1 ,4-dihydro-3-quinoUnecarboxamide (0.41 g) from Preparation No. 10, DMAP (0.030 g), and 2,4,6-coUidine (0J9 mL) in anhydrous DMF (15 mL).
  • the mixture is stirred at room temperature for 12 h and then benzomorpholine (1.60 g) from above is added.
  • the reaction mixture is stirred at room temperature for 2 h and is then heated to 65 °C overnight.
  • the mixture is cooled to room temperature and poured water.
  • soUd is dissolved in CH 2 Cl?/MeOH and adsorbed onto sUica. Purification by column chromatography (eluent CH 2 Ch (IL), 1% MeOH/CH 2 Ch (2L)) and then recrystaUization from CH 2 Ch/hexanes affords 0.56 g (100%) of the title compound as a pale gold soUd.
  • MethanesuU ' onyl chloride (0J93 mL) is added to a solution of N-(4-chlorobenzyl)-6- (hydroxymethyl)-l-methyl-4-oxo- l ,4-dihydro-3-quinoUnecarboxamide (357 mg) from Preparation No. 10, DMAP (20 mg), and 2,4,6-coUidine (0.33 mL) in DMF (20 mL). The mixture is stirred at room temperature for 3 h and then N-benzylethanolamine (1.42 mL) is added. The reaction mixture is stirred at room temperature for 20 h, poured into water (60 mL), and extracted with ethyl acetate (3 x 50 mL).
  • N-(4-chlorobenzyl)-6-(chloromethyl)-l-methyl-4-oxo-l ,4-dihydro- 3-quinolinecarboxamide from Preparation No. 35 (60 mg) in l-methyl-2-pyrroUdinone (3 mL) is added N,N-d ⁇ sopropylethylamine (0.075 mL) and 4-fluoro- 1 ,2,3,6- tetrahydropyridme hydrochloride from Preparation No. 38 (1 19 mg).
  • the reaction mixture is stirred at room temperature overnight and then heated at 60 °C for 4 hrs.
  • the mixture is cooled to room temperature and poured into water to precipitate the product.
  • the crude soUd is adsorbed onto silica and purified by chromatography (eluent 100% CH 2 Ch ( IL). 0.25% MeOH in CH 2 Ch (IL), 0.5% MeOH in CH 2 C1? (IL), 0.75% MeOH in CH 2 Ch (IL), 1% MeOH in CH?C1? (IL), 1.25% MeOH in CH 2 Ch (IL), 1.5% MeOH in CH 2 Ch (2L)). Fractions homogenous by TLC are combined and concentrated to afford 32.2 mg (46%) of the desired product as a white soUd.
  • Preparation No. 4 and potassium carbonate (5.70 g) are disolved in DMF (90 mL). Iodomethane (2J mL) is added and the mixture is stirred at room temperature for 1 h. The resulting suspension is poured into water (500 mL) and filtered. The crude soUd is washed with water (50 mL) and diethyl ether (100 mL) and then is recrystaUized from ethanol to afford 10.6 g (85%) of the title compound as a white soUd.
  • Tributylvinylstannane (0.32 mL) is added to a solution of N-(4-chlorobenzyl)-6-iodo- l-methyl-4-oxo- l ,4-dihydro-3-quinolinecarboxamide (0.45 g) from Preparation No. 39 and PdCl 2 (PPh 3 ) 2 (70 mg). The mixture is stirred at room temperature for 1 h and then is heated to 60 °C for 30 min. After cooUng to room temperature, the reaction mixture is poured into water (60 mL), fUtered, and washed with water (20 mL) and diethyl ether (20 mL). The crude product is purified by recrystaUization from acetonitrUe to afford 0.20 g (57%) of the title compound as a white soUd.
  • the crude product is purUied by flash column chromatography eluting with 2% to 8% methanol in dichloromethane and then by recrystaUization from ethyl acetate-heptane to afford 164 mg of the title compound as a white soUd.
  • the crude product is purUied by flash column chromatography eluting with 10% to 40% methanol in ethyl acetate and then by recrystaUization from ethyl acetate to afford 68 mg of the title compound as a white soUd.
  • the crude product is purUied by flash column chromatography eluting with 2% to 6% methanol in dichloromethane and then by recrystaUization from ethanol-cyclohexane to afford 0J 1 gm of the title compound as a white soUd.
  • the crude product is purUied by flash column chromatography eluting with 2% to 6% methanol in dichloromethane and then by recrystaUization from toluene-cyclo hexane to afford 0.14 gm of the title compound as a white soUd.
  • the reaction mixture is dUuted with dichloromethane, washed with saturated aqueous sodium suUite, saturated aqueous sodium bicarbonate, brine, dried (Na 2 SO ) and concentrated under reduced pressure.
  • the crude product is purified by flash column chromatography eluting with 3% to 9% methanol in dichloromethane.
  • the product fractions are combined and recrystaUized from ethyl acetate-methanol-hexanes to afford 0.07 gm of the title compound as a white soUd. Physical characteristics are as foUows:
  • the reaction mixture is dUuted with dichloromethane, washed with saturated aqueous sodium sulfite, saturated aqueous sodium bicarbonate, brine, dried (Na SO ) and concentrated under reduced pressure.
  • the crude product is purUied by flash column chromatography eluting with 3% to 9% methanol in dichloromethane and then by recrystaUization from acetonitrUe to afford 0.05 gm of the title compound as a white soUd.
  • Physical characteristics are as foUows: ⁇ NMR (DMSO-fife) ⁇ 10.4, 8.9, 8.3, 7.9, 7.8, 7.4-7.3, 4.9, 4.6, 3.6, 3.3, 3J, 2.8-

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Abstract

The present invention provides a compound of formula (I) which is useful as antiviral agents, in particular, as agents against viruses of the herpes family.

Description

QUINOLINECARBOXAMIDES AS ANTIVIRAL AGENTS
FIELD OF THE INVENTION The present invention provides 4-oxo- 1 ,4-dihydro-3-quinolinecarboxamide derivatives. These compounds are useful as antiviral agents, in particular, as agents against viruses of the herpes family.
BACKGROUND OF THE INVENTION The herpesviruses comprise a large family of double stranded DNA viruses. They are also a source of the most common viral illnesses in man. Eight of the herpes viruses, herpes simplex virus types 1 and 2 (HSV-1 and HSV-2), varicella zoster virus (VZV), human cytomegalovirus (HCMV), epstein-Barr virus (EBV), and human herpes viruses 6, 7, and 8 (HHV-6, HHV-7, and (HHV-8), have been shown to infect humans. HSV-1 and HSV-2 cause herpetic lesions on the lips and genitals, respectively. They also occasionally cause infections of the eye and encephalitis. HCMV causes birth defects in infants and a variety of diseases in immunocompromised patients such as retinitis, pneumonia, and gastrointestinal disease. VZV is the causitive agent of chicken pox and shingles. EBV causes infectious mononucleosis. It can also cause lymphomas in immunocompromised patients and has been associated with Burkitt's lymphoma, nasopharyngeal carcinoma, and Hodgkins disease. HHV-6 is the causitive agent of roseola and may be associated with multiple sclerosis and chronic fatigue syndrome. HHV-7 disease association is unclear, but it may be involved in some cases of roseola. HHV-8 has been associated with Karposi s sarcoma, body cavity based lymphomas, and multiple myeloma. Compounds of the present invention are distinct from other hydro xyquinoline antiviral agents in that the 4-substituent on the benzyl amide of the present invention (i.e. the chloro, bromo, cyano, or nitro substituent) provides significantly improved antiviral activity.
Certain compounds of formula (I) also possess unique substituents R4 that provide improved antiviral activity.
INFORMATION DISCLOSURE U.S. patent 5,891,878 and WO 97/04775 disclose compounds that are reported to be useful in the treatment of a disease state capable of being modulated by inhibition of production of phosphodiesterase IV or tumor necrosis factor. The genera of compounds disclosed in these applications are believed to overlap with the compounds of formula I disclosed herein. However, no specific compounds are prepared in these PCT applications having the 4-substitutedbenzamide group of the compounds of formula I herein..
U.S. Patent 3,960,868 discloses derivatives of 6, 7. or 8 cycloalkyl-4-oxoquinoline- 3-carboxylic acid that are reported to possess analgesic, anti- inflammatory, anti- micro bial. and histamine liberating properties. The structure of these compounds differs from the structure of the compounds of formula I by requiring a cycloalkyl substituent at the 6, 7. or 8 position of the quinoline ring.
U.S. Patent 4,959,363 discloses quinolonecarboxamide compounds that are reported to possess antiviral activity. The structure of these compounds differs from the structure of the compounds of formula I disclosed herein at the 3-position by not including a 4-substitutedbenzamide, and at the 6-position by requiring a hydrogen or fluoro substituent. U.S. Patent 5,175,151. discloses quinolone compounds that are reported to possess antihypertensive and antiviral activity. The structure of these compounds differs from the structure of the compounds of formula I disclosed herein at the 3-position by not including a 4-substitutedbenzamide, and at the 2-position by requiring an oxygen linked substituent.
U.K. Patent Application 1,191,443 discloses quinoline derivatives that are reported to possess antiviral activity. The structure of these compounds differs from the structure of the compounds of formula I disclosed herein by not including a 4-substitutedbenzamide at the 3-position. and by requiring a fused furan heterocyclic ring at the 5,6-, 6.7-. or 7,8- position of the quinolone.
WO 97/14682 discloses quinoline derivatives that are reported to be useful to treat specific hormone dependent diseases. The structure of these compounds differs from the structure of the compounds of formula I disclosed herein at the 3-position by not including a 4-substitutedbenzamide. at the 1 -position, by requiring a halogenoaralkyl. and at the 7- position by requiring an acylaminoaryl group.
U.S. Patent 4,786,644, discloses 1 -aryl-3-quinolinecarboxamides that are reported to be useful to treat pain and inflammation. The structure of these compounds differs from the structure of the compounds of formula I disclosed herein at the 3-position by not including a 4-substitutedbenzamide, and at the 1 -position by requiring an optionally substituted phenyl substituent.
U.S. Patent 4,835,163, discloses N-alkoxyalkyl derivatives of quinolone carboxamides that are reported to possess anticonvulsive and psychotonic activity. The structure of these compounds differs from the structure of the compounds of formula I disclosed herein at the 3-position by not including a 4-substitutedbenzamide substituent.
U.S. Patent 5,096,901; U.K. Application Number 2 236 751; and TJ. Ward et al., Med. Chem. Res. (1993), 4, 267-272 disclose quinolone-3-(azabicyclo)carboxamides that are reported to possess 5-HT3 activity and to be useful to treat neuro -psychiatric disorders. The structure of these compounds differs from the structure of the compounds of formula I disclosed herein by requiring an azabicyclo containing substituent at the 3-position.
JP 02124871 discloses quinolone compounds that are reported to possess 5- lipoxygenase activity. The structure of these compounds differs from the structure of the compounds of formula I disclosed herein at the 3-position by not including a 4- substitutedbenzamide substituent.
EP 0 332 930A2, discloses quinolone compounds that are reported to possess antibacterial antiviral activity. The structure of these compounds differs from the structure of the compounds of formula I disclosed herein at the 3-position by not including a 4- substitutedbenzamide, and at the 6-position by requiring a hydrogen, halo, or nitro substituent.
Chem . Abstracts (1969), 71, 101735q, discloses quinolone compounds that are reported to possess antiinflamatory activity. The structure of these compounds differs from the structure of the compounds of formula I disclosed herein at the 3-position by not including a 4-substitutedbenzamide substituent.
U.S. Patents 5,051,418 and 4,908,366, disclose 8-cyano-quinolone compounds that are reported to possess antibacterial activity. The structure of these compounds differs from the structure of the compounds of formula I disclosed herein at the 3-position by not including a 4-substitutedbenzamide, and at the 8-position by requiring a cyano substituent. EP 0 370 686, discloses a process for preparing quinolone carboxylic acid intermediates. The structure of the disclosed compounds differs from the structure of the compounds of formula I disclosed herein at the 3-position by not including a 4- substitutedbenzamide, and at the 6-position by requiring a fluoro substituent.
U.S. Patent 4,621,088, discloses quinolone amino acid derivatives that are reported to possess antiallergic activity, central nervous system activity and cardiovascular activity. The structure of these compounds differs from the structure of the compounds of formula I disclosed herein at the 3-position by not including a 4-substitutedbenzamide. U.S. Patent 5,328,887 discloses an array of compounds including numerous quinolone compounds that are reported to be useful as fluorescent donor elements for use in a thermal transfer possess. The single specific 4-quinolone compound prepared and tested in the application differs from the compounds of formula I disclosed herein at the 3-position by not including a 4-substitutedbenzamide, at the 2-position by having a phenyl substituent. at the 6-position by having a hydrogen, and at the 1 -position by being unsubstituted.
U.S. Patent 4,855,291, discloses quinolone compounds that are reported to possess antihypertensive activity. The structure of these compounds differs from the structure of the compounds of formula I disclosed herein at the 3-position by not including a 4- substitutedbenzamide.
U.S. Patent 3,524,858, discloses quinolone compounds that are reported to possess anti-microbial activity. The structure of these compounds differs from the structure of the compounds of formula I disclosed herein at the 3-position by not including a 4- substitutedbenzamide, and at the 6J-positions by requiring a methylenedioxy substituent. WO 98/23608 discloses quinolone compounds that are reported to possess integrin antagonist activity. The structure of these compounds differs from the structure of the compounds of formula I disclosed herein at the 3-position by not including a 4- substitutedbenzamide.
U.S. Patent 5,026,856, discloses isoindoline compounds that are reported to possess antibacterial activity. The structure of these compounds differs from the structure of the compounds of formula I disclosed herein at the 3-position by not including a 4- substitutedbenzamide, and at the 6-position by requiring a halo, hydroxy. or loweralkoxy substituent.
U.S. Patent 5,563,141, discloses an array of compounds that are reported to inhibit cell adhesion. Although the disclosed genus of compounds may include 3aminocarbonyl-4- quinolones, these compounds do not comprise a 4-substituted-benzamide at the 3-position. All of final compounds specifically prepared in the patent comprise a 4-pyridyl(piperazin- 1 - yl) ring system.
WO 9932450 discloses compounds of the following generic formula which are useful for the treatment of herpesvirus infections.
Figure imgf000006_0001
Liebigs Ann. Chem. 1987, 871-879 describes the synthesis of the following structure through the combination of an aryl acid chloride and a β-hydrazidoalkenyl amide.
Figure imgf000007_0001
EP 343560 discloses antibacterial agents having the following structure.
Figure imgf000007_0002
JP 02040379 discloses compounds useful as antibacterials having generic structure.
Figure imgf000007_0003
US 5,412,104 discloses the following generic structure as being useful as antiviral agents against DNA containing viruses such as herpes group viruses.
Figure imgf000007_0004
SUMMARY OF THE INVENTION
The present invention provides a compound of formula I.
Figure imgf000007_0005
or a pharmaceutically acceptable salt thereof wherein, X is a) O, or b) S; W is a) R2; b) NR7R8, c) OR9, or d) SO,R9;
' is a) Cl, b) F, c) Br, d) CN, or e) NO2;
R2 is a) (CH2CH2O)mR10. b) het, wherein said het is bonded via a carbon atom, c) Ci-7 alkyl which may be partially unsaturated and is optionaUy substituted by one or more substituents selected from a group consisting of NR7R8. R11. CN, SO,R9, or OC2. alkyl which is further substituted by het, OR10, OC(=O)aryl. or NR7R8. or d) C3_8 cycloalkyl. which may be partially unsaturated and is optionally substituted by Rπ, NR7R8, SO,R9, or Cι-7 alkyl optionaUy substituted by R11. NR7R8. or SO.R9; R3 is a) H, b) halo, or c) Cι-4 alkyl, optionaUy substituted by one to three halo:
R4 is a) H, b) aryl, c) het, d) SO2NHR12, e) CONHR12,
1) NR7R8, g) NHCOR12, h) NHSO2R'2, i) OC9.7 alkyl optionaUy substituted by -OH, j) SC7.7 alkyl optionaUy substituted by OH, or k) Ci„8 alkyl which may be partiaUy unsaturated and is optionaUy substituted by one or more substituents selected from a group consisting of N , OR10, NR7R8. halo, SO,R9, OR1 or Rn; R5 is a) H, b) halo, c) C≡CR14, d) NR7R8, e) SO2NHR12, t) het, or g) Cj_7 alkyl, optionaUy substituted by OH;
R6 is a) H, b) halo, c) SCι-7 alkyl, d) C1-7 alkoxy, optionaUy substituted by one or more halo or OH, or e) C1-7 alkyl. which may be partiaUy unsaturated and is optionaUy substituted by halo. NR10R10, (CH2)„OR13. R11. OC ,.7 alkyl which is further substituted with het, NR7R8. or SO.R9:
R7 and R8 are independently a) H, b) aryl, c) Cι_7alkyl which may be partiaUy unsaturated and is optionally substituted by one or more substituents selected from a group consisting of NR10R10. CONR10R10. R11, SO,R9. halo: or d) R7 and R8 together with the nitrogen to which they are attached to form a het;
R9 is a) aryl, b) het, c) C3_8cycloalkyl. or d) Cι_7alkyl which may be partiaUy unsaturated and optionaUy substituted by one or more OR10, Oaryl, het, aryl, NR10R10, CN. SH, SOiC-β alkyl, SO, aryl, halo, or CONR10R10: R10 is a) H, or b) Ci-7 alkyl, optionaUy substituted by OH; Rn is a) OR10, b) Ohet, c) Oaryl, d) CO2R10, e) het, f) aryl, or g) CN;
R12 is a) H, b) het, c) aryl, d) C3-8 cycloalkyl, or e) Ci-7 alkyl optional >7r> 8 i l l .
R13 is a) (P=O)(OH)2, b) (P=O)(Cι-7 alkoxy),, c) CO(CH2)nCON(CH3)(CH2)„SO3-MJ d) an amino acid, e) C(=O)aryl, f)
Figure imgf000010_0001
optionaUy substituted by NR10R10, or g) CO(CH2)nCO2H;
RI4 is a) het, b) (CH2)nOR13, or c) Ci- alkyl substituted by one or more substituents selected from a group consisting of R11, OC ι-7 alkyl which is further substituted with het, NR7R8, or SO,R9; aryl is a phenyl radical or an ortho-fused bicyclic carbocychc radical wherein at least one ring is aromatic: het is a four- (4), five- (5), six- (6), or seven- (7) membered saturated or unsaturated heterocycUc ring having 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, suttur, and nitrogen, which is optionaUy fused to a benzene ring, or any bicycUc heterocycle group; wherein any aryl is optionaUy substituted with one or more substituents selected from the group consisting of halo, OH, CF3, Cι_6alkoxy, and Cι_6 alkyl which maybe further substituted by one to three SR10. NRlϋR10, OR10, or CO2R10: wherein any het is optionaUy substituted with one or more substituents selected from the group consisting of halo, OH, CF3, Cι.6alkoxy, oxo, oxine, and Cι_6 alkyl which maybe further substituted by one to three SR10, NR10R!0, OR10, or CO2R10; i is 0. 1. or 2: m is 1. 2. or 3: n is 1, 2. 3, 4, 5, or 6: and
M is sodium, potassium, or Uthium:
With the proviso that R1 is not Cl, Br, F. or CN; when
X is O:
R2 is C ? alkyl optionaUy substituted by R15: R3 is H. methyl, or halo;
R4 is H. CONH(Cι-7alkyl), NR16R17, or C,.7 alkyl optionaUy substituted by OR10. CN.
COOH. or NR16R17:
R5 is H. halo, SO2NHR10, NR16R17, or C,-7 alkyl optionaUy substituted by OR10:
R6 is H. halo, Cι-7 alkoxy, or Cι- alkyl optionaUy substituted by halo, OR10, CO2R10 or NR16R17:
R15 is NR16R17, OR10, CN, or CO2R10; and
R16 and R17 are independently H or d-7alkyl; or NR16R17 together with the nitrogen to which they are attached form a 5- or 6-membered ring such as pyrroUdine. piperidine. morpholine. or piperazine. In another aspect, the present invention also provides: a pharmaceutical composition comprising a compound of formula I. or a pharmaceuticaUy acceptable salt thereof, and a pharmaceuticaUy acceptable carrier, a method of treating or preventing a herpesviral infection, comprising administering to a mammal in need of such treatment, a compound of formula (I) or a pharmaceuticaUy acceptable salt thereof, a compound of formula (I) or a pharmaceuticaUy acceptable salt thereof for use in medical treatment or prevention of a herpesviral infection. the use of a compound of formula (I) or a pharmaceuticaUy acceptable salt thereof to prepare a medicament for treating or preventing a herpesviral infection in a mammal, and a method for inhibiting a viral DNA polymerase. comprising contacting (in vitro or in vivo) the polymerase with an effective inhibitory amount of a compound of formula I. or a pharmaceuticaUy acceptable salt thereof.
The invention also provides novel intermediates and processes disclosed herein that are useful for preparing compounds of formula I.
DETAILED DESCRIPTION OF THE INVENTION The foUowing definitions are used, unless otherwise described. Halo denotes fluoro, chloro. bromo, or iodo. Alkyl, alkoxy, etc. denote both straight and branched groups; but reference to an individual radical such as "propyl"" embraces only the straight chain radical, a branched chain isomer such as "'isopropyl" being specificaUy referred to. When alkyl can be partiaUy unsaturated. the alkyl chain may comprise one or more (e.g. 1 , 2, 3. or 4) double or triple bonds in the chain.
Aryl denotes a phenyl radical or an ortho-fused bicycUc carbocycUc radical wherein at least one ring is aromatic. Aryl is optionaUy substituted with one or more substituents selected from the group consisting of halo, OH, CF , Cj.6alkoxy. and Cι-6 alkyl which maybe further substituted by one to three SR10, NR10R10, OR10, or CO2R'°: Het denotes a four- (4), live- (5), six- (6). or seven- (7) membered saturated or unsaturated heterocychc ring having 1 , 2, or 3 heteroatoms selected from the group consisting of oxygen, sutfur. and nitrogen, which is optionaUy fused to a benzene ring, or any bicycUc heterocycle group. Het is optionaUy substituted with one or more substituents selected from the group consisting of halo, OH, CF3, Ci-βalkoxy. oxo. oxine. and Cι-6 alkyl which maybe further substituted by one to three SR10. NR10R10. OR10, or CO2R10:
"Amino acid," includes a residue of natural amino acid (e.g. Ala. Arg. Asn. Asp, Cys, Glu, Gin. Gly, His, Hyl, Hyp, He, Leu, Lys, Met, Phe, Pro. Ser. Thr. Trp, Tyr, and Val) in D or L form, as weU as unnatural amino acids (e.g. phosphoserine. phosphothreonine, phosphotyrosine, hydroxyproline, gamma-carboxyglutamate: hippuric acid, octahydroindole-2-carboxyUc acid, statine, l JJ.4.-tetrahydroisoquinoline-3-carboxyUc acid, penicillamine, ornithine, citruline, -methyl- alanine, para-benzoylphenylalanine, phenylglycine, propargylglycine, sarcosine. and tert-butylglycine). An amino acid can conveniently be linked to the remainder of a compound of formula I through the carboxy terminus, the amino terminus, or through any other convenient point of attachment, such as. for example, through the suUur of cysteine. In particular, an amino acid can conveniently be linked to the remainder of a compound of formula I through the carboxy terminus. Mammal denotes human and animals. It wUl be appreciated by those skiUed in the art that compounds of the invention having a chiral center may exist in and be isolated in optically active and racemic forms. Some compounds may exhibit polymorphism. It is to be understood that the present invention encompasses any racemic, opticaUy-active, polymorphic, tautomeric. or stereoisomeric form, or mixture thereof, of a compound of the invention, which possesses the useful properties described herein, it being weU known in the art how to prepare opticaUy active forms (for example, by resolution of the racemic form by recrystaUization techniques, by synthesis from opticaUy- active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase) and how to determine antiviral activity using the standard tests described herein, or using other similar tests which are weU known in the art.
The carbon atom content of various hydrocarbon-containing moieties is indicated by a prefix designating the minimum and maximum number of carbon atoms in the moiety, i.e.. the prefix C ,_, indicates a moiety of the integer to the integer *'j" carbon atoms, inclusive. Thus, for example. Cι_7alkyl refers to alkyl of one to seven carbon atoms, inclusive. The compounds of the present invention are generally named according to the
IUPAC or CAS nomenclature system. Abbreviations which are weU known to one of ordinary skill in the art may be used (e.g. "Ph" for phenyl, 'Me"" for methyl. "Et" for ethyl, "h" for hour or hours and "rf * for room temperature).
Specific and preferred values Usted below for radicals, substituents, and ranges, are for illustration only; they do not exclude other defined values or other values within defined ranges for the radicals and substituents
SpecificaUy, alkyl can be methyl, ethyl, propyl, isopropyl. butyl, iso-butyl, sec-butyl, pentyl, 3-pentyl, hexyl, heptyl, etc.; C3-8cyclo alkyl can be cyclopropyl. cyclobutyl, cyclopentyl, cyclohexyl. cycloheptyl, or cyclooctyl; alkoxy can be methoxy, ethoxy, propoxy, isopropoxy. butoxy, iso-butoxy, sec-butoxy, pentoxy, 3-pentoxy. hexyloxy. 1- methylhexyloxy, or heptyloxy; het can be azetidinyl, 3,3-dihydroxy-l-azetinyl, pyrroUdino. piperidino, morphoUno. thiomorphoUno. or heteroaryl; and heteroaryl can be furyl. imidazolyl. triazolyl, triazinyl, oxazoyl, isoxazoyl, thiazolyl, isothiazoyl, pyrazolyl, pyrrolyl. pyrazinyl, tetrazolyl, pyridyl, (or its N-oxide). thienyl, pyrimidinyl (or its N-oxide). indolyl, isoquinolyl (or its N-oxide) or quinolyl (or its N-oxide).
A specific value for R1 is Cl.
A specific value for R1 is F. A specific value for R1 is CN, or NO?.
A specific value for R2 is (CH2CH2O)mH. or (CH2CH2O)mCι_4 alkyl, wherein m is 2. or 3.
A specific value for R2 is Cv8cycloalkyl optionaUy substituted by R11. NR7R8, SO,R9. or Cι.7 alkyl optionaUy substituted by R11, NR7R8, or SO,R9; wherein R7. R8, R9, Ru and I are the same as defined above.
A specific value for R2 is cyclopropyl.
A specific value for R2 is het wherein said het is bonded via a carbon atom and is the same as defined above.
A specific value for R2 is tetrahydro-2H-pyranyl, piperdinyl, 1 -methyl-piperidinyl, or 1 J -dioxo-tetrahydro-2H-thiopyran.
A specific value for R2 is C2.7 alkyl which is partiaUy unsaturated and optionaUy substituted by NR7R8, R11, SO,R9, or OCz^ alkyl which is further substituted by het. OR10, or OC(=O)aryl; wherein R7, R8, R9, R10 are the same as defined above.
A specific value for R2 is (Z or E)-CH=CHRIϋ, or -C-C≡CR10; wherein said R10 is H. or Cι-7 alkyl optionaUy substituted by OH.
A specific value for R2 is C,_7 alkyl substituted by NR7R8. R11, SO,R9, or OC,^ alkyl which is further substituted by het, OR10, or OC(=O)aryl wherein R7, R8, R9, R10 and R11 are the same as defined above.
A specific value for R2 is Cj_7 alkyl substituted by OC?.4 alkyl which is further substituted by het, OH. OC alkyl, or OC(=O)aryl.
A specific value for R2 is Cι_7 alkyl substituted by SO,R9 wherein R9 and i are the same as defined above. A specific value for R2 is C1-7 alkyl substituted by SO,R9 ; wherein R9 is C,.4 alkyl, optionaUy substituted by OH, or R9 is phenyl. optionaUy substituted by Cl; wherein i is 0. 1. or 2.
A specific value for R2 is methyl. A specific value for W is NR7R8, wherein R7 and R8 are the same as defined above.
A specific value for W is NR7R8. wherein R7 and R8 together with the nitrogen to which they are attached to form a het wherein said het is the same as defined above.
A specific value for W is morpholine. piperidine. pyrroUdine, piperazine, or 4- methyl-piperazine. A specific value for W is NR7R8, wherein R7 and R8 are independently H or Cμ alkyl optionaUy substituted by OH.
A specific value for W is morpholine.
A specific value for W is OR9, or SO,R9 wherein R9 is Cι.6alkyl which may be partiaUy unsaturated and optionaUy substituted by OR10. Oaryl, het. aryl, NR10R10, CN. CONR10R10, or halo: wherein R10 is H or C alkyl .
A specific value for R3 is H.
A specific value for is CF , or halo.
A specific value for R4 is aryl or het.
A specific value for R4 is SO2NHR12. CONHR12, NHCOR12. or NHSO2R12. wherein R12 is the same as defined above.
A specUic value for R4 is C?„8 alkyl which is partiaUy unsaturated and optionaUy substituted by OR10. NR7R8, halo, SO,R9, ORπ or R11. wherein R7. R8, R9. R10, R11 and R13 are the same as defined above.
A specific value for R4 is (Z or E)-CH=CHCι-4 alkyl, optionaUy substituted by OH. A specific value for R4 is -C≡Cd- alkyl, optionaUy substituted by OH or OR13, wherein R13 is (P=O)(OH)2, (P=O)(C,.7 alkoxy)?, or CO(CH2)6CON(CH3)(CH?)nSO3 "MJ
A specific value for R4 is Cι-8 alkyl substituted by OR13 wherein R13 is (P=O)(OH)2. (P=O)(C,_7 alkoxy)?, or CO(CH2)„CON(CH (CH2)5SO "M+.
A specific value for R4 is Cι-8 alkyl substituted by SO,R9. wherein R9 is the same as defined above.
A specific value for R4 is NR7R8, wherein R7 and R8 are the same as defined above.
A specific value for R4 is d-8 alkyl substituted by NR7R8. wherein R7 and R8 are the same as defined above. A specific value for R4 is Cι.8 alkyl substituted by NR7R8, wherein R7 and R8 together with the nitrogen to which they are attached to form a het. wherein het is the same as defined above.
A specific value for R4 is d_8 alkyl substituted by NR7R8, wherein R7 and R8 are independently Cι_6 alkyl, optionaUy substituted by one or more substituents selected from a group consisting of OH, aryl, or CN wherein aryl is the same as defined above.
A specific value for R4 is Cι-8 alkyl substituted by N3.
A specific value for R4 is Cι_8 alkyl substituted by het wherein het is the same as defined above. A specific value for R4 is 4-morpholine methyl.
A specific value for R4 is Cι-7 alkyl substituted by R11. wherein R! l is the same as defined above.
A specific value for R^ is H or Cι.7 alkyl optionaUy substituted by OH.
A specific value for R6 is OC1.7 alkyl optionally substituted by one or more OH. A specific value for R6 is halo.
A specific value for R6 is C≡CCι-7 alkyl substituted by one or more OH. or C2-7 alkoxy substituted by one or more OH.
A specific value for R6 is H or d.7 alkyl. optionally substituted by halo. NR10R10, OH, CO?R10, or het: wherein R10 and het are the same as defined above. A specific value for M is sodium, potassium, or Uthium.
A specific value is where X is S: W. R1. R2, R3. R4. R\ R6 are the same as defined above.
A specific value is where X is O; R1, R3. R4, R\ R6 are the same as defined above, W is NR7R8, OR9. SO,R9 or R2; wherein R2 is: a) (CH?CH2O)nR10. b) het, wherein said het is bonded via a carbon atom. c) Cι_7 alkyl which is partiaUy unsaturated and optionaUy substituted by OH, d) -8 cycloalkyl. or e) C1-7 alkyl which is optionaUy substituted by one or more substituents selected from a group consisting of Ohet, Oaryl. SO,R9, or OC2-4 alkyl which is further substituted by het, OR10, or OC(=O)aryl; wherein R7, R8. R9, R10 and n are the same as defined above.
A specific value is where X is O or S; R1 is Cl; R3 is H: R' is H: R6 is H or F: R4 is 4-morpholinylmethyl; and R2 is: a) Cι_4 alkyl substituted by SO,R9. or C1-4 alkoxy which is further substituted by OH, het. OC1-4 alkyl, or OC(=O)pheyl, b) (CH2CH2O)2d_4alkyl, c) Cι-6alkyl which is partiaUy unsaturated and optionaUy substituted by OH. d) cyclopropyl. tetrahydro-2H-pyranyl, piperdinyl, mopholinyl. 1 -methyl-piperidinyl, or lJ-dioxo-tetrahydro-2H-thiopyran; wherein R9 is phenyl optionaUy substituted by Cl, or R9 is Ci-βalkyl optionaUy substituted by OH.
A specific value is where X is O or S; R1 is Cl: R3 is H: R5 is H: R° is H or F: R4 is Cι_6alkyl which is partiaUy unsaturated and optionaUy substituted by OH or OR13; or R4 is Cι.4alkyl substituted with OR13; W is NR10R10, cyclopropyl, (CH2CH2O)2OR10, or d_6 alkyl which may be partiaUy unsaturated and is optionaUy substituted by OH. mopholinyl. NR10R10: C(=O)OCι_4alkyl. wherein R10 is H or d_4alkyl: R13 is (P=O)(C,_7 alkoxy)?, CO(CH?)nCON(CH3)(CH2)nSO3 "M+. or (P=O)(OH)2.
A specific value is where X is O or S: R1 is Cl; R3 is H: R' is H: R6 is C≡CCι-4 alkyl optionaUy substituted by OH; R4 is H or
Figure imgf000017_0001
which may be partially unsaturated and optionaUy substituted by OH, and W is Cι-4 alkyl optionaUy substituted by OH.
When alkyl is partiaUy unsaturated . it can be vinyl, aUyl. 1 -propenyl, 2-propenyl. 1 - butenyl, 2-butenyl. 3-butenyl, 1 J-butadienyl, 1-pentenyl. 2-pentenyl. 3-pentenyl. 4-pentenyl, 1-hexenyl, 2-hexenyl. 3-hexenyl, 4-hexenyl. 5-hexenyl. ethynyl, 1-propynyl. 2-propynyl, 1- butynyl, 2-butynyl. 3-butynyl. 1-pentynyl, 2-pentynyl, 3-pentynyl. 4-pentynyl, 5-hexene- l- ynyl. 2-hexynyl. 3-hexynyl. 4-hexynyl, or 5-hexynyl; Examples of the present invention are (1) N-(4-chlorobenzyl)-6-(3-hydroxy-l-propynyl)- l-isopropyl-4-oxo- 1.4-dihydro-3- quinolinecarboxamide; (2) 1 -(sec-butyl)-N-(4-chlorobenzyl)-6-(3-hydroxy- 1 -propynyl)-4-oxo- 1 ,4-dihydro-3- quino linec arbo xamid :
(3) l-(sec-butyl)-N-(4-chlorobenzyl)-6-(3-hydroxy-l-propynyl)-8-methoxy-4-oxo-l,4- dihydro-3-quinolinecarboxamide;
(4) N-(4-chlorobenzyl)-8-(2-hydroxyethoxy)-6-(3-hydroxypropyl)- 1 -methyl-4-oxo- 1 ,4- dihydro-3-quinoUnecarboxamide:
(5) N-(4-chlorobenzyl)-8-[2-hydroxy-l-(hydroxymethyl)ethoxy]-6-(3-hydroxypropyl)- l-methyl-4-oxo- 1 ,4-dihydro-3-quinoUnecarboxamide; (6) N-(4-chlorobenzyl)-8-fluoro-6-(hydroxymethyl)-4-oxo-l-[3-(tetrahydro-2H-pyran- 2-yloxy)propyl]- 1 ,4-dihydro-3-quinolinecarboxamide:
(7) N-(4-chlorobenzyl)-6-[3-hydroxy-l-propenyl]-l-[2-(4-morpholinyl)ethyl]-4-oxo- 1.4-dihydro-3-quinolinecarboxamide; (8) N-(4-chlorobenzyl)-8-fluoro-6-(3-hydroxy- 1 -propynyl)- 1 -methyl-4-oxo- 1.4- dihydro-3-quinoUnecarboxamide;
(9) N-(4-chlorobenzyl)-8-tluoro-6-[(Z)-3-hydroxy- 1 -propenyl]- 1 -methyl-4-oxo- 1.4- dihydro-3-quinolinecarboxamide:
(10) N-(4-chlorobenzyl)-l-[2-(diethylamino)ethyl]-8-iluoro-6-(3-hydroxy-l-propynyl)- 4-oxo- 1 ,4-dihydro-3-quinoUnecarboxamide;
(11) N-(4-chlorobenzyl)-6-(3-hydroxy- 1 -propynyl)-4-oxo- 1 -propyl- 1.4-dihydro-3- quinolinecarboxamide:
(12) N-(4-chlorobenzyl)-l-[2-(diethylamino)ethyl]-6-(3-hydroxy- l-propynyl)-4-oxo- 1 ,4-dihydro-3-quinolinecarboxamide; (13) N-(4-chlorobenzyl)- l-[2-(dimethylamino)ethylJ-6-(3-hydroxy-l-propynyl)-4-oxo-
1 ,4-dihydro-3-quinolinecarboxamide hydrochloride:
(14) N-(4-chlorobenzyl)-6-(3-hydroxy- l-propynyl)-4-oxo- l-[2-(l -piperidmyl)ethyl]- l ,4-dihydro-3-quinoUnecarboxamide:
(15) N-(4-chlorobenzyl)-6-(3-hydroxy-l-propynyl)-4-oxo-l-[3-(l-piperidinyl)propyl]- 1 ,4-dihydro-3-quinolinecarboxamide:
( 16) N-(4-chlorobenzyl)-6-(3-hydroxy- 1 -propynyl)- 1 -[2-( 1 -methyl-2-pyrrolidinyl)ethyl]- 4-oxo- 1.4-dihydro-3-quinolinecarboxamide;
(17) N-(4-chlorobenzyl)-l-[2-(diisopropylamino)ethyl]-6-(3-hydroxy-l-propynyl)-4- oxo- 1.4-dihydro-3-quinolinecarboxamide: (18) N-(4-chlorobenzyl)-6-(3-hydroxy- 1 -propynyl)-4-oxo- 1 -[2-( 1 -pyrroUdinyl)ethyl]-
1 ,4-dihydro-3-quinoUnecarboxamide;
(19) N-(4-chlorobenzyl)-6-(3-hydroxy-l -propynyl)- l-[2-(4-morphoUnyl)ethyl]-4-oxo- 1 ,4-dihydro-3-quinolinecarboxamide;
(20) N-(4-chlorobenzyl)J-[3-(dimethylamino)propyl]-6-(3-hydroxy- l-propynyl)-4-oxo- 1 ,4-dihydro-3-quinolinecarboxamide:
(21 ) N-(4-chlorobenzyl)-6-(3-hydroxy- 1 -propynyl)-4-oxo- 1 -vinyl- 1.4-dihydro-3- quinolinecarboxamide; (22) N-(4-chlorobenzyl)-6-[(E)-3-hydroxy-l-propenyl]-l-methyl-4-oxo-1.4-dihydro-3- quinolinecarboxamide;
(23) N-(4-chlorobenzyl)-6-[(Z)-3-hydroxy-l-propenyl]-l-methyl-4-oxo-l ,4-dihydro-3- quinolinecarboxamide : (24) N-(4-chlorobenzyl)-6-[ethyl(2-hydroxyethyl)amino]- l-methyl-4-oxo-1.4-dihydro-
3-quinolinecarboxamide:
(25) N-(4-chlorobenzyl)- 1 -cyclopropyl-6-(3-hydroxy- 1 -propynyl)-4-oxo- 1.4-dihydro-3- quinolinecarboxamide;
(26) N-(4-chlorobenzyl)- 1 -cyclopropyl-6-(3-hydroxypropyl)-4-oxo- 1 ,4-dihydro-3- quinolinecarboxamide:
(27) N-(4-chlorobenzyl)-l-cyclopropyl-6-(4-morphoUnylmethyl)-4-oxo- lJ-dihydro-3- quinolinecarboxamide:
(28) tert-butyl 2-[3-{ [(4-chlorobenzyl)amino]carbonyl}-6-(3-hydroxy- l-propynyl)-4- oxo- 1 (4H)-quinolinyl] acetate; (29) 2-[3-{ [(4-chlorobenzyl)amino]carbonyl}-6-(3-hydroxy-l-propynyl)-4-oxo-l (4H)- quinoUnyl] acetic acid:
(30) N-(4-chlorobenzyl)-l-(2-hydroxyethyl)-6-(3-hydroxy- l-propynyl)-4-oxo- 1.4- dihydro-3-quinolinecarboxamide;
(31 ) N-(4-chlorobenzyl)-6-(3-hydroxy- 1 -propynyl)- 1 -methyl-4-oxo- 1 ,4-dihydro-3- quinolinecarboxamide;
(32) di(tert-butyl) 3-(3-{ [(4-chlorobenzyl)amino]carbonyl}- l-methyl-4-oxo- 1.4- dihydro-6-quinoUnyl)propyl phosphate;
(33) 3-(3-{ [(4-chlorobenzyl)amino]carbonyl}- l-methyl-4-oxo- 1.4-dihydro-6- quinolinyl)propyl dihydrogen phosphate; (34) di(tert-butyl) 3-(3-{ [(4-chlorobenzyl)amino]carbonyl}- l-cyclopropyl-4-oxo-1.4- dihydro-6-quinolinyl)propyl phosphate;
(35) sodium 2-[{8-[3-(3-{[(4-chlorobenzyl)amino]carbonyl}- l-cyclopropyl-4-oxo-l,4- dihydro-6-quinoUnyl)propoxy]-8-oxooctanoyl}(methyl)amino]-l-ethanesuU'onate:
(36) sodium 2-[(8-{ [3-(3-{ [(4-chlorobenzyl)amino]carbonyl}- l-methyl-4-oxo-l , 4- dihydro-6-quinolinyl)-2-propynyl]oxy}-8-oxooctanoyl)(methyl)amino]-l -ethanesulfonate:
(37) sodium 2-[(8-{ [3-(3-{ [(4-chlorobenzyl)amino]carbonyl}-l-methyl-4-oxo-1.4- dihydro-6-quinolinyl)-2-propynylJoxy}-8-oxooctanoyl)(methyl)amino]-l-ethanesuUOnate; (38) sodium 2-[(8-{ [3-(3-{ [(4-chlorobenzyl)amino]carbonyl}-l-cyclopropyl-4-oxo-l.4- dihydro-6-quinolinyl)-2-propynyl]oxy}-8-oxooctanoyl)(methyl)amino]- l-ethanesuU'onate:
(39) 1 -(tert-butyl)-N-(4-chlorobenzyl)-6-(3-hydroxy- 1 -propynyl)-4-oxo- 1 ,4-dihydro-3- quinolinecarboxamide; (40) sodium 2-[{8-[3-(l-(tert-butyl)-3-{[(4-chlorobenzyl)amino]-carbonyl}-4-oxo-l,4- dihydro-6-quinoUnyl)propoxy]-8-oxooctanoyl}(methyl)amino]- l-ethanesuU nate:
(41) sodium 2-[(8-{[3-(l-(tert-butyl)-3-{ [(4-chlorobenzyl)amino]-carbonyl}-4-oxo-l, 4- dihydro-6-quinolinyl)-2-propynyl]oxy}-8-oxooctanoyl)(methyl)amino]-l -ethanesulfonate;
(42) N-(4-chlorobenzyl)-6-(3-hydroxy- l -propynyl)- l-[2-(2-methoxyethoxy)-ethyl]-4- oxo- 1.4-dihydro-3-quinolinecarboxamide;
(43) N-(4-cyanobenzyl)-6-(3-hydroxy- 1 -propynyl)- 1 -methyl-4-oxo- 1 ,4-dihydro-3- quinolinecarboxamide;
(44) 6-{ [bis(2-hydroxyethyl)amino]methyl }-N-(4-chlorobenzyl)- 1 -methyl-4-oxo- 1.4- dihydro-3-quinolinecarboxamide: (45) N-(4-chlorobenzyl)-6-{ [(2-hydroxyethyl)(methyl)amino]methyl}-l-methyl-4-oxo-
1.4-dihydro-3-quinolinecarboxamide:
(46) N-(4-chlorobenzyl)- 1 -methyl-6-( 1 ,4-oxazepan-4-ylmethyl)-4-oxo- 1.4-dihydro-3- quinolinecarboxamide;
(47) N-(4-chlorobenzyl)- 1 -methyl-4-oxo-6-( 1.4-thiazepan-4-ylmethyl)- 1.4-dihydro-3- quinolinecarboxamide;
(48) N-(4-chlorobenzyl)-l-methyl-6-(2-oxa-5-azabicyclof2JJ]hept-5-ylmethyl)-4-oxo- l,4-dihydro-3-quinolinecarboxamide:
(49) N-(4-chlorobenzyl)-6-(2.3-dihydro-4H- 1 ,4-benzoxazin-4-ylmethyl)- 1 -methyl-4- oxo- 1 ,4-dihydro-3-quinoUnecarboxamide; (50) 6-((benzyl(2-hydroxyethyl)amino)methyl)-N-(4-chlorobenzyl)- 1 -methyl-4-oxo- 1.4- dUιydro-3-quinolinecarboxamide;
(51 ) 6-(azidomethyl)-N-(4-chlorobenzyl)- l-methyl-4-oxo- 1 J-dihydro-3-quinoline- carboxamide;
(52) N-(4-chlorobenzyl)-6-[(4.4-difluoro- 1 -piperidinyl)methyl]- 1 -methyl-4-oxo- 1 ,4- dihydro-3-quinolinecarboxamide;
(53) N-(4-chlorobenzyl)-6-{ [4-fluoro-3,6-dihydro-l(2H)-pyridinyl]methyl}-l-methyl-4- oxo- 1 ,4-dihydro-3-quinolinecarboxamide;
(54) N-(4-chlorobenzyl)- 1 -methyl-4-oxo-6- vinyl- 1 ,4-dihydro-3-quinoline-carboxamide: (55) N-(4-chlorobenzyl)- l-[2-(2-hydroxyethoxy)ethyl]-6-(3-hydroxy- 1 -propynyl)-4- oxo- 1 ,4-dihydro-3-quinolinecarboxamide;
(56) N-(4-chlorobenzyl)-l-{2-[2-(2-methoxyethoxy)ethoxy]ethyl}-6-(4- morphoUnylmethyl)-4-oxo- 1 ,4-dihydro-3-quinoUnecarboxamide: (57) N-(4-chlorobenzyl)-l-[2-(2-hydroxyethoxy)ethyl]-6-(4-morphoUnylmethyl)-4-oxo-
1 ,4-dihydro-3-quinohnecarboxamide:
(58) N-(4-chlorobenzyl)-l-[2-(2-ethoxyethoxy)ethyl]-6-(4-morphoUnylmethyl)-4-oxo- 1 ,4-dihydro-3-quinolinecarboxamide:
(59) N-(4-chlorobenzyl)-6-(4-morpholinylmethyl)-4-oxo- l-(2-propynyl)-l,4-dmydro-3- quinolinecarboxamide;
(60) N-(4-chlorobenzyl)-l-[2-(ethylsuU'anyl)ethyl]-6-(4-morphoUnylmethyl)-4-oxo-l,4- dihydro-3-quinolinecarboxamide;
(61) N-(4-chlorobenzyl)- l-[3-(methylsuU'anyl)propyl]-6-(4-morphofinylmethyl)-4-oxo- 1 ,4-dihydro-3-quinolinecarboxamide; (62) N-(4-chlorobenzyl)-l-(4-hydroxy-2-butynyl)-6-(4-morphoUnylmethyl)-4-oxo-l,4- dihydro-3-quinolinecarboxamide;
(63) N-(4-chlorobenzyl)-6-{ [(2-hydroxy-2-phenylethyl)(methyl)amino]methyl}- 1- methyl-4-oxo- 1 ,4-dihydro-3-quinoUnecarboxamide;
(64) l-{2-[bis(2-hydroxyethyl)amino]ethyl}-N-(4-chlorobenzyl)-6-(4-morphoUnyl- methyl)-4-oxo- 1 ,4-dihydro-3-quinoUnecarboxamide:
(65) N-(4-chlorobenzyl)-l-[3-(methylsuUinyl)propyl]-6-(4-morpholinylnιethyl)-4-oxo- L4-dihydro-3-quinolinecarboxamide:
(66) N-(4-chlorobenzyl)-l-{ 3-[(3-hydroxypropyl)suU'anyl]propyl}-6-(4- morphoUnylmethyl)-4-oxo- 1 ,4-dϋ ydro-3-quinolinecarboxamide: (67) N-(4-chlorobenzyl)-l-[3-(methylsuU'onyl)propyl]-6-(4-morphoUnylmethyl)-4-oxo-
1 ,4-dihydro-3-quinolinecarboxamide:
(68) N-(4-chlorobenzyl)- l-[2-(ethylsuUinyl)ethyll-6-(4-morphohnylmethyl)-4-oxo- 1 ,4- dihydro-3-quinohnecarboxamide;
(69) N-(4-chlorobenzyl)-l-[2-(ethylsuUonyl)ethyl]-6-(4-morpholinylmethyl)-4-oxo-l,4- dihydro-3-quinoUnecarboxamide;
(70) N-(4-chlorobenzyl)- 1 - { 3-[(3-hydroxypropyl)suUιnyl]propyl } -6-(4- morphoUnylmethyl)-4-oxo- 1 ,4-dihydro-3-quinolinecarboxamide: (71) N-(4-chlorobenzyl)-l-{ 3-[(3-hydroxypropyl)suU'onyl]propyl}-6-(4- morpholinylmethyl)-4-oxo- 1 ,4-dihydro-3-quinolinecarboxamide:
(72) N-(4-chlorobenzyl)-6-(4-morpholinylmethyl)-4-oxo- 1 -[2-(phenylsuU'anyl)ethyl]- 1 ,4-dihydro-3-quinolinecarboxamide; (73) N-(4-chlorobenzyl)-l-[(methylsuU"anyl)methyl]-6-(4-morphoUnylmethyl)-4-oxo-
1 ,4-dihydro-3-quinolinecarboxamide:
(74) N-(4-chlorobenzyl)-6-{ [[2-hydroxy-2-(4-hydroxyphenyl)ethyl](methyl)- amino]methyl}-l-methyl-4-oxo-1.4-dU ydro-3-quinohnecarboxamide;
(75) N-(4-chlorobenzyl)-6-[(3-hydroxy- 1 - azetidinyl) methyl] - 1 -methyl-4-oxo- 1 ,4- dϋιydro-3-quinolinecarboxamide;
(76) N-(4-chlorobenzyl)-6-(4-morpholinylmethyl)-4-oxo-l-[(phenylsuUanyl)-methyl]- 1.4-dihydro-3-quinoUnecarboxamide:
(77) N-(4-chlorobenzyl)-6-{ [[2-hydroxy-2-(4-hydroxy-3-methoxyphenyl)ethyl]- (methyl)amino]methyl}- l-methyl-4-oxo-l ,4-dihydro-3-quιnolinecarboxamide; (78) N-(4-chlorobenzyl)-6-[(3.3-dihydroxy- l-azetidinyl)methyl]- 1 -methyl-4-oxo- 1 ,4- dihydro-3-quinoUnecarboxamide;
(79) N-(4-chlorobenzyl)- 1 -[(methylsuUinyl)methyl]-6-(4-moφhoUnylmethyl)-4-oxo- 1.4- dihydro-3-quinolinecarboxamide;
(80) N-(4-chlorobenzyl)-l-[(methylsuU"onyl)methyl]-6-(4-morphoUnylmethyl)-4-oxo- 1 ,4-dihydro-3-quinolinecarboxamide;
(81 ) N-(4-chlorobenzyl)-6-(4-morpholinylmethyl)-4-oxo- 1 -[(phenylsuUinyl)-methyl]- 1 ,4-dihydro-3-quinoUnecarboxamide;
(82) N-(4-chlorobenzyl)-6-(4-morphoUnylmethyl)-4-oxo-l-l(phenylsuUOnyl)-methyl]- 1.4-dihydro-3-quinolinecarboxamide; (83) N-(4-chlorobenzyl)-6-(3-hydroxypropyl)-l-[2-(2-methoxyethoxy)ethyl]-4-oxo- 1.4- di ydro-3-quinoUnecarboxamide;
(84) N-(4-chlorobenzyl)- 1 -[2-(2-methoxyethoxy)ethyl]-6-(4-morphoUnylmethyl)-4-oxo- l ,4-dihydro-3-quinoUnecarboxamide:
(85) N-(4-chlorobenzyl)- l-[2-(2-methoxyethoxy)ethyl]-4-oxo-6-[(4-oxo- l- piperidinyl) methyl]- 1.4-dihydro-3-quinolinecarboxamide:
(86) N-(4-chlorobenzyl)-6-{ [(cyanomethyl)(methyl)amino]methyl}-l-[2-(2- methoxyethoxy)ethyl] -4-oxo- 1 ,4-dihydro-3-quinolinecarboxamide; (87) N-(4-chlorobenzyl)-6-{ [(3R)-3-hydroxypyrroUdinyl]methyl}-l-[2-(2- methoxyethoxy)ethyl]-4-oxo-l ,4-dihydro-3-quinolinecarboxamide:
(88) N-(4-chlorobenzyl)- l-[2-(2-methoxyethoxy)ethyl]-6-[(methylsulfanyl)methyl]-4- oxo- 1 ,4-dihydro-3-quinolinecarboxamide; (89) N-(4-chlorobenzyl)-6-{ [[(lRJ5)-2-hydroxy-l-methyl-2-phenylethyl](methyl)- amino]methyl}-l-[2-(2-methoxyethoxy)ethyl]-4-oxo- l ,4-dihydro-3-quinoline-carboxamide:
(90) N-(4-chlorobenzyl)-6-{ [(2-hydroxy-2-phenylethyl)(methyl)amino]methyl}- 1 -[2-(2- methoxyethoxy)ethyl]-4-oxo-l,4-dihydro-3-quinolinecarboxamide;
(91) N-(4-chlorobenzyl)-6-{ [[2-hydroxy-2-(4-hydroxyphenyl)ethyl](methyl)amino]- methyl}- l-[2-(2-methoxyethoxy)ethyl]-4-oxo- l ,4-dihydro-3-quinolinecarboxamide:
(92) l-{2-[2-(tert-butoxy)ethoxy]ethyl-N-(4-chlorobenzyl)-6-(4-morpholinyl-methyl)-4- oxo- 1 ,4-dihydro-3-quinolinecarboxamide:
(93) l-{2-[2-(tert-butoxy)ethoxy|ethyl-N-(4-chlorobenzyl)-6-{ [L2-hydroxy-2-(4- hydroxyphenyl)ethyl](methyl)amino)methyl-4-oxo- l J-dihydro-3-quinoUne-carboxamide; (94) N-(4-chlorobenzyl)-6-(3-hydroxy-l -propynyl)- l-methyl-4-oxo- 1 ,4-dihydro-3- quinolinecarbothioamide:
(95) N- (4- chloro benzyl)- 1 -methyl-6-(4-morpholinylmethyl)-4-oxo- 1 J-dihydro-3- quinoϋnecarbothio amide ;
(96) N-(4-chlorobenzyl)-8-(3-hydroxy- 1 -propynyl)- 1 -methyl-4-oxo- 1 ,4-dihydro-3- quinolinecarboxamide:
(97) N-(4-chlorobenzyl)-8-(4-hydroxy- 1 -butynyl)- 1 -methyl-4-oxo- 1.4-dihydro-3- quinoUnecarboxamide:
(98) Ν-(4-chlorobenzyl)- l-methyl-4-oxo-6-(tetrahydro-2H-pyran-4-ylmethyl)-1.4- dihydro-3-quinoUnecarboxamide; (99) N-(4-chlorobenzyl)-6- { f 3-(hydroxyimino)- 1 - azetidinyl] methyl }- 1 -methyl-4-oxo-
1.4-dU ydro-3-quinolinecarboxamide:
(100) N-(4-chlorobenzyl)-l-{2-[2-(4-morphoUnyl)ethoxy]ethyl}-6-(4- morpholinylmethyl)-4-oxo- 1 ,4-dihydro-3-quinoUnecarboxamide:
(101) N-(4-chlorobenzyl)-l-([(4-chlorophenyl)suU'anyl]methyl)- 6-(4- morphoUnylmethyl)-4-oxo- 1 ,4-dihydro-3-quinolinecarboxamide:
(102) N-(4-chlorobenzyl)-l-([(4-chlorophenyl)suUinyl]methyl)-6-(4- morphoUnylmethyl)-4-oxo- 1 ,4-dihydro-3-quinolinecarboxamide; (103) N-(4-chlorobenzyl)- l-([(4-chlorophenyl)sulfonyl]methyl)-6-(4- morphoUnylmethyl)-4-oxo- 1 ,4-dihydro-3-quinoUnecarboxamide:
(104) N-(4-hlorobenzyl)-l-[(4-chlorophenoxy) methyl]-6-(4-morpholinylmethyl)-4-oxo- 1.4-dihydro-3-quinolinecarboxamide; (105) N-(4-chlorobenzyl)-l-[(2-methoxyethoxy)methyl]-6-(4-morphoUnylmethyl)-4- oxo- 1 ,4-dihydro-3-quinoUnecarboxamide;
(106) 2-{ [3-{ [(4-chlorobenzyl)amino]carbonyl}-6-(4-morphoUnylmethyl)-4-oxo-l (4H)- quinoUnyl]methoxy} ethyl benzoate;
(107) N-(4-chlorobenzyl)- 1 -[(2-hydroxyethoxy)methyl]-6-(4-morpholinylmethyl)-4- oxo- 1 ,4-dihydro-3-quinolinecarboxamide:
(108) N-(4-chlorobenzyl)-6-(4-morphoUnylmethyl)-4-oxo- l-tetrahydro-2H-pyran-4-yl- 1.4-dihydro-3-quinoUnecarboxamide;
(109) N-(4-chlorobenzyl)- l-(l-methyl-4-piperidinyl)-6-(4-morphoknylmethyl)-4-oxo- 1 ,4-dihydro-3-quinolinecarboxamide; (1 10) N-(4-chlorobenzyl)-6-(4-morphoUnylmethy])-4-oxo- l-(4-piperidinyl)- l , 4-dihydro-
3-quinolinecarboxamide;
(1 11) N-(4-chlorobenzyl)- l-(l . l-dioxohexahydrothiopyran-4-yl)-6-(4- morphoUnylmethyl)-4-oxo- 1 ,4-dihydro-3-quinoUnecarboxamide:
(1 12) N-(4-chlorobenzyl)- 1 -(4-morpholinyl)-6-(4-morpholinylmethyl)-4-oxo- 1.4- dihydro-3-quinolinecarboxamide:
(113) N-(4-chloro benzyl)- l-(4-methyl- l -piperazinyl)-6-(4-morphoUnylmethyl)-4-oxo- 1 ,4-dihydro-3-quinoϋnecarboxamide;
(1 14) N-(4-chlorobenzyl)-6-(4-morpholinylmethyl)-4-oxo- 1-( 1 -piperidinyl)- 1.4-dihydro- 3-quinolinecarboxamide; (115) N-(4-chlorobenzyl)-6-(4-morpholinylmethyl)-4-oxo- 1-( 1-pyrroUdinyl)- 1 ,4- dihydro-3-quinolinecarboxamide;
(1 16) N-(4-chlorobenzyl)-l-[(2R)-2-(methoxymethyl)pyrroUdinyl]-6-(4- morpholinylmethyl)-4-oxo- 1.4-dihydro-3-quinolinecarboxamide;
(117) N-(4-chlorobenzyl)- 1 -(dimethylamino)-6-(4-morphoUnylmethyl)-4-oxo- 1 ,4- dihydro-3-quinolinecarboxamide;
(118) 1 -amino-N-(4-chlorobenzyl)-6-(3-hydroxy- 1 -propynyl)-4-oxo- 1.4-dihydro-3- quinolinecarboxamide; (119) l-amino-N-(4-chlorobenzyl)-6-(3-hydroxypropyl)-4-oxo-l ,4-dihydro-3- quinolinecarboxamide ;
( 120) N-(4-chlorobenzyl)- 1 -(dimethylamino)-6-(3-hydroxy- 1 -propynyl)-4-oxo- 1 ,4- dihydro-3-quinolinecarboxamide; (121) N-(4-chloro benzyl)- l-(dimethylamino)-4-oxo-l,4-dihydro-3- quinolinecarboxamide;
(122) l-(Aalyloxy)-N-(4-chlorobenzyl)-4-oxo- 1 ,4-dihydro-3-quinolinecarboxamide;
(123) N-(4-chlorobenzyl)-l-methoxy-4-oxo- 1 ,4-dihydro-3-quinoUnecarboxamide;
( 124) N-(4-bromobenzyl)- 1 -(4-morpholinyl)-6-(4-morpholinylmethyl)-4-oxo- 1 ,4- dihydro-3-quinolinecarboxamide;
( 125) N-(4-fluorobenzyl)- 1 -(4-morphoUnyl)-6-(4-morphoUnylmethyl)-4-oxo- 1 ,4- dihydro-3-quinoUnecarboxamide;
(125) N-(4-chlorobenzyl)-l-{ [2-(4-morphoUnyl)ethoxy]methyl}-6-(4- morphoUnylmethyl)-4-oxo- 1 ,4-dihydro-3-quinolinecarboxamide: (126) N-(4-chlorobenzyl)-l-{ [2-(dimethylamino)ethoxy]methyl}-6-(4- morpholinylmethyl)-4-oxo- 1 ,4-dihydro-3-quinolinecarboxamide:
( 127) N-(4-chlorobenzyl)- 1 - { [2-(4-methyl- 1 -piperazinyl)ethoxy] methyl }-6-(4- morphoUnylmethyl)-4-oxo- 1 ,4-dihydro-3-quinolinecarboxamide:
( 128) N-(4-chlorobenzyl)-6-(4-morphoUnylmethyl)-4-oxo- 1 -{ [2-( 1 - piperidinyl)ethoxy] methyl}- 1 ,4-dihydro-3-quinolinecarboxamide:
( 129) N-(4-chlorobenzyl)-6-(4-morphoUnylmethyl)-4-oxo- 1 - { [2-( 1 - pyrroUdinyl)ethoxy]methyl}- l,4-dihydro-3-quinohnecarboxamide: or a pharmaceuticaUy acceptable salt thereof.
The foUowing Charts A - AA describe the preparation of the compounds of the present invention. AU of the starting materials are prepared by procedures described in these charts or by procedures analogous thereto, which would be weU known to one of ordinary skiU in organic chemistry. All of the final compounds of the present invention are prepared by procedures described in these charts or by procedures analogous thereto, which would be weU known to one of ordinary skill in organic chemistry. All of the variables used in the charts are as defined below or as in the claims. Chart A.
The ethyl ester of Formula A- 1 , which is ethyl 4-hydroxy-6-iodo-3- quinolinecarboxylate, is prepared by heating 4-iodoaniline with diethyl ethoxymethylene malonate, first at about 150°C. then in refluxing diphenyl ether. Aminolysis of compound A- 1 with 4-substituted-benzylamine at about 160°C provides amide A-2. Palladium and copper mediated coupling of A-2 with propargyl alcohol leads to compound A-3. Alkylation of the pyridone nitrogen is accompUshed with potassium carbonate and an optionaUy substituted alkyl haUde, affording the compound of Formula A-4. Alternatively, compound A-3 is partiaUy hydrogenated to the alkenyl derivative, compound A-5 (E or Z). SimUarly. 4-quinolone structures of Formula A-4 are partiaUy hydrogenated to afford alkenyl derivatives of Formula A-6 (E or Z). Alkylation of compound A-5 with optionaUy substituted alkyl haUdes and potassium carbonate also provides compounds of Formula A-6.
Figure imgf000026_0001
Figure imgf000026_0002
A-4 A-3
Figure imgf000026_0003
A-6 A-5 Chart B.
The compound of Formula B-l, which is 2-fluoro-5-iodobenzoic acid, is prepared by carbonation of the anion of 4-fluoroiodobenzene, which is prepared by deprotonation of 4- fluoroiodobenzene with LDA. Reaction of acid B-l with carbonyldiimidazole, followed by treatment of the resulting acyl imidazoUde with ethyl trimethylsUyl malonate and subsequent decarboxylation, affords β-ketoester B-2. The ketoester is converted to quinoUnones B-3 by sequential treatment with triethyl orthoformate, an amine, and potassium tert-butoxide. Aminolysis of the ester is accompUshed with 4-chlorobenzylamine, giving compounds of Formula B-4. Coupling of propargyl alcohol is effected using paUadium and copper catalysis, leading to compounds of Formula B-5. Hydrogenation of the triple bond using hydrogen gas and platinum catalyst provides hydroxypropyl derivatives B-6.
Figure imgf000027_0001
B-6 B-5
- Chart C.
PaUadium catalyzed carbonylation of the 6-iodo-4-hydroxyquinoline-3-carboxamide A-2 affords the corresponding ester C-l which is then reduced with LAH to afford the alcohol C-2. Alkylation of the pyridone nitrogen with an alkyl bromide, iodide, or tosylate (X = I, Br, Ts, R2 is the same as defined above) in the presence of an alkaU metal carbonate provides compounds of the general structure C-3. Treatment of compound C-3 with methanesuU nyl chloride foUowed by displacement with an amine, HNR7R8 wherein R7 and R8 are the same as defined above, affords compounds of the structure described by Formula C-4.
Figure imgf000028_0001
Figure imgf000028_0002
C-4
Chart D.
Compounds of Formula D-l are phosphitylated with di-tert-butyl diethyl phosphoramidite to give an intermediate phosphite, which is oxidized in situ with m- chloroperbenzoic acid to provide di-tert-butyl phosphates of Formula D-2. Treatment of the phosphates with trifluoroacetic acid cleaves the tert-butyl groups, providing phosphoric acids of Formula D-3.
Figure imgf000029_0001
D-1 D-2
Figure imgf000029_0002
D-3
Chart E.
Alcohols of Formula D- 1 are coupled with suleptanic acid triethylammonium salt, which is triethylammonium 2-[(7-carboxyheptanoyl)(methyl)amino]-l-ethanesuU"onate, using dusopropylcarbodiimide and 4- dimethylamino yridine, to provide the corresponding esters. Exchanse of the triethvlammonium salt with sodium ion affords sodium salts E-l.
Figure imgf000030_0001
D-1
Figure imgf000030_0002
E-1
Chart F.
4-Iodoaniline (F-0) is reductively alkylated with [(l-ethoxycyclopropyl)oxy]- trimethylsUane and sodium cyanoborohydride to give the N-cyclopropyl aniline (F-l). Treatment with diethyl ethoxymethylenemalonate in pyridine affords the enamine (F-2) which is cycUzed with polyphosphoric acid to the quinoUne (F-3). Treatment with p- chlorobenzylamine at elevated temperature converts the ester to the amide (F-4). PaUadium catalyzed coupling of the iodide with propargyl alcohol affords F-5. Reaction with platinum and hydrogen gas affords the saturated propyl alcohol (F-6).
Figure imgf000031_0001
F-0 F-1 \
Figure imgf000031_0002
F-4 F-2
F-3
Figure imgf000031_0003
Chart G.
4-Nitrobenzyl bromide is treated with morpholine and potassium carbonate in acetone to give 4-(4-Nitrobenzyl)morpholine (G-l). The nitro group is reduced with platinum and hydrogen gas to afford the aniline (G-2) which is then treated with [(1- ethoxycyclopropyl)-oxy]trimethylsUane and sodium cyanoborohydride to give the N- cyclopropyl aniline (G-3). Reaction with diethyl ethoxymethylenemalonate in pyridine affords the enamine (G-4) which is cycUzed with polyphosphoric acid to the quinoline (G-5). Treatment with p-chlorobenzylamine at elevated temperature converts the ester to the amide (G-6).
Figure imgf000032_0001
Chart H.
Alkylation of N-(4-chlorobenzyl)-6-iodo-4-oxo- 1 ,4-dihydro-3-quinolinecarboxamide with potassium carbonate and tert-butylbromoacetate affords H-1. PaUadium catalyzed coupling of the iodide with propargyl alcohol affords H-2. Reaction with platinum and hydrogen gas affords the saturated propyl alcohol (H-3). Treatment with tritluoroactic acid affords the free acid (H-4). Alternatively. H-2 is treated with trifluoroacetic acid to give H-5.
Figure imgf000033_0001
Figure imgf000033_0002
H-4
Chart I. l-Fluoro-4-nitrobenzene (I-l) is converted to 2-(4-nitroanilino-N-ethyl)-l -ethanol (I- 2) by heating with the N-ethylethanolamine in ethanol. Compound 1-2 is converted to the corresponding acetate (1-3) by treatment with acetyl chloride. The nitro group is reduced to the free amine with paUadium on carbon and hydrogen gas. The resulting aniline is treated with diethyl ethoxymethylenemalonate to give compound 1-4. The resulting enamine is cycUzed by heating in diphenyl ether to give the quinoline (1-5). Compound 1-5 is N- alkylated at the pyridone nitrogen by treatment with iodoalkyl and potassium carbonate to afford compound 1-6. Aminolysis o the diester with 4-chlorobenzylamine affords (1-7).
Figure imgf000034_0001
^ O O AcO f O O
R' R
I"7 I — I-5 R' = H
I-6 R' = alkyl
Chart J.
2-Fluoro-6-iodoaniline is condensed with diethyl ethoxymethylenemalonate and then heated in diphenyl ether to afford the 4-hydroxyquinoline ethyl ester (J-1). Aminolysis of compound J- 1 with 4-chlorobenzylamine affords the corresponding amide (J-2). Compound J-2 is heated in the presence of an alkoxide to afford compound J-3. PaUadium catalyzed coupling of the resulting quinoUne with propargyl alcohol affords alkyne J-4. The pyridone nitrogen of J-4 is then N-alkylated with an alkyl haUde and potassium carbonate to afford 4- quinolones of Formula J-5. Hydrogenation of compound J-5 affords the hydroxypropyl derivate of Formula J-6.
Figure imgf000035_0001
Figure imgf000035_0002
J-6
Chart K.
PaUadium catalyzed carbonylation of the 6-iodo-8-fluoro-4-hydroxyquinoline-3- carboxamide J-2 affords the corresponding ester K- 1 which is then reduced with LAH to afford the alcohol K-2. Alkylation of the pyridone nitrogen with an alkyl haUde and potassium carbonate affords compounds of Formula K-3.
Figure imgf000036_0001
Chart L.
PaUadium catalyzed coupling of the 6-iodo-8-fluoro-4-hydroxyquinoline-3- carboxamide J-2 with propargyl alcohol affords alkyne L-1. The pyridone nitrogen of L- 1 is then N-alkylated with an alkyl haUde and potassium carbonate to afford 4-quinolones of Formula L-2. Subsequent semi-hydro genation of compound L-2 affords hydro xyalkenyl derivatives o f Fo rmula L- 3.
Figure imgf000036_0002
sub. alkyl
Figure imgf000036_0003
L-3 Chart M.
Treatment of compound C-2 with methanesuU'onyl chloride foUowed by reaction with morpholine affords compound M-1. Alkylation of the pyridone nitrogen with an alkyl bromide, iodide, or tosylate (X = I, Br, Ts, R is alkyl) in the presence of an alkaU metal carbonate or alternatively with the corresponding alkyl alcohol under Mitsunobu conditions affords compounds of Formula M-2.
Figure imgf000037_0001
C-2 / M-1
Figure imgf000037_0002
Chart N. Treatment of compound C-3 with methanesuU'onyl chloride affords the benzyhc chloride N- 1. Treatment of compound N- 1 with a corresponding primary or secondary amine affords compounds of Formula C-4 or the chloride atom may be displaced by other nucleophUes (e.g. azide).
Figure imgf000037_0003
Chart O.
Treatment of compound M- 1 with a thiol-containing alkyl hakdes in the presence of an inorganic base or alternatively with the corresponding thiol-containing alkyl alcohols under Mitsunobu conditions affords compounds of Formula O- 1 (wherein R9 is the same as defined above). Oxidation of the suUides of Formula O-l with m-chloroperoxybenzoic acid in the presence of /?-toluenesuU'onic acid affords compounds of Formula O-2.
Figure imgf000038_0001
M-1 θ-1
/
Figure imgf000038_0002
θ-2
Chart P.
Compound A-2 may be reacted with an alkyl bromide, iodide, or tosylate (X = Br, I, Ts. R is alkyl) in the presence of an alkaU metal carbonate to afford compounds of the formula P-1. The resulting 6-iodo-4-quinolones are coupled with trialkyl alkenyl stannanes (e.g. tributyl vinyl stannane) catalyzed by PdCl2(PPh3)2 to afford compounds such as those described by formula P-2
Figure imgf000038_0003
Chart Q.
Alkyl chloride N- 1 is treated with the sodium salt of an alkyl thiol to afford suUides of the general formula Q-l (wherein R2 and R9 is the same as defined above).
Figure imgf000039_0001
Chart R.
Compounds with the 3-thioamide substitution are prepared from compound A-2 (see Chart A) by reaction with PCI5 to provide the chloroimidate R-l. Subsequent treatment of" chloroimidate R-l with H2S provides the thioamide R-2 which is alkylated under Mitsunobu conditions to provide R-3. Compound R-3 may then be transformed to the desired analogs employing chemistry analogous to the carboxamide derivatives depicted in Charts A-E, N, P. or Q.
Figure imgf000039_0002
Figure imgf000039_0003
Chart S.
N-(4-chlorobenzyl)-4-hydroxy-6-iodo-3-quinoUnecarboxamide (Chart A-2, R = Cl) is treated with phosphorus pentachloride to form the quinoUnecarboximidoyl chloride S-1. This is then treated with hydrogen suUide to form the thioamide S-2. Alkylation under Mitsonobu conditions gives S-3 (wherein R is alkyl) which is coupled to propargyl alcohol using paUadium catalysis to afford S-4.
Figure imgf000040_0001
S-4
Chart T.
PaUadium catalyzed carbomethylation of N-(4-chlorobenzyl)-4-hydroxy-6-iodo-3- quinoUnecarbothioamide (S-2) provides the quinoline 6-methyl ester T- 1. Reduction to the alcohol foUowed by mesylation and displacement with morpholine provides the 6- morpholinylmethyl quinoline T-3. Methylation under Mitsonobu conditions gives N-(4- chlorobenzyl)- 1 -methyl-6-(4-morphoUnylmethyl)-4-oxo- 1 ,4-dihydro-3- quinoUnecarbothioamide (T-4).
Figure imgf000040_0002
T-1 T-2
Figure imgf000040_0003
Chart U.
2-Iodoaniline is treated with diethyl ethoxyethylenemalonate at 130 °C. The resulting enamine is then dissolved in Ph2O and heated to 250 °C to give the ethyl quinoUnecarboxylate U- 1. Condensation with neat 4-chlorobenzylamine at 180 °C gives the 4-chlorobenzylamide U-2 which is methylated with iodomethane to provide N-(4- chlorobenzyl)-8-iodo- 1 -methyl-4-oxo- 1 ,4-dihydro-3-quinolinecarboxamide (U-3). PaUadium catalyzed coupling to acetylenes or alkenes provides compounds of the general formula U-4.
Figure imgf000041_0001
Chart N.
4-Νitrobenzylbromide is treated with triphenylphosphine to form the phosphonium salt V- 1. Deprotonation to form the Wittig reagent and condensation with tetrahydropyran- 4-one gives the nitrobenzyUdene V-2. Hydrogenation to the saturated amine and condensation with diethyl ethoxymethylenemalonate foUowed by thermal cycUzation of the resulting enamine gives the quinoUnecarboxyUc ester N-3. The resulting ester is condensed with 4-chlorobenzylamine and methylated to afford V-5.
Figure imgf000042_0001
V-2
Figure imgf000042_0002
Chart W.
Aniline of Formula G-2 is reductively alkylated with a substituted cyclohexanone (W-l ; Z = O, NMe, NBoc) to give the N-alkylated aniline (W-2; Z = O, ΝMe, ΝBoc). Reaction with diethyl ethoxymethylenemalonate affords the enamine (W-3: Z = O, ΝMe, ΝBoc) which is cycUzed with polyphosphoric acid to the quinoUne (W-4; Z = O, ΝMe, ΝH). Treatment with 4-chlorobenzylamine at elevated temperature converts the ester to the amide (W-5; Z = O, ΝMe, ΝH). Likewise, Aniline of Formula G-2 is reductively alkylated with tetrahydrothiopyran-4-one (W-l ; Z = S) to give the N-alkylated aniline (W-2: Z = S). Reaction with diethyl ethoxymethylenemalonate affords the enamine (W-3: Z = S). Oxidation with m-chloroperoxybenzoic acid affords the suU'one (W-2; Z = SO2) which is reacted with diethyl ethoxymethylenemalonate to afford the enamine (W-3; Z = SO2) then cycUzed with polyphosphoric acid to the quinoUne (W-4: Z = SO?). Treatment with 4- chlorobenzylamine at elevated temperature converts the ester to the amide (W-5: Z = SO?).
Figure imgf000043_0001
Chart X.
Reductive animation of 3-bromo-4-fluorobenzaldehyde with morpholine and sodium triacetoxyborohydride affords aryl bromide X-l. Halogen-kthium exchange foUowed by acetylation with a N-methoxy-N-methylacetamide gives methyl ketone X-2. The resulting ketone is then converted to β-keto ester X-3 with diethyl carbonate under basic conditions. Refluxing β-keto ester X-3 in triethylorthoformate and acetic anhydride produces an intermediate enol ether which is then reacted with a selected hydrazide. The resulting enamine X-4 is then cycUzed by heating with sodium hydride in THF to afford the corresponding quinolone-3-ester X-5. Direct thermolysis of the ester with 4-substituted- benzylamine (X = Cl, Br, F, or CΝ, R7 and R8 are the same as defined above) at 190 °C affords amides of the general formula X-6.
Figure imgf000044_0001
J
Figure imgf000044_0002
X-4
Figure imgf000044_0003
Chart Y.
Butyl acetate sUyl ketene acetal is reacted with 2-chloro-5-iodobenzoylchloride to afford β-ketoester Y- l . Refluxing Y-l in triethylorthoformate and acetic anhydride produces an intermediate enol ether which is then reacted with a selected hydrazide. The resulting enamine Y-2 (wherein R7 and R8 are the same as defined above) is then cycUzed by heating with sodium hydride to afford the corresponding quinolone-3-ester Y-3. Direct thermolysis of the ester with 4-chlorobenzylamine affords amides of the general formula Y- 4. PaUadium catalyzed coupling of Y-4 with propargyl alcohol affords compounds of general formula Y-5. Subsequent catalytic hydrogenation of the alkyne provides hydroxypropyl derivatives of the general formula Y-6.
Figure imgf000045_0001
Y-5 Y-6
Chart Z.
Alternatively where the NI -substituent is amino, N-(4-chlorobenzyl)-4-hydroxy-6- iodo-3-quinolinecarboxamide (A-2) is treated with O-(mesitylsuU nyl)hydroxylamine to afford 1-amino-quinolone Z- 1. Compound Z-1 may then be transformed in a simUar fashion to that described for general intermediate Y-4 above.
Figure imgf000046_0001
Chart AA.
Ethyl 3-(2-fluorophenyl)-3-oxopropanoate (AA-1) is refluxed in triethylorthoformate and acetic anhydride to afford an intermediate enol ether which is then reacted with a selected N-alkoxyamine. The resulting enamine AA-2 is then cycUzed by heating with sodium hydride to afford the corresponding quinolone-3-ester AA-3. Direct thermolysis of the ester with 4-chlorobenzylamine affords amides of the general formula AA-4.
Figure imgf000046_0002
/
Figure imgf000046_0003
In cases where compounds are sufficiently basic or acidic to form stable nontoxic acid or base salts, administration of the compounds as salts may be appropriate. Examples of pharmaceuticaUy acceptable salts are organic acid addition salts formed with acids which form a physiological acceptable anion. for example, tosylate. methanesuU'onate, acetate, citrate, malonate. tartarate, succinate. benzoate. ascorbate, etoglutarate, and glycerophosphate. Suitable inorganic salts may also be formed, including hydrochloride. sulfate, nitrate, bicarbonate, and carbonate salts.
PharmaceuticaUy acceptable salts may be obtained using standard procedures weU known in the art, for example by reacting a sufficiently basic compound such as an amine with a suitable acid affording a physiologicaUy acceptable anion. AlkaU metal (for example, sodium, potassium or hthium) or alkaline earth metal (for example calcium) salts of carboxyUc acids can also be made.
Compounds of the present invention can conveniently be administered in a pharmaceutical composition containing the compound in combination with a suitable excipient. the composition being useful in combating viral infections. Pharmaceutical compositions containing a compound appropriate for antiviral use are prepared by methods and contain excipients which are weU known in the art. A generally recognized compendium of such methods and ingredients is Remington's Pharmaceutical Sciences by E.W. Martin (Mark Publ. Co., 15th Ed.. 1975). The compounds and compositions of the present invention can be administered parenteraUy (for example, by intravenous, intraperitoneal or intramuscular injection), topicaUy. oraUy. or rectally. depending on whether the preparation is used to treat internal or external viral infections.
For oral therapeutic administration, the active compound may be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. Such compositions and preparations should contain at least 0.1 % of active compound. The percentage of the compositions and preparations may. of course, be varied and may conveniently be between about 2 to about 60% of the weight of a given unit dosage form. The amount of active compound in such therapeuticaUy useful compositions is such that an effective dosage level wiU be obtained.
The tablets, troches, piUs, capsules, and the like may also contain the foUowing: binders such as gum tragacanth, acacia, corn starch or gelatin: excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate: and a sweetening agent such as sucrose, fructose, lactose or aspartame or a flavoring agent such as peppermint, oU of wintergreen, or cherry flavoring may be added. When the unit dosage form is a capsule, it may contain, in addition to materials of the above type, a Uquid carrier, such as a vegetable oU or a polyethylene glycol. Various other materials may be present as coatings or to otherwise modU'y the physical form of the soUd unit dosage form. For instance, tablets, pills, or capsules may be coated with gelatin, wax, sheUac or sugar and the like. A syrup or elixir may contain the active compound, sucrose or fructose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor. Of course, any material used in preparing any unit dosage form should be pharmaceuticaUy acceptable and substantiaUy non-toxic in the amounts employed. In addition, the active compound may be incorporated into sustained-release preparations and devices.
The compounds or compositions can also be administered intravenously or intraperitoneally by infusion or injection. Solutions of" the active compound or its salts can be prepared in water, optionaUy mixed with a nontoxic surfactant. Dispersions can also be prepared in glycerol, Uquid polyethylene glycols, triacetin, and mixtures thereof and in oUs. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
Pharmaceutical dosage forms suitable for injection or infusion can include sterUe aqueous solutions or dispersions or sterUe powders comprising the active ingredient which are adapted for the extemporaneous preparation of sterUe injectable or infusible solutions or dispersions, optionaUy encapsulated in Uposomes. In aU cases, the ultimate dosage form should be sterUe, fluid and stable under the conditions of manufacture and storage. The Uquid carrier or vehicle can be a solvent or Uquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the formation of Uposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antif'ungal agents, for example, parabens. chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it wiU be preferable to include isotonic agents, for example, sugars, buffers or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.
SterUe injectable solutions can be prepared by incorporating the active compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, foUowed by filter sterilization. In the case of sterUe powders for the preparation of sterUe injectable solutions, the preferred methods of preparation are vacuum drying and the freeze drying techniques, which yield a powder of the active ingredient plus any additional desired ingredient present in the previously sterile-filtered solutions. For topical administration, the present compounds may be appUed in pure form, i.e.. when they are Uquids. However, it will generaUy be desirable to administer them to the skin as compositions or formulations, in combination with a dermatologically acceptable carrier, which may be a soUd or a Uquid.
Useful soUd carriers include finely divided solids such as talc. clay, microcrystalline ceUulose, siUca. alumina and the like. Useful Uquid carriers include water, alcohols or glycols or water-alcohol/glycol blends, in which the present compounds can be dissolved or dispersed at effective levels, optionaUy with the aid of non-toxic surfactants. Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize the properties for a given use. The resultant Uquid compositions can be appUed from absorbent pads, used to impregnate bandages and other dressings, or sprayed onto the affected area using pump-type or aerosol sprayers. Thickeners such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols. modUied ceUuloses or modified mineral materials can also be employed with Uquid carriers to form spreadable pastes, gels, ointments, soaps, and the like, for appUcation directly to the skin of the user. Examples of useful dermatological compositions which can be used to deUver the compounds of formula I to the skin are known to the art: for example, see Jacquet et al. (U.S. Pat. No. 4.608392), Geria (U.S. Pat. No. 4.992,478). Smith et al. (U.S. Pat. No. 4,559,157) and Wortzman (U.S. Pat. No. 4.820.508).
Useful dosages of the compounds of formula I can be determined by comparing their in vitro activity, and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to the art: for example, see U.S. Pat. No. 4,938,949. The compound is conveniently administered in unit dosage form; for example, containing 5 to 1000 mg, conveniently 10 to 750 mg, most conveniently, 50 to 500 mg of active ingredient per unit dosage form. The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day. The sub-dose itseU' may be further divided, e.g., into a number of discrete loosely spaced administrations: such as multiple inhalations from an insufflator or by appUcation of a pluraUty of drops into the eye.
For internal infections, the compositions can be administered oraUy or parenteraUy at dose levels, calculated as the free base, of" about 0.1 to 300 mg/kg, preferably 1.0 to 30 mg/kg of mammal body weight, and can be used in man in a unit dosage form, administered one to four times daUy in the amount of 1 to 1000 mg per unit dose.
For parenteral administration or for administration as drops, as for eye infections, the compounds are presented in aqueous solution in a concentration of from about 0.1 to about 10%, more preferably about 0J to about 1%. The solution may contain other ingredients, such as emulsUiers, antioxidants or buffers.
GeneraUy, the concentration of" the compound(s) of" formula I in a Uquid composition, such as a lotion, wUl be from about 0J-25 wt-%, preferably from about 0.5-10 wt-%. The concentration in a semi-soUd or soUd composition such as a gel or a powder wiU be about 0J-5 wt-%, preferably about 0.5-2.5 wt-%. The exact regimen for administration of the compounds and compositions disclosed herein wiU necessarUy be dependent upon the needs of the individual subject being treated, the type of treatment and, of" course, the judgment of the attending practitioner.
The antiviral activity of" a compound of the invention can be determined using pharmacological models which are weU known to the art, or using Test A described below. The compounds of formula (I) and pharmaceuticaUy acceptable salts thereof" are useful as antiviral agents. Thus, they are useful to combat viral infections in animals, including man. The compounds are generaUy active against herpes viruses, and are particularly useful against the variceUa zoster virus, the Epstein-Barr virus, the herpes simplex virus, the human herpes virus type 8 (HHV-8) and the cytomegalovirus (CMV). WhUe many of the compounds of the present invention have shown activity against the CMV polymerase, these compounds may be active against the cytomegalovirus by this or other mechanisms of action. Thus, the description below of" these compounds' activity against the CMV polymerase is not meant to limit the present invention to a specUic mechanism of action. Test A
The HCMV polymerase assay is performed using a scintillation proximity assay (SPA) as described in several references, such as N.D. Cook, et al., Pharmaceutical Manufacturing International, pages 49-53 (1992); K. Takeuchi, Laboratory Practice, September issue (1992); US Patent No. 4,568,649 (1986); which are incorporated by reference herein. Reactions are performed in 96-weU plates. The assay is conducted in 100 μl volume with 5.4 mM HEPES (pH 7.5), 1 1.7 mM KCI, 4.5 mM MgCl2, 0.36 mg/ml BSA, and 90 nM 3H-dTTP. Assays are run with and without CHAPS, (3-[(3-Cholamidopropyl)- dimethylammonio]- l-propane-suU"onate) at a final concentration of 2 mM. HCMV polymerase is dUuted in enzyme dUution buffer containing 50% glycerol, 250 mM NaCl, 10 mM HEPES (pH 7.5), 100 μg/ml BSA, and 0.01 % sodium azide. The HCMV polymerase. which is expressed in recombinant baculovirus-infected SF-9 ceUs and purified according to Uterature procedures, is added at 10% (or 10 μl) of the final reaction volume, i.e., 100 μl. Compounds are dUuted in 50% DMSO and 10 μl are added to each weU. Control wells contain an equivalent concentration of DMSO. Unless noted otherwise, reactions are initiated via the addition of 6 nM biotinylated poly(dA)-oUgo(dT) template/primer to reaction mixtures containing the enzyme, substrate, and compounds of interest. Plates are incubated in a 25 C or 37 C H?O bath and terminated via the addition of 40 μl/reaction of 0.5 M EDTA (pH 8) per well. Reactions are terminated within the time-frame during which substrate incorporation is linear and varied depending upon the enzyme and conditions used, i.e., 30 min. for HCMV polymerase. Ten μl of streptavidin-SPA beads (20 mg/ml in PBS/10% glycerol) are added foUowing termination of the reaction. Plates are incubated 10 min. at 37 C, then equUibrated to room temperature, and counted on a Packard Topcount. Linear regressions are performed and IC50's are calculated using computer software.
A modUied version of the above HCMV polymerase assay is performed as described above, but with the foUowing changes: Compounds are diluted in 100% DMSO untU final dUution into assay buffer. In the previous assay, compounds are dUuted in 50% DMSO. 4.5 mM dithiotherotol (DTT) is added to the polymerase buffer. Also, a dUferent lot of CMV polymerase is used, which appears to be more active resulting in a more rapid polymerase reaction. Results of the testing of" representative compounds of formula I in this assay are shown in Table 1 below. Table 1. Biological Data polymerase IC50 (μM)
Example HCMV HSV VZV
1 1.7 nd nd
2 1.6 nd nd
3 2.3 nd nd
4 0.6 1.0 1.2
5 1.6 nd nd
6 7.2 nd nd
7 1.0 1J 0.77
8 1.0 nd nd
9 <0.78 nd nd
10 1.7 nd nd
1 1 1.5 nd nd
12 2 3.0 1.9
13 2.9 nd nd
14 1.3 1.2 1.1
15 4J nd nd
16 2.8 nd nd
17 0.8 2.0 1J
18 2.7 nd nd
19 1.8 nd nd
20 3.8 nd nd
21 1.4 nd nd
22 0.81 nd nd
23 0.62 nd nd
24 23.6 nd nd
25 1.6 1.6 1.5
26 0.53 0.78 0.49
27 0.61 nd nd
28 1.8 nd nd
29 1.0 nd nd
30 0.95 nd nd
31 1J 1.3 1.0
32 27.2 nd nd
33 3.7 nd nd
34 >20 nd nd
36 >2() nd nd
37 >2() nd nd
39 2.2 nd nd
42 1.2 nd nd
43 9.4 nd nd Tabel 1. Biological Data (continued)
polymerase ICSo (μM)
Example HCMV HSV VZV
44 9.3 nd nd
45 11.9 nd nd
46 5.5 nd nd
47 7.2 nd nd
48 13.6 nd nd
49 2.2 nd nd
50 1 1.5 nd nd
51 1.3 nd nd
52 9.6 nd nd
53 11.7 nd nd
54 3.3 nd nd
55 2.3 2.4 1.4
56 3.0 nd nd
57 1.2 nd nd
58 1.4 nd nd
59 1.9 n nd
60 1 J nd nd
61 1J 0.9 0.5
62 13 1J 0.61
63 13 nd nd
64 0.95 nd nd
65 0.9 1.0 0.63
66 1J nd nd
67 0J nd nd
68 0.93 nd nd
69 0.9 nd nd
70 0.87 nd nd
71 0.8 nd nd
72 3.0 nd nd
73 1J nd nd
74 0.89 2.8 1.6
75 33 4.4 4.0
76 0J8 <0.31 <0.31
77 13 4.1 2.1
78 0.27 nd nd
79 1J nd nd
80 1J nd nd Tabel 1. Biological Data (continued)
polymer ase IC50 (μM)
Example HCMV HSV VZV
81 035 nd nd
82 0.53 nd nd
83 0.6 nd nd
84 1.2 nd nd
85 6.0 nd nd
86 2.5 nd nd
87 4.0 nd nd
88 5.9 nd nd
89 6.7 nd nd
90 4.4 nd nd
91 2J nd nd
93 6.2 nd nd
94 0.77 nd nd
95 0.3 nd nd
96 1.0 nd nd
97 1.5 nd nd
98 0.31 nd nd
99 8.0 nd nd
100 2.9 nd nd
101 03 nd nd
102 0.59 nd nd
103 0.83 nd nd
104 1.6 nd nd
105 1.3 nd nd
106 3J nd nd
107 0.84 nd nd
108 0.82 nd nd
109 0.48 nd nd
110 0.67 nd nd
111 0.73 nd nd
112 0.42 nd nd
113 0.64 nd nd
1 14 0.88 nd nd
115 0.62 nd nd
116 14.0 nd nd
117 1.5 nd nd 118 1 J nd nd
119 0.5 nd nd
120 2.5 nd nd
121 3.9 nd nd
122 2.8 nd nd
123 8.2 nd nd
124 1.2 nd nd
125 1J nd nd
DESCRIPTION OF PREFERRED EMBODIMENTS PREPARATION 1. N-(4-Chlorobenzyl)-8-fluoro-4-hydroxy-6-iodo-3- quinolinecarboxamide
Figure imgf000056_0001
A mixture of 11.85 g of 2-fluoro-4-iodoaniline and 10.81 g of diethylethoxy- methylene malonate is heated to 130 °C in a flask equipped with a Dean-Stark trap to coUect formed ethanol. The mixture is then cooled to 75 °C and dUuted with hexanes. The resulting soUd is coUected and dried. The soUd is then dissolved in 60 mL diphenyl ether and heated to 250 °C for 3 h in a flask equipped with a Dean- Stark trap to coUect the ethanol. The solution is aUowed to cool to room temperature and the resulting soUd is coUected and dried to yield 1 1.73 g of ethyl 8-fluoro-4-hydroxy-6-iodo-3-quinolinecarboxylate. This material (0.55 g) and 3 mL of" 4-chlorobenzylamine are heated at 180°C for 1 h. The reaction is cooled and poured into 75 mL diethyl ether. The resulting soUd is filtered and recrystaUized from ethyl acetate/hexanes to give the title compound as an off-white soUd (0.45 g).
Physical characteristics are as foUows: Mp 268-270 °C; !H ΝMR (DMSO) 610.17.8.59.8.29.8.05, 7.37, 7.33, 4.51; IR (muU) 3180.3078, 3059, 3004, 1647.1607, 1551.1524, 1489.1344, 1297.1285, 1240, 1183.805 cm"1: MS (ES-) 454.9 (M-H+); HRMS (FAB) found 456.9628.
PREPARATION S N-(4-Chlorobenzyl)-4-hydroxy-6-ιodo-8-methoxy-3-quinoUne- carboxamide
Figure imgf000056_0002
N-(4-Chlorobenzyl)-8-tluoro-4-hydroxy-6-iodo-3-quinoUnecarboxamide (2.95 g) from Preparation No. 1 and sodium hydride (60% dispersion, 520 mg) is suspended in DMF (60 mL) and to the mixture is added methanol (288 μL). After being heated for 1 h at 135 °C, additional sodium hydride (200 mg) is added, and the mixture is heated for an additional 1 h. The reaction mixture is aUowed to cool to rt and then is poured into saturated aqueous ammonium chloride (200 mL). The resulting precipitate is filtered and washed with water (20 mL). tert- butyl methyl ether (20 mL). and heptane (20 mL). The crude product is purified by column chromatography (heptane/2-propanol. 9/1 : 4/1) to afford 1.68 g (56%) of the title compound as a white soUd. RecrystaUization (acetic acid, water) affords a hydrate (1H20).
Physical characteristics are as follows:
Mp 241-243 °C; Η NMR (OMSO-d6) δ 12.43, 10.28. 8.57. 8.09. 7.61 , 7.41-734, 4.53. 4.04: 13C NMR (CF3CO2D) δ 173.3. 167.3. 149.0. 141.4. 134.8. 133.2, 129.8, 129.2. 129.0. 124.9. 124.5. 122.5. 106.7. 94.4. 56.4, 44.0: IR (drift) 3072, 1646. 1612, 1594. 1558. 1530. 1492, 1306, 1298. 1255. 1202. 1082. 851. 846. 804 cm"1: MS (ESI-) for m/z 467 (M-H)". Anal. Found for C,8H14CUN?O3.H?O: C. 44.39: H. 3.46: N. 5.76: Cl. 7.34. Water (KF): 3.67.
PREPARATION S. N-(4-Chlorobenzyl)-4-hydroxy-6-(3-hydroxy-l-propynyl)-8- methoxy-3-quinohnecarboxamide
Figure imgf000057_0001
N-((4-Chlorobenzyl)-4-hydroxy-6-iodo-8-methoxy-3-quinoUnecarboxamide (469 mg) from Preparation No. 2. copper (I) iodide (57 mg). and bis(triphenylphosphine)- paUadium (II) chloride (35 mg) are suspended in diethylamine (15 mL). Propargyl alcohol (70 μL) is added and the mixture is aUowed to stir at rt for 16 h. The reaction mixture is poured into water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The organic layer is washed with saturated aqueous ammonium chloride (3 x 10 mL) and brine (10 mL). The aqueous layer is back-extracted with ethyl acetate (20 mL). The combined organic layers are dried (MgSO ) and concentrated. The crude product is purified by column chromatography (dichloromethane/ methanol, 50/1 : 33/1 : 25/1 : 20/1) to afford 289 mg (73%) of" the title compound as a white soUd. Physical characteristics are as f'oUows: Mp 207-208 °C: Η NMR (OMSO-d6) δ 12.45, 10.3, 8.58, 7.79, 7.42-734. 5.38, 4.53, 4.34, 4.05; 13C NMR (DMSO-d6) δ 178.0, 167J, 151.8, 145.9, 141.5, 134.2, 132.6, 132J, 131.2, 129.6, 122.5, 121.7, 117.0, 114.4, 933, 86J, 59.5, 52.3, 44.3; IR (drift) 3196, 3157, 3074, 2234, 1649. 1603, 1568, 1562, 1523, 1491, 1314, 1200, 1089, 1021, 805 cm"1: MS (ESI-) m/z. 395 (M-H)". Anal. Found for C2ιHι7ClN2O4: C, 63.26; H, 4.35; N, 7.07; Cl, 8.94.
PREPARATION 4. N-(4-Chlorobenzyl)-4-hydroxy-6-iodo-3-quinoline- carboxamide
Figure imgf000058_0001
4-Iodoaniline (8.60 g) and diethyl ethoxymethylenemalonate (7.90 mL) are heated at 130 °C for 1 hour. The reaction is cooled to room temperature and 60 mL diphenyl ether is added. The solution is heated at 250 °C for 1.5 hours with removal of ethanol by a Dean- Stark trap. The reaction is cooled to room temperature and the resulting soUd is filtered, washed with hexanes, and dried to yield 1 1J0 g of ethyl 4-hydroxy-6-iodoquinoline-3- carboxylate. A mixture of this ester (0.58 g) and 4-chlorobenzylamine (4.0 mL) are heated at 180 °C for 1.5 hours. The reaction is cooled and poured into 50 mL diethyl ether. The resulting soUd is filtered, triturated in ethyl acetate, and filtered again to give the desired product (0.50 g).
Physical characteristics are as foUows:
Mp 297-299 °C: Η ΝMR (300 MHz. DMSO- 6) 12.71, 10.27, 8.76. 8.50, 8.02, 7.50, 7.38, 7.33, 4.52: IR (mull) 3151, 3078. 3039. 1631, 1610, 1572, 1563, 1545, 1527, 1512, 1491, 1433, 1351, 1303, 799 cm"1; MS (ES) 438.9 (M+H), 460.9 (M+Νa), 436.9 (M- H). Anal. Found: C, 46.61 ; H, 2.81 ; Ν, 6.34: Cl, 8J9.
PREPARATION 5. N-(4-Chlorobenzyl)-4-hydroxy-6-(3-hydroxy- 1 -propynyl)-3- quinolinecarboxamide
Figure imgf000059_0001
To a mixture of N-(4-chlorobenzyl)-4-hydroxy-6-iodo-3-quinolinecarboxamide from Preparation No. 4 (0.494 g) in Et?NH (12.9 mL) is added Cul (10.8 mg) and (Ph3P)?PdCl? (39.7 mg). DMF (2 mL) is added to solubiUze the reactants. To this solution is added propargyl alcohol (0.066 mL) and the reaction is stirred at room temperature for 2 days. The reaction mixture is concentrated to remove Et?NH. The resulting residue is partitioned between CH?C12 (3X) and H2O. A brown soUd precipitated from the CH?C12 layer is filtered and coUected to obtain pure product as indicated by NMR. The organic layers are combined, dried over Na2SO , and concentrateed to obtain a brown residue. The residue is placed under high vac to remove residual DMF. The residue is adsorbed onto sUica and chromatographed eluting with 2% MeOH in CH?C1? and 3% MeOH in CH2Ck Fractions homogenous by TLC are combined, condensed and recrystaUized with EtOAc/hexanes to obtain a creme soUd. The two crops yielded 325.4 mg (79%) of the desired product as a tan soUd.
Physical characteristics are as foUows:
MP 248-250 C; Η NMR (300 MHz, DMSO) 12.85, 10.31, 8.78, 8.22, 7.78, 7.70, 7.38, 5.39, 4.55, 433: IR (drift) 3161 , 3073, 3003, 2960, 2914, 1656. 1614. 1557, 1517, 1487, 1299, 1014, 1006, 826, 805 cm"1; MS (ESI) 367.0 (M+H)\ 365J (M-H)". Anal. Found: C, 65.23; H, 4.24; N, 7.60.
PREPARATION 6. Methyl 3-(((4-Chlorobenzyl)amino)carbonyl)-8-tluoro-4- hydroxy-6-quinoUnecarboxylate.
Figure imgf000059_0002
A solution of N-[(4-chlorobenzyl]-8-tluoro-4-hydroxy-6-iodo-3-quinoline- carboxamide from Preparation No. 1 (1.0 g), Et N (0.61 mL), methanol (3.55 mL), Pd(OAc)2 (13.7 mg), and l,3-bis(diphenylphosphino)propane (25.2 mg) in DMSO (12 mL) is stirred at rt untU dissolution. CO(g) is slowly bubbled through the reaction for 3 h and the mixture is heated at 70 °C overnight. CO(g) is bubbled through the reaction mixture again for 4 h. The mixture is cooled to rt and dUuted with water. The white soUd that precipitates is coUected and the filtrate partitioned against CH2C1?. The aqueous layer is washed with CH?C1?. The combined organic layers are dried (Na?SO4) and condensed to obtain an orange residue. The residue is placed under high vacumn to remove residual DMSO. The previously coUected soUd is combined with the residue, dissolved in methanol. and absorbed onto silica. The crude product is chromatagraphed eluting with 2% methanol/CH?Cl?. Fractions homogeneous by TLC are combined, condensed , and recrystaUized from EtOAc/hexanes to yield 0.418 g of the title compound as a white soUd. Physical characteristics are as foUows:
MP 288-290 °C: JH NMR (300 MHz. DMSO) δ 13.17. 10.09, 8.63, 8.58, 8.04. 7.39, 7.34. 4.54, 3.30 ppm: IR (drift) 3071 , 1727. 1660. 1634. 1611, 1576, 1557. 1527. 1496. 131 1, 1288, 1234, 1191. 803. 765 cm"1: HRMS (FAB) found 389.0706. Anal. Found: C, 58.64: H. 3.84: N. 7.24.
PREPARATION 7. N-(4-Chlorobenzyl)-8-fluoro-4-hydroxy-6-(hydroxymethyl)-3- quinoUnecarboxamide
Figure imgf000060_0001
Methyl 3-{ f(4-chlorobenzyl)amino]carbonyl}-8-fluoro-4-hydroxy-6- quinolinecarboxylate from Preparation No. 6 (150 mg) was dissolved in distilled THF (45 mL). The solution was heated to 35 °C to get the starting material into solution, then cooled to 18 °C for addition oi" LiAlH4 (27.0 mg). After 2 hours additional LiAlH4 (27.0 mg) was added because not much progress was seen in complete conversion to product. Complete conversion to product was achieved in 6 1/2 hrs. The reaction was quenched by adding 0.1 mL H2O, 0.1 mL 15% NaOH, and 0.1 mL to the reaction mixture. The reaction mixture was filtered to get rid of the aluminum salt that had precipitated.. The filtrate was condensed to obtain a green residue. The green residue was adsorbed onto sUica and chromatographed eluting with 2% MeOH in CH2C1? and 3% MeOH in CH2C12. Fractions homogenous by TLC were condensed to yield 76.8 mg (55%) of the desired product as a white sokd.
Physical characteristics are as foUows:
MP 263-265 C; 1H NMR (300 MHz, DMSO) δ 12.85, 10.32, 8.62, 8.03, 7.63, 7.41, 7.36, 5.49, 4.62, 4.55; IR (drift) 3082, 2939. 1658, 1614, 1575, 1543, 1514, 1495, 1346, 1301, 1292, 1265, 891, 800, 679 cm"1: MS (ESI) 361J (M+H)+. 359J (M-H)". Anal. Found: C, 59.76; H, 4.00; N, 7.85.
PREPARATION 8. Methyl 3-{ [(4-chlorobenzyl)amino]carbonyl}-4-hydroxy-6- quinoUnecarboxylate
Figure imgf000061_0001
A solution of N-(4-chlorobenzyl)-4-hydroxy-6-iodo-3-quinoUnecarboxamide from
Preparation No. 4 (30.0 g), Et3N (19J mL), MeOH (110.6 mL), Pd(OAc)? (431 mg), and 1.3-bis (diphenylphosphino) propane (791.9 mg) in 375 mL anhydrous DMF is stirred at room temperature untU everything dissolves. CO(g) is slowly bubbled through for 2 days and the reaction is maintained at 70 ϋC. The reaction is cooled to room temperature. The product is precipitated by adding 160 mL IN HCl to the reaction mixture. An orange soUd precipitates and is coUected. The soUd is triturated with EtOAc, filtered, and washed with CH?C1? to afford 23.8 g (93%) of the title compound as an off-white soUd. Physical characteristics are as foUows: Mp 290-292 υC; "H NMR (300 MHz, DMSO) δ 12.96, 10.26, 8.83, 8.25, 7.80, 7.39, 4.57, 3.9; IR (drift) 3222, 1724, 1646, 1619, 1574. 1544, 1512, 1489, 1404, 1359, 1288, 1277. 1242, 1210, 738 cm "'; HRMS (FAB) Found 371.0794. Anal. Found: C, 61.54; H, 3.88; N, 7.51.
PREPARATION 9. N-(4-Chlorobenzyl)-4-hydroxy-6-(hydroxymethyl)-3- quinolinecarboxamide
Figure imgf000062_0001
In a flame-dried IL 3-necked roundbottom, methyl 3-{ [(4-chlorobenzyl)amino]- carbonyl} -4- hydro xy-6-quinolinecarboxylate from Preparation No. 8 (3.0 g) is dissolved in 700 mL distilled THF. The suspension is heated to 67 °C to solubilize the starting material. The reaction is aUowed to cool to room temperature and then cooled in an ice bath to 10 °C. Lithium aluminum hydride (552.2 mg) is added in one portion. The reaction is stirred at 25 °C and monitored by mass spectroscopy for conversion to desired product. The reaction is quenched by adding 2 mL H?O, 2 mL 15% NaOH, and 2 mL H O to the reaction mixture. The reaction mixture is filtered to remove the aluminum salt that had precipitated. The filtrate is condensed to obtain a yeUow-green residue. The residue is adsorbed onto siUca and chromatographed eluting with 2% MeOH in CH2C1? ( IL), 3% MeOH in CH2C1? (2L), 4% MeOH in CH?_C12 (2L), 5% MeOH in CH2C12 (IL), 6% MeOH in CH?_C1? (IL), and 7% MeOH in CH2C12 (2L). The desired product elutes with 4-7% MeOH in CH2C12. Fractions homogenous by TLC are condensed to yield 1.85 g (67%) of the title compound as yeUow crystals.
Physical characteristics are as follows:
Mp 288-289 °C; Η NMR (300 MHz, DMSO) δ 12.71, 10.48, 8.74, 8.21. 7.71, 7.66, 7.39, 538, 4.63, 4.56; MS (ESI) 343.3 (M+H)+, 3413 (M-H)".
PREPARATION 10. N-(4-Chlorobenzyl)-6-(hydroxymethyl)- 1 -methyl-4-oxo- 1 ,4- dϋ ydro-3-quinolinecarboxamide
Figure imgf000062_0002
A solution of" N-(4-chlorobenzyl)-4-hydroxy-6-(hydroxymethyl)-3- quinolinecarboxamide from Preparation No. 9 (300 mg,), K2CO3 (485J mg), and CH3I (0.11 mL) in 4 mL anhydrous DMF is heated at 90 °C for 3 h. The reaction is cooled to room temperature and dUuted with H2O to dissolve any salts and precipitate the product. The crude product is adsorbed onto silica and chromatographed eluting with 3% MeOH in CH2C1 . Fractions homogenous by TLC are combined and condensed to afford 154J mg (49%) of the title compound as a white soUd.
Physical characteristics are as foUows:
Mp 168-170 °C: 1H NMR (300 MHz, DMSO) δ 10.45. 8.87, 830, 7.80, 7.38, 5.42, 4.66, 4.57, 4.02; MS (ESI) 357.2 (M+H)+, 355.3 (M-H)". Anal. Found: C, 63.73; H, 4.62: N, 7.70.
PREPARATION 11. N-(4-Chlorobenzyl)- 1 ,4-dihydro-6-[( lZ)-3-hydroxy- 1 - propenyl]-4-oxo-3-quinolinecarboxamide and PREPARATION 12. N-(4-Chlorobenzyl)- l,4-dihydro-6-[(lE)-3-hydroxy-l-propenyl]-4-oxo-3-quinolinecarboxamide
Figure imgf000063_0001
A mixture of"N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxy- l-propynyl)-3- quinolinecarboxamide from Preparation No. 5 (5.48 g) and Pd/C (10%. 0.55 g) in 3: 1 CH2Cl2/MeOH (150 mL) are placed on a Parr hydrogenator under 50 psi of H? and shaken for 4 h. Another 0.30 g of Pd/C was added, and the resulting mixture was shaken for 2 h. The reaction mixture is then filtered through CeUte, 0.55 g of fresh catalyst is added, and the resulting mixture is shaken under H2 for 3 h. The reaction mixture is then filtered through CeUte and concentrated in vacuo. Trituration from CHC MeOH affords a soUd which is purified by HPLC chromatography on a 0.46 X 25 cm Chiralcel OD-H column eluting with ΕtOH at a rate of" 0.3 mL/min to give 0383 g of N-(4-chlorobenzyl)-l,4-dihydro-6-[(lZ)-3- hydroxy-l-propenyl]-4-oxo-3-quinoUnecarboxamide (cis title compound), and 0.492 g of N- (4-chlorobenzyl)-l ,4-dihydro-6-[(lΕ)-3-hydroxy-l-propenyl]-4-oxo- 3- quinolinecarboxamide (trans title compound). CrystaUization of the cis isomer from ethyl acetate gave 0.29 g of" the title cis compound as a soUd. CrystaUization of" the trans isomer from CH2Cl2/MeOH gave 0.289 g of" the title trans compound as a soUd.
Physical characteristics of N-(4-Chlorobenzyl)-l ,4-dihydro-6-[(lZ)-3-hydroxy-l- propenyl]-4-oxo-3-quinolinecarboxamide (PREPARATION 1 1) are as foUows:
Mp 188-191 °C; 1H NMR (400 MHz, OMSO-de) δ 12.77, 10.47-10.41, 8.75, 8.05, 7.71-7.65, 7.42-736, 6.58, 5.91, 4.98, 4.56, 430 ppm; IR (drift) 3257, 3249, 3210, 3166,
3083, 3063, 3018, 2971, 2941, 1646, 1616, 1552, 1525, 1489, 798 cm"1; MS (EI ) mz 368 (M+), 228, 201 , 154, 142, 140, 127, 125. 1 15, 89, 77; HRMS (FAB) calcd for C20H17CIN2O3+H 369.1006, found 369.0996.
Physical characteristics of N-(4-Chlorobenzyl)- l ,4-dihydro-6-[(lE)-3-hydroxy-l - propenyl]-4-oxo-3-quinolinecarboxamide (PREPARATION 12) are as foUows:
Mp 212-215 °C; 1H NMR (400 MHz, OMSO-d6) δ 12.74, 10.45, 8.73, 8J6, 7.92, 7.66, 7.42-733, 6.72, 6.54-6.47, 4.92, 4.56, 4.17 ppm: IR (drift) 3078, 3059, 3053. 3026, 3010, 2971, 2928, 1651, 1615, 1576, 1552. 1525, 1490, 1297, 802 cm"1; MS (EI ) m z 368 (M+), 228, 201, 198, 142, 140, 127, 125, 89, 77, 73: HRMS (FAB) calcd for C2oH17ClN?O3+H 369.1006, found 369.0993.
PREPARATION 13. Ethyl 8-fluoro-6-iodo- 1 -methyl-4-oxo- 1 ,4-dihydro-3- quino linec arbo xylate
Figure imgf000064_0001
Ethyl 8-fluoro-4-hydroxy-6-iodo-3-quinolinecarboxylate (18J g ) prepared as an intermediate in Preparation No. 1 is dissolved in DMF (430 mL). and K2CO3 (36J g, 261 mmol) and methyl iodide (3.25 mL, 52.3 mmol) are added. The reaction mixture is heated to 95 °C for 6 h, then aUowed to stir at room temperature overnight. The mixture is spUt into two parts. The first part is poured into H?O and extracted with five 100-mL portions of CH?C1?. The combined organic layers are washed with five 200-mL H?O, dried over MgSO , filtered, and concentrated in vacuo. The work-up is then repeated on the second portion of the reaction mixture to give a total of 15.8 g of" the title compound. Physical characteristics are as foUows:
1H NMR (300 MHz, CDC13) δ 8.49. 8.23, 7.95-7.89. 5.73, 4J9, 4.00, 1.26 ppm.
PREPARATION 14. N-(4-Chlorobenzyl)-8-tluoro-6-iodo- 1 -methyl-4-oxo- 1 ,4- dihydro-3-quinolinecarboxamide
Figure imgf000064_0002
A solution of ethyl 8-fluoro-6-iodo- l-methyl-4-oxo- l,4-dihydro-3- quinolinecarboxylate from Preparation No. 13 (15.8 g) in p-chlorobenzylamine (15.4 mL) is warmed to 190 °C. The mixture is then cooled to room temperature, and hexane is added. The resulting precipitate is coUected by filtration to give the title compound as a soUd. An analytical sample is prepared by recrystallization from EtOH.
Physical characteristics are as foUows:
Mp 243.3-244.8 °C; 1H NMR (400 MHz, DMSO-^6) δ 10.17-10.12, 8.80, 8.43, 8J2, 7.40, 7.35, 4.55, 4.15 ppm; IR (drift) 3051, 3039, 1657, 1603, 1575, 1552, 1491, 1468, 1359, 1314, 1251, 1131 , 880, 803, 705 cm"1; MS (EI ) m/z 486 (M+). Anal, found: C, 45.94; H, 2.71; N, 5.94.
PREPARATION 15. N-(4-Chlorobenzyl)-8-fluoro-4-hydroxy-6-(3-hydroxy- 1- propynyl)-3-quinolinecarboxamide
Figure imgf000065_0001
To a mixture of N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-iodo-3- quinolinecarboxamide of" Preparation No. 1 (0.466 g) in 15 mL diethylamine is added Cul (0.010 g) and (Ph3P) PdCl2 (0.035 g). Propargyl alcohol (0.058 mL) is then added and the reaction is stirred overnight at room temperature. The diethylamine is removed in vacuo. The residue is partitioned between EtOAc and water. The insoluble material is filtered off and saved. The organic layer is washed with brine, dried and condensed. The residue is combined with the insoluble material and adsorbed onto sUica and chromatographed, eluting with 3% MeOH/CH2Cl2. Fractions homogeneous by TLC are combined and condensed to yield 0J92 g of" the desired product as a tan soUd. Physical characteristics are as foUows: Mp 277-279 °C; 1H NMR (300 MHz, DMSO) 13.02, 10.15, 8.59, 8.00, 7,76, 7.40,
7.33, 5.41 , 4.52, 4.32: IR (mull) 3137, 3070. 3008. 1661, 1632, 1608. 1577, 1550, 1520, 1495, 1307, 1289, 1198, 1017, 802 cm"1: MS (EI ) m/z 384 (M+), 386, 384, 271, 244, 217, 142, 141, 140, 125, 60: HRMS (FAB) found 385.0773. PREPARATION 16. Ethyl 6-[[2-(acetyloxy)ethyl](ethyl)amino]-l-methyl-4-oxo- 1 ,4-dihydro-3-quinolinecarboxylate
Figure imgf000066_0001
To a pressure tube containing l-lluoro-4-nitrobenzene (5.3 mL) and is added 2- (ethylamino)-l -ethanol (10.7 g). The reaction is tightly sealed and heated to 135 °C with stirring. After 1 hour, the reaction is cooled to room temperature and concentrated under reduced pressure. The residue is dried in vacuo. The residue is chromatographed on siUca eluting with ethyl acetate. The product-containing fractions are evaporated to give 1 J g of 2-(ethyl-4-nitroanilino)- l -ethanol as an orange soUd. To a flask containing 2-(ethyl-4-nitroanUino)- l -ethanol (4.2 g) and 4- dimethylaminopyridine (0J2 g) in pyridine (20 mL) at 0 °C under a drying tube is added acetic anhydride (5.0 mL) dropwise. The reaction mixture is aUowed to warm to room temperature overnight. The reaction mixture is dUuted with ethyl acetate and partioned against saturated aqueous sodium carbonate. The layers are separated and the aqueous phase extracted with two additional portions of" ethyl acetate. The combined organic phases are washed with brine, dried over sodium suU'ate and concentrated under reduced pressure. The residue is azeotroped three times with toluene to remove residual pyridine. The residue is adsorbed onto sUica and chromatographed on sUica eluting with 50% ethyl acetate in heptane. The product-containing fractions are evaporated to give 4.9 g ol" 2-(ethyl-4- nitro anilino) ethyl acetate as a yeUow oU.
To a Parr bottle containing 2-(ethyl-4-nitroanUino)ethyl acetate (2.5 g) and ethyl acetate (25 mL) is added 10% paUadium on carbon (0J 1 g). The reaction mixture is shaken for 1 hour under 50 psi of hydrogen gas. The reaction mixture is filtered through CeUte with ethyl acetate washes. The filtrate is concentrated under reduced pressure. The residue is treated with diethyl ethoxymethylenemalonate (2.4 mL) and heated to 140 °C under a flow of argon gas. After 1 hour the reaction is cooled to room temperature, adsorbed onto sUica gel, and chromatographed on sUica eluting with 50% ethyl acetate in heptane. The product- containing fractions are evaporated to give crude diethyl 2-({4-[[2-(acetyloxy)ethyf|- (ethyl)amino]anUino}methylene)malonate as an orange oU.
To a flask containing crude diethyl 2-({4-[[2-(acetyloxy)ethyl](ethyl)amino]- anilino }methylene)malonate (2.2 g) is added diphenyl ether ( 15 mL). The reaction mixture is heated from room temperature to 260 °C over 45 minutes under a flow of" argon gas.
After 1 hour at 260 °C the hot reaction is slowly and carefuUy added to stirred diethyl ether (150 mL). The resulting precipitate is filtered and washed repeatedly with heptane. The residue is adsorbed onto silica and chromatographed on silica eluting with 3% to 10% methanol in dichloromethane. The product-containing fractions are evaporated to give 0.68 g of ethyl 6-[[2-(acetyloxy)ethyl](ethyl)amino]-4-hydroxy-3-quinoUnecarboxylate as a brown soUd.
To a flask containing ethyl 6-[[2-(acetyloxy)ethyl](ethyl)amino]-4-hydroxy-3- quinoUnecarboxylate (0J7 g) in DMF (5 mL) is added potassium carbonate (0.21 g) and iodomethane (0.05 mL). The reaction is tightly capped and heated to 90 υC. After 3 hours, the reaction is cooled to room temperature, dUuted with dichloromethane. filtered and concentrated under reduced pressure. The residue is adsorbed onto sUica and chromatographed on sUica eluting with 4% to 8% methanol in dichloromethane. The product-containing fractions are evaporated to give 0.22 g of the title compound as a orange soUd. Physical characteristics are as foUows:
1H NMR (300 MHz, CDC13) 8.7, 7.6, 7.3, 7J , 4.3, 4.2, 3.8. 3.6. 3.4. 2.0, 1.4, 1.2: MS (ESI) m/z 399 (M+K+).
PREPARATION 17. N-Cyclopropyl-4-iodoaniline
To a flask containing 4-iodoanUine (2J9 g) is added methanol (25 mL) and a few dozen dry molecular sieves (3A). The mixture is treated with acetic acid (6 mL) foUowed by [(l-ethoxycyclopropyl)oxy]trimethylsUane (2.5 mL). After 1 hour, the reaction mixture is carefuUy treated with sodium cyanoborohydride (2.8 g) and heated to reflux under a nitrogen atmosphere overnight. The reaction mixture is cooled to room temperature, filtered, and concentrated under reduced pressure. The residue is dUuted with ethyl acetate and washed with aqueous sodium hydroxide (2N). The aqueous is back-extracted once with ethyl acetate and the combined organic layers are washed with brine, dried over sodium suUate, and concentarted under reduced pressure. The residue is adsorbed onto sUica and chromatographed on siUca eluting with 3% to 9% ethyl acetate in heptane. The product- containing fractions are combined and evaporated to afford 1.85 g of the title compound as a tan oU.
Physical characteristics are as follows:
1H NMR (300 MHz, CDC13) 7.5, 6.8, 2.4, 0.9, 0.7; MS (ESI) m/z 260 (M+H+).
PREPARATION 18. Diethyl 2-[(cyclopropyl-4-iodoanUino)methylene]-malonate To a flask containing N-yclopropyl-iodoaniline from Preparation No. 17 (0.85 g) is added diethyl ethoxymethylenemalonate (0.9 mL) and pyridine (0.5 mL). The flask is tightly capped and heated to 130 υC overnight. The reaction is cooled to room temperature and azeotroped under reduced with toluene (3x). The residue is dissolved in dichloromethane and washed with brine, dried and concentrated under reduced pressure. The residue is adsorbed onto siUca gel and chromatographed on silica eluting with 25% to 75% ethyl acetate in heptane. The product-containing fractions are evaporated to give 0.78 g of the title compound as a tan soUd. Physical characteristics are as foUows:
1H NMR (300 MHz. CDC13) 7.8, 7.7, 7.0, 4.2, 4J, 3J, 1.3, 0.9, 0.7; MS (ESI) m/z 430 (M+H+).
PREPARATION 19. Ethyl l-cyclopropyl-6-iodo-4-oxo-l ,4-dihydro-3- quinoUnecarboxylate. To a flask containing diethyl 2-[(cyclopropyl-4-iodoanilino)methylene]malonate from Preparation No. 18 (0.22 g) is added polyphosphoric acid (1.4 g). The reaction mixture is capped and heated to 120 °C over 1 hour. After 2 hours at 120 °C the reaction is cooled to room temperature, treated with ice and partioned between dichloromethane and saturated aqueous bicarbonate. The basic aqueous layer is extracted with two additional portions of dichloromethane. The combined organic layers are washed with brine, dried over sodium suU'ate and concentrated under reduced pressure to afford 0J9 g of" the title compound as a tan soUd.
Physical characteristics are as foUows: 1H NMR (300 MHz, CDCI3) 8.8, 8.6, 7.9. 7.7. 4.4, 3.4, 1.4, 1.3, 1J: MS (ESI) m/z 384 (M+H+).
PREPARATION 20. N-(4-Chlorobenzyl)- 1 -cyclopropyl-6-iodo-4-oxo- 1.4- dihydro-3-quinolinecarboxamide
Figure imgf000069_0001
To a flask containing ethyl 1 -cyclopropyl-6-iodo-4-oxo- 1.4-dihydro-3- quinolinecarboxylate from Preparation No. 19 (0J9 g) is added p-chlorobenzylamine (1.0 mL). The reaction is tightly capped and heated to 180 υC for 1 hour. The reaction is cooled to room temperature and partioned between dichloromethane containing methanol and dUute hydrochloric acid. The aqueous layer is extracted with dichloromethane and the combined organic layers are washed with brine, dried and concentarted under reduced pressure. The residue is adsorbed onto sUica and chromatographed on sUica eluting with 2% to 6% methanol in dichloromethane. The product containing fractions are evaporated to give 0.10 g of" the title compound as a tan soUd.
Physical characteristics are as foUows: 1H NMR (300 MHz. DMSO- 6) 10.2, 8.7. 8.6. 8.2, 8.0, 1.4, 4.5. 3.7, 3.5, 1.3. 1J ;
MS (ESI) m/z 479 (M+H+).
PREPARATION 21. 4-(4-Nitrobenzyl)morphoUne To a flask containing 4-nitrobenzyl bromide (21.6 g) in dry acetone (100 mL) is added potassium carbonate (34.5 g) and morpholine (10 mL). The mixure is heated to reflux overnight under a drying tube. The reaction is partioned between ethyl aceate and water and separated. The basic aqueous layer is extracted with two additional portions of ethyl acetate. The combined organic layers are washed with brine, dried, and concentrated under reduced pressure to afford 21.3 g of the title compound as a soUd.
Physical characteristics are as foUows:
Mp 75-79 °C: 1H NMR (300 MHz, CDC13) 8.2, 7.6, 3.7, 3.6, 2.4.
PREPARATION 22. 4-(4-Aminobenzyl)morpholine
To a solution of 4-(4-Nitrobenzyl)morpholine from Preparation No. 21 (0.89 g) in ethyl acetate (10 mL) is added 5% platinuim on carbon (0.04 g). The reaction is shaken under 30 psi of hydrogen gas for 1 hour. The mixrture is filtered with ethyl acetate washes. The filtrate is concentrated under reduced pressure to afford 0.71 g of the title compound as a yeUow soUd.
Physical characteristics are as foUows:
Η NMR (300 MHz. CDC13) 7J, 6.6. 3.7. 3.6. 3.4. 2.4: MS (ESI) /z 193 (M+H+).
PREPARATION 23. N-Cyclopropyl-4-(4-morpholinylmethyl)anUine To a flask containing 4-(4-aminobenzyl)morpholine from Preparation No. 22 (0.96 g) is added methanol (12 mL) and a few dozen dry molecular sieves (3A). The mixture is treated with acetic acid (3 mL) followed by [(l-ethoxycyclopropyl)oxy]-trimethylsUane (1.25 mL). After 15 minutes, the reaction mixture is carefully treated with sodium cyanoborohydride (1.4 g) and heated to reflux under a nitrogen atmosphere overnight. The reaction mixture is cooled to romm temperature, filtered with methanol washes, and concentrated under reduced pressure. The residue is dUuted with diethyl ether and washed with aqueous sodium hydroxide (2N). The aqueous is back-extracted once with diethyl ether and once with dichloromethane. The combined organic layers are washed with brine, dried over sodium suU'ate. and concentarted under reduced pressure. The residue is adsorbed onto silica and chromatographed on sUica eluting with 2% to 8% methanol in dichloromethane. The product-containing fractions are combine and evaporated to afford 0J3 g of the title compound as a pink soUd. Physical characteristics are as foUows: Η NMR (300 MHz. CDCI3) 7.1 , 6.8, 3.7, 3.4, 2.4, 0.7, 0.5: MS (ESI) m/z 233
(M+H+).
PREPARATION 24. Diethyl 2-{ [cyclopropyl-4-(4-morphoUnylmethyl)- anilino]methylene}malonate
To a flask containing N-cyclopropyl-4-(4-morpholinylmethyl)anUine (0.55 g) from Preparation No. 23 is added diethyl ethoxymethylenemalonate (0.45 mL) and pyridine (0.33 mL). The flask is tightly capped and heated to 145 °C for 2 hours. The reaction is cooled to room temperature and azeotroped under reduced pressure with toluene (3x). The residue is dissolved in dichloromethane and washed with brine, dried and concentrated under reduced pressure. The residue is chromatographed on sUica eluting with 2% to 6% methanol in dichloromethane. The product-containing fractions are evaporated to give 0.77 g of" the title compound as an oil.
Physical characteristics are as foUows: 1H NMR (300 MHz, CDCI3) 7.8, 7.3, 7.1. 4.2. 4.1. 3.8. 3.1. 2.4. 1.3. 0.8, 0.7: MS
(ESI) m/z 403 (M+H+).
PREPARATION 25. Ethyl l -cyclopropyl-6-(4-morphoUnylmethyl)-4-oxo- 1.4- dihydro-3-quinolinecarboxylate
Figure imgf000071_0001
To a flask containing diethyl 2-{ [cyclopropyl-4-(4-morpholinylmethyl)anilino]- methylene} malonate from Preparation No. 24 (0.77 g) is added polyphosphoric acid (4.4 g). The reaction mixture is tightly capped and heated to 120 υC. After 1 hour the reaction is cooled to room temperature. The reaction mixture is carefuUy added to a vigorously stirred mixture of dichloromethane and saturated aqueous bicarbonate. The layers are separated and the basic aqueous layer is extracted with two additional portions of dichloromethane. The combined organic layers are washed with brine, dried over sodium suU'ate and concentrated under reduced pressure. The residue is chromatographed on siUca eluting with 3% to 15% methanol in dichloromethane to afford 0.38 g of the title compound as a yeUow soUd.
Physical characteristics are as foUows:
1H NMR (300 MHz, CDC13) 8.6. 8.4, 7.9. 7.7, 4.4, 3.7, 3.6, 3.5, 2.5, 1.4, 1.3, 1 J ; MS (ESI) m/z 357 (M+H+).
PREPARATION 26. tert-Butyl 2-[3-{ [(4-chlorobenzyl)amino]carbonyl}-6-iodo-4- oxo- 1 (4H)-quinoUnyl] acetate
Figure imgf000072_0001
To a flask containing N-(4-chlorobenzyl)-6-iodo-4-hydoxy-3-quinolinecarboxamide (0.22 g) obtained as described in Preparation No. 4 in DMF (5 mL) is added potassium carbonate (0.21 g) and tert-butylbromoacetate (OJ 1 mL). After stirring overnight, the reaction is dUuted with dichloromethane and partioned against water. The organic phase is washed with brine, dried over sodium suU'ate, concentrated under reduced pressure, and dried in vacuo to give 0.26 g of the title compound as a white soUd. Physical characteristics are as foUows:
Η NMR (300 MHz, CDC13) 10.2, 8.9, 8.6, 8J , 1.4, 73, 5.4, 4.5, 1.4. Anal, found: C, 49.91 ; H, 4.09; N, 5.08.
EXAMPLE 1. N-(4-Chlorobenzyl)-6-(3-hydroxy- 1 -propynyl)- l-isopropyl-4-oxo- 1 ,4-dihydro-3-quinolinecarboxamide
Figure imgf000072_0002
N-((4-Chlorobenzyl)-4-hydroxy-6-(3-hydroxy- l-propynyl)-3-quinofinecarboxamide (366 mg) from Preparation No. 5 and potassium carbonate (276 mg) are dissolved in DMF (5 mL). 2-Bromopropane (470 μL) is added and the mixture is heated to 100 °C for 1 h. The reaction mixture is aUowed to cool to rt, poured into water (25 mL) and extracted with ethyl acetate (2 x 50 mL). The organic layer is washed with sat. aqueous brine (10 mL). The aqueous layer is back-extracted with ethyl acetate (20 mL). The combined organic layers are dried (MgSO4) and concentrated. The crude product is purified by column chromatography (EtO Ac/heptane, 1/1 to 1/0) and recrystaUization (EtOH) to afford 70 mg (17%) of the title compound as a white soUd.
Physical characteristics are as foUows:
Mp 189-191 °C dec; 1H NMR (OMSO-d6) δ 10.28, 8.87. 8.34, 8.08, 7.85, 7.42- 7.35. 5.40. 5J8, 4.55. 4.35, 1.53: IR (drift) 3314, 2227 (w), 1902 (w). 1648 (s), 1597. 1572, 1547, 1491 (s). 1342, 1321. 1214, 1037. 1025. 813. 682 cm"1. Anal. Found for C23H21ClN2O3: C, 67.53; H, 5J4: N, 6.66.
EXAMPLE 2. 1 Mec-butyl)-/V-(4-chlorobenzyl)-6-(3-hydroxy- 1 -propynyl)-4-oxo- 1 ,4-dihydro-3-quinolinecarboxamide
Figure imgf000073_0001
N-((4-Chlorobenzyl)-4-hydroxy-6-(3-hydroxy- 1 -propynyl)-3-quinolinecarboxamide
(366 mg) from Preparation No. 5 and potassium carbonate (276 mg) are dissolved in DMF (5 mL). 2-Iodobutane (575 μL) is added and the mixture is heated to 100 °C for 1 h. The reaction mixture is aUowed to cool to rt, poured into water (25 mL) and extracted with ethyl acetate (2 x 50 mL). The organic layer is washed with sat. aqueous brine (10 mL). The aqueous layer is back-extracted with ethyl acetate (20 mL). The combined organic layers are dried (MgSO4) and concentrated. The crude product is purUied by column chromatography (dichloromethane/methanol. 100/1 : 50/1: 20/1) to afford 80 mg (19%) of the title compound as a white soUd.
Physical characteristics are as foUows: Mp 200-201 °C dec: Η NMR (OMSO-d6) δ 10.27.8.80.8.34.8J2.7.84, 7.42- 735, 539.5.02, 4.55, 4.35, 1.90, 1.51, 0.85: IR (drift) 3412, 1657.1597.1575, 1547, 1490, 1458.1422, 1341, 1324, 1213, 1088, 1047.812, 804 cm"1. Anal. Found for C24H?_3ClN?O3: C.68.07; H, 5.52; N, 6.45: Cl.8J5. EXAMPLE 3. 1 -(sec-butyl)-N-(4-chlorobenzyl)-6-(3-hydroxy- 1 -propynyl)-8- methoxy-4-oxo- 1 ,4-dihydro-3-quinolinecarboxamide
Figure imgf000074_0001
N-((4-Chlorobenzy])-4-hydroxy-6-(3-hydroxy- l-propynyl)-8-methoxy-3-quinoline- carboxamide (300 mg) from Preparation No. 3 and potassium carbonate (310 mg) are dissolved in DMF (5 mL). 2-Iodobutane (345 μL) is added and the mixture is heated to 120 °C for 4 h. Additional 2-Iodobutane (200 μL) and potassium carbonate (100 mg) is added and the mixture is heated for 16 h. The reaction mixture is aUowed to cool to rt, poured into water (75 mL) and extracted with ethyl acetate (3 x 50 mL). The organic layer is washed with sat. aqueous brine (10 mL). The aqueous layer is back-extracted with ethyl acetate (20 mL). The combined organic layers are dried (MgSO4) and concentrated. The crude product is purified by column chromatography (EtOAc/heptane, 30/1 ; 10/1) to afford 60 mg (18%) of the title compound as a white soUd.
Physical characteristics are as foUows: Mp 139- 142 °C dec; Η NMR DMSO-d6) δ 10.20. 8.74, 7.95, 7.43-735, 5.62,
5.40, 4.54, 4.35, 4.04. 1.83, 1.50, 0.77; IR (drift) 2480, 2214, 2015, 1909, 1649. 1597, 1550, 1483, 1340, 1327. 1278, 1211, 1078, 1064, 807 cm"1; HRMS (FAB) calcd for C25H25CIN2O4+H 453.1581, found 453.1593.
EXAMPLE 4. N-(4-Chlorobenzyl)-8-(2-hydroxyethoxy)-6-(3-hydroxypropyl)-l- methyl-4-oxo- 1 ,4-dU ydro-3-quinoUnecarboxamide]
Figure imgf000074_0002
To a suspension of"N-(4-chlorobenzyl)-8-fluoro-6-iodo-3-quinolinecarboxamide from Preparation No. 1 (2.28 g) in DMF (75 mL) is added sodium hydride (60% oU dispersion; 0.600 g) foUowed by addition of 2-benzyloxyethanol (1.42 mL). The reaction is heated to 135 °C and stirred for 1 h. The reaction mixture is cooled to room temperature and poured into saturated aqueous ammonium chloride (200 mL). The aqueous layer is extracted with dichloromethane (4 x 100 mL). The combined organic layers are washed with brine (50 mL), dried with MgSO4, filtered, and concentrated in vacuo. The resulting yeUow soUd is purified by column chromatography (dichloromethane/methanol. 98/2). Fractions homogeneous by TLC are combined and concentrated in vacuo to yield a yeUow soUd which is recrystaUized from ethanol to yield 1.568 g (53%) of the intermediate amide as an off-white solid. To a suspension of this material (1J49 g) in diethylamine (24 mL) are added copper iodide (0.1 11 g) and Pd(PPh3)?Cl (0.069 g) foUowed by addition of" propargyl alcohol (0J6 mL). The reaction is stirred at room temperature for 3 d. The reaction mixture is concentrated in vacuo and partitioned between H2O (50 mL) and dichloromethane (50 mL). The aqueous layer is extracted with dichloromethane (3 x 50 mL). Combined organic layers are washed with saturated aqueous ammonium chloride (50 mL). dried with MgSO4, filtered, and concentrated in vacuo. The resulting brown soUd is purified by column chromatography (dichloromethane/methanol, 98/2). Fractions homogeneous by TLC are combined and concentrated in vacuo to yield a tan soUd which is recrystaUized from ethanol to yield 0J81 g (18%) of the propargyl compound as a tan, crystaUine soUd. To a solution of this material (0.394 g) in DMF (3 mL) is added potassium carbonate (0.317 g) foUowed by iodomethane (0J4 mL). The reaction is heated to 90 °C and stirred for 18 h. The reaction mixture is concentrated in vacuo and the resulting residue is purified by column chromatography (dichloromethane: dichloromethane/methanol. 98/2). Fractions homogeneous by TLC are combined and concentrated in vacuo to yield a yeUow soUd which is recrystaUized from EtOH to yield 0.273 g (67%) of the N- methyl pyridone as a yellow soUd. The pyridone (0.350 g) is dissolved in 1/1 dichloromethane/ethanol (100 mL) and hydrogenated over 10% Pd/C (53 mg) at 35 psi for 18 h. The reaction mixture is filtered through a CeUte pad, and the filtrate is concentrated in vacuo. The resulting yeUow oU is dissolved in methanol (60 mL) and hydrogenated over Pd Black (35 mg) for 4 h. The reaction mixture is filtered through a CeUte pad, and the filtrate is concentrated in vacuo. The resulting yeUow oU is purified by column chromatography (dichloromethane/methanol, 98/2: 95/5). Fractions homogeneous by TLC are combined and concentrated in vacuo to yield a pale yeUow soUd which is recrystaUized from ethyl acetate to yield 0J04 g (35%) of" the title compound as a pale yeUow soUd.
Physical characteristics are as foUows:
Mp 175-179 °C; Η NMR (300 MHz, OMSO-d6) δ 10.43, 8.65, 7.75. 7.42-734, 7.29, 4.97, 4.57, 4.50. 4.27, 4J8, 3.82, 3.44, 2.73, 1.77; 13C NMR (75 MHz, DMSO- 6) δ 175J, 164.9, 164.8, 150.8, 150.6, 140.7. 140.0. 139.2, 131.8, 129.8, 129.6, 128.9, 128.8, 127.8, 127.3, 1 17.5, 117.1, 1 10.3, 110.2, 72.4, 60.4, 59.9, 48.2, 42.6, 41.9, 34.4, 31.9; IR (drift) 3341, 331 1, 1903, 1657, 1605, 1556. 1494, 1452, 1346, 1323, 1276, 1084, 1058, 1044, 804 cm "'; MS (ESI+) m/z. 445 (M+H)+. Anal. Found: C, 62.86; H, 5.87; N, 6.29: Cl, 6.26.
EXAMPLE 5. N-(4-Chlorobenzyl)-8-[2-hydroxy-l-(hydroxymethyl)ethoxy]-6-(3- hydroxypropyl) l-methyl-4-oxo- 1 ,4-dihydro-3-quinolinecarboxamide
Figure imgf000076_0001
To a suspension of N-(4-chlorobenzyl)-8-fluoro-6-iodo-3-quinolinecarboxamide
Preparation No. 1 (2.28 g) in DMF (75 mL) is added sodium hydride (60% oU dispersion; 0.600 g) foUowed by addition of l,3-dibenzyloxy-2-propanol (2.47 mL). The reaction is heated to 135 °C and is stirred for 2 h. The reaction mixture is cooled to room temperature and poured into saturated aqueous ammonium chloride (200 mL). The aqueous layer is extracted with CH2C12 (4 x 100 mL). The combined organic layers are washed with brine (50 mL), dried with MgSO4, filtered, and concentrated in vacuo. The resulting brown oU is purified by column chromatography (dichloromethane / methanol, 98/2). Mixed fractions are combined and re-purified (ethyl acetate/heptane, 1/1). Fractions homogeneous by TLC are combined and concentrated in vacuo to yield a yeUow soUd which is recrystaUized from ethyl acetate to yield 1.701 g (48%) of the intermediate amide as a pale yeUow soUd. To a suspension of this material (1.330 g) in diethylamine (23 mL) are added copper iodide (0J07 g) and Pd(PPh3)2Cl2 (0.066 g) foUowed by addition of propargyl alcohol (0J5 mL). The reaction is stirred at room temperature for 18 h. The reaction mixture is concentrated in vacuo. The resulting brown sohd is purified by column chromatography (dichloromethane. dichloromethane/methanol, 98/2). Fractions homogeneous by TLC are combined and concentrated in vacuo to yield an orange soUd which is recrystaUized from diethyl ether/ethyl acetate to yield 0.727 g (61 %) of the propargyl derivative as an off- white soUd. To a solution of this material (0.500 g) in DMF (3 mL) is added potassium carbonate (0.325 g) foUowed by addition of" iodomethane (0J5 mL). The reaction is heated to 90 °C and is stirred for 18 h. The reaction mixture is concentrated in vacuo, and the residue is purified by column chromatography (dichloromethane/methanol, 98/2). Fractions homogeneous by TLC are combined and concentrated in vacuo to yield a yeUow soUd which is recrystalUzed from ethyl acetate/methanol to yield 0.383 g (75%) of the N-methyl pyridone as a yeUow soUd. A solution of the pyridone (0.310 g) in 1/1 dichloromethane/ethanol (30 mL) is hydrogenated over 10% Pd/C (62 mg) at 35 psi for 5.5 h. The reaction mixture is filtered through a CeUte pad, and the filtrate is concentrated in vacuo. The resulting yeUow oU is purUied by column chromatography (dichloromethane/methanol; 98/2, 95/5, 90/10). Fractions homogeneous by TLC are combined and concentrated in vacuo to yield a pale yeUow soUd which is recrystaUized from ethyl acetate/methanol to yield 0.050 g (22%) of the title compound as a white soUd.
Physical characteristics are as foUows:
Mp 120-123 °C: Η ΝMR (300 MHz, DMSO- 6) δ 10.44, 8.64, 7.74, 7.42-734, 4.92, 4.56, 4.50, 4.29.3.77-3.64, 3.44, 2.72.1.77: 1?C ΝMR (75 MHz. OMSO-d6) δ 175J , 164.9, 150.8.150J , 140.6, 139.2, 131.8, 130.3.130.0, 129.6, 128.9, 128.8.127.8.118.4. 117.0, 110J, 82.6.60.5, 60.2.48.2, 41.9, 34.5, 31.9, 21.2.14.6; IR (drift) 3388, 3343, 3326,2350, 1970, 1902, 1651, 1601, 1552, 1499.1268, 1118, 1077, 1052,807 cm"1; MS (ESI+) for m/z 475 (M+H)+. Anal. Found: C.60.59: H, 5.72: Ν, 5.88.
EXAMPLE 6. N-(4-Chlorobenzyl)-8-tluoro-6-(hydroxymethyl)-4-oxo-l-[3- (tetrahydro-2H-pyran-2-yloxy)propyl]-l,4-dUιydro-3-quinolinecarboxamide
Figure imgf000077_0001
To a suspension of NaH (60% dispersion in oU. 1 1.1 mg) in 2.5 mL anhydrous DMF is added N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(hydroxymethyl)-3-quinolinecarboxamide from Preparation No. 7 (100 mg). After stirring the reaction mixture at room temperature for 15-20 min., 2-(3-bromopropoxy) tetrahydro-2H-pyran (89.4 mg) is added. The reaction is stirred at room temperature for 3 days. The reaction mixture is treated with saturated aqueous NaHCO3. then extracted with CH C12 (3X). The combined organic layers are washed with 15% K2CO3 and H O (2X), dried over Na2SO4, and condensed to obtain a yeUow residue. The residue is chromatographed eluting with 2% MeOH in CH2C12. Fractions homogenous by TLC are combined and condensed to afford 34.0 mg (24%) of" the title compound as a white soUd.
Physical characteristics are as foUows:
Mp 148-150 ϋC: 1H NMR (300 MHz, DMSO) δ 10.26, 8.77, 8.17, 7.65, 7.38. 5.50, 4.60, 4.46. 3.67, 3.35, 2.05, 1.61, 1.53, 1.37; IR (drift) 3333, 2940, 2918, 1651. 1603, 1563, 1490, 1352, 1281, 1 120, 1069, 1036, 1018, 990, 805 cm"1 ; MS (ESI) 503J (M+H)+, 501 J (M-H)". Anal. Found: C, 62.03; H, 5.57; N, 5.58.
EXAMPLE 7. N-(4-Chlorobenzyl)-6-(3-hydroxy- 1 -propenyl)- 1 -[2-(4- morphoUnyl)ethyl] -4-oxo- 1 ,4-dihydro 3 -quinolinecarboxamide
Figure imgf000078_0001
A mixture of"N-(4-chlorobenzyl)-l ,4-dihydro-6-[3-hydroxy-l-propenyl]-4-oxo-3- quinolinecarboxamide from Preparations No. 11 and 12 (0.52 g) is dissolved in DMF (4 mL). and potassium carbonate (0.78 g) and N-(2-chloroethyl)morphoUne hydrochloride (0.52 g) are added. The mixture is heated at 90 °C for 2 h and then partitioned between water and chloroform. The organic layer is concentrated in vacuo to give a brown oU. Column chromatography (elution with l-7%MeOH/CHCl ) foUowed by CrystaUization from EtOAc/hexane gave the title compound as a mixture of isomers. The mixture is then purified by HPLC chromatography on a 0.46 X 25 cm Chiralcel OD-H column eluting with EtOH at a rate of 0.5 mL/min. This gave 0J61 g of the alkene mixture as approximately a 2:1 mixture of the transxis isomers. which is crystaUized from ethyl acetate to give 0J3 g of the title compound as a hydrate.
Physical characteristics are as foUows:
Mp 146-148.5 °C; Η NMR (400 MHz. OMSO-d6) δ 10.40, 8.79, 8.32, 7.77-7.70. 7.45. 7.34-7.28, 7.17-7.10, 6.65, 6.49, 6.53, 6.48, 4.79, 4.62, 4.35, 4.04-3.67, 3.20-2.46, 2.25, 1.87-1.80, 1 J3 ppm; IR (drift) 3293. 2956, 1744, 1670, 1648. 1600. 1555, 1512. 1491, 1450, 1229, 1117, 1092, 1000, 807 cm"1 ; HRMS (FAB) calcd for C26H28ClN3O4+H 482.1846, found 482.1849.
EXAMPLE 8. N-(4-Chlorobenzyl)-8-fluoro-6-(3-hydroxy- 1 -propynyl)- l-methyl-4- oxo- 1 ,4-dihydro-3-quinolinecarboxamide
Figure imgf000079_0001
A mixture of N-(4-chlorobenzyl)-8-fluoro-6-iodo- l-methyl-4-oxo- 1 ,4-dihydro-3- quinolinecarboxamide from Preparation No. 14 (0.600 g), propargyl alcohol (0.11 mL, 1.90 mmol), Cul (0.048 g, 0.25 mmol), and PdCl2(PPh3)2 (OJ78 g. 0.25 mmol) in diethylamine (42.5 mL) and CH2C12 (50 mL) are warmed to 65 °C overnight. The reaction mixture is then concentratred in vacuo. Column chromatography (elution with 5- 10% MeOH/CH?Cl2) gave the title compound as a soUd.
Physical characteristics are as foUows:
Mp 186-188 °C; 1H NMR (400 MHz, DMSO- 6) δ 10J8-10J3. 8.78, 8J 1 , 7.77, 7.40, 7.36, 5.45, 4.56, 4.35, 4J6 ppm: 13C NMR (100 MHz, OMSO-d6) δ 173.8, 182.6, 151.6, 139.0, 131.8, 129.9, 129.6, 128.7, 125.2, 121.9, 1 19.7, 1 1 1.4. 92.4, 81.9, 49.8. 46.0, 41.8 ppm; IR (drift) 3410, 1657, 1600, 1569, 1551, 1541, 1493, 1472, 1362, 1342, 1284, 1127, 806, 799, 726 cm"1; MS (EI ) m/z 398 (M+); HRMS (EI) calcd for C2iHι6ClFN2O3 398.0833, found 398.0838.
EXAMPLE 9. N-(4-Chlorobenzyl)-8-fluoro-6-[(Z)-3-hydroxy- l-propenyl)-l- methyl-4-oxo- 1 ,4-dihydro-3-quinoUnecarboxamide
Figure imgf000080_0001
A mixture of" N-(4-chlorobenzyl)-8-fluoro- 1 ,4-dihydro-6-(3-hydroxy- 1 -propynyl)- 1 - methyl-4-oxo-3-quinoUnecarboxamide from Example No. 8 (0.200 g) and Pd/C (10%. 0.040 g) in MeOH (10 mL) and CH2C12 (10 mL) is placed on a Parr shaker under 50 psi of" H2 for 6 h. The reaction mixture is filtered through CeUte and concentrated in vacuo. RecrystaUization from EtOAc gave the title compound as a soUd. Physical characteristics are as foUows:
Mp 182-184 °C: Η NMR (400 MHz, OMSO-d6) δ 10.28- 10.21 , 8.76, 7.98. 7.64. 7.40, 736. 6.55, 6.00-5.93, 5.04-5.02. 4.56, 4.30-4.28. 4J8-4J6 ppm: IR (drift) 3048. 1658, 1626, 1601. 1579, 1552, 1493. 1361, 1284. 1271. 1 122. 1039. 1016, 806. 798 cm"1; MS (EI ) m/z 400 (M+). Anal, found: C. 62.76; H. 4.61 ; N, 6.86.
EXAMPLE 10. N-(4-Chlorobenzyl)- 1 -[2-(diethylamino)ethyl]-8-fluoro-6-(3- hydroxy- 1 -propynyl)-4-oxo- 1.4-dihydro-3-quinoUnecarboxamide
Figure imgf000080_0002
A solution of N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(3-hydroxy- l-propynyl)-3- qumoUnecarboxamide from Preparation No. 15 (0.96 g) is dissolved in DMF (7 mL), and K2CO3 (1.38 g) and 2-bromo-N,N-diethylethylamine hydrobromide (1.30 g) are added. The reaction mixture is heated to 95 °C for 16. Water is added and an oUy soUd formed, which is isolated by decanting the Uquid. Column chromatography (elution with 1-3% MeOH CHCl3) gave 0.373 g of the title compound which is crystaUized from ethyl acetate to give 0.163 g of" a soUd.
Physical characteristics are as foUows:
Mp 148-150 °C; 1H ΝMR (400 MHz. DMSO-J6) δ 10J. 8.7. 8.2, 7.82, 7.4-7.3, 5.4, 4.5, 4.3, 2.7, 2.4, 0.7 ppm; IR (drift) 2967, 1650, 1625. 1596. 1580. 1555. 1485. 1369, 1282, 1232, 1083, 1065, 1018, 1009, 806 cm"1; MS (EI ) m/z 483 (M+). Anal, found: C, 64.23; H, 5.69; N, 8.49.
EXAMPLE 11. N-(4-Chlorobenzyl)-6-(3-hydroxy- 1 -propynyl)-4-oxo- 1 -propyl- 1 ,4- dihydro-3-quinolinecarboxamide
Figure imgf000081_0001
A suspension of 0.50 g of N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxy-l-propynyl)- 3-quinolinecarboxamide from Preparation No. 5, potassium carbonate (0.76 g), and 1- iodopropane (0.47 g) in DMF is heated to 100 °C for 6 hrs and stirred at room temperature overnight. The reaction mixture is filtered, and the solvent is evaporated at reduced pressure leaving a Ught brown soUd. The soUd is stirred with ethyl acetate for an hour and filtered. The solvent is evaporated from the filtrate under reduced pressure, leaving 0J 2 g of the title compound as a yeUowish- white soUd. Physical characteristics are as foUows:
Mp 183-184 °C; Η NMR
Figure imgf000081_0002
δ 10.3, 8.9, 8.3, 7.9, 7.8, 7.4. 5.4, 4.5, 4.4. 4.3, 1.8, 0.9: MS (ESI+) for m/z 431.2 (M+Na)+.
EXAMPLE 12. N-(4-Chlorobenzyl)- l-[2-(diethylamino)ethyl]-6-(3-hydroxy- 1- propynyl)-4-oxo- 1 ,4-dihydro-3-quinolinecarboxamide
Figure imgf000081_0003
A solution of N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxy-l-propynyl)-3- qumoUnecarboxamide from Preparation No. 5 (0.616 g) is dissolved in DMF (4 mL), and K2CO3 (0.93 g, 6.72 mmol) and 2-bromo-N,N-diethylethylamine hydrobromide (0.88 g, 3.35 mmol) are added. The reaction mixture is heated to 90 °C for 16. The mixture is partitioned between CHC13 and water. The organic layer is concentrated in vacuo to give an oU. Column chromatography (elution with 1-5% MeOH/CHCl3) gave 0J0 g of a brown oU. CrystaUization from ethyl acetate/hexane gave 0.013 g of the title compound as a soUd.
Physical characteristics are as foUows:
Mp 145-148 °C: Η NMR (400 MHz. CDC13) δ 8.7. 8.5, 7.7, 7.4. 7.3, 4.6, 4.5. 4.2, 2.8, 2.5, 0.9 ppm: MS (EI ) m/z 465 (M+); HRMS (FAB) calcd for C26H28ClN3O3+H 466.1897, found 466.1898.
EXAMPLE 13. N-(4-Chlorobenzyl)-l-[2-(dimethylamino)ethyl]-6-(3-hydroxy-l- propynyl)-4-oxo- 1.4-dihydro-3-quinolinecarboxamide, hydrochloride salt
Figure imgf000082_0001
A solution of N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxy- 1 -propynyl)-3- quinolinecarboxamide from Preparation No. 5 (0.515 g) is dissolved in DMF (10 mL). and K2CO (0.778 g) and dusoproplyaminoethyl chloride-hydrochloride (0.56 g) are added. The reaction mixture is heated to 95 °C for 14 h, then aUowed to stir at room temperature overnight. The mixture is then poured into H2O and an oU formed, which is isolated by decanting the Uquid. The oU is dissolved in MeOH/CH?Cl2. and etheral HCl is added to adjust the pH to 2. The mixture is concentrated in vacuo to give the title compound as the hydrochloride salt.
Physical characteristics are as foUows:
Mp 187-188 °C; lU NMR (400 MHz. DMSO- d6) δ 1 1.21 , 10.25- 10.21. 8.97. 8.31. 8.11. 7.84, 7.40. 7.36. 5.44, 4.93-4.90. 4.57. 4.36, 3.51-3.49. 2.84 ppm: 13C NMR (100 MHz, DMSO- 6) δ 174.8, 163.7, 149.2, 138.5. 138.4, 135.2, 131.3, 129.2. 128.8, 128.2, 127J, 1 19.2, 118.1, 111.6, 91.2, 82.3, 53.6. 49.4, 47.6, 42.6 ppm; IR (drift) 3332. 3281. 3252, 3044, 2591, 2451. 1663, 1599, 1579, 1551. 1489, 1373, 1228, 813, 808 cm"1; MS (EI ) m/z 437 (M+); HRMS (FAB) calcd for C24H24ClN3O3+H 438.1584. found 438.1580. EXAMPLE 14. N-(4-Chlorobenzyl)-6-(3-hydroxy-l-propynyl)-l-[2-(l- piperidinyl)ethyl] -4-oxo- 1 ,4-dihydro-3-quinolinecarboxamide
Figure imgf000083_0001
A solution of N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxy- l-propynyl)-3- quinolinecarboxamide from Preparation No. 5 (0.367 g) is dissolved in DMF (10 mL), and K2CO3 (0.55 g, 4.0 mmol) and l-(2-chloroethyl)piperidιne hydrochloride (0.375 g. 2.0 mmol) are added. The reaction mixture is heated to 90 °C for 3 h. and then aUowed to stir at room temperature for 48h. Water is added and a precipitate formed. The precipitate is filtered and allowed to dry at room temperature and then under reduced pressure to give 0J71 g of a soUd. The soUd is dissolved in CHCI3 and filtered. The filtrate is concentrated in vacuo and crystalUzed from ethyl acetate to give 0.066 g of the title compound as a soUd. Physical characteristics are as foUows:
Mp 176- 180 °C; Η NMR (400 MHz. OMSO-d6) δ 10.3. 8.8. 8.3, 7.9. 7.8, 7.4, 5.4. 4.6-4.5, 4.3. 2.6. 2.4. 1.4, 1.3 ppm; IR (drift) 2934. 2919, 1655. 1598. 1579. 1552, 1489, 1452. 1368. 1316, 1227, 1026. 1016, 816. 806 cm"1; MS (EI ) m z 477 (M+): MS (FAB) m/z 478 (MH+): HRMS (FAB) calcd for C27H28ClN3θ3+H 478.1897. found 478.1907.
EXAMPLE 15. N-(4-Chlorobenzyl)-6-(3-hydroxy- 1 -propynyl)- 1 -[3-( 1 - piperidinyl)propyl]-4-oxo-1.4-dihydro-3-quinolinecarboxamide
Figure imgf000083_0002
A solution of N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxy- l-propynyl)-3- quinoUnecarboxamide from Preparation No. 5 (0.367 g) is dissolved in DMF (10 mL). and K2CO3 (0.55 g) and N-(3-chloropropyl)piperidine hydrochloride (0.408 g) are added. The reaction mixture is heated to 90 °C for 10 h, and then aUowed to stir at room temperature for 38h. Water is added and a precipitate formed. The precipitate is filtered and aUowed to dry at room temperature and then under reduced pressure to give 0J87 g of a soUd. The soUd is dissolved in CHC1 and filtered to remove 0.045 g of a precipitate. The filtrate is concentrated in vacuo and crystaUized from ethyl acetate to give 0.065 g of the title compound as a soUd.
Physical characteristics are as foUows:
Mp 160-163 °C; 1H NMR (400 MHz, OMSO-d6) δ 10.3, 8.9, 8.3, 7.9, 7.8, 7.4, 5.4, 4.6, 4.5, 4.4, 2J-2J, 1.9, 1.4, 1.3 ppm; IR (drift) 3371, 2938, 2918, 1655, 1599, 1569, 1551, 1489, 1374, 1228, 1089, 1042, 1037, 816, 806 cm"1; MS (EI ) m/z 491 (M+); MS (FAB) m z 492 (MH+), 494, 493, 492, 491, 490, 126, 124, 98, 96, 45: HRMS (FAB) calcd for C28H30CIN3O3+H 492.2054. found 492.2061.
EXAMPLE 16. N-(4-Chlorobenzyl)- 1 ,4-dihydro-6-(3-hydroxy- 1 -propynyl)- 1 -[2- (1 -methyl-2-pyrrolindinyl)ethyl]-4-oxo-3-quinoUnecarboxamide
Figure imgf000084_0001
A solution of N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxy- l-propynyl)-3- quinolinecarboxamide from Prepartion No. 5 (0.458 g) is dissolved in DMF (10 mL), and K2CO3 (0.69 g, 5.0 mmol) and 3-chloromethyl-l-methylpiperidine hydrochloride (0.47 g, 2.5 mmol) are added. The reaction mixture is heated to 90 °C for 2.5 h. Water is added and a precipitate formed. The precipitate is filtered and aUowed to dry at room temperature to give 0.41 g of a soUd. The soUd is triturated with CHC1 and filtered to give 0.33 g of the title compound as a soUd.
Physical characteristics are as foUows: Mp 154-158 °C; lH NMR (400 MHz, DMSO- 6) δ 10.3, 8.9, 8.3, 7.9.7.4-7.3, 5.4, 4.6, 4.5, 4.3, 2.9, 2.2, 2J-2.0, 1.9, 1.8, 1.6, 1.5 ppm: IR (drift) 2963, 2941, 2784, 1656, 1620, 1599, 1551, 1490.1457, 1359, 1316, 1222, 1032, 815, 807 cm"1; HRMS (FAB) calcd for C27H28ClN3θ3+H 478.1897, found 478.1907. % Water (KF): 4.69. Anal, found: C, 64.67; H, 6.03; N, 8.32.
EXAMPLE 17. N-(4-Chlorobenzyl)- 1 -[2-(dnsopropylamino)ethyl]-6-(3-hydroxy- propynyl)-4-oxo- 1 ,4-dihydro-3-quinolinecarboxamide
Figure imgf000085_0001
A solution of N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxy- 1 -propynyl)-3- quinolinecarboxamide from Preparation No. 5 (0.458 g) is dissolved in DMF (10 mL), and K2CO3 (0.69 g) and 2-(dusoproplyamino)ethyl chloride hydrochloride (0.50 g) are added. The reaction mixture is heated to 90 °C for 2 h, then aUowed to stir at room temperature overnight. A drop of water is added and the mixture is heated for 20 h. An additional equivalent of 2-(dusoproplyamino)ethyl chloride hydrochloride (0.25 g, 1.25 mmol) is added and the mixture is heated at 100 °C for 5h, and then stirred at room temperature overnight. Water is added and an oUy soUd formed, which is isolated by decanting the Uquid. Column chromatography (elution with 1-2% MeOH/CHCh) gave 0.45 g of a soUd. CrystaUization by dissolving in CH2C1 with a few drops of" MeOH and adding to a 1: 1 solution of pentane/Et2O gave 0.22 g of the title compound as a soUd. Physical characteristics are as foUows: Mp 188-191 °C: 1H NMR (300 MHz, CDCh) δ 10.4. 8.7, 8.4, 7.6, 7.4, 7.3, 4.6, 4.5, 4.2, 3.0, 2.8, 0.9 ppm; IR (drift) 2967, 1650. 1597. 1575, 1551 , 1490, 1366, 1225, 1178, 1 165. 1040, 1028, 1019, 816, 807 cm"1; MS (EI ) m z 493 (M+). Anal, found: C, 67.96; H, 6.59; N, 8.33.
EXAMPLE 18. N-(4-Chlorobenzyl)- 6-(3-hydroxy-l-propynyl)-l-[2-(l- pyroUdinyl)ethyl] -4-oxo- 1 ,4-dihydro-3-quinolinecarboxamide
Figure imgf000086_0001
A solution of N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxy- l-propynyl)-3- quinolinecarboxamide from Preparation No. 5 (0.458 g) is dissolved in DMF (10 mL), and K2CO (0.69 g) and l-(2-chloroethyl)pyrroUdine hydrochloride (0.425 g) are added. The reaction mixture is heated to 90 °C for 3 h. Water is added and a dark soUd formed, which is isolated by decanting the Uquid. Column chromatography (elution with 1-5%
MeOH/CHCh) gave 0J7 g of" a soUd. CrystaUization by dissolving in CH?Ch with a few drops of MeOH and adding to a 1 : 1 solution of pentane/Et?O gave OJ53 g of the title compound as a soUd.
Physical characteristics are as foUows: Mp 189-192 °C: 1H NMR (400 MHz. DMSO- 6) δ 10.2, 8.8, 8.3, 7.9. 7.8. 7.4, 5.4,
4.6-4.5. 4.3, 2.8. 2.5. 1.6 ppm; IR (drift) 3358, 2965, 1656. 1598. 1580, 1555. 1489, 1371. 1357. 1229. 1143. 1025, 819, 806, 746 cm"1.
EXAMPLE 19. N-(4-Chlorobenzyl)-6-(3-hydroxy- 1 -propynyl)- 1 -[2-(4- morphoUnyl)ethyl]-4-oxo- 1 ,4-dihydro-3-quinolinecarboxamide
Figure imgf000086_0002
A solution of N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxy- l-propynyl)-3- quinolmecarboxamide from Preparation No. 5 (0.458 g) is dissolved in DMF ( 10 mL), and K2CO (0.69 g) and 4-(2-chloroethyl)morpholine hydrochloride (0.47 g) are added. The reaction mixture is heated to 90 °C for 2 h. Water is added and a dark soUd formed, which is isolated by decanting the Uquid. Column chromatography (elution with 1-5% MeOH/CHCh) gave OJ83 g of a soUd. CrystaUization by dissolving in CH?Ch with a few drops of MeOH and adding to a 1 :1 solution of pentane/Et2O gave 0J3 g of the title compound as a soUd.
Physical characteristics are as foUows:
Mp 215-218 °C; Η NMR (300 MHz, CDCh) δ 10.4, 8.7, 8.4, 7.6, 7.4, 7.3, 4.6, 4.5, 4.3, 3.7, 2.8. 2.5 ppm: IR (drift) 1650, 1597, 1559, 1491 , 1454, 1361, 1353, 1318, 1302, 1231 , 1 1 16, 1026, 1016, 820, 807 cm"1: MS (EI ) m/z 479 (M+).
EXAMPLE 20. N-(4-Chlorobenzyl)-l-[3-(dimethylamino)propyl]-6-(3-hydroxy- propynyl)-4-oxo- 1 ,4-dihydro-3-quinolinecarboxamide
Figure imgf000087_0001
A solution of N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxy- 1 -propynyl)-3- quinolinecarboxamide from Preparation No. 5 (0.458 g) is dissolved in DMF (10 mL), and K2CO3 (0.69 g) and 3-dimethylaminopropyl chloride hydrochloride (0.42 g) are added. The reaction mixture is heated to 90 °C for 6 h. Water is added and a dark soUd formed, which is isolated by decanting the Uquid. Column chromatography (elution with 1-20% MeOH/CHCh) gave 0J03 g of a soUd. CrystaUization by dissolving in CH2Ch with a few drops of MeOH and adding to a 1 : 1 solution of pentane/Et?O gave 0.072 g of the title compound as a soUd.
Physical characteristics are as foUows:
Mp 172-175 °C; 1H NMR (400 MHz, CDCh) δ 10.5, 8.8. 8.2, 7.6. 7.5. 7.4-7.3. 4.6, 4.4, 4.3, 2.8, 2.5, 2.2 ppm; IR (drU't) 1655, 1597, 1580, 1556, 1489, 1455, 1379. 1315, 1228, 1092, 1035, 1026, 818. 805, 747 cm"1; MS (EI ) m/z 451 (M+).
EXAMPLE 21. N-(4-Chlorobenzyl)-6-(3-hydroxy-l-propynyl)-4-oxo-l -vinyl- 1,4- dihydro-3-quinolinecarboxamide
Figure imgf000088_0001
A solution of N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxy- 1 -propynyl)-3- quinolinecarboxamide from Preparation No. 5 (1.83 g) is dissolved in DMF (25 mL), and K2CO3 (1.38 g) and lJ-dibromoethane (4.3 mL) are added. The reaction mixture is heated to 90 °C for 2 h. Water is added and the mixture is extracted with ethyl acetate and then chloroform. The combined organic layers are concentrated in vacuo to give 2.5 g of a dark oU. Column chromatography (elution with 1 -3% MeOH/CHCh) gave 0.378 g of 1-(1- bromoethyl)-N-(4-chlorobenzyl)-6-(3-hydroxy- 1 -propynyl)-4-oxo- 1 ,4-dihydro-3- quinolinecarboxamide as a soUd which is used without further purification. 1-(1- bromoethyl)-N-(4-chlorobenzyl)-6-(3-hydroxy- 1 -propynyl)-4-oxo- 1 ,4-dihydro-3- quinoUnecarboxamide (0.347 g) is suspended in 1 : 1 THF/CH CΝ (15 mL) and sodium carbonate (0J6 g) and ethylamine (0.4 mL) are added and the mixture is refluxed for 16 h. An additional amount of ethylamine (0.80 mL) is added and the mixture is refluxed for 16 h. An additional amount of ethylamine (0.80 mL) and DMF (5 mL) is added and the mixture is heated at 100 °C for 6 h. and then held at room temperature for 48 h. Potassium carbonate (0J93 g) is added and the mixture is heated at 100 °C for 3 h. The mixture is concentrated in vacuo and partitioned between ethyl acetate and water. The organic layer is concentrated in vacuo to give 0.60 g of an oU. Column chromatography (elution with 1-5% MeOH/CHCh) gave 0J 18 g of the title compound as a soUd. Physical characteristics are as foUows: Mp 171- 174 °C: !H NMR (400 MHz, DMSO- 6) δ 10.2. 8.8, 8.3, 7.9-7.8, 7.6, 7.4- 7.3, 5.8, 5.6, 5.4, 4.5, 4.3 ppm; IR (drift) 3299, 1650, 1594, 1578. 1550, 1487, 1355, 1338, 1320, 1227, 1087, 1025, 821 , 807, 688 cm"1. Anal, found: C, 66.95; H, 4.20: N, 7.05.
EXAMPLE 22. N-(4-chlorobenzyl)-6-[(E)-3-hydroxy-l-propenyl]- l-methyl-4-oxo- 1 ,4-dihydro-3-quinoUnecarboxamide
Figure imgf000089_0001
A mixture of N-(4-Chlorobenzyl)-6-[(lE)-3-hydroxy-l-propenyl]-4-hydroxy-3- quinolinecarboxamide from Preparation No. 12 (0J 84 g), K2CO3 (0.276 g) and iodomethane (0.062 mL) in DMF (2 mL) is heated in a stoppered flask at 90 °C for 1 h. Water is added and the mixture is aUowed to cool and stir at room temperature for 16 h during which a precipitate formed. The precipitate is filtered and dried in vacuo at 60 °C for 48 h to give 0J64 g of the title compound as a soUd. Physical characteristics are as foUows:
Mp 103-106 °C; Η NMR (400 MHz, OMSO-dβ) δ 10.4, 8.8, 8.2. 8.0, 7.8, 7.4-7.3. 6.7, 6.6-6.5, 4.9, 4.6, 4.2, 4.0 ppm: IR (drift) 3044, 1656. 1603, 1552, 1497, 1423, 1362, 1319, 1238, 1128, 1093, 1017, 967, 827, 807 cm"1: HRMS (FAB) calcd for C2iH19ClN2O3+H 383.1 162, found 383.1170.
EXAMPLE 23. N-(4-chlorobenzyl)-6-[(Z)-3-hydroxy- l -propenyl]-l-methyl-4-oxo- 1 ,4-dUιydro-3-quinoUnecarboxamide
Figure imgf000089_0002
A mixture of N-(4-chlorobenzyl)-6-[(lZ)-3-hydroxy- l-propenyl]-4-hydroxy- 3- quinolinecarboxamide from Preparation No. 1 1 (0J 84 g), K2CO3 (0.276 g) and iodomethane (0.062 mL) in DMF (2 mL) is heated in a stoppered flask at 90 °C for 1 h. Water is added and the mixture is aUowed to cool and stir at room temperature for 16 h during which a precipitate formed. The precipitate is filtered and dried in vacuo at 60 °C for 48 h to give a soUd. CrystaUization by dissolving in CH2C12 with a few drops of MeOH and adding to a 1 :1 solution of pentane/Et2O gave 0.085 g of the title compound as a soUd. Physical characteristics are as foUows:
Mp 137-141 °C; :H NMR (400 MHz, DMSO- 6) δ 10.4, 8.8, 8J , 7.8, 7.7, 7.4-7.3, 6.6, 5.9. 5.0, 4.5, 4.3, 4.0 ppm; IR (drift) 1656, 1603, 1550, 1497, 1363, 1317, 1242, 1124. 1089, 1037, 1017, 822. 808, 799, 723 cm"1; HRMS (FAB) calcd for C2iH,9CLN?O3+Hi 383.1162, found 383.1154.
EXAMPLE 24. N-(4-Chlorobenzyl)-6-[ethyl(2-hydroxyethyl)amino]- 1 -methyl-4- oxo- 1 ,4-dihydro-3-quinolinecarboxamide
H3C- O II
HO XX>CMOICI
CH,
To a flask containing ethyl 6-[[2-(acetyloxy)ethyl](ethyl)amino]-l-methyl-4-oxo-1.4- dihydro-3-quinolinecarboxylate from Preparation No. 16 (0.22 g) is added p- chlorobenzylamine (1.0 mL). The reaction is tightly capped and heated to 190 υC overnight. The reaction is cooled to room temperature. The residue is adsorbed onto sUica and chromatographed on sUica eluting with 4% to 8% methanol in dichloromethane. The product-containing fractions are evaporated to give 0J2 g of the title compound as a off- white soUd.
Physical characteristics are as foUows:
Η NMR (300 MHz, DMSO-J6) 10.6. 8.7, 7.6, 7.4, 4.8. 4.5. 4.0, 3.6. 3.5, 1J ; HRMS (FAB) found 414.1573.
EXAMPLE 25. N-(4-Chlorobenzyl)- 1 -cyclopropyl-6-(3-hydroxy- 1 -propynyl)-4- oxo- 1 ,4-dihydro-3-quinolinecarboxamide
Figure imgf000090_0001
To a dry flask under an atmosphere of argon gas containing 0.24 g of N-(4- chlorobenzyl)- 1 -cyclopropyl-6-iodo-4-oxo- 1.4-dihydro-3-quinolinecarboxamide from Preparation No. 20, 0.01 g of copper (I) iodide and 0.04 g of" dichlorobis(triphenyl- phosphine)paUadium (II) is added diethylamine (1.5 mL) and propargyl alcohol (0.04 mL). After 3 hours reaction is dUuted with DMF (0.5 mL) and left to stir overnight. The reaction is concentrated under reduced pressure. dUuted with dichloromethane containing a smaU amount of" methanol. and partioned against water. The organic layer is washed with brine, dried and concentrated under reduced pressure. The residue is adsorbed onto sUica and chromatographed on sUica eluting with 2% to 6% methanol in dichloromethane . The product-containing fractions are combined and concentrated under reduced pressure to afford 0J7 g of the title compound as a soUd.
Physical characteristics are as foUows:
1H NMR (300 MHz, DMSO- 6) 10.2, 8.7, 8.3. 8.2, 7.9. 1.4. 5.4, 4.5. 4.4, 3.7, 1.3. 1J; HRMS (FAB) 407.1170 (M+H+).
EXAMPLE 26. N-(4-Chlorobenzyl)- 1 -cyclopropyl-6-(3-hydroxypropyl)-4-oxo- 1.4- dihydro-3-quinolinecarboxamide
Figure imgf000091_0001
To a solution of N-(4-chlorobenzyl)-l-cyclopropyl-6-(3-hydroxy-l-propynyl)-4-oxo- 1.4-dihydro-3-quinolinecarboxamide (0J7g) from Example No. 25 in THF (3 mL) and methanol (3 mL) is added platinuim oxide (0.01 g). The mixture is placed under an atmosphere of hydrogen gas. After 1 hour, the mixture is filtered through CeUte with THF:methanol washes. The filtrate is concentrated under reduced pressure. The residue is adsorbed onto sUica and chromatographed on siUca eluting with 2% to 4% methanol in dichloromethane. The product-containmg fractions are concentrated under reduced pressure to afford 0J3 g of the title compound as a white soUd.
Physical characteristics are as follows:
1H NMR (300 MHz. OMSO-d6) 10.4, 8.7, 8J, 7.7, 7.4. 4.5. 3.7. 3.4, 2.8, 1.7, 1.3, 1J . Anal. Found: C, 67.05: H, 5.46; N, 6.68.
EXAMPLE 27. N-(4-Chlorobenzyl)-l-cyclopropyl-6-(4-morphoUnylmethyl)-4-oxo-
1 ,4-dihydro-3-quinolinecarboxamide
Figure imgf000092_0001
To a flask conatining ethyl l-cyclopropyl-6-(4-morpholinylmethyl)-4-oxo-1.4- dihydro-3-quinoUnecarboxylate (0.38 g) from Preparation No. 25 is added 4-chlorobenzylamine (2.0 mL). The reaction is tightly capped and heated to 165 °C overnight. The reaction is cooled to room temperature, adsorbed onto silica and chromatographed on siUca eluting with 1 % to 6% methanol in dichloromethane. The product-containing fractions are evaporated to give a soUd which is dissolved in a minimal amount of dichloromethane. The solution is added to 1 : 1 diethyl etheπpentane to precipitate the title compound as a white soUd. This soUd is coUected by filtration and dried in vacuo to afford 0.36 g of the title compound.
Physical characteristics are as foUows: 1H NMR (300 MHz. CDCh) 10-4. 8.9. 8.4. 8.0, 7.8, 73. 4.6, 3.7, 3.5, 2.5, 1.3. 1.2.
Anal, found C, 66.30; H, 6.07; N, 8.97.
EXAMPLE 28. tert-Butyl 2-[3-{ [(4-chlorobenzyl)amino]carbonyl}-6-(3-hydroxy- 1 -pro pynyl)-4-oxo-l(4H)-quinolinyl] acetate
Figure imgf000092_0002
To a dry flask under an atmosphere of argon gas containing 0.23 g of tert-butyl 2-[3- { [(4-chlorobenzyl)amino]carbonyl}-6-iodo-4-oxo-l(4H)-quinoUnyl]acetate from Preparation No. 26, 0.01 g of copper (I) iodide and 0.03 g of dichlorobis(triphenyl- phosphine)paUadium (II) is added diethylamine (2.0 mL) and propargyl alcohol (0.03 mL). After 1 hour the reaction is dUuted with DMF (1.0 mL) and left to stir overnight. The reaction is concentrated under reduced pressure, dUuted with dichloromethane containing a small amount of methanol, and partioned against water. The organic layer is washed with brine, dried and concentrated under reduced pressure. The residue is adsorbed onto sUica and chromatographed on sUica eluting with 2% to 4% methanol in dichloromethane . The product-containing fractions are combined and concentrated under reduced pressure to afford 0J3 g of" the title compound as a soUd.
Physical characteristics are as foUows:
Η NMR (300 MHz, DMSO- 6) 10.2, 8.9, 8.3. 7.8, 7.6, 1.4, 5.4, 4.5, 4.3, 3.7, 1.4; MS (ESI) m/z 481 (M+H+).
EXAMPLE 29. 2-[3-{ [(4-Chlorobenzyl)amino]carbonyl}-6-(3-hydroxy-l- propynyl)-4-oxo-l(4H)-quinolinyl]acetic acid
Figure imgf000093_0001
To a suspension of tert-butyl 2-[3-{ [(4-chlorobenzyl)amino]carbonyl}-6-(3-hydroxy- l-propynyl)-4-oxo-l(4H)-quinoUnyl] acetate (0.07 g) from Example No. 28 in dichloromethane (1 mL) is added trifluoroacetic acid (1 mL). After 3 hours, the resulting solution is concentrated under reduced pressure. The residue is dissolved in a smaU amount of" dichloromethane:methanol:DMF and slowly added to vigorously stirring 1 : 1 diethyl etheπpentane. The resulting precipitate is coUected filtration to afford 0.05 g of the title compound as a soUd.
Physical characteristics are as foUows:
1H NMR (300 MHz, DMSO-d6) 10.2. 8.9, 8.3, 7.9, 7.8, 7.7, 7.3, 5.4, 4.5, 4.3 ppm: MS (ESI) m/z 425 (M+H+).
EXAMPLE 30. N-(4-Chlorobenzyl)- l-(2-hydroxyethyl)-6-(3-hydroxy-l-propynyl)- 4-oxo- 1 ,4-dihydro-3-quinolinecarboxamide
Figure imgf000093_0002
To a flask containing N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxy-l-propynyl)-3- quinolinecarboxamide from Preparation No. 5 (0.37 g) is added potassium carbonate (2.75 g) and bromoethanol (0.71 mL). The flask is tightly capped and heated to 100 °C. After 4 hours the reaction is cooled to room temperature and partioned between dichloromethane containing methanol and water. The organic layer is washed with two additional portions of water, brine, dried and concentrated under reduced pressure. The residue is adsorbed onto sUica and chromatographed on sUica eluting with 2% to 10% methanol in dichloromethane to afford 0.09 g of the title compound as a white soUd.
Physical characteristics are as foUows: Η NMR (300 MHz, OMSO-d6) 10.2, 8.8, 8.3. 7.9, 7.8. 1.4, 5.4, 5.0. 4.5. 4.3, 3.7 ppm: MS (ESI) m/z 433 (M+Na+).
EXAMPLE 31. N-(4-Chlorobenzyl)-6-(3-hydroxy- 1 -propynyl)- 1 -methyl-4-oxo- 1.4-dihydro-3-quinolinecarboxamide
Figure imgf000094_0001
A suspension of 6.90 g of N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxy- 1-propynyl)-
3-quinoUnecarboxamide from Preparation No. 5. 10.4 g of potassium carbonate, and 2.3 mL of methyl iodide in 40 mL of" DMF is stirred at 90°C for 4 h. then cooled and dUuted with 350 mL of" water. The resulting soUd is filtered, washed well with water, and dried under vacuum. Flash chromatography of the soUd on siUca using 3-5% methanol in dichloromethane provides 6.02 g of the title compound as a yeUow soUd. Physical properties as foUows:
Η NMR (CDCI3+CD3OD) δ 4.03, 4.45, 4.6, 7.3, 7.6. 7.8, 8.5. 8.8 ppm: HRMS 381.1006
PREPARATION 27. N-(4-Chlorobenzyl)-6-(3-hydroxypropyl)-l-methyl-4-oxo-
1.4-dihydro-3-quinoUnecarboxamide
Figure imgf000095_0001
A mixture of 0.50 g of N-(4-chlorobenzyl)-6-(3-hydroxy-l -propynyl)- l-methyl-4- oxo-1.4-dihydro-3-quinolinecarboxamide from Example No. 31 and 50 mg of 5% platinum on carbon catalyst in 20 mL of 1 : 1 THF-methanol is stirred under 1 atm hydrogen for 3 h. then filtered through diatomaceous earth. The filtrate is concentrated under reduced pressure and the residual soUd flash chromatographed on siUca gel using 4-5% methanol in dichloromethane to afford 0.45 g of the title compound as a yeUow soUd. Further purification is achieved by recrystaUization of" the soUd from 15 mL of acetonitrUe.
Physical properties as foUows:
Η NMR (CDCh+CU3θD) δ 1.9. 2.9, 3.6. 4.0. 4.6. 7.3. 7.5. 7.7, 8.3. 8.8 ppm: HRMS 385.1310.
EXAMPLE 32. Di(tert-butyl) 3-(3-{ [(4-chlorobenzyl)amino]carbonyl}-l-methyl-4- oxo- 1.4-dihydro-6-quinoUnyl)propyl phosphate
Figure imgf000095_0002
To a suspension of" 77 mg of N-(4-chlorobenzyl)-6-(3-hydroxypropyl)- l-methyl-4- oxo-1.4-dihydro-3-quinolinecarboxamide from Preparation No. 27 and 25 mg of 1H- tetrazole in 2 mL of 1 : 1 chloroform-TΗF, stirred under argon, is added 90 μL of άi-tert- butyl diethyl phosphoramidite. After 18 h the solution is cooled to 0°C. and a sUght excess of m-CPBA (ca 110 mg) is added. After 10 min, the mixture is partitioned between ethyl acetate and aqeuous NaΗSO3. The organic phase is washed with dUute aqueous HCl. water, and aqueous NaHCO3. dried (Na2SO4), and concentrated under reduced pressure. Flash chromatography of the residue on sUica using 2% methanol in dichloromethane provides 111 mg of the title compound as a white crystalline soUd. Physical properties as foUows: 1H NMR (CDCh) δ 1.49, 2.0, 2.9, 3.94, 4.0, 4.6, 7.3, 7.5, 7.6, 83, 8.8 ppm; IR 2981, 1662, 1609, 1551, 1500, 1369, 1266. 1000, 810 cm"1; HRMS 577.2241.
EXAMPLE 33. 3-(3-{[(4-Chlorobenzyl)amino]carbonyl}-l-methyl-4-oxo-l,4- dihydro-6-quinolinyl)propyl dihydrogen phosphate
Figure imgf000096_0001
A solution of 77.8 mg of di(tert-butyl) 3-(3-{ [(4-chlorobenzyl)amino]carbonyl}-l- methyl-4-oxo- 1 ,4-dihydro-6-quinolinyl)propyl phosphate from Example No. 32 in 1 mL of 1 : 1 TFA-dichloromethane is stirred for 1 h. then added slowly to 20 mL of rapidly stirred 1 : 1 ether-hexane. The precipitated soUd is fUtered, washed with hexane, and dried under vacuum to afford 67 mg of the title compound as a white soUd. Physical properties as foUows:
Η NMR (CDCI3+CD3OD+TFA) δ 2J. 3.0, 4.0, 4.11. 4.7. 7.3, 7.7, 8.3, 9.0 ppm; HRMS 465.0981
EXAMPLE 34. Di(tert-butyl) 3-(3-{ [(4-chlorobenzyl)amino]carbonyl}- l- cyclopropyl-4-oxo- 1 ,4-dihydro-6-quinolinyl)propyl phosphate
Figure imgf000096_0002
The title compound was prepared from N-(4-chlorobenzyl)- l-cyclopropyl-6-(3- hydroxypropyl)-4-oxo-l,4-dihydro-3-quinolinecarboxamide (Example No. 26) foUowing procedures analogous to those described in Example No. 32. Physical properties as foUows:
Η NMR (CDCh) 1.2, 1.3, 1.52, 2J, 2.9, 3.5. 4.0, 4.6, 7.3, 7.6, 8.0, 8.3, 8.91 , 10.5 ppm; IR 1666, 1606, 1547, 1490, 1266, 1039, 996 cm"1: HRMS 603.2382. EXAMPLE 35. Sodium 2-[{ 8-[3-(3-{ [(4-chlorobenzyl)amino]carbonyl}- l-methyl- 4-oxo- 1.4-dihydro-6-quinoUnyl)propoxy]-8-oxooctanoyl}(methyl)amino]-l-ethanesuU'onate
Figure imgf000097_0001
A solution of" 77 mg of" N-(4-chlorobenzyl)-6-(3-hydroxypropyl)-l-methyl-4-oxo- l,4-dihydro-3-quinolinecarboxamide from Preparation No. 27, 0.46 mL of a 0.65 M solution of suleptanic acid triethylammonium salt in acetonitrile. 27 mg of DMAP. and 38 μL of DIC in 1 mL of" DMF is stirred at room temperature for 18 h. then concentrated under reduced pressure. Flash chromatography of" the residue on siUca using 5-20% methanol in dichloromethane affords a soUd, which is dissolved in chloroform and butanol. This solution is stirred with 25 mL of saturated aqueous sodium suU'ate. then fUtered through anhydrous sodium suU'ate and concentrated under reduced pressure to afford 1 13 mg of the title compound as a white soUd.
Physical properties as foUows:
]H NMR (CDCh) δ 1.3, 1.6. 2.0, 2.3. 2.8-3.2. 3.7, 3.9. 4J. 4.6, 7J-7.3, 7.5, 7.6. 8.3. 8.8 ppm: MS ES- 660; HRMS 662.2289
EXAMPLE 36. Sodium 2-[{ 8-[3-(3-{ [(4-chlorobenzyl)amιno]carbonyl}-l- cyclopropyl-4-oxo- 1.4-dihydro-6-quinolinyl)propoxy]-8-oxooctanoyl } (methyl)amino]- 1 - ethanesuU'onate
Figure imgf000097_0002
The title compound was prepared from N-(4-chlorobenzyl)- l-cyclopropyl-6-(3- hydroxypropyl)-4-oxo-l ,4-dihydro-3-quinoUnecarboxamide (Example No. 26) foUowing procedures analogous to those described in Example 35. Physical properties as foUows:
1H NMR (CDCh) δ 1.3, 1.4, 1.6, 2.0, 2.3, 2.7-3.3, 3.5, 3.7, 4J, 4.6, 7J-7.3, 7.5, 7.9, 8.3, 8.9, 10.5 ppm: IR 2936, 1732, 1664. 1606, 1547, 1490, 1348, 1 192, 1060, 1036, 809, 732 cm"1: MS ES- 686; HRMS 688.2447
EXAMPLE 37. Sodium 2-[(8-{[3-(3-{[(4-chlorobenzyl)amino]carbonyl}- l-methyl- 4-oxo-l , 4-dihydro-6-quinolinyl)-2-propynyl]oxy}-8-oxooctanoyl)(methyl)amino]-l- ethanesulfonate
Figure imgf000098_0001
The title compound was prepared from N-(4-chlorobenzyl)-6-(3-hydroxy-l- propynyl)-l-methyl-4-oxo-l,4-dihydro-3-quinoUnecarboxamide (Example No. 31) following procedures analogous to those described in Example 35. Physical properties as foUows: 1H NMR (CDCI3+CD3OD) δ 1.3, 1.6. 2.3, 3.0-3.4, 3.7, 4.0, 4J, 4.6. 4.9, 6.8. 7.3.
7.6, 7.8, 8J , 8.5, 8.8 ppm; HRMS 680.1797.
EXAMPLE 38. Sodium 2-[(8-{ [3-(3-{ [(4-chlorobenzyl)amino]carbonyl}- l- cyclopropyl-4-oxo- l,4-dihydro-6-quinolinyl)-2-propynyl]oxy}-8- oxooctanoyl)(methyl)amino]- 1 -ethanesulfonate
Figure imgf000098_0002
The title compound was prepared from N-(4-chlorobenzyl)-l-cyclopropyl-6-(3- hydroxy-l-propynyl)-4-oxo-l ,4-dihydro-3-quinoUnecarboxamide (Example No. 25) foUowing procedures analogous to those described in Example 35.
Physical properties as foUows: Η NMR (CDCh) δ 1J, 1.2- 1.4, 1.6, 2.2-2.4, 2.9-3.2, 3.5. 3.8. 4.6. 4.9, 7.3, 7.8,
7.9, 8.4, 8.9, 10.3 ppm: MS ES- 682: HRMS 684.2159.
PREPARATION 28. 2-Fluoro-5-iodobenzoic acid
To an argon-covered, stirred solution of 16.8 mL of diisopropylethylamine in 200 mL of THF, cooled at -78°C, is added dropwise 67 mL of a 1.6 M solution of butyUithium in hexane. The solution is aUowed to warm to 0°C and then recooled to -78°C. To this solution is added dropwise 1 1.5 mL of 4-fluoroiodobenzene in 10 mL of THF. The solution is stirred for 90 min at -78°C, then cannulated rapidly onto a Dry Ice-ether slurry. The mixture is allowed to warm to room temperature, then extracted with 300 mL of 0.3 M NaOH. The aqueous phase is chiUed in ice and acidUied with 40 mL of 6N HCl. The precipitate is extracted with two portions of ether, and the organic phase dried (MgSO4) and concentrated under reduced pressure. RecrystaUization of the residue with ethyl acetate- hexane provides 19.57 g of" the title compound as white needles. A second crop of 3.78 g is obtained by recrystaUization of the mother Uquor residue. Physical properties as foUows:
1H NMR (CDCh) δ 6.97, 7.88, 8.33 ppm. Anal found: C. 1.57: H, 1.59.
PREPARATION 29. Ethyl 3-(2-fluoro-5-iodophenyl)-3-oxopropanoate To a stirred solution of 5.32 g of" 2-fluoro-5-iodobenzoic acid from Preparation No. 28 in 20 mL of THF, under argon, is added 3.9 g of carbonyldUmidazole. In a separate flask, 2.8 mL of chlorotrimethylsUane is added to a mixture of 3.74 g of potassium ethyl malonate in 20 mL of acetonitrUe. The mixture is stirred under argon for 18 h, then cooled to 0°C for the dropwise addition of 6.6 mL of DBU. The mixture is stirred for 3 h at 0°C, then the solution of" acyl imidazoUde prepared above is added via cannula. After 2 h, the mixture is partitioned between ether and excess dUute HCl, and the organic phase is washed with dUute HCl and brine and dried (MgSO4). Removal of the solvent under reduced pressure left a colorless oU, which is flash chromatographed on siUca using 10% ethyl acetate in hexane to provide 5.07 g of the title compound as dense pinkish prisms. Physical properties as foUows:
Η NMR (CDCh) δ 1.34. 4.27. 5.82, 6.89, 7.7, 8.2 ppm; IR 1624. 1485. 1419. 1245. 1193. 1070, 1028, 813 cm"1.
PREPARATION 30. Ethyl l-(tert-butyl)-6-iodo-4-oxo- l,4-dihydro-3- quinolinecarboxylate
A solution of 2.36 g of ethyl 3-(2-fluoro-5-iodophenyl)-3-oxopropanoate from Preparation No. 29. 2.0 mL of triethyl orthoformate. and 15 mL of acetic anhydride is refluxed under argon for 2 h, then the solvents are distiUed off under reduced pressure. To the residual oU is added 10 mL of dry tert-butanol and 0.74 mL of tert-butylamine, and the solution is stirred at 80°C for 2 h. Potassium tert-butoxide (0.87 g) is then added, and stirring continued at 80°C under argon for 18 h. The mixture is then cooled and partitioned between dUute HCl and chloroform-methanol. The organic phase is dried (MgSO4) and concentrated under reduced pressure. Flash chromatography of the residue on silica using 2-4% methanol in dichloromethane provides 132 g of the title compound as an off-white soUd.
Physical properties as foUows:
1H NMR (CDCh) δ 1.42, 1.87, 4.4. 7.7. 7.9. 8.9 ppm: HRMS 400.0414. Anal. Found: C, 48.05; H. 4.50: N. 3.52.
PREPARATION 31. l-(tert-Butyl)-N-(4-chlorobenzyl)-6-iodo-4-oxo- 1.4-dihydro-
3-quinolinecarboxamide
Figure imgf000100_0001
A slurry of 1.11 g of ethyl l-(tert-butyl)-6-iodo-4-oxo-1.4-dihydro-3- quinolinecarboxylate from Preparation No. 30 in 2.0 g of 4-chlorobenzylamine is heated under argon at 160°C for 18 h. then cooled to room temperature and triturated with IN HCl. The soUd is fUtered. washed weU with water, and dried under vacuum. Flash chromatography using 20% ethyl acetate in dichloromethane provides 1.22 g of" the title compound as a white soUd.
Physical properties as foUows: Η NMR (CDCh) δ 1.89, 4.6, 7.3, 7.7, 7.9, 8.9, 9.22, 10.4 ppm: IR 1664, 1536, 1468, 1342. 1 180 cm"1. Anal. Found: C, 51.27; H, 4J9; N, 5.62.
EXAMPLE 39. 1 -(tert-Butyl)-N-(4-chlorobenzyl)-6-(3-hydroxy- 1 -propynyl)-4-oxo- 1 ,4-dihydro-3-quinolinecarboxamide
Figure imgf000101_0001
To a stirred slurry of 1J5 g of l-(tert-butyl)-N-(4-chlorobenzyl)-6-iodo-4-oxo-l ,4- dihydro-3-quinolinecarboxamide from Preparation No. 31 , 156 mg of copper (I) iodide, and 66 mg of dichlorobis(triphenylphosphine)paUadium (II) in 23 mL of diethylamine, under argon, is added 0J6 mL of propargyl alcohol. The mixture is stirred for 18 h at room temperature, then concentrated under reduced pressure. The residue is partitioned between water and chloroform-methanol, and the organic phase dried (MgSO ) and concentrated under reduced pressure. Flash chromatography of the residue on sUica using 2-4% methanol in dichloromethane affords 977 mg of' tan sohd. RecrystaUization from ethanol provides 850 mg of the title compound as a beige soUd. Physical properties as foUows:
Η NMR (CDCh) δ 1.92, 4.47, 4.6, 73. 7.7, 8.0, 8.5, 9J9. 10.5 ppm: HRMS 423.1466. Anal. Found: C, 67.74: H, 5.53: N. 6.61.
PREPARATION 32. l-(tert-Butyl)-N-(4-chlorobenzyl)-6-(3-hydroxypropyl)-4- oxo- 1 ,4-dihydro-3-quinolinecarboxamide
Figure imgf000101_0002
A mixture of 303 mg of l-(tert-butyl)-N-(4-chlorobenzyl)-6-(3-hydroxy-l-propynyl)- 4-oxo- l,4-d ydro-3-quinolinecarboxamide from Example No. 39 and 15 mg of platinum oxide in 10 mL of 1 :1 THF-methanol is stirred under 1 atm of hydrogen gas for 3 h, then filtered through diatomaceous earth and concentrated under reduced pressure. The mixture was purified by flash chromatography on siUca using 2-3% methanol in dichloromethane to afford 294 mg of the title compound. Physical properties as foUows: Η NMR (CDCh) δ 1.89, 1.9, 2.9, 3.7, 4.6, 7.3, 7.5. 7.9, 8.4, 9.21, 10.6 ppm; IR
1658, 1596, 1548, 1484, 1349, 1184, 810, 731 era"1; HRMS 427.1762
EXAMPLE 40. Sodium 2-[{ 8-[3-(l-(tert-butyl)-3-{ [(4-chlorobenzyl)amino]- carbonyl}-4-oxo- l,4-dihydro-6-quinolinyl)propoxy]-8-oxooctanoyl}(methyl)aminol-l- ethanesuUonate
Figure imgf000102_0001
The title compound was prepared from l-(tert-butyl)-N-(4-chlorobenzyl)-6-(3- hydroxypropyl)-4-oxo-l ,4-dihydro-3-quinolUιecarboxamide (Preparation No. 32) foUowing procedures analogous to those described in Example 35. Physical properties as foUows: lE. NMR (CDCh) δ 1.2-1.4, 1.6, 1.9, 2.0, 2.2-2.4, 2.8-3.2, 3.7, 4J, 4.6. 7J-7.3, 7.5, 7.9. 8.4, 9.2, 10.5 ppm: IR 2937. 1732, 1663, 1596. 1546. 1484, 1 184 cm"1: HRMS 748.2394.
EXAMPLE 41. Sodium 2-[(8-{ [3-(l-(tert-butyl)-3-{ [(4-chlorobenzyl)amino]- carbonyl}-4-oxo-l ,4-dihydro-6-quinolinyl)-2-propynyl]oxy}-8-oxooctanoyl)(methyl)amino]- 1 -ethanesuUonate
Figure imgf000103_0001
The title compound was prepared from l-(tert-butyl)-N-(4-chlorobenzyl)-6-(3- hydroxy- l-propynyl)-4-oxo- l ,4-dihydro-3-quinolinecarboxamide (Example No. 39) foUowing procedures analogous to those described in Example 35. Physical properties as foUows:
Η NMR (CDCh) δ 1.3, 1.6, 1.9, 2.2-2.4, 2.6, 2.8-3.2, 3.7, 4.6, 4.9, 7J-7.3, 7.7, 7.9, 8.6, 9.2, 10.4 ppm: IR 2936, 1741 , 1666, 1592, 1544, 1482. 1341 , 1 182 cm"1: MS ES- 698; HRMS 700.2496
EXAMPLE 42. N-(4-Chlorobenzyl)-6-(3-hydroxy- 1 -propynyl)- 1-[2-(2- methoxyethoxy)ethyl] -4-oxo- 1 ,4-dihydro-3-quinolinecarboxamide
Figure imgf000103_0002
The title compound is prepared according to procedures analogous to those descibed in Preparation No 30 - 31 and Example No. 39 from ethyl l-(tert-butyl)-6-iodo-4-oxo- l ,4- dihydro-3-quinolinecarboxylate.
Physical properties as foUows:
1H NMR (CDCh) δ 3.29, 3.5, 3.6, 3.8-4.0, 4.3-4.5. 4.7. 7.3, 7.5, 8.2, 8.76, 10.4 ppm; MS ES+ 469; HRMS 469.1508. Anal. Found: C, 63.98: H, 5.42; N, 6.04.
PREPARATION 32b. 4-(Aminomethyl)benzonitrUe
A mixture of'4-(bromomethyl)benzonitrUe (7J g) and sodium azide (2.6 g) in DMF (40 mL) is stirred for 19 hrs. The reaction mixture is then dUuted with water (150 mL) and extracted with ether (2 x 50 mL). The organic phases are combined, washed with water (50 mL) and brine (50 mL). and dried with MgSO . FUtration and evaporation of the solvent leaves 5.5 g of 4-(azidomethyl)benzonitrile as a clear, colorless oU.
Triphenylphosphine (7.67 g) is added to a solution of 4-(azidomethyl)-benzonitrUe (4J9 g) in THF (30 mL) and stirred for 1 hr. Water (10 mL) is added, and the solution is stirred for 16 hrs. The reaction mixture is dUuted with ether (50 mL) and extracted with HCl (3 N. 3 x 25 mL) and water ( 1 x 25 mL). The aqueous phases are combined and washed with ether (50 mL). Sodium hydroxide is added untU the pH = 12. After extracting with ether (2 x 50 mL). the solution is dried with MgSO and filtered. The solvent is evaporated under reduced pressure. The resulting crude mixture is then purUied via bulb to bulb distUlation at 150 °C and 1 torr to afford 1.74 g (50%) of the title compound as a clear, colorless oU.
Physical characteristics are as foUows:
Η NMR (DMSO-^) δ 7.7. 7.5. 3.8. 1.9
EXAMPLE 43. N-(4-Cyanobenzyl)-6-(3-hydroxy- l -propynyl)- l-methyl-4-oxo- 1.4- dihydro-3-quinolinecarboxamide
Figure imgf000104_0001
Ethyl 4-hydroxy-6-iodo-3-quinoUnecarboxylate prepared as an intermediate in Preparation No. 4 (5.0 g) , potassium carbonate (10.4 g) and methyl iodide (0.94 mL) are suspended in DMF (100 mL) and heated to 95°C under a nitrogen atmosphere for 6.5 hrs. After the mixture is brought to room temperature potassium carbonate is filtered off. and the solvent is evaporated under reduced pressure untU a white soUd precipitates out of solution. This white soUd is fUtered, washed with water and dried in a stream of air. A sample of this soUd (2.0 g) is suspended in ethanol (12 mL) and sodium hydroxide (8 mL. 3 N) is added. The mixture is stirred overnight. The mixture is then acidUied with 3 N HCl. The resulting soUd is fUtered. washed with 3 x 30 mL water and dried in a stream of air. A sample of this soUd (1.0 g) and 1 , 1 ' -carbonyldUmidazole (1.0 g) are suspended in DMF (20 mL) and heated to 70°C for 2 hrs. The mixture is brought to room temperature and treated with water (0.054 mL). A solution of 0.42 g of" 4-(aminomethyl)benzonitrile from Preparation No. 32b in 10 mL DMF is added to the mixture and aUowed to stir at room temperature for 24 hrs. DUution with 30 mL H2O causes a white soUd to precipitate out of" solution. The soUd is fUtered and washed with 3 x 20 mL 1 : 1 DMF: water. A sample of this white soUd (0.5 g) is suspended in diethylamine (17 mL) and treated with copper iodide (0.06 g), bis-triphenylphosphine paUadium chloride (0.04 g). and propargyl alcohol (0.08 mL). The reaction is stirred at room temperature overnight, and the volume is reduced by evaporation under reduced pressure to a brown, viscous oU. The oU is dUuted with CH2C12 producing an off-white soUd. This soUd is fUtered and then dissolved in hot acetic acid. The insoluble impurities are fUtered from the solution whUe still hot, and the product precipitates as the solution cools. The soUd is fUtered, washed with 3 x 25 mL water and dried in a stream of air on a fritted funnel. The procedure affords 0.31 g of the title compound as an off-white soUd.
Physical characteristics are as foUows:
Mp 230-232 °C; Η NMR (OMSO-d6) δ 10.3, 8.8, 8.3, 7.8, 7.7, 7.5, 5.4, 4.6. 43, 4.0.
EXAMPLE 44. 6-((Bis(2-hydroxyethyl)amino)methyl)-N-(4-chlorobenzyl)-l- methyl-4-oxo- 1.4-dihydro-3-quinolinecarboxamide.
Figure imgf000105_0001
MethanesuU'onyl chloride (0.048 mL) is added to a cold (0 °C) solution of N-(4- chlorobenzyl)-6-(hydroxymethyl)- 1 -methyl-4-oxo- 1 ,4-dihydro-3-quinolinecarboxamide (200 mg) from Preparation No. 10, DMAP (11.5 mg), and 2,4,6-coUidine (0.087 mL) in anhydrous DMF (9.5 mL). The mixture is stirred at room temperature untU starting material is consumed and diethanolamine (0.54 mL) is added. The reaction mixture is heated to 56 °C for 1.5 h. The reaction mixture is cooled to room temperature and partitioned between CH2C12 and water. The aqueous layer is extracted with CH?Ch three times. The combined organic layers are washed with brine, dried (Na2SO ), and concentrated to afford a yeUow residue. The resulting soUd was adsorbed onto sUica and purified by chromatography (eluent 1% MeOH in CH2C12 (IL), 2% MeOH in CH2Ch (IL), 3% MeOH in CH2Ch (IL), 4% MeOH in CH2Ch (2L)). Fractions homogenous by TLC were combined and concentrated to afford 69.3 mg (28%) of the title compound as a white soUd.
Physical characteristics are as foUows:
Mp 165-166 °C: Η NMR (300 MHz, OMS -d6) δ 10.45, 8.86, 8.24, 7.86, 7.79, 7.38, 4.56, 4.38, 4.02, 3.81, 3.46, 2.56; IR (drift) 3324. 2935, 2923, 2820, 1667, 161 1 , 1551 , 1491 , 1362, 1235, 1087, 1080, 814. 808, 796 cm"1: Anal, found for C23H26ClN3O4: C, 61.90; H, 5.94; N, 9.35.
EXAMPLE 45. N-(4-Chlorobenzyl)-6-(((2-hydroxyethyl)(methyl)amino)-methyl)- 1 -methyl-4-oxo- 1 ,4-dihydro-3-quinolinecarboxamide
Figure imgf000106_0001
MethanesuU'onyl chloride (0.065 mL) is added to a cold (0 °C) solution of N-(4- chlorobenzyl)-6-(hydroxymethyl)- 1 -methyl-4-oxo- 1 ,4-dihydro-3-quinolinecarboxamide (0.27 g) from Preparation No. 10, DMAP (0.017 g). and 2,4.6-coUidine (0J2 mL) in anhydrous DMF ( 14 mL). The mixture is stirred at room temperature overnight and 2- (methylamino)ethanol (0.61 mL) is added. The reaction mixture is stirred at room temperature for 2 h, poured into water, and extracted with CH2Ch (3x). The organic layers are combined, dried (Na2SO4), filtered, and concentrated in vacuo. The residue is dissolved in CH2Ch/MeOH and adsorbed onto silica. Purification by chromatography (eluent CH2C1? (IL), 1.5% MeOH/CH2Ch (IL), 2.5% MeOH/CH2Ch (IL), 3.5% MeOH/CH2Cl2 (IL). 5% MeOH/CH2Ch (IL), 6% MeOH/CH2Ch (IL)) affords the product as a clear residue. The residue is crystaUized by addition of CH2Ch/hexanes followed by removal of the solvents in vacuo to give 0J1 g (69%) of the title compound as a white soUd. Physical characteristics are as foUows:
Mp 130-131 °C; Η NMR (DMSO-d6) δ 10.44, 8.86, 8.23, 7.80. 7.40, 7.36, 4.56, 4.42, 4.02, 3.67, 3.52, 2.46, 2J7; IR (drift) 3435, 1665, 1610, 1549. 1497, 1367, 1352, 1316, 1233, 1123, 1090, 1020, 819, 808, 662 cm"1; Anal. Found for C2?H24ClN3O3: C, 63.70; H, 5.98; N, 9.85. PREPARATION 33. 1 ,4-Oxazepane
To a stirred solution of" tetrahydro-4H-pyran-4-one (4J9 mL) in cone. HCl (23 mL) cooled to 0 °C is added portion-wise sodium azide (4.42 mL). After addition was complete, the reaction is stirred at room temperature for 4 h. SoUd sodium carbonate is added portion- wise untU the solution was sUghtly alkaline (pH=9). Water is added during addition of sodium carbonate to dissolve the salt. The alkaline solution is dUuted with CHCh (125 mL) and the phases are separated. The aqueous layer are extracted with CHCh (2 x 75 mL). The combined organic layers are dried (Na2SO ), fUtered, and concentrated to afford 2.5 g (48%) of" l,4-oxazepan-5-one as an orange-brown residue. Η NMR (300 MHz. CDCh) δ 6.66. 3.80, 3.35, 2.72.
To a solution of l ,4-oxazepan-5-one (2.5 g) in distilled THF (86 mL) cooled to 0 °C is added dropwise a solution of" LiAlH4 in THF (1M. 21.9 mL). The reaction mixture is stirred at room temperature for 2.5 h during which additional LiAlH ( 1 1 mL) is added. The reaction is quenched by successive addition of water (4 mL). 15% NaOH (4 mL). and water (4 mL). The reaction mixture is fUtered, and the filtrate is dried (Na2SO4), fUtered. and concentrated to obtain 963 mg (44%) of 1.4-oxazepane as a residue.
Physical characteristics are as follows:
Η NMR (300 MHz. CDCh) δ 3.82. 3.73. 2.96, 1.88
EXAMPLE 46. N-(4-Chlorobenzyl)- l-methyl-6-(1.4-oxazepan-4-ylmethyl)-4-oxo-
1.4-dihydro-3-quinolinecarboxamide
Figure imgf000107_0001
MethanesuU'onyl chloride (0.080 mL) is added to a cold (0 °C) solution of N-(4- chlorobenzyl)-6-(hydroxymethyl)- 1 -methyl-4-oxo- 1.4-dihydro-3-quinolinecarboxamιde (330 mg) from Preparation No. 10, DMAP (19J mg). and 2,4,6-coUidine (0J4 mL) in anhydrous DMF (15.7 mL). The mixture is stirred at room temperature until the starting material is consumed and a solution of 1.4-oxepane (0.963 g) from Preparation No. 33 in anhydrous DMF (3 mL) is added. The reaction mixture is heated to 56 °C for 1.5 h. The mixture is cooled to room temperature and the product is precipitated by addition of water (125 mL). The soUd was adsorbed onto sUica and purified by column chromatography (eluent 100% CH2C1? (IL), 1 % MeOH in CH?Ch (2L), 1.5% MeOH in CH2Ch (IL), 2% MeOH in CH2Ch (3L)). Fractions homogenous by TLC are combined and concentrated to afford 124.5 mg (31 %) of the title compound as a white soUd. Physical characteristics are as foUows: Mp 178-179 °C: 1H NMR (300 MHz. DMSO-^) δ 10.43, 8.87, 8.27, 7.81 , 7.38,
4.56. 4.02, 3.79, 3.70. 3.61. 2.64. 1.81 : IR (drift) 2939. 1655. 1606. 1573. 1551, 1502, 1363, 1351, 1344. 1 132. 1091 , 1080. 828. 816. 808 cm "-1: Anal, found for C2Λ6CIN3O3: C, 65.14; H, 6.01 ; N, 9.39.
PREPARATION 34. 1.4-Thiazepane
To a stirred solution of tetrahydrothiopyran-4-one (4.74 g) in cone. HCl (20.7 mL) cooled to 0 °C is added portion-wise sodium azide (3.98 g. 61 J mmol). After addition is complete, the reaction is stirred at room temperature for 4 h. Solid sodium carbonate is then added portion-wise untU the solution was sUghtly alkaline (pH=9). Water is added during addition of sodium carbonate to dissolve the salt. The alkaUne solution is dUuted with
CHCh (125 mL), and the phases are separated. The aqueous layer is extracted with CHCh (2 x 75 mL). The combined organic layers are dried (Na?SO4). fUtered, and concentrated. The crude product is recrystaUized from CH2Cl?/hexanes to afford 4.30 g (81%) of 1.4- thiazepan-5-one as a white soUd. Physical characteristics are as foUows:
Mp 1 14-116 °C: Η NMR (300 MHz. CDCh) δ 6.41. 3.66. 2.96. 2.76. To a solution of 1.4-thiazepan-5-one (3.0 g) in distilled THF (90 mL) cooled to 0 °C is added dropwise a solution of' LiAlH4 in THF (1M solution. 22.9 mL). The mixture is stirred at room temperature for 2 h. The reaction is quenched by successive addition of water (2 mL), 15% NaOH (2 mL) and water (2 mL). The reaction mixture is filtered to remove the aluminum salt that had precipitated. The filtrate was dried (Na2SO4), fUtered, and concentrated to obtain 2.63 g (98%) of 1.4-thiazepane as a yeUow residue. Physical characteristics are as foUows: Η NMR (300 MHz, CDCh) δ 3.07. 2.96. 2.75..1.92. EXAMPLE 47. N-(4-Chlorobenzyl)- 1 -methyl-4-oxo-6-( 1 ,4-thiazepan-4-ylmethyl)- 1 ,4-dihydro-3-quinolinecarboxamide
Figure imgf000109_0001
MethanesuU'onyl chloride (0.096 mL) is added to a cold (0 °C) solution of N-(4- chlorobenzyl)-6-(hydroxymethyl)-l-methyl-4-oxo-l ,4-dUiydro-3-quinolinecarboxamide (400 mg) from Preparation No. 10, DMAP (23 mg). and 2.4.6-coUidine (0J7 mL) in anhydrous DMF (19 mL). The mixture is stirred at room temperature until the starting material is consumed and 1.4 thiazepane (1 J3 g) from Preparation No. 34 is added. The reaction mixture is heated to 65 °C for 1.5 h. The mixture is cooled to room temperature and the product is precipitated by addition of water ( 125 mL). The soUd is adsorbed onto silica and purified by column chromatography (eluent 100% CH2Ch (IL), 0.5% MeOH in CH2C12 (IL). 1% MeOH in CH?C12 (IL), 1.5% MeOH in CH?Ch (2.5L)). Fractions homogenous by TLC are combined and concentrated to afford 338J mg (66%) of the title compound as a white soUd.
Physical characteristics are as foUows:
Mp 166- 167 °C: Η NMR (300 MHz. DMSO-ri6) δ 10.44. 8.86. 8.28. 7.84. 7.80, 7.38. 4.56. 4.02. 3.88, 2.91, 2.83, 2.76, 2.68. 1.80: IR (drift) 2919. 1656. 1605. 1573, 1551. 1501. 1420. 1363, 1317. 1240, 1131, 1 109, 819. 808. 661 cm"1 : Anal, found for C24H26ClN,O2S: C, 63.13; H, 5.73: N, 9J5.
EXAMPLE 48. N-(4-Chlorobenzyl)- l-methyl-6-(2-oxa-5-azabιcyclo[2JJ]-hept-5- ylmethyl)-4-oxo- 1 ,4-dihydro-3-qumoUnecarboxamide
Figure imgf000109_0002
MethanesuU'onyl chloride (0.06 mL) is added to a cold (0 °C) solution of N-(4- chlorobenzyl)-6-(hydroxymethyl)-l-methyl-4-oxo-1.4-dihydro-3-quinohnecarboxamide (250 mg) from Preparation No. 10, DMAP (14.4 mg), and 2.4,6-coUidine (0.1 1 mL) in anhydrous DMF (12 mL). The mixture is stirred at room temperature untU the starting material is consumed. (15, 45)-(+)-2-Aza-5-oxabicyclo[2JJ]heptane hydrochloride (475.9 mg) and Et3N (0.49 mL) are added to the solution. The reaction mixture is heated to 65 °C overnight. The mixture is cooled to room temperature and filtered to remove the salt that had precipitated out of solution. The filtrate is diluted with water (125 mL) to precipitate the product. The soUd is adsorbed onto sUica and purified by column chromatography (eluent 1% MeOH in CH2Ch (IL), 2% MeOH in CH2Ch (IL), 3% MeOH in CH?C1?
(2.5L)). Fractions homogenous by TLC are combined, concentrated, and recrystaUized from CH?Ch/hexanes to afford 164.0 mg (53%) of the title compound as a white soUd.
Physical characteristics are as foUows:
Mp 162- 163 °C; Η NMR (300 MHz, DMSO-^ δ 10.44. 8.86. 8.28, 7.84, 7.79, 7.38, 4.56, 4.36, 4.02, 3.94, 3.88, 3.54, 3.46, 2.73, 2.43, 1.84, 1.61 : IR (drift) 1655, 1605, 1573, 1550, 1500, 1364, 1316, 1222, 1 131. 1091 , 844, 822, 810. 721 , 662 cm "' ; [α]D 25 = +35 (c = 0.89. methanol): Anal, found for C24H24CIN3O3: C, 65.86; H, 5.58: N, 9.58.
EXAMPLE 49. N-(4-Chlorobenzyl)-6-(23-dihydro-4H- 1 J-benzoxazin-4- ylmethyl)- l-methyl-4-oxo- 1 ,4-dihydro-3-quinolinecarboxamide
Figure imgf000110_0001
A solution of LiAlH4 (34 mL, 1M in THF) is added dropwise via addition funnel to a cold (0 υC) solution of (2H)1.4-benzoxazin-3(4H)-one (5.04 g) in freshly distUled TΗF (1 10 mL). The LiAJΗ is added at such a rate to keep the reaction temperature below 10 °C. The mixture is stirred at room temperature for 2 h and then is quenched successively with water (5 mL), 15% ΝaOH (5 mL), and water (5 mL) again. The resulting precipitate is filtered and the filtrate is concentrated in vacuo. The residue is dissolved in CH Ch and dried (Νa2SO4), fUtered, and concentrated to afford the product benzomorpholine as a yeUow oU which was used without further purification in the next step.
MethanesuU'onyl chloride (0J0 mL) is added to a cold (0 °C) solution of N-(4- chlorobenzyl)-6-(hydroxymethyl)- 1 -methyl-4-oxo- 1 ,4-dihydro-3-quinoUnecarboxamide (0.41 g) from Preparation No. 10, DMAP (0.030 g), and 2,4,6-coUidine (0J9 mL) in anhydrous DMF (15 mL). The mixture is stirred at room temperature for 12 h and then benzomorpholine (1.60 g) from above is added. The reaction mixture is stirred at room temperature for 2 h and is then heated to 65 °C overnight. The mixture is cooled to room temperature and poured water. The soUd is dissolved in CH2Cl?/MeOH and adsorbed onto sUica. Purification by column chromatography (eluent CH2Ch (IL), 1% MeOH/CH2Ch (2L)) and then recrystaUization from CH2Ch/hexanes affords 0.56 g (100%) of the title compound as a pale gold soUd.
Physical characteristics are as foUows:
Mp 193-194 °C: Η NMR (OMSO-d6) δ 10.40, 8.86, 8.24, 7.82, 739, 7.35, 6.68, 6.53, 4.65, 4.54, 4.24. 4.01 , 3.44; IR (drift) 1653, 1604, 1576, 1551, 1502, 1365, 1347, 1329, 1307, 1254, 1235, 1214, 818, 81 1 , 733 cm"1; Anal. Found for
Figure imgf000111_0001
C, 68.06: H, 5.09: N, 8.80
EXAMPLE 50. 6-((Benzyl(2-hydroxyethyl)amino)methyl)-N-(4-chlorobenzyl)- 1- methyl-4-oxo- 1.4-dihydro-3-quinolinecarboxamide
Figure imgf000111_0002
MethanesuU'onyl chloride (0J93 mL) is added to a solution of N-(4-chlorobenzyl)-6- (hydroxymethyl)-l-methyl-4-oxo- l ,4-dihydro-3-quinoUnecarboxamide (357 mg) from Preparation No. 10, DMAP (20 mg), and 2,4,6-coUidine (0.33 mL) in DMF (20 mL). The mixture is stirred at room temperature for 3 h and then N-benzylethanolamine (1.42 mL) is added. The reaction mixture is stirred at room temperature for 20 h, poured into water (60 mL), and extracted with ethyl acetate (3 x 50 mL). The organic layers are washed with sat. aq. sodium bicarbonate (10 mL) and brine (10 mL), dried (Νa SO ). and concentrated. The crude product was purified by column chromatography (CH2Cl?/methanol, 100/1 : 50/1) to afford 0.35 g (71%) of the title compound as a white soUd. Physical characteristics are as foUows:
Mp 133-135 °C; Η NMR (DMSO-d6) δ 10.44, 8.86, 8.29, 7.89-7.79, 7.42-7.21, 4.56, 4.42, 4.02, 3.76, 3.62, 3.5; 13C NMR (OMSO-d6) δ 175.4.164.4, 148.6, 139.4, 138.9, 138.7, 136.9, 133.5, 131.4, 129J , 128.5, 128.3, 128.2, 126.8, 126.7, 125.2, 117.5, 110.4, 59.2, 58J , 57.5, 55.2, 41.4, 41.2; IR (drift) 1653, 1606, 1549, 1499, 1456, 1362, 1318,
1234, 1224, 1128, 1062, 817, 810, 799, 739 cm"1; HRMS (FAB) calcd for C28H28ClN3O3+H m/z 490.1897, found 490.1900. Anal. Found for CjjJ sClNjO?: C, 68.62; H, 5.89: N, 8.54; Cl, 7J7. PREPARATION 35. N-(4-Chlorobenzyl)-6-(chloromethyl)- 1 -methyl-4-oxo- 1 ,4- dihydro-3-quinolinecarboxamide
Figure imgf000112_0001
A solution of" N-(4-chlorobenzyl)-6-(hydroxymethyl)-l-methyl-4-oxo- l,4-dihydro-3- quinolinecarboxamide from Preparation No. 10 (1.0 g), coUidine (0.44 mL), and DMAP (57.9 mg) in anhydrous DMF (48 mL) is cooled to 0 °C. MethanesuU'onyl chloride (0.24 mL) is added dropwise. The reaction is stirred at room temperature. The crude product is precipitated by addition of water and is fUtered. The resulting soUd is adsorbed onto siUca and purified by chromatography (eluent 100% CH2Ch (IL). 1 % MeOH in CH2Ch (IL)). Product-containing fractions were combined and concentrated to afford 948.8 mg (90%) of the title compound as a white soUd.
Physical characteristics are as foUows:
Mp 241-242 °C; 1H NMR (300 MHz, DMSO- 6) δ 10.36, 8.89, 8.39, 7.92, 7.86. 7.36, 4.98, 4.57, 4.03; IR (drift) 1658, 1605, 1578, 1550, 1544, 1503, 1364, 1348, 1275, 1222, 820, 808, 798, 694, 656 cm _1: Anal, found for C,9H16C N?O2: C, 60.81; H. 4J6: N. 7.49.
EXAMPLE 51. 6-(Azidomethyl)-N-(4-chlorobenzyl)- l-methyl-4-oxo- 1 ,4-dihydro- 3-quinoUnecarboxamide
Figure imgf000112_0002
A solution of N-(4-chlorobenzyl)-6-(chloromethyl)- 1 -methyl-4-oxo- 1 ,4-dihydro-3- quinoUnecarboxamide from Preparation No. 35 (200 mg) and sodium azide (176.8 mg) in anhydrous DMF (7 mL) is heated at 60 °C overnight. The reaction is cooled to room temperature and poured into water to precipitate the product. The soUd is adsorbed onto s ica and purified by chromatography (eluent 100% CH?Ch (IL), 0.5% MeOH in CH2Ch (IL), and 1% MeOH in CH Ch (IL)). Fractions homogenous by TLC were combined and concentrated to afford 182.7 mg (90%) of the title compound as a white soUd. Physical characteristics are as foUows:
Mp 219-220 °C: 1H NMR (300 MHz. DMSO- 5) δ 1038, 8.90, 8.33, 7.88, 7.38, 4.67, 4.57, 4.04: IR (drift) 2107, 2075, 1656, 1603, 1580. 1550, 1543, 1501, 1362, 1241, 1221, 822, 808. 798, 722 cm _1; Anal, found for Cι9H|6ClN5O2: C, 59.62; H, 4J5; N, 18.08.
PREPARATION 36. t-Butyl 4,4-difluoro-l-piperidinecarboxylate and t-butyl 4-fluoro-3,6- dihydro-1 [2H]-pyridinecarboxylate
Diethylaminosul ur trUluoride (4.39 mL) is added to a solution of" l-(t- butoxycarbonyl) 4-piperidone in distUled THF (41 mL). The reaction is heated at 60 °C for 6 hrs, then aUowed to cool to room temperature overnight. The reaction mixture is poured into 120 mL ice water. The phases are separated, and the aqueous layer is extracted with EtOAc three times. The combined organic layers are dried over Na2SO4, filtered, and concentrated to afford yeUow crystals. The crude product is adsorbed onto sUica and purified by chromatography (eluent 1 % EtOAc in hexanes (IL), 2% EtOAc in hexanes (IL), 3% EtOAc in hexanes (IL)). Fractions homogenous by TLC are combined and concentrated to yield a mixture of two products. The products are separated by HPLC to afford 543.8 mg (16%) of" t-butyl 4,4-dUluoro- 1 -piperidine-carboxylate [!H NMR (300 MHz, CDCh) δ 3.56, 1.94, 1.48] as a white soUd and 196 mg (7%) of t-butyl 4-fluoro-3,6- dihydro- 1 [2H]-pyridinecarboxylate [1H NMR (300 MHz, CDCh) δ 5.21, 3.93, 3.62, 2.31, 1.48] as a yeUow residue.
PREPARATION 37. 4,4-DUluoropiperidine
To a solution of t-butyl 4,4-dUluoro- 1-piperidinecarboxylate from Preparation No. 36 (510 mg) in CH2Ch (2 mL) is added trUluoro acetic acid (0.71 mL). The reaction is stirred at room temperature for 2.5 hours, and is then partitioned between saturated NaHCO3 and CH2C12. The aqueous layer is extracted with CH Ch (3x). The combined organic layers are dried (Na?SO4), fUtered, and concentrated untU product began to evaporate (vigorous bubbling seen). At least 50 mg (18%) of 4,4-difluoropiperidine was obtained as a clear Uquid.
Physical characteristics are as foUows:
- ill - 1H NMR (300 MHz, CDCh) δ 2.98. 1.94. 1.84.
EXAMPLE 52. N-(4-chlorobenzyl)-6-((4.4-dUluoro- 1 -piperidinyl)methyl)- 1 - methyl-4-oxo- 1.4-dihydro-3-quinolinecarboxamide
Figure imgf000114_0001
To a solution of N-(4-chlorobenzyl)-6-(chloromethyl)- l-methyl-4-oxo-1.4-dihydro- 3-quinolinecarboxamide from Preparation No. 35 (50 mg) in 1 -methyl-2-pyrroUdinone (3 mL) is added N.N-dnsopropylethylamine (0.03 mL) and 4.4-dUluoropiperidine from Preparation No. 37 (50 mg). The reaction mixture is stirred at room temperature overnight and then heated at 50 °C for 4 hrs. The mixture is cooled to room temperature and poured into water to precipitate the product. The crude soUd is recrystaUized from CH2Ch/hexanes to afford 51.5 mg (84%) of" the title compound as a white soUd. Physical characteristics are as foUows:
Mp 214-215 °C; Η NMR (300 MHz. OMSO-d6) δ 10.43. 8.88. 8.25. 7.81. 7.38. 4.56, 4.02. 3.72. 2.51. 1.96: IR (drift) 2823, 1655. 1606, 1574. 1551. 1502. 1490. 1362, 1132, 1085, 1017, 949, 830. 808. 802 cm _1; HRMS (FAB) calcd for C24H24CIF2N3O2+H 460.1603. found 460.1598: Anal, found for
Figure imgf000114_0002
C. 62.12: H. 5.26: N, 8.99.
PREPARATION 38. 4-Fluoro- l,2,3,6-tetrahydropyridine hydrochloride
Dry HCl is passed over the surface of a cold (0 °C) solution of t-butyl 4-fluoro-3.6- dihydro- 1 [2H]-pyridinecarboxylate from Preparation No. 36 (196 mg) in MeOH (3 mL) for 1 min. The reaction mixture is stoppered and stirred at 0 °C for 15 rain., then at room temperature for 15 min. The mixture is concentrated to afford 1 19 mg (100%) of 4-fluoro- 1,23,6-tetrahydropyridine hydrochloride as an orange-brown residue. EXAMPLE 53. N-(4-Chlorobenzyl)-6-((4-fluoro-3,6-dihydro- l (2H)- pyrid yl)methyl)-l-methyl-4-oxo-l ,4-dmydro-3-quinolinecarboxamide
Figure imgf000115_0001
To a solution of N-(4-chlorobenzyl)-6-(chloromethyl)-l-methyl-4-oxo-l ,4-dihydro- 3-quinolinecarboxamide from Preparation No. 35 (60 mg) in l-methyl-2-pyrroUdinone (3 mL) is added N,N-dϋsopropylethylamine (0.075 mL) and 4-fluoro- 1 ,2,3,6- tetrahydropyridme hydrochloride from Preparation No. 38 (1 19 mg). The reaction mixture is stirred at room temperature overnight and then heated at 60 °C for 4 hrs. The mixture is cooled to room temperature and poured into water to precipitate the product. The crude soUd is adsorbed onto silica and purified by chromatography (eluent 100% CH2Ch ( IL). 0.25% MeOH in CH2Ch (IL), 0.5% MeOH in CH2C1? (IL), 0.75% MeOH in CH2Ch (IL), 1% MeOH in CH?C1? (IL), 1.25% MeOH in CH2Ch (IL), 1.5% MeOH in CH2Ch (2L)). Fractions homogenous by TLC are combined and concentrated to afford 32.2 mg (46%) of the desired product as a white soUd.
Physical characteristics are as foUows:
Mp 221-223 °C: 1H NMR (300 MHz, OMSO-d6) δ 10.43, 8.88, 8.25, 7.82, 7.38, 5.24, 4.57, 4.03, 3.75, 2.94, 2.66, 2.26: IR (drift) 1656, 1607, 1574, 1553, 1501 , 1364, 1131, 1 1 19, 1 109, 832, 819, 808, 781, 730, 661 cm _1: Anal, found for C24H23CIFN3O2: C. 65.29; H, 5.27; N, 9.44.
PREPARATION 39. N-(4-Chlorobenzyl)-6-iodo- 1 -methyl-4-oxo- 1 ,4-dihydro-3- qumoUnecarboxamide
Figure imgf000115_0002
N-(4-Chlorobenzyl)-4-hydroxy-6-iodo-3-quinolinecarboxamide (12.07 g) from
Preparation No. 4 and potassium carbonate (5.70 g) are disolved in DMF (90 mL). Iodomethane (2J mL) is added and the mixture is stirred at room temperature for 1 h. The resulting suspension is poured into water (500 mL) and filtered. The crude soUd is washed with water (50 mL) and diethyl ether (100 mL) and then is recrystaUized from ethanol to afford 10.6 g (85%) of the title compound as a white soUd.
Physical characteristics are as foUows:
Mp 205-208 °C: 1H NMR (DMSO- *) δ 10.25, 8.89, 8.59, 8J4, 7.66, 7.42-733. 4.55, 4.00; 13C NMR (CF3CO,D) δ 173.3, 167.6, 147.9, 147.3, 140J, 135.5, 135.4, 133.9. 129.6, 1233, 1 19.1 , 106.7, 95.3, 44.5, 44.2: IR (drU't) 3044, 1656, 1602, 1575, 1551, 1493, 1469, 1438, 1361 , 1312. 1241, 1126, 810, 801 , 663 cm"'. Anal. Found for C18Hι4CUN2O2: C, 47.71 ; H, 3.23: N, 6.08; Cl, 7.67; I, 28.52..
EXAMPLE 54. N-(4-Chlorobenzyl)- 1 -methyl-4-oxo-6- vinyl- 1 ,4-dihydro-3- quinolinecarboxamide [321 12-mes-57B]
Figure imgf000116_0001
Tributylvinylstannane (0.32 mL) is added to a solution of N-(4-chlorobenzyl)-6-iodo- l-methyl-4-oxo- l ,4-dihydro-3-quinolinecarboxamide (0.45 g) from Preparation No. 39 and PdCl2(PPh3)2 (70 mg). The mixture is stirred at room temperature for 1 h and then is heated to 60 °C for 30 min. After cooUng to room temperature, the reaction mixture is poured into water (60 mL), fUtered, and washed with water (20 mL) and diethyl ether (20 mL). The crude product is purified by recrystaUization from acetonitrUe to afford 0.20 g (57%) of the title compound as a white soUd.
Physical characteristics are as foUows:
Mp 193-196 °C: Η NMR (OMSO-d6) δ 10.40, 8.86, 8.31 , 8.04, 7.82. 7.42-735, 6.93, 5.99, 5.39, 4.56, 4.03; 13C NMR (CF3CO2D) δ 173.9, 167.7, 146.7, 141J , 140.0, 135.9, 135.4, 133.4, 129.6, 129.5, 123J , 122.4, 1 19.8. 1 18.2, 106.2, 44.4, 44.2: IR (drift) 1654, 1618, 1602, 1550, 1541 , 1498, 1362, 1318, 1238, 1225, 91 1, 822, 806. 798, 717 cm" ': MS (EI ) m/z 352 (M+, 26). Anal. Found for CzoHπClNjO?: Found: C, 68.08: H, 4.92: N, 7.91 ; Cl, 10.01. PREPARATION 40. N-(4-Chlorobenzyl)-4-hydroxy-6-(4-morphoUnylmethyl)-3- quinolinecarboxamide
Figure imgf000117_0001
A solution of N-(4-chlorobenzyl)-4-hydroxy-6-(hydroxymethyl)-3-quinoline- carboxamide (1.71 gm) from Preparation No. 9 in DMF (50 mL) at 0 °C under a drying tube is treated with 4-dimethylaminopyridine (0J2 gm). 2,4,6-coUidine (1.05 mL) and methanesuUonylchloride (0.60 mL). The mixture is aUowed to slowly warm to room temperature overnight. The reaction mixture is then treated with morpholine (8.0 mL) and stirred for 4 hrs. The reaction mixture is poured into water (250 mL) and extracted with dichloromethane (5 x 50 mL). The combined organic layers are washed with water, brine, dried (Na?SO ) and concentrated under reduced pressure. The crude product is purified by recrystaUization from methanol-acetonitrUe (1/1 , 150 mL) to afford 1.1 gm of the title compound as a white soUd.
Physical characteristics are as foUows:
1H NMR (DMSO-d6) δ 12.7, 10.4, 8.7. 8J . 7.8-7.6, 7.4-7.3, 4.5, 3.6. 2.3: MS (ESI+) m/z 412, MS (ESI-) m/z 410.
EXAMPLE 55. N-(4-Chlorobenzyl)- l-[2-(2-hydroxyethoxy)ethyl]-6-(3-hydroxy- propynyl)-4-oxo- 1.4-dihydro-3-quinolinecarboxamide
Figure imgf000117_0002
A solution of N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxy- 1 -propynyl)-3-quinoline- carboxamide (0.37gm) from Preparation No. 5 in DMF (10 mL) is treated with potassium carbonate (2.75 gm), potassium iodide (1.66 gm) and 2-(2-chloroethoxy)ethanol (1.0 mL). The mixture is tightly capped and heated to 100 °C for 48 hrs. The reaction mixture is aUowed to cool to room temperature, poured into water and extracted with dichloromethane. The layers are separated and the aqueous layer is re-extracted with dichloromethane containing a smaU amount of methanol and finally again with dichloromethane. The combined organic layers are washed with brine, dried (Na2SO4) and concentrated under reduced pressure. The crude product is purUied by flash column chromatography eluting with 3% to 15% methanol in dichloromethane and then by recrystaUization from methanol to afford 82 mg of the title compound as a Ught yeUow soUd. Physical characteristics are as foUows:
Η NMR (DMSO-J6) δ 10.2, 8.8, 8.3, 7.9. 7.8, 7.4-7.3. 5.4. 4.6, 4.5, 3.8, 3.4; MS (ESI+) m/z 455.
EXAMPLE 56. N-(4-Chlorobenzyl)-l-{2-[2-(2-methoxyethoxy)ethoxy]ethyl}-6- (4-morpholinylmethyl)-4-oxo- 1 ,4-dihydro-3-quinolinecarboxamide
Figure imgf000118_0001
A dry flask containing N-(4-chlorobenzyl)-4-hydroxy-6-(4-morpholinylmethyl)-3- quinolinecarboxamide (0.20 gm) from Preparation No. 40 in dry THF (5 mL) under an argon atmosphere is added triphenylphosphine ( 165 mg), triethyleneglycol monomethyl ether (0J0 mL) and diethyl azodicarboxylate (0J0 mL). The mixture is stirred at room temperature for 2 hrs. The reaction mixture is concentrated under reduced pressure. The crude product is purUied by flash column chromatography eluting with 2% to 8% methanol in dichloromethane and then by recrystaUization from ethyl acetate-heptane to afford 164 mg of the title compound as a white soUd.
Physical characteristics are as foUows:
Η NMR (CDCh) δ 10.5, 8.8, 8.4, 7.8, 7.5, 7.3-7.2, 4.6, 4A 3.9. 3.7-3.3, 2.4; MS (ESI+) m/z 558. Anal, found for C29H36ClN3O6: C, 62.17; H. 6.64: N, 7.63.
EXAMPLE 57. N-(4-Chlorobenzyl)- l-[2-(2-hydroxyethoxy)ethyl]-6-(4- morpholinylmethyl)-4-oxo- 1 ,4-dihydro-3-quinolinecarboxamide
Figure imgf000118_0002
A dry flask containing N-(4-chlorobenzyl)-4-hydroxy-6-(4-morpholinylmethyl)-3- quinoUnecarboxamide (0.20 gm) from Preparation No. 40 in dry THF (5 mL) under an argon atmosphere is added triphenylphosphine (165 mg), diethyleneglycol (0.20 mL) and diethyl azodicarboxylate (0J0 mL). The mixture is stirred at room temperature for 2 hrs. The reaction mixture is concentrated under reduced pressure. The crude product is purUied by flash column chromatography eluting with 10% to 40% methanol in ethyl acetate and then by recrystaUization from ethyl acetate to afford 68 mg of the title compound as a white soUd.
Physical characteristics are as foUows: 1H NMR (CDCh) δ 10.5, 8.9, 8.4, 7.8, 7.5, 7.3-7.2, 4.6, 4.4, 3.9, 3.7-3.5, 2.4; MS
(ESI+) m/z 500; Anal, found for C26H3oClN3Os: C, 62.23: H, 6J2; N, 8.29.
EXAMPLE 58. N-(4-Chlorobenzyl)- 1 -[2-(2-ethoxyethoxy)ethyl]-6-(4- morphoUnylmethyl)-4-oxo- 1 ,4-dihydro-3-quinolinecarboxamide
Figure imgf000119_0001
A dry flask containing N-(4-chlorobenzyl)-4-hydroxy-6-(4-morpholinylmethyl)-3- qumoUnecarboxamide (0.20 gm) from Preparation No. 40 in dry THF (5 mL) under an argon atmosphere is added triphenylphosphine (164 mg). 2-ethoxy-(2-ethoxy)ethanol (0.09 mL) and diethyl azodicarboxylate (0J0 mL). The mixture is stirred at room temperature overnight. The reaction mixture is again treated with triphenylphosphine (164 mg), 2- ethoxy-(2-ethoxy)ethanol (0.09 mL) and diethyl azodicarboxylate (0.10 mL). After 4 hours, the reaction mixture is concentrated under reduced pressure. The crude product is purUied by flash column chromatography eluting with acetone and then by recrystaUization from ethyl acetate-heptane to afford 0.18 gm of" the title compound as a white soUd. Physical characteristics are as foUows:
Η NMR (CDCh) δ 10.5, 8.8, 8.4, 7.8, 7.5, 7.3-7.2, 4.6, 4.4, 3.9, 3.7-3.4, 2.5, 1 J ; MS (ESI+) m/z 528. Anal, found for C28H34CIN3O5: C, 63.67; H, 6.55; N, 7.90. EXAMPLE 59. N-(4-Chlorobenzyl)-6-(4-morphoUnylmethyl)-4-oxo- l-(2- propynyl)- 1 ,4-dUιydro-3-quinoUnecarboxamide
Figure imgf000120_0001
A dry flask containing N-(4-chlorobenzyl)-4-hydroxy-6-(4-morphoUnylmethyl)-3- quinolinecarboxamide (0.20 gm) from Preparation No. 40 in dry THF (5 mL) under an argon atmosphere is added triphenylphosphine (393 mg), propargyl alcohol (0.09 mL) and diethyl azodicarboxylate (0J 8 mL). The mixture is stirred at room temperature overnight. The reaction mixture is concentrated under reduced pressure and adsorbed onto sUica gel. The crude product is purUied by flash column chromatography eluting with 2% to 6% methanol in dichloromethane and then by recrystaUization from acetonitrUe to afford 0.20 gm of the title compound as a white soUd. Physical characteristics are as foUows:
Mp 221-224 °C (dec); Η NMR (CDCh) δ 10.4, 8.9, 8.4, 7.8, 7.6, 7.3, 5.0, 4.6, 3.7. 3.6, 2.4: MS (ESI+) m/z. 450. Anal, found for C25H24CIN3O3: C, 66.57: H, 5.41 : N, 9.28.
EXAMPLE 60. N-(4-Chlorobenzyl)- l-[2-(ethylsuUanyl)ethyl]-6-(4- morphoUnylmethyl)-4-oxo- 1.4-dihydro-3-quinolinecarboxamide
Figure imgf000120_0002
A dry flask containing N-(4-chlorobenzyl)-4-hydroxy-6-(4-morpholinylmethyl)-3- quinolinecarboxamide (0.20 gm) from Preparation No. 40 in dry THF (5 mL) under an argon atmosphere is added triphenylphosphine (393 mg), ethyl 2-hydroxyethylsuUide (0J6 mL) and diethyl azodicarboxylate (0J 8 mL). The mixture is stirred at room temperature overnight then concentrated under reduced pressure. The crude product is purUied by flash column chromatography eluting with 2% to 6% methanol in dichloromethane and then by recrystaUization from ethanol-cyclohexane to afford 0J 1 gm of the title compound as a white soUd.
Physical characteristics are as foUows: Mp 140-142 °C: 1H NMR (CDCh) δ 10.4, 8.8, 8.4, 7.8, 7.5, 7.3, 4.6, 4.4, 3.7, 3.6. 3.0, 2.6, 2.4, 1.3; MS (ESI+) m/z 500. Anal, found for C26H30CIN3O3S: C, 62.36; H, 6J6:
N, 8.37.
EXAMPLE 61. N-(4-Chlorobenzyl)- l-[3-(methylsuU"anyl)propyl]-6-(4- morpholinylmethyl)-4-oxo- 1 ,4-dihydro-3-quinolinecarboxamide
Figure imgf000121_0001
A dry flask containing N-(4-chlorobenzyl)-4-hydroxy-6-(4-morpholinylmethyl)-3- quinoUnecarboxamide (0.20 gm) from Preparation No. 40 in dry THF (5 mL) under an argon atmosphere is added triphenylphosphme (396 mg), 3-methylthiolpropanol (0J6 mL) and diethyl azodicarboxylate (0J 8 mL). The mixture is stirred at room temperature 48 hours and then concentrated under reduced pressure. The crude product is purUied by flash column chromatography eluting with 2% to 6% methanol in dichloromethane and then by recrystaUization from toluene-cyclo hexane to afford 0.14 gm of the title compound as a white soUd.
Physical characteristics are as foUows: Mp 102-104 °C: Η NMR (CDCh) δ 10.5, 8.8, 8.4, 7.8, 7.6, 7.3-7.2, 4.6, 4.4, 3.7,
3.6. 3.0, 2.6, 2.5, 2.2: MS (ESI+) m/z 500; HRMS (FAB) found 500.1779 for
Figure imgf000121_0002
EXAMPLE 62. N-(4-Chlorobenzyl)- l-(4-hydroxy-2-butynyl)-6-(4- morphoUnylmethyl)-4-oxo- 1 ,4-dihydro-3-quinolinecarboxamide
Figure imgf000121_0003
A dry flask containing N-(4-chlorobenzyl)-4-hydroxy-6-(4-morpholinylmethyl)-3- quinolinecarboxamide (0.20 gm) from Preparation No. 40 in dry THF (5 mL) under an argon atmosphere is added triphenylphosphine (393 mg), 1 ,4-butyne diol (0.45 gm) and diethyl azodicarboxylate (0J8 mL). The mixture is stirred at room temperature overnight, concentrated under reduced pressure and adsorbed onto sUica gel. The crude product is purified by flash column chromatography eluting with 2% to 6% methanol in dichloromethane and then by recrystaUization from methanol-acetonitrUe to afford 0J6 gm of the title compound as a white soUd. Physical characteristics are as foUows:
Mp 215-217 °C (dec); 1H NMR (CDCh) δ 10.4, 8.9, 8.4. 7.8. 7.6, 7.3, 5.0, 4.6. 4.3, 3.7, 3.6, 2.5; MS (ESI+) m/z 480; Anal, found for C26H26CIN3O4: C, 64.68; H, 5.52; N, 8.62.
EXAMPLE 63. N-(4-Chlorobenzyl)-6-{ [(2-hydroxy-2-phenylethyl)(methyl)- amino]methyl}- l-methyl-4-oxo- 1 ,4-dihydro-3-quinolinecarboxamide
Figure imgf000122_0001
A solution of N-(4-chlorobenzyl)-6-(chloromethyl)- l-methyl-4-oxo- 1 ,4-dihydro-3- quinolinecarboxamide (0.06 gm) from Preparation No. 35 in dry NMP (2 mL) containing dusopropylethylamine (0.04 mL) is treated with α-(methylaminomethyl)-benzyl alcohol (0.04 gm). The reaction mixture is shaken at room temperature for 3 days then concentrated under reduced pressure. The residue is partioned between dichloromethane and water. The separated organic layer is washed with two additional portions of water, brine, dried (Na2SO4) and concentrated under reduced pressure. The residue is adsorbed onto silica and purUied by flash column chromatography eluting with 2% to 6 methanol in dichloromethane and then by recrystaUization from ethyl acetate-hexanes to afford 0.05 gm of the title compound as a white soUd.
Physical characteristics are as foUows:
Η NMR (CDCh) δ 10.4, 8.8, 8.4, 7.8, 7.5, 7.3, 5.0, 4.8. 4.6, 4.0, 3.9-3.6, 2.6, 2.3; MS (ESI+) m/z 490: HRMS (FAB) found for C∑βHzβClNsOs+H: 490.1895. EXAMPLE 64. l-{2-[Bis(2-hydroxyethyl)amino]ethyl}-N-(4-chlorobenzyl)-6-(4- morphoUnylmethyl)-4-oxo- 1.4-dihydro-3-quinoUnecarboxamide
Figure imgf000123_0001
A dry flask containing N-(4-chlorobenzyl)-4-hydroxy-6-(4-morphoUnyknethyl)-3- quinolinecarboxamide (0J0 gm) from Preparation No.40 in dry THF (5 mL) under an argon atmosphere is added triphenylphosphine (363 mg), triethanolamine (1.3 mL) and diethyl azodicarboxylate (0J8 mL). The mixture is stirred at room temperature for 4 days. The reaction mixture is concentrated under reduced pressure and the crude product is purified by flash column chromatography eluting with 3% to 9% methanol in dichloromethane. The product fractions are concentrated under reduced pressure, dissolved in a smaU volume of ethyl acetate - diethyl ether and added dropwise to a large volume of hexanes. The resulting precipitant is coUected by filtration, washed with diethyl ether foUowed by hexanes to afford 0.04 gm of the title compound as a white solid. Physical characteristics are as foUows:
Η NMR (CDCh) δ 10.5, 9.0. 8.4. 7.8, 7.5. 73, 4.6, 4.3. 3.7-3.4. 3.0. 2.7. 2.4: MS (ESI+) m/z 543; HRMS (FAB) found 543.2369 for C28H35ClN4O,+H.
EXAMPLE 65. N- (4- Chlorobenzyl)- l-[3-(methylsuUinyl)propyl]-6-(4- morpholinylmethyl)-4-oxo- 1.4-dihydro-3-quinolinecarboxamide
Figure imgf000123_0002
A solution of N-(4-chlorobenzyl)-l-[3-(methylsuffanyl)propyl]-6-(4- morphoUnylmethyl)-4-oxo-l,4-dihydro-3-quinoUnecarboxamide (0J0 gm) from Example No. 61 in dichloromethane (2 mL) at 0 °C is added p-toluenesuU'onic acid hydrate (0.04 gm) foUowed by m-chloroperoxybenzoic acid (~85%)(0.045 gm). The mixture is stirred for 0.5 hrs. The reaction mixture is dUuted with dichloromethane, washed with saturated aqueous sodium suUite, saturated aqueous sodium bicarbonate, brine, dried (Na2SO ) and concentrated under reduced pressure. The crude product is purified by flash column chromatography eluting with 3% to 9% methanol in dichloromethane. The product fractions are combined and recrystaUized from ethyl acetate-methanol-hexanes to afford 0.07 gm of the title compound as a white soUd. Physical characteristics are as foUows:
Η NMR (DMSO-d6) δ 10.4, 8.9, 8.2, 7.9. 7.8, 7.4, 4.6, 3.6, 2.9-2.7, 2.5, 2.4, 2.0; MS (ESI+) m/z 516; HRMS (FAB) found 516.1729 for C26H30CIN3O4S+H.
EXAMPLE 66. N-(4-Chlorobenzyl)-l-{3-[(3-hydroxypropyl)suU'anyl]propyl}-6-(4- morphoUnylmethyl)-4-oxo-l ,4-dihydro-3-quinolinecarboxamide
Figure imgf000124_0001
A dry flask containing N-(4-chlorobenzyl)-4-hydroxy-6-(4-morphoUnylmethyl)-3- quinolinecarboxamide (0.20 gm) from Preparation No. 40 in dry THF (5 mL) under an argon atmosphere is added triphenylphosphine (314 mg), 3,3'-thiodipropanol (0J mL) and diethyl azodicarboxylate (0J8 mL). The mixture is stirred at room temperature overnight. The reaction mixture is concentrated under reduced pressure and the crude product is purUied by flash column chromatography eluting with 5% to 15% methanol in dichloromethane. The product fractions are concentrated under reduced pressure and recrystaUized from ethyl acetate-hexanes to afford 0J0 gm of the title compound as a white soUd.
Physical characteristics are as foUows: Η NMR (DMSO- 5) δ 10.4, 8.9, 8.2. 7.9, 7.8, 7.3, 4.5, 4.3, 3.6, 3.4, 2.5-2.3, 2.0,
1.6; MS (ESI+) m/z 544; Anal, found for C28H34CIN3O4S: C, 61.69; H, 6.30; N. 7.67. EXAMPLE 67. N-(4-Chlorobenzyl)- 1 -[3-(methylsuU'onyl)propyl]-6-(4- morphoUnylmethyl)-4-oxo- 1.4-dihydro-3-quinolinecarboxamide
Figure imgf000125_0001
A solution of'N-(4-chlorobenzyl)-l-[3-(methylsurfanyl)propyl]-6-(4- morpholinyknethyl)-4-oxo-l,4-dihydro-3-quinolinecarboxamide (0J0 gm) from Example No. 61 in dichloromethane (2 mL) at 0 °C is added /?-toluenesuU'onic acid hydrate (0.04 gm) foUowed by m-chloroperoxybenzoic acid (-85%) (0.09 gm). The mixture is stirred for 0.5 hrs. The reaction mixture is dUuted with dichloromethane. washed with saturated aqueous sodium suUite, saturated aqueous sodium bicarbonate, brine, dried (Na2SO4) and concentrated under reduced pressure. The crude product is purUied by flash column chromatography eluting with 3% to 6% methanol in dichloromethane to afford 0.07 gm of" the title compound as a white soUd.
Physical characteristics are as foUows:
1H NMR (CDCh) δ 10.4, 8.8, 8.4, 7.8, 7.6, 7.3. 4.6, 4.5, 3.7, 3.6, 3J, 2.5: MS (ESI+) m/z 532: Anal, found for
Figure imgf000125_0002
C, 58.29: H, 5.72: N, 7.77.
EXAMPLE 68. N-(4-Chlorobenzyl)-l-[2-(ethylsuUinyl)ethyl]-6-(4- morphoUnylmethyl)-4-oxo- 1 ,4-dihydro-3-quinolinecarboxamide
Figure imgf000125_0003
A solution of N-(4-chlorobenzyl)- 1 -[2-(ethylsuU"anyl)ethyl]-6-(4-morphoUnylmethyl)- 4-oxo- l,4-dihydro-3-quinolinecarboxamide (0J0 gm) from Example No. 60 in dichloromethane (2 mL) at 0 °C is added /?-toluenesuU"onic acid hydrate (0.04 gm) foUowed by m-chloroperoxybenzoic acid (-85%) (0.045 gm). The mixture is stirred for 0.5 hrs. The reaction mixture is dUuted with dichloromethane, washed with saturated aqueous sodium sulfite, saturated aqueous sodium bicarbonate, brine, dried (Na SO ) and concentrated under reduced pressure. The crude product is purUied by flash column chromatography eluting with 3% to 9% methanol in dichloromethane and then by recrystaUization from acetonitrUe to afford 0.05 gm of the title compound as a white soUd. Physical characteristics are as foUows: Η NMR (DMSO-fife) δ 10.4, 8.9, 8.3, 7.9, 7.8, 7.4-7.3, 4.9, 4.6, 3.6, 3.3, 3J, 2.8-
2.7, 2.4, 1.2; MS (ESI+) m/z 516; HRMS (FAB) found 516.1729 for C26H30CIN3O4S+H; Anal, found for C26H30CIN3O4S: C, 60.55; H, 5.95; N, 8.04.
EXAMPLE 69. N-(4-Chlorobenzyl)-l-[2-(ethylsuU"onyl)ethyl]-6-(4- morpholinylmethyl)-4-oxo-l,4-d ydro-3-quinolinecarboxamide
Figure imgf000126_0001
A solution of V-(4-chlorobenzyl)- 1 -[2-(ethylsuU"anyl)ethyl]-6-(4-morpholinylmethyl)- 4-oxo- l,4-dihydro-3-quinolinecarboxamide (0.10 gm) from Example No. 60 in dichloromethane (2 mL) at 0 °C is added -toluenesuU'onic acid hydrate (0.04 gm) foUowed by m-chloroperoxybenzoic acid (-85%) (0.085 gm). The mixture is stirred for 0.5 hrs. The reaction mixture is dUuted with dichloromethane, washed with saturated aqueous sodium suUite. saturated aqueous sodium bicarbonate, brine, dried (Na SO ) and concentrated under reduced pressure. The crude product is purUied by recrystaUization from acetonitrUe to afford 0.08 gm of" the title compound as a white soUd. Physical characteristics are as foUows: 1H NMR (DMSO-ύfe) δ 10.4, 8.9, 8.3, 7.8, 7.4-7.3, 4.9, 4.6, 3.7, 3.6, 3.2, 2.4, 1.2;
MS (ESI+) m/z. 532; HRMS (FAB) found 532.1677 for C26H30CIN3O5S+H. EXAMPLE 70. N-(4-Chlorobenzyl)- 1 -(3-[(3-hydroxypropyl)suUinyl]propyl)-6-(4- morphoUnylmethyl)-4-oxo- 1 ,4-dinydro-3-quinolinecarboxamide
Figure imgf000127_0001
A solution ol"N-(4-chlorobenzyl)-l-(3-[(3-hydroxypropyl)suU'anyl]propyl)-6-(4- morpholinylmethyl)-4-oxo-1.4-dihydro-3-quinolinecarboxamide (0.27 gm) from Example No. 66 in dichloromethane (5 mL) at 0 °C is added /?-toluenesuU'onic acid hydrate (0J0 gm) foUowed by m-chloroperoxybenzoic acid (-85%) (0J0 gm). The mixture is stirred for 0.5 hrs. The reaction mixture is dUuted with dichloromethane. washed with saturated aqueous sodium suUite, saturated aqueous sodium bicarbonate, brme. dried (Na2SO4) and concentrated under reduced pressure. The crude product is purUied by flash column chromatography eluting with 3% to 25% methanol in dichloromethane to afford 0J7 gm of the title compound as a white soUd.
Physical characteristics are as foUows:
Η NMR (CDCh) δ 10.5, 8.8, 8.4. 7.8. 7.6. 7.3. 4.6. 4.5. 3.8-3.5. 3.0-2.7. 2.5. 2.0: MS (ESI+) m/z 560: HRMS (FAB) found 560.1988 for C28H34ClN3O,S+H.
EXAMPLE 71. N-(4-Chlorobenzyl)- 1 -(3-[(3-hydroxypropyl)suU'onyl]propyl)-6-(4- morpholinylmethyl)-4-oxo- 1 ,4-dihydro-3-quinolinecarboxamide
Figure imgf000127_0002
A solution of N-(4-chlorobenzyl)-l-(3-[(3-hydroxypropyl)sulfanyl]propyl)-6-(4- morphoUnylmethyl)-4-oxo- l ,4-dihydro-3-quinoUnecarboxamide (0.27 gm) from Example No. 66 in dichloromethane (5 mL) at 0 °C is added -toluenesulfonic acid hydrate (0J0 gm) foUowed by m-chloroperoxybenzoic acid (-85%) (0J0 gm). The mixture is stirred for 0.5 hrs. The reaction mixture is dUuted with dichloromethane. washed with saturated aqueous sodium suUite, saturated aqueous sodium bicarbonate, brine, dried (Na2SO ) and concentrated under reduced pressure. The crude product is purUied by flash column chromatography eluting with 3% to 9% methanol in dichloromethane and then by recrystallization from acetonitrUe to afford 0.08 gm of the title compound as a white soUd. Physical characteristics are as foUows:
Η NMR (CDCh) δ 10.5. 8.8, 8.4, 7.8, 7.6, 7.3, 4.9, 4.6, 4.5, 3.8-3.6, 3.2-3.1, 2.5, 2.1; MS (ESI+) m/z 576; Anal, found for C28H34ClN3O6S: C, 58.12: H. 6.06; N, 7.33.
EXAMPLE 72. N-(4-Chlorobenzyl)-6-(4-morphoUnyUnethyl)-4-oxo-l-[2- (phenylsuUanyl)ethyl]- 1 ,4-di ydro-3-quinolinecarboxamide
Figure imgf000128_0001
A dry flask containing N-(4-chlorobenzyl)-4-hydroxy-6-(4-morpholinylmethyl)-3- quinoUnecarboxamide (0.20 gm) from Preparation No. 40 in dry THF (5 mL) under an argon atmosphere is added triphenylphosphme (284 mg), 2-hydroxyethyl phenyl suUide (0.27 mL) and diethyl azodicarboxylate (0J7 mL). The mixture is stirred at room temperature overnight. The reaction mixture is concentrated under reduced pressure and the crude product is purUied by flash column chromatography eluting with 5% to 15% methanol in dichloromethane. The product fractions are concentrated under reduced pressure and recrystaUized from acetonitrUe to afford 0J1 gm of the title compound as a white soUd. Physical characteristics are as foUows: Mp 166-167°C: 1H NMR (DMSO-d6) δ 10.4. 8.9, 8.2, 7.9, 7.8. 73. 4.5. 4.3. 3.6.
3.4, 2.5-2.3, 2.0, 1.6; MS (ESI+) m/z 544: Anal, found for C28H34CI 3O4S: C. 61.69; H. 6.30; N. 7.67. EXAMPLE 73. N-(4-Chlorobenzyl)-l-[(methylsuU"anyl)methyl]-6- (morphoUnylmethyl)-4-oxo- 1 ,4-dihydro-3-quinolinecarboxamide
Figure imgf000129_0001
A solution of N-(4-chlorobenzyl)-4-hydroxy-6-(4-morpholinylmethyl)-3-quinoUne- carboxamide (0.21 gm) from Preparation No. 40 in DMF (4 mL) is treated with cesium carbonate (0.33 gm) and chlormethyl methyl suUIde (0.05 mL). The mixture is tightly capped, stirred at room temperature for 3 hrs and then heated to 90 °C for lhr. The reaction mixture is aUowed to cool to room temperature, dUuted with dichloromethane (50 mL) and washed with water (2x), brine, dried (Na2SO4) and concentrated under reduced pressure. The crude product is purUied by flash column chromatography eluting with 2% to 4% methanol in dichloromethane and then by recrystaUization from acetonitrUe to afford 0.1 gm of" the title compound as a white soUd.
Physical characteristics are as foUows:
Mp 199-201°C: lH NMR DMSO-d6) δ 10.3, 9.0, 8.2, 7.9. 7.8, 7.4-7.3, 5.7, 4.5, 3.6, 2.4, 2.1 : MS (ESI+) m/z 472: Anal, found for C24H26CIN3O3S: C, 61.00: H, 5.62; N, 8.92.
EXAMPLE 74. N-(4-Chlorobenzyl)- 6J[(2-hydroxy-2J4-hydroxyphenyl]- ethyl)[methyl]amino]methyl)- l-methyl-4-oxo- 1 ,4-dihydro-3-quinolinecarboxamide
Figure imgf000129_0002
A solution of N-(4-chlorobenzyl)-6-(chloromethyl)- 1 -methyl-4-oxo- 1 ,4-dihydro-3- quinolinecarboxamide (0.09 gm) from Preparation No. 35 in dry DMF (2 mL) containing dnsopropylethylamine (0.07 mL) is treated with synephrine (0.05 gm). The reaction mixture is stirred overnight. The reaction mixture is dUuted with dichloromethane (50 mL) and washed with water (2 x 10 mL), brine (10 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue is purUied by flash column chromatography eluting with 3% to 6% methanol in dichloromethane and then by recrystaUization from toluene to afford 0.09 gm of the title compound as a tan soUd.
Physical characteristics are as foUows:
Η NMR (CDCh) δ 10.5, 8.8, 8.4, 7.8, 7.5. 7.3, 7J, 6.7, 4.6, 3.9. 3.8, 3.6. 2.6-2.4, 2.3: MS (ESI+) m/z 506; HRMS (FAB) found 506.1848 for C?8H28Cl 3θ4+H.
EXAMPLE 75. N-(4-Chlorobenzyl)-6-[(3-hydroxy-l-azetidinyl)methyl]-l-methyl- 4-oxo- 1 ,4-dihydro-3-quinolinecarboxamide
Figure imgf000130_0001
A solution of N-(4-chlorobenzyl)-6-(chloromethyl)- 1 -methyl-4-oxo- 1.4-dihydro-3- quinolinecarboxamide (0.09 gm) from Preparation No. 35 in dry NMP (2 mL) containing dUsopropylethylamine (0J4 mL) is treated with 3-azetidinol hydrochloride (0.04 gm) (prepared as described in Helv. Chim. Acta 1988. 1035). The reaction mixture is stirred overnight. The reaction mixture is dUuted with dichloromethane (50 mL) and washed with water (2 x 10 mL), brine (10 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue is purUied by flash column chromatography eluting with 5% to 20% methanol in dichloromethane and then by recrystalUzation from methanol-acetonitrUe to afford 0.08 gm of" the title compound as an off-white soUd.
Physical characteristics are as foUows:
1H NMR (DMSO-ctø δ 10.4, 8.8, 8.2, 7.8, 7.4, 53, 4.5. 4.2. 4.0. 3.7, 3.5, 2.8; MS (ESI+) m/z 412: HRMS (FAB) found 412.1412 for C22H22ClN<Oι+H.
EXAMPLE 76. N-(4-Chlorobenzyl)- 6-(morpholinylmethyl)-4-oxo- [(phenylsuU'anyl) methyl]- 1 ,4-dihydro-3-quinolinecarboxamide
Figure imgf000130_0002
A solution of N-(4-chlorobenzyl)-4-hydroxy-6-(4-morpholinylmethyl)-3-quinoline- carboxamide (0.21 gm) from Preparation No. 40 in DMF (4 mL) is treated with cesium carbonate (0.30 gm) and chloromethyl phenyl suUide (0.08 mL). The mixture is tightly capped and heated to 75 °C for 8 hrs. The reaction mixture is aUowed to cool to room temperature, dUuted with dichloromethane (50 mL) and washed with water (2 x 10 mL), brine, dried (Na?SO4) and concentrated under reduced pressure. The crude product is purUied by flash column chromatography eluting with 2% to 4% methanol in dichloromethane and then by recrystaUization from ethyl acetate-hexanes to afford 0J9 gm of the title compound as a white soUd.
Physical characteristics are as foUows:
1H NMR (DMSO-cfe) δ 10.2, 8.4, 8.2, 7.9, 7.8, 7.4-7.3, 6.0, 4.5, 3.6, 2.4; MS (ESI+) m/z 534: Anal, found for C29H28CIN3O3S: C, 64.88; H, 5.27; N, 7.75.
EXAMPLE 77. N- (4- Chlorobenzyl)- 6-([(2-hydroxy-2-[4-hydroxy-3- methoxyphenyl]ethyl)[methyl]amino]methyl)-l-methyl-4-oxo- l ,4-dihydro-3- quinolinecarboxamide
Figure imgf000131_0001
A solution of N-(4-chlorobenzyl)-6-(chloro methyl)- 1 -methyl-4-oxo- 1.4-dihydro-3- qumoUnecarboxamide (0.09 gm) from Preparation No. 35 in dry DMF (2 mL) containing dUsopropylethylamine (0J 8 mL) is treated with ^/-metanephrine hydrochloride (0J2 gm). The reaction mixture is stirred at room temperature for 3 days. The reaction mixture is dUuted with dichloromethane (50 mL) and washed with water (2 x 10 mL), brine (10 mL), dried (Na SO4) and concentrated under reduced pressure. The residue is purUied by flash column chromatography elutmg with 2% to 5% methanol in dichloromethane and then by recrystaUization from methanol-toluene to afford 0.08 gm of the title compound as an off- white soUd.
Physical characteristics are as foUows:
Η NMR (DMSO-cfe) δ 10.4. 8.9, 8.7, 8.2, 7.7, 7.4, 6.8, 6.7, 4.9. 4.6, 4.0, 3.7, 2.5, 2.2; MS (ESI+) m/z 536; HRMS (FAB) found 536.1949 for C29H3oClN3θ5+H. EXAMPLE 78. N-(4-Chlorobenzyl)-6-[(3,3-dUιydroxy- l-azetidinyl)methyl]-l- methyl-4-oxo- 1 ,4-dihydro-3-quinolιnecarboxamide
Figure imgf000132_0001
A solution of N-(4-chlorobenzyl)-6-[(3-hydroxy-l-azetidinyl)methyl]- l-methyl-4- oxo-l,4-dihydro-3-quinoUnecarboxamide (OJO gm) from Example No. 75 in dry DMSO (3 mL) containing triethylamine (0.35 mL) is treated with pyridine-suU'ur trioxide complex (0J5 gm). The reaction mixture is stirred at room temperature for 2 hrs. The reaction mixture is dUuted with ethyl acetate and washed with water (2x). brine, dried (Na2SO ) and concentrated under reduced pressure. The residue is purified by recrysraUization from acetonitrUe to afford 0.06 gm of the title compound as a tan soUd. Physical characteristics are as foUows: 1H NMR (OMSO-d6) δ 10.4. 8.9, 8.3. 7.8. 7.4. 4.6. 4.2. 4.0: MS (ESI+) m/z. 442
(MeOH adduct): HRMS (FAB) found 428.1381 for C22H??ClN,O4+H.
EXAMPLE 79. N-(4-Chlorobenzyl)- H(methylsuUinyl)methyl]-6-(4- morpholinylmethyl)-4-oxo- 1.4-dihydro-3-quinolinecarboxamide
Figure imgf000132_0002
A solution of N-(4-chlorobenzyl)- 1 -[(methylsulfanyl)methyl]-6-(4- morpholinylmethyl)-4-oxo-l ,4-dihydro-3-quinolinecarboxamide (0J4 gm) from Example No. 73 in dichloromethane (4 mL) at 0 °C is added -toluenesuU'onic acid hydrate (0.06 gm) foUowed by m-chloroperoxybenzoic acid (-85%) (0.06 gm). The mixture is stirred for 1 hr. The reaction mixture is dUuted with dichloromethane, washed with saturated aqueous sodium sulfite, saturated aqueous sodium bicarbonate, brine, dried (Na2SO ) and concentrated under reduced pressure. The crude product is purUied by recrystaUization from methanol-acetonitrUe to afford 0.1 1 gm of the title compound as a white soUd. Physical characteristics are as foUows:
Η NMR (CDCh) δ 10.3, 8.9, 8.4. 7.8, 7.6, 7.3, 5.3, 4.6, 3.7, 3.6, 2.8, 2.5; MS (ESI+) m/z 488; Anal, found for C24H26CIN3O4S: C, 58.71; H, 5.38; N, 8.57.
EXAMPLE 80. N-(4-Chlorobenzyl)-l-[(methylsuU"onyl)methyl]-6-(4- morpholinylmethyι)-4-oxo- 1 ,4-dihydro-3-quinoUnecarboxamide
Figure imgf000133_0001
A solution of N-(4-chlorobenzyl)- 1 -[(methylsuU'anyl)methyl]-6-(4- morpholinylmethyl)-4-oxo-l,4-dihydro-3-quinolinecarboxamide (0J4 gm) from Example No. 73 in dichloromethane (4 mL) at 0 °C is added -toluenesulfonic acid hydrate (0.06 gm) foUowed by m-chloroperoxybenzoic acid (-85%) (0J3 gm). The mixture is stirred for 1 hr. The reaction mixture is dUuted with dichloromethane, washed with saturated aqueous sodium suUite, saturated aqueous sodium bicarbonate, brine, dried (Na2SO4) and concentrated under reduced pressure. The crude product is purUied by flash column chromatography eluting with 3% to 9% methanol in dichloromethane and then by recrystaUization from ethyl acetate-hexanes to afford 0.08 gm of the title compound as a white soUd.
Physical characteristics are as foUows:
Η NMR (CDCh) δ 10.4, 9J, 8.4, 7.8, 7.7, 7.3, 5.6, 4.7, 3.7, 3.6, 3.0, 2.5; MS (ESI+) m/z 504. Anal, found for C24H26CIN3O5S: C, 56.85: H, 5.20; N, 8.20.
EXAMPLE 81. N-(4-Chlorobenzyl)-6-(4-morphoUnylmethyl)-4-oxo- [(phenylsuUinyl)methyl]- 1 ,4-dihydro-3-quinolinecarboxamide
Figure imgf000133_0002
A solution of N-(4-chlorobenzyl)-6-(4-morpholinylmethyl)-4-oxo- 1 - [(phenylsuU"anyl)methyl]- l ,4-dUiydro-3-qumolinecarboxamide (0.08 gm) from Example No. 76 in dichloromethane (2 mL) at 0 °C is added -toluenesuU'onic acid hydrate (0.03 gm) foUowed by m-chloroperoxybenzoic acid (-85%) (0.03 gm). The mixture is stirred for 1 hr. The reaction mixture is dUuted with dichloromethane. washed with saturated aqueous sodium suUite, saturated aqueous sodium bicarbonate, brine, dried (Na2SO4) and concentrated under reduced pressure. The crude product is purUied by recrystallization from acetonitrUe to afford 0.06 gm of the title compound as a white soUd. Physical characteristics are as foUows: Η NMR (CDCh) δ 10.2, 8.4, 7.8, 7.6, 7.3, 5.2. 4.6, 3.7, 3.6, 2.4: MS (ESI+) m/z
550: HRMS (FAB) found 550.1569 for C29H28CIN3O4S+H.
EXAMPLE 82. N-(4-Chlorobenzyl)-6-(4-morphoUnylmethyl)-4-oxo- l- [(phenylsuU'onyl)methyl]- 1 ,4-dihydro-3-quinolinecarboxamide
Figure imgf000134_0001
A solution of N-(4-chlorobenzyl)-6-(4-morpholinylmethyl)-4-oxo- 1 -
[(phenylsulfanyl)methyl]-l,4-dihydro-3-quinolinecarboxamide (0.08 gm) from Example No. 76 in dichloromethane (4 mL) at 0 °C is added 77-toluenesulfonic acid hydrate (0.03 gm) foUowed by m-chloroperoxybenzoic acid (-85%) (0.06 gm). The mixture is stirred for 1 hr. The reaction mixture is dUuted with dichloromethane. washed with saturated aqueous sodium suUite, saturated aqueous sodium bicarbonate, brine, dried (Na2SO4) and concentrated under reduced pressure. The crude product is purUied by recrystaUization from acetonitrUe to afford 0.07 gm of the title compound as a white soUd. Physical characteristics are as foUows: 1H NMR (CDCh) δ 10J , 8.3, 7.8-7.5, 7.3, 5.5, 4.6, 3.7, 3.6, 2.5; MS (ESI+) m/z 566: HRMS (FAB) found 566.1516 for C29H28CIN3O5S+H. EXAMPLE 83. N-(4-chlorobenzyl)-6-(3-hydroxypropyl)-l-[2-(2- methoxyethoxy)ethyl]-4-oxo- 1 ,4-dihydro-3-quinolinecarboxamide
Figure imgf000135_0001
The title compound is prepared from N-(4-chlorobenzyl)-6-(3-hydroxy- 1-propynyl)- l-[2-(2-methoxyethoxy)ethyl]-4-oxo-l ,4-dihydro-3-quinolinecarboxamide. which is the product of" Example No. 42. according to the procedure described in Preparation No. 27.
PREPARATION 41. /V-(4-Chlorobenzyl)-6-(hydroxymethyl)- l-[2-(2- methoxyethoxy)-ethyl] -4-oxo- 1 ,4-dihydro-3-quinolinecarboxamide
Figure imgf000135_0002
A stirred mixture of"N-(4-chlorobenzyl)-4-hydroxy-6-(hydroxymethyl)-3- qumolinecarboxamide (3.3 g) from Preparation No. 9. cesium carbonate (6.33 g). and 2-(2- methoxyethoxy)ethyl/?-toluenesuU'onate (4.0 g) in of DMF (10 mL) is heated at 50°C for 18 h, then cooled and partitioned between ethyl acetate and dUute HCl. The organic phase is washed with water and brine, dried over MgSO4. and concentrated under reduced pressure.
Flash chromatography of the residue on siUca using 4-5% methanol in dichloromethane provides 3.0 g of the title compound.
Physical characteristics are as foUows: Mp 161-162.5 °C: 1H NMR (CDCh) δ 3J9, 3.45, 3.57, 3.88. 4.39, 4.61. 4.77. 7.2-
7.4, 7.58, 830, 8.55. 10.4 ppm; IR 3381, 2876, 1655. 1605, 1551. 1495, 1226. 1106 cm"1.
HRMS (m+H) 445.1525; Anal. Found for C2 H25N?O,Cl1: C. 62.06; H. 5.72: N. 6.42. EXAMPLE 84. N-(4-Chlorobenzyl)- l-[2-(2-methoxyethoxy)ethyl]-6-(4- morpholinylmethyl)-4-oxo- 1 ,4-dihydro-3-quinolinecarboxamide
Figure imgf000136_0001
To a stirred solution of N-(4-chlorobenzyl)-6-(hydroxymethyl)-l-[2-(2- methoxyethoxy)ethyl]-4-oxo-1.4-dihydro-3-qumolinecarboxamide (197 mg) from Preparation No. 41 in DMF ( 1 mL) is added 2.4.6-coUidine (0J4 mL) and DMAP (8 mg). The solution is cooled to 0 °C, and methanesuU'onyl choride (69 μL) is added. After 18 h. the mixture is added to 20 mL of rapidly stirred water containing 0.75 mL of IN HCl. The resulting precipitate is fUtered. washed well with water, and dried in vacuo to afford 183 mg of'N-(4-chlorobenzyl)-6-(chloromethyl)- l-[2-(2-methoxyethoxy)ethyl]-4-oxo- l,4-dihydro-3- quino linec arbo xamide . To a solution of the above chloride (93 mg) in DMF (1 mL) is added morpholine (53 μL). The solution is stirred for 18 h, then concentrated under reduced pressure. Flash chromatography of the residue on silica using 3-4% methanol in dichloromethane provides 98J mg of the title compound as a white crystalline soUd. An analytical sample may be prepared by recrystaUization from ethyl acetate in hexane. Physical characteristics are as foUows:
Mp 116-118 °C; Η ΝMR δ 2.46. 3.46. 3.58, 3.63. 3.70. 3.91, 4.45. 4.64. 7.3, 7.54. 7.77. 8.41 , 8.82, 10.5 ppm: IR 2815. 1662, 1606, 1549, 1494. 1224, 1116 cm"1. HRMS (M+H) 514.2114; Anal. Found for C27H32Ν3O5CI: C, 63.00: H, 6J8: N, 8.09.
EXAMPLE 85. N-(4-Chlorobenzyl)- l-[2-(2-methoxyethoxy)ethyl]-4-oxo-6-[(4- oxo- 1 -piperidinyl)methyl]- 1.4-dihydro-3-quinoUnecarboxamide
Figure imgf000136_0002
The title compound is prepared in a manner analogous to that described in Example No. 84. Physical characteristics are as foUows: 1H NMR (CDCh) δ 2.45, 2.77, 3.30, 3.46. 3.58, 3.76. 3.92. 4.47, 4.64, 7.3, 7.59, 7.80, 8.01, 8.45, 8.83, 10.5 ppm: IR 3060, 2912. 1717. 1663, 1606, 1550, 1494, 1224, 1091 cm"1. HRMS (M+H) 526.2107.
EXAMPLE 86. N-(4-Chlorobenzyl)-6-{ L(cyanomethyl)(methyl)amino]methyl}-l- [2-(2-methoxyethoxy)ethyl]-4-oxo-1.4-dihydro-3-quinolinecarboxamide
Figure imgf000137_0001
The title compound is prepared in a manner analogous to that described in Example No. 84. Physical characteristics are as foUows:
Mp 118-120 °C: Η NMR (CDCh) δ 2.43. 3.29. 3.4-3.5. 3.58. 3.75, 3.91, 4.46, 4.64. 7.3, 7.58, 7.71, 8.45, 8.83. 10.5 ppm. IR 3062. 2877. 1662. 1606, 1550, 1495. 1224. 1 107, 81 1 cm"1. HRMS (M+H) 497.1950: Anal. Found for C?^^©^ : C. 62.71 ; H. 5.96; N, 11.24.
EXAMPLE 87. N-(4-Chlorobenzyl)-6-{ [(3R)-3-hydroxypyrroUdinyl]methyl}-l-[2- (2-methoxyethoxy)ethyl]-4-oxo-l ,4-dihydro-3-quinolinecarboxamide
Figure imgf000137_0002
The title compound is prepared in a manner analogous to that described in Example
No. 84. Physical characteristics are as foUows:
Mp 106-109 °C: 1H NMR (CDCh) δ 1.74. 2.20. 2.35, 2.56, 2.66. 2.87, 3.29. 3.45. 3.58, 3.76, 3.90, 4.33. 4.45, 4.63, 7.3, 7.54, 7.77. 8.39. 8.81. 10.5 ppm; IR 3239, 2915, 1659, 1605, 1550, 1494, 1225, 1093, 810 cm"1: HRMS (M+H) 514.21 14: Anal Found for C27H32N3O5Clι: C, 62.89; H, 6.34; N, 8.10. EXAMPLE 88. N-(4-Chlorobenzyl)-6- { [[( lRJS)-2-hydroxy- 1 -methyl-2- phenylethyl](methyl)amino]methyl}-l-[2-(2-methoxyethoxy)ethyl]-4-oxo-l,4-dihydro-3- quinolinecarboxamide
Figure imgf000138_0001
The title compound is prepared in a manner analogous to that described in Example No. 84. Physical characteristics are as foUows:
Mp 106-109 °C: Η NMR (CDCh) δ 1.05, 2.20, 2.94, 3.29. 3.46. 3.57. 3.74, 3.89, 4.43. 4.63. 4.87. 7.3, 7.46, 7.54, 8.33, 8.80. 10.5 ppm: IR 3404, 2876. 1658. 1605. 1549. 1494. 1 106. 810 cm"1: HRMS (M+H) 592.2576.
EXAMPLE 89. N-(4-Chlorobenzyl)-6-{ [(2-hydroxy-2-phenylethyl)(methyl)- amino]methyl}- l-[2-(2-methoxyethoxy)ethyl]-4-oxo-1.4-dihydro-3-quinoline-carboxamide
Figure imgf000138_0002
The title compound is prepared in a manner analogous to that described in Example No. 84. Physical characteristics are as foUows:
Η NMR (CDCh) δ 2.33, 2.6, 3J9, 3.46, 3.58, 3.67, 3.89, 4.45, 4.63. 4.78. 7.3, 7.57. 7.76. 8.38. 8.83. 10.5 ppm: IR 3240, 2878, 1661. 1606. 1550, 1494, 1225. 1093, 810 cm"1: HRMS (M+H) 578.2410.
EXAMPLE 90. N-(4-Chlorobenzyl)-6-{ [[2-hydroxy-2-(4-hydroxyphenyl)ethyl]- (methyl)amino]methyl}-l-[2-(2-methoxyethoxy)ethyl]-4-oxo-l ,4-dihydro-3- quinolinecarboxamide
Figure imgf000138_0003
The title compound is prepared in a manner analogous to that described in Example No. 84. Physical characteristics are as foUows:
JH NMR (CDCh) δ 2.30, 2.4-2.7, 3.28, 3.45. 3.55, 3.63, 3.84, 4.40, 4.65, 6.74, 7.11. 73, 7.53, 7.73. 836, 8.80. 10.55 ppm: IR 3240, 2879, 1654. 1605, 1550, 1495, 1226. 81 1, 731 cm"1: HRMS (M+H) 594.2363.
EXAMPLE 91. l-{2-[2-(tert-Butoxy)ethoxy]ethyl}-N-(4-chlorobenzyl)-6-(4- morphoUnylmethyl)-4-oxo- 1 ,4-dihydro-3-quinolinecarboxamide
Figure imgf000139_0001
The title compound is prepared in a manner analogous to that described in Example No. 84. Physical characteristics are as foUows: Mp 130-132.5 °C: :H NMR (CDCh) δ 1 J0. 2.46, 3.41, 3.53, 3.63. 3.70. 3.92, 4.44.
4.64, 7.3. 7.56, 7.77. 8.41. 8.81. 10.50 ppm: IR 2972, 1663, 1506. 1550. 1494. 1364. 1224. 1 1 17. 1092, 809 cm"1: HRMS (M+H) 556.2578; Anal. Found for
Figure imgf000139_0002
C. 64.79: H, 6.87; N, 7.51.
EXAMPLE 92. l-{2-[2-(t^rt-Butoxy)ethoxy]ethyl}-N-(4-chlorobenzyl)-6-{ [[2- hydroxy-2-(4-hydroxyphenyl)ethyl](methyl)am o]methyl 1-4-oxo- 1.4-dihydro-3- quinolinecarboxamide
Figure imgf000139_0003
The title compound is prepared in a manner analogous to that described in Example No. 84. Physical characteristics are as foUows: 1H NMR (CDCh) δ 1J2. 2.32. 2.5-2.7. 3.43, 3.54, 3.6. 3.8, 4.41 , 4.64. 4.70. 6.77.
7.13, 7.3, 7.52, 7.75. 8.36. 8.80. 10.51 ppm; IR 3238, 2974, 1654. 1605, 1550, 1494, 1365, 1226, 1092, 811, 731 cm"1. Example 93. N-(4-Chlorobenzyl)-l-[2-(2-methoxyethoxy)ethyl]-6- [(methylsuU"anyl)methyl]-4-oxo-l ,4-dUιydro-3-quinolinecarboxamide
Figure imgf000140_0001
To a suspension of N-(4-chlorobenzyl)-6-(chloromethyl)-l-[2-(2- methoxyethoxy)ethyl]-4-oxo-l ,4-dihydro-3-quinolinecarboxamide (175 mg) prepared as described in Example No. 84, in DMF (1.5 ml) is added sodium thiomethoxide (40 mg). The mixture is stirred for 18 h, then added to 25 ml of rapidly stirred water. The soUd is fUtered, washed weU with water, dried in vacuo, and recrystaUized from acetonitrile to afford 139 mg of the title compound as pale yeUow crystals. Physical characteristics are as foUows: Mp 154-155 °C: HRMS m/z 475.1457; Anal. Found for C24H27N2O4CIS: C, 60.63:
H, 5.75; N, 5.91.
PREPARATION 42. N-(4-Chlorobenzyl)-4-hydroxy-6-iodo-3-quinoUne- carboximidoyl chloride.
Figure imgf000140_0002
A suspension of"N-(4-chlorobenzyl)-4-hydroxy-6-iodo-3-quinoUnecarboxamide (0.75 g) from Preparation No. 4 in dichloroethane (15 mL) is heated to 65 °C. Phosphorus pentachloride (0.57 g) is added in one portion. After 1.25 h, the reaction mixture is cooled to room temperature and the solvent is evaporated in a stream of nitrogen. Dichloromethane (20 mL) is added foUowed by toluene (6 mL) and the resulting soUd is fUtered and dried to give N-(4-chlorobenzyl)-4-hydroxy-6-iodo-3-quinolinecarbox nidoyl chloride (0.77 g). Physical characteristics are as foUows:
Mp 172-174 °C; Η ΝMR (300 MHz, DMSO- s) δ 14.44, 13.13, 10.29, 8.76, 8.52, 8.05, 7.57, 7.40, 7.35, 4.55 ppm; IR (drift) 3025, 2410, 1660, 1615, 1573, 1556, 1529, 1494, 1462, 1398, 1367, 1324, 1316, 1302, 928 cm"1: MS (FAB) /z 439, 577, 576, 575, 442, 441, 440, 439, 298. 127, 125.
PREPARATION 43. N-(4-Chlorobenzyl)-4-hydroxy-6-iodo-3-quinoUne- carbothioamide.
Figure imgf000141_0001
Hydrogen suUide is bubbled for 30 minutes into a solution of anhydrous pyridine (40 mL) cooled to 0 °C. N-(4-Chlorobenzyl)-4-hydroxy-6-iodo-3-quinolinecarboximidoyl chloride (1J4 g) from Preparation No. 42 is added in one portion. After 15 minutes, the ice bath is removed and the reaction is stirred at room temperature for 18 h with continuous bubbling of H2S. The reaction mixture is poured into ice water and the resulting soUd is fUtered and dried. The soUd is dissolved in CH Ch/MeOH, adsorbed onto silica, and purUied by chromatography (eluent CH?C12 ( IL), 0.5% MeOH:CH2Ch (IL), 0.75% MeOH:CH2Ch (6L)) to give N-(4-chlorobenzyl)-4-hydroxy-6-iodo-3- quinoUnecarbothioamide (0.90 g) as a yeUow soUd. Physical characteristics are as foUows:
Mp 275-276 °C: 1H ΝMR (300 MHz, OMSO-d6) δ 13.09, 9.44, 8.55, 8.09, 7.56, 7.44, 5.02 ppm; IR (drU't) 3069, 3061, 1620, 1607, 1557, 1534, 1518. 1493, 1381 , 1352, 1344. 1288, 1194, 813, 745 cm"1; MS (FAB) m/z 455 (MH+), 531. 457, 455, 454, 417, 262. 247, 125, 124, 107.
PREPARATION 44. N-(4-Chlorobenzyl)-6-iodo- 1 -methyl-4-oxo- 1 ,4-dihydro-3- quinolinecarbothioamide
Figure imgf000141_0002
To a suspension of N-(4-chlorobenzyl)-4-hydroxy-6-iodo-3-quinoUnecarbothioamide (0J0 g) from Preparation No. 43 and triphenylphosphine (0J5 g) in freshly distilled tetrahydroluran (5 mL) is added MeOH (0.027 mL) foUowed by diethyl azodicarboxylate. After an initial exotherm, the reaction is stirred at room temperature for 3 h. To drive the reaction to completion, additional triphenylphosphine (0.030 g), methanol (0.010 mL), and diethyl azodicarboxylate (0.020 mL) are added. The reaction is stirred at room temperature overnight. The reaction is concentrated in vacuo. The residue is dissolved in CH?Ch and adsorbed onto sUica. PurUication by chromatography (eluent CH2C1 (IL), 1% MeOH:CH2Cl? (IL)) affords N-(4-chlorobenzyl)-6-iodo-l-methyl-4-oxo- l ,4-dihydro-3- quinolinecarbothioamide (0.065 g) as a yeUow soUd. Physical characteristics are as foUows:
Mp 153-155 °C: lH ΝMR (300 MHz, OMSO-d6) δ 13.04, 9.50, 8.61, 8J8, 7.71, 7.44, 5.02, 4.06 ppm: IR (drift) 1619, 1597, 1576, 1528, 1489, 1385, 1365, 1352, 1332, 1307, 1220, 1180, 1117, 812, 650 cm"1; MS (FAB) m/z 469 (MH+), 547, 545, 471, 470, 469, 468, 371, 328, 125, 123.
EXAMPLE 94. N-(4-chlorobenzyl)-6-(3-hydroxy- 1 -propynyl)- 1 -methyl-4-oxo- 1.4- dihydro-3-quinolinecarbo thioamide
Figure imgf000142_0001
A suspension of N-(4-chlorobenzyl)-6-iodo- 1 -methyl-4-oxo- 1 ,4-dihydro-3- quinolinecarbo thioamide (0.20 g) from Preparation No. 44, propargyl alcohol (0.030 mL), copper iodide (0.028 g), and bis(triphenylphosphine)paUadium(II) chloride (0.0095 g) in diethylamine ( 10 mL) is stirred at room temperature for 18 h. The soUd in the reaction mixture is filtered, then dissolved in CH2Ch/MeOH, and adsorbed onto silica. PurUication by chromatography (eluent 1 % MeOH:CH2Ch (IL), 2% MeOH:CH2Cl2 (IL)) affords the title compound as a yeUow soUd (0J2 g). Physical characteristics are as foUows:
Mp 200-201 °C: l NMR (300 MHz. OMSO-d6) δ 13.04, 9.47, 8.30, 7.89, 7.44, 5.42, 5.04, 435, 4.08 ppm; IR (drift) 3311, 1625, 1602, 1572, 1535, 1490, 1392, 1368, 1352, 1337, 1312, 1030, 1015, 831, 801 cm"1: MS (ESI) m/z 397.0 (M+H)+ PREPARATION 45. Methyl 3-{ [(4-Chlorobenzyl)amino]carbothioyl}-4-hydroxy- 6-quinolinecarboxylate.
Figure imgf000143_0001
Dimethylformamide (anhydrous, 5 mL) is added to a flame-dried flask. The solution is purged with nitrogen for 15 minutes. To this solution is added N-(4-chlorobenzyl)-4- hydroxy-6-iodo-3-qumoUnecarbothioamide (0.25 g) from Preparation No. 44, methanol (0.90 mL), triethylamine (0.16 mL), and dichlorobis(triphenylphosphine)paUadium (0.068 g). The reaction is placed under a CO baUoon and stirred at 70 °C for 3 h. The reaction is cooled to room temperature and poured into IN HCl (40 mL). The resulting soUd is fUtered and dried. The soUd is dissolved in CH2Ch/MeOH and adsorbed onto sUica. PurUication by chromatography (eluent CT Ch (IL). 1 % MeOH:CH2Ch (2L). 3% MeOH:CH2Ch (IL)) affords methyl 3-{ l(4-chlorobenzyl)amino]carbothioyl}-4-hydroxy-6-quinoUnecarboxylate (0.090 g) as a yeUow soUd.
Physical characteristics are as foUows:
Mp 259-261 °C: 1H NMR (300 MHz, DMSO-cfc) δ 13.24, 13.03, 9.46. 8.85, 8.28, 7.84, 7.45, 5.04, 3.91 ppm; IR (drift) 1713, 1630, 1572, 1564, 1539, 1519, 1494, 1483, 1436. 1296, 1275, 1237, 1201 , 799, 769 cm"1; MS (FAB) m/z 387 (MH+), 389. 388, 387. 386, 371, 246, 127, 125, 92, 45.
PREPARATION 46. N-(4-chlorobenzyl)-4-hydroxy-6-(hydroxymethyl)-3- quinolinecarbothioamide.
Figure imgf000143_0002
To a suspension of methyl 3-{ [(4-chlorobenzyl)ammo]carbothioyl}-4-hydroxy-6- quinolinecarboxylate (0.062 g) from Preparation No. 45 in freshly distilled THF (8 mL) at room temperature is added Uthium aluminum hydride (1M in THF, 0.34 mL) dropwise. After 45 mmutes, the reaction is quenched sequentiaUy with 1 mL water, 1 mL 15% NaOH, and 1 mL water. The reaction mixture is concentrated in vacuo. The residue is adsorbed onto sUica. Purification by chromatography (eluent 1 % MeOH:CH2Ch (IL), 2% MeOH:CH2Cl2 (IL). 3% MeOH:CH2Cl2 (IL)) affords N-(4-chlorobenzyl)-4-hydroxy-6- (hydroxymethyl)-3-quinoUnecarbothioamide (0.038 g). Physical characteristics are as foUows:
Mp 240-242 °C; Η ΝMR (300 MHz, OMSO-d6) δ 13.35, 13.01 , 9.41, 8.23, 7.75, 7.70, 7.45, 5.42, 5.04, 4.64 ppm; IR (drift) 2962, 2943, 2907, 2889, 1631, 1588, 1530, 1493, 1439, 1414, 1217, 1003, 883, 822, 812 cm"1 ; HRMS (FAB) calcd for C18H15ClΝ2O2S+H1 359.0621, found 359.0638.
PREPARATION 47. N-(4-chlorobenzyl)-4-hydroxy-6-(4-morphoUnylmethyl)-3- quinolinecarbothioamide.
Figure imgf000144_0001
To a solution of N-(4-chlorobenzyl)-4-hydroxy-6-(hydroxymethyl)-3- quinolinecarbothioamide (0.082 g) from Preparation No. 46 in anhydrous dimethyU'ormamide (4 mL) in a flame-dried flask is added dimethylamino pyridine (0.01 1 g), 2,4,6-coUidine (0.035 mL), and methanesuU'onyl chloride (0.017 mL). The reaction mixture is stirred at room temperature for 1 h after which time thin layer chromatography indicates starting material is nearly consumed. Morpholine (0.20 mL) is added in one portion. The reaction is stirred for 1.5 h and then poured into water. The aqueous solution is extracted 2X with CH2Ch and 2X with 3% MeOH:CH2Ch. The organics are combined, dried over Na2SO4, fUtered, and concentrated. Residual DMF is removed on the vacuum pump. The residue is dissolved in CH2Ch and hexanes was added to give a soUd (starting material) which is fUtered and dried. Upon aUowing this filtrate to evaporate overnight, a second soUd is obtained. This soUd is dissolved in CH?C12 and adsorbed onto siUca. PurUication by chromatography (eluent CH2Ch (IL), 1 % MeOH:CH:Ch (IL), 2% MeOH:CH2Ch (IL) 2.5% MeOH:CH2Cl?_ (IL), 3% MeOH:CH2Ch (2L)) affords N-(4-chlorobenzyl)-4-hydroxy- 6-(4-morpholiny nethyl)-3-qumoUnecarbothioamide (0.028 g) as a yeUow soUd. Physical characteristics are as foUows: Mp 215-216 °C; 1H ΝMR (300 MHz, OMSO-d6) δ 13.35, 13.04, 9.41, 8J8, 7.75,
7.70, 7.45, 5.03, 3.60, 3.57, 2.37 ppm; IR (drift) 1621 , 1591, 1575, 1540, 1524, 1490, 1352, 1297, 1287, 1115, 1107, 923, 855, 831, 798 cm"1; HRMS (FAB) calcd for C22H22CIΝ3O2S+H1 428.1199. found 428.1 198. EXAMPLE 95. N-(4-Chloro benzyl)- 1 -methyl-6-(4-morpholinylmethyl)-4-oxo- 1 ,4- dihydro-3-quinoUnecarbothioamide
Figure imgf000145_0001
A flame-dried flask is charged with N-(4-chlorobenzyl)-4-hydroxy-6-(4- morpholinylmethyl)-3-quinolinecarbothioamide (0.060 g) from Preparation No. 47, triphenylphosphine (0.045 g), and freshly distUled THF (1.5 mL). To this solution is added methanol (8.00 μL) and diethyl azodicarboxylate (28.00 μL). The reaction is stirred at room temperature for 18 h. Monitoring of the reaction still shows a signUlcant amount of starting material left. Additional PPh3 (0.025 g). methanol (5.00 μL). and diethyl azodicarboxylate (14.00 μL) are added and the reaction is stirred for 18 h. Since monitoring of the reaction still shows some starting material. 10 equivalents each of PPh,. methanol. and diethyl azodicarboxylate are added. A reasonable exotherm is seen after adding diethyl azodicarboxylate. The reaction is immediately monitored by TLC and starting material is consumed. The solvents are removed and the residue is dissolved in CH2Ch/MeOH and adsorbed onto sUica. PurUication by column chromatography (eluent CH2C12 (IL), 1 % MeOH:CH2Ch (IL), 2% MeOH:CH2Ch (2L). 4% MeOH:CH2Ch (IL). 7% MeOH:CH2Ch (IL)) affords the title compound contaminated with triphenylphosphine oxide. These fractions are combined and concentrated and the residue is again adsorbed onto siUca. PurUication by a second chromatography (eluent 1:1 hexanes:ethyl acetate (IL), 45:55 hexanes:ethyl acetate (IL), 4:6 hexanes:ethyl acetate (IL). 35:65 hexanes:ethyl acetate (IL). 1 :3 hexanes:ethyl acetate (IL), 2:8 hexanes:ethyl acetate (IL). 1 :9 hexanes:ethyl acetate (IL). 100% ethyl acetate (IL), 2% MeOH:CH?Ch (IL). 4% MeOH:CH2Ch (IL)) affords the title compound as a Ught yeUow residue. The residue is dissolved in CH?C1? and hexanes are added untU cloudy. The solution is placed in the freezer overnight and the title compound as a soUd is subsequently filtered and dried (0.020 g). Physical characteristics are as foUows: Mp 167-169 °C; 1H NMR (300 MHz. DMSO- 6) δ 13.24, 9.45, 8.25, 7.84. 7.42,
5.01. 4.07. 3.62, 3.55, 2.35 ppm; HRMS (FAB) calcd for C21H24CIN3O2S+H1 442.1356, found 442.1357. PREPARATION 48. N-(4-Chlorobenzyl)-8-iodo- 1 -methyl-4-oxo- 1 ,4-dihydro-3- quinolinecarboxamide
Figure imgf000146_0001
A solution of 2-iodoaniline (8J2 g) and diethyl ethoxymethylenemalonate (8.00 mL) is heated at 130 °C for 1 h. The reaction is cooled to room temperature. Diphenyl ether (100 mL) is added and the reaction is heated at 250 °C for 1.25 h. The reaction is cooled to room temperature and the resulting soUd is filtered, washed thoroughly with hexanes, and dried to give ethyl 4-hydroxy-8-iodo-3-quinoUnecarboxylate (6.84 g).
A portion of the resulting ethyl 4-hydroxy-8-iodo-3-quinoUnecarboxylate (4.01 g) and 4-chlorobenzylamine (20.00 mL) are heated at 180 °C for 1.5 h. The reaction is cooled to room temperature. Ethyl acetate is added. foUowed by hexanes, and the soUd is fUtered, washed with hexanes, and dried to give N-(4-chlorobenzyl)-4-hydroxy-8-iodo-3- quinolinecarboxamide (3.98 g).
A suspension of the above N-(4-chlorobenzyl)-4-hydroxy-8-iodo-3-quinoline- carboxamide (0.88 g), K2CO3 (1J2 g), and iodomethane (0J4 mL) in anhydrous dimethyU'ormamide (25 mL) is heated at 90 °C untU the reaction is complete by TLC. The reaction mixture is cooled to room temperature and poured into water (150 mL). The resulting soUd is fUtered and dried. The soUd is dissolved in CH?Ch/MeOH and adsorbed onto silica. PurUication by chromatography (eluent CH2Ch (IL), 0.5% MeOH:CH2C (IL), 1% MeOH:CH2Ch (IL), 1.5% MeOH:CH2Ch (IL), 2% MeOH:CH2Ch (IL)) affords the title compound as a white soUd (0.50 g). Physical characteristics are as foUows:
Mp 222-223 °C; 1H ΝMR (300 MHz, OMSO-d6) δ 10.16, 8.77, 8.51.8.36.7.38, 7.34, 7.21, 4.53, 4.38 ppm; IR (drU't) 1662, 1600.1574, 1551, 1536, 1489, 1436.1418, 1358, 1116, 1105, 798, 779, 750, 724 cm"1; MS (EI) m/z 452, 285, 159, 156.140.130, 128, 103, 102, 77, 76. EXAMPLE 96. N-(4-Chlorobenzyl)-8-(3-hydroxy- 1 -propynyl)- 1 -methyl-4-oxo- 1 ,4-dihydro-3-qumolinecarboxamide
Figure imgf000147_0001
A solution of N-(4-chlorobenzyl)-8-iodo- 1 -methyl-4-oxo- 1.4-dihydro-3- quinoUnecarboxamide (0.21 g) from Preparation No. 48, copper iodide (0.029 g), bis(triphenylphosphine)paUadium(II) chloride (0.012 g), and propargyl alcohol (0.035 mL) in diethylamine (15 mL) is stirred at room temperature for 18 h. Dichloromethane foUowed by hexanes is added to the reaction mixture. The resulting soUd is fUtered, washed thoroughly with hexanes. and dried. The soUd is dissolved in CH2Ch/MeOH and adsorbed onto sUica. PurUication by chromatography (eluent CH2Ch (IL). 0.5% MeOH:CH2Cl2 (IL), 1 % MeOH:CH2Ch (IL), 1.5% MeOH:CH2Cl?_ (IL), 2% MeOH:CH2Ch (IL), 3% MeOH:CH2Ch (IL)) affords the title compound as a yeUow soUd (0J3 g). Physical characteristics are as foUows:
Mp 228-230 °C: 1H NMR (300 MHz, DMSO- ) δ 10.26, 8.78, 8.38, 7.92, 7.51 , 7.40, 7.36, 5.44, 4.56, 4.44. 4.39 ppm: IR (drift) 3358, 1660, 1606. 1551 , 1492, 1431 , 1360, 1243, 1123, 1042. 801, 784, 758, 750, 695 cm"1: MS (ESI) for m/z 381.0 (M+H)+, 379.0 (M-H)".
EXAMPLE 97. N-(4-Chlorobenzyl)-8-(4-hydroxy- 1 -butynyl)- 1 -methyl-4-oxo- 1 ,4- dihydro-3-quinolinecarboxamide
Figure imgf000147_0002
A solution of N-(4-chlorobenzyl)-8-iodo-l-methyl-4-oxo-l ,4-dihydro-3- quinolinecarboxamide (0.22 g) from Preparation No. 48, copper iodide (0.029 g), bis(triphenylphosphine)paUadium(II) chloride (0.013 g), and 3-butyn-l-ol (0.040 mL) in diethylamine (15 mL) is stirred at room temperature for 18 h. Hexanes are added to the reaction mixture and the resulting soUd is fUtered and dried. The soUd is dissolved in CH2Ch/MeOH and adsorbed onto silica. PurUication by chromatography (eluent CH?Ch (IL), 1.5% MeOH:CH2Ch (IL), 2% MeOH:CH2Ch (2L), 3% MeOH:CH2Ch (IL)) affords the title compound as a Ught yeUow soUd (0J6 g). Physical characteristics are as foUows:
Mp 195-197 °C: Η NMR (300 MHz. DMSO-^) δ 10.27, 8.77, 8.35, 7.91. 7.48, 7.41, 7.36, 4.97, 4.55. 4.45, 3.64, 2.65 ppm: IR (drift) 1661, 1604. 1555, 1489, 1427, 1359. 1242, 11 18. 1090, 1073, 839, 803, 782. 753, 695 cm"1: MS (ESI) for m/z 395.0 (M+H)+.
PREPARATION 49. (4-Nitrobenzyl)triphenylphosphonium bromide.
To a solution of triphenylphosphine (15.34 g) in Et2O (150 mL) is added 4- nitrobenzylbromide (12.96 g). The solution is aUowed to stir overnight and the resulting soUd is fUtered and dried to yield 10.95 g of (4-nitrobenzyl)(triphenyl)phosphonium bromide as a white soUd. Physical characteristics are as foUows:
Η NMR (300 MHz. CDCh) δ 7.79. 7.63. 7.48, 5.99 ppm.
PREPARATION 50. 4-(4-NitrobenzyUdene)tetrahydro-2H-pyran. To a 100 mL flask under N is added NaΗ (0.40 g of a 60% solution in mineral oU) and anhydrous DMSO (7 mL). The resulting solution is heated at 80 °C for 1 h and then cooled in an ice-water bath. To this is added a suspension of the phosphonium bromide (4.78 g) from Preparation No. 49 in warm DMSO (40 mL). The mixture is stirred at room temperature for 10 min. Tetrahydro-4-Η-pyran-4-one (0.92 mL) is then added dropwise. The mixture is aUowed to stir at room temperature overnight and then at 80 °C for 8 h. The mixture is poured over ice and extracted with Et2O. The combined extracts are combined and concentrated. The crude product is chromatographed (Biotage flash 40 M. eluent gradient from hexane to 60/40 CH2Ch/hexanes) to yield 0.464 g of 4-(4- nitrobenzyUdene)tetrahydro-2H-pyran as a yeUow soUd. Physical characteristics are as foUows: Η NMR (300 MHz. CDCh) δ 8.20, 7.36, 6.39, 3.83. 3.70. 2.55, 2.46 ppm. PREPARATION 51. Ethyl 4-Hydroxy-6-(tetrahydro-2H-pyran-4-ylmethyl)-3- quinolinecarboxylate.
Figure imgf000149_0001
A mixture of"4-(4-nitrobenzyUdene)tetrahydro-2Η-pyran (400 mg) from Preparation No. 50 and platinum (IV) oxide (40 mg) in MeOH (40 mL) is hydrogenated at 40 psi H2 for 4 h. The reaction mixture is filtered through CeUte and concentrated. CH?Ch (50 mL) and diethyl ethoxymethylenemalonate (0.37 mL) are then added to the residue and the mixture was concentrated at 40 °C. To this residue is then added diphenyl ether (20 mL). The mixture is heated to 250 °C for 1 h. The mixture is then cooled and dUuted with hexanes. The resulting product is coUected, washed with hexanes and dried to yield 0.453 g of ethyl 4-hydroxy-6-(tetrahydro-2H-pyran-4-ylmethyl)-3-quinolinecarboxylate. Physical characteristics are as foUows: Mp 275-280 °C; 1H NMR (300 MHz, OMSO-d6) δ 12.30, 8.49, 7.90, 7.52, 4J8,
3.78, 3.20, 2.61, 1 ,73, 1 ,43, 1.25 ppm: IR (drift) 2952, 2928. 1699, 1615, 1581 , 1562, 1524, 1377, 1296, 1208, 1 175, 1 103, 1096, 808. 610 cm"1: MS (ESI+) for C,8H2,NO4 m/z 316.2 (M+H)+.
PREPARATION 52. N-(4-Chlorobenzyl)-4-hydroxy-6-(tetrahydro-2H-pyran-4- ylmethyl)-3-quinolinecarboxamide.
Figure imgf000149_0002
A solution of ethyl 4-hydroxy-6-(tetrahydro-2H-pyran-4-ylmethyl)-3- quinoUnecarboxylate (0.315 g) from Preparation No. 51 and 4-chlorobenzylamine (0.61 mL) is heated to 180 °C for 1 h. The reaction mixture is cooled to 65 °C and dUuted with CΗ2Ch. Hexanes are added to initiate precipitation of the product. The resulting soUd is coUected and dried to yield 0.33 g of" N-(4-chlorobenzyl)-4-hydroxy-6-(tetrahydro-2H- pyran-4-ylmethyl)-3-quinoUnecarboxamide as an off-white soUd. Physical characteristics are as foUows:
Mp 184-185 °C; Η ΝMR (300 MHz, OMSO-d6) δ 12.71, 10.50, 8.71, 7.99, 7.60, 736. 4.53. 3.78, 3.19, 2.64, 1.74, 1.43. 1.21 ppm: IR (drift) 2968, 2959, 2924, 2916, 2842, 1660. 1620, 1538, 1489. 1365, 1094, 851, 833, 806, 797 cm"1: MS (ESI+) for C23H23CIN2O3 m/z 41 1. 1 (M+H)+.
EXAMPLE 98. N-(4-ChlorobenzyI)-l-methyl-4-oxo-6-(tetrahydro-2H-pyran-4- ylmethyl)-l,4-dihydro-3-quinolinecarboxamide
Figure imgf000150_0001
To a solution of N-(4-chlorobenzyl)-4-hydroxy-6-(tetrahydro-2H-pyran-4-ylmethyl)- 3-quinolinecarboxamide (0J00 g) from Preparation No. 52 in anhydrous DMF (10 mL) is added K2CO3 (0.269 g) and CΗ3I (0.04 mL). The mixture is stirred for 15 min. Water (10 mL) is then added and the resulting soUd is coUected and dried. The crude product is chromatographed (Biotage flash 40 S, gradient CH2Ch. then 1 % MeOH/CH?Ch then 2% MeOH CH2Cl2) to yield 0J 61 g of the title compound as a white soUd. Physical characteristics are as foUows:
Mp 219-221 °C: Η NMR (300 MHz. OMSO-d6) δ 10.45. 8.83, 8.08. 7.75, 7.68, 7.36. 4.54. 3.99. 3.78. 3J9, 2.67, 1.76, 1.43. 1.22 ppm: IR (drU't) 2929. 2914. 2850. 1655, 1606, 1572. 1551. 1501, 1487, 1364, 1133. 1088, 847, 826, 808 cm"1.
EXAMPLE 99. N-(4-Chlorobenzyl)-6-{ [3-(hydroxyimino)-l-azetidinyl]methyl}-l- methyl-4-oxo- 1 ,4-dihydro-3-quinoUnecarboxamide
Figure imgf000150_0002
A suspension of N-(4-chlorobenzyl)-6-[(3-hydroxy- 1 -azetidinyl)methyl]- 1 -methyl-4- oxo-l,4-dihydro-3-quinolinecarboxamide (0.09 gm) of Example No. 75 in methyl suU'oxide (3 mL) is treated with triethylamine (0.35 mL) and cooled in a water bath. The mixture is treated with suUur trioxide pyridine complex (0.25 gm) and aUowed to stir for 2 hours. The mixture is dUuted with diethyl ether containing a smaU amount of methanol and dichloromethane. The organic phase is washed with three portions of water, brine, dried over sodium suU'ate, filtered, and concentrated under reduced pressure. The residue is suspended in ethanol (95%. 2 mL) and treated with hydroxylamine hydrochloride (0.03 gm) and sodium hydroxide (0.02 gm). The flask is tightly capped and heated at 65 °C overnight. The reaction mixture is cooled to room temperature and partitioned between dichloromethane containing methanol and water. The aqueous phase is extracted with dichloromethane containing methanol and dichloromethane. The combined organic phase is washed with water, brine, dried over sodium suU'ate, and concentrated under reduced pressure. The residue is purUied by flash column chromatography on siUca gel eluting with a smaU amount of methanol in dichloromethane and then by recrystaUization from acetonitrUe - methanol to afford 14 mg of the title compound as a tan soUd. Physical characteristics are as foUows: Η NMR DMSO-d6) δ 10.7, 10.4. 8.9. 8.2, 7.8. 7.4. 4.6. 4.0, 3.9. 3.3: MS (ESI+) m/z 425; HRMS (FAB) found 425.1379 for C22H21CIN4O3+H.
EXAMPLE 100. N-(4-Chlorobenzyl)-l-{2-[2-(4-morphoUnyl)ethoxy]ethyl}-6-(4- morpholinylmethyl)-4-oxo- 1 ,4-dihydro-3-quinolinecarboxamide
Figure imgf000151_0001
A solution of N-(4-chlorobenzyl)-l-[2-(2-hydroxyethoxy)ethyl]-6-(4- morpholinylmethyl)-4-oxo-1.4-dihydro-3-quinolinecarboxamide (0J0 gm) of Example No. 57 and 4-dimethylaminopyridine (0.002 gm) in pyridine (2 mL) at 0 °C is treated with tosyl chloride (0.05 gm). The mixture is aUowed to warm to room temperature overnight. The mixture is treated with an additional portion of tosyl chloride (0.05 gm). stirred 4 hours, then treated with morphoUne (0.20 mL) and aUowed to stir overnight. The mixture is concentrated under reduced pressure and the residual pyridine azeotropicaUy removed with toluene. The residue is purUied by flash column chromatography on siUca gel eluting with 2% to 10% methanol containing ammonia in dichloromethane and then by recrystalUzation from ethyl acetate - hexanes to afford 29 mg of the title compound as a white soUd. Physical characteristics are as follows:
1H NMR (DMSO- 5) δ 10.4, 8.8, 8.2, 7.9, 7.7, 7.4, 4.6, 4,5. 3.7. 3.6. 3.5, 3.4, 3.3, 2.4, 2.3, 2.2; MS (ESI+) m/z 569: HRMS (FAB) found 569.2531 for C,0H37C1N4O5+H. EXAMPLE 101. N-(4-Chlorobenzyl)-l-([(4-chlorophenyl)suU'anyl]methyl)- 6-(4- morphoUnylmethyl)-4-oxo- 1.4-dihydro-3-quinolinecarboxamide
Figure imgf000152_0001
A suspension of"N-(4-chlorobenzyl)-4-hydroxy-6-(4-morphoUnylmethyl)-3- qumoUnecarboxamide (0.25 gm) from Preparation No. 40 and cesium carbonate (039 gm) in DMF (3 mL) is treated with chloromethyl 4-chlorophenyl suUide (0.13 mL). The mixture is tightly capped and heated to 105 °C for 2 hrs. The reaction mixture is aUowed to cool to room temperature. dUuted with dichloromethane (50 mL). washed with water (2 x 10 mL), brine, dried (Na2SO4) and concentrated under reduced pressure. The crude product is purUied by flash column chromatography eluting with 1 % to 3% methanol in dichloromethane and then by trituration with ethyl acetate to afford 0.26 gm of the title compound as a white soUd.
Physical characteristics are as foUows:
Η NMR DMSO-dβ) δ 10.2, 8.5, 8.2. 7.9, 7.8. 7.4-7.3, 6.0. 4.5, 3.6. 3.5, 2.4: MS (ESI+) m/z 568: Anal. Found: C, 61.14: H, 4.77; N, 7.30.
EXAMPLE 102. N- (4- Chlorobenzyl)- 1 -([(4-chlorophenyl)suUinyl]methyl)-6-(4- morpholinylmethyl)-4-oxo- 1 ,4-dihydro-3-quinolinecarboxamide
Figure imgf000152_0002
A solution ol'N-(4-chlorobenzyl)-l-([(4-chlorophenyl)suU'anyl]methyl)-6-(4- morpholinylmethyl)-4-oxo- 1 ,4-dihydro-3-quinolinecarboxamide (0.1 1 gm) from Example No. 101 in dichloromethane (2 mL) at 0 °C is treated with /?-toluenesuU'onic acid hydrate (0.04 gm) foUowed by m-chloroperoxybenzoic acid (-85%) (0.04 gm). The mixture is stirred for 0.75 hr. The reaction mixture is dUuted with dichloromethane, washed with saturated aqueous sodium suUite, saturated aqueous sodium bicarbonate, brine, dried (Na SO4) and concentrated under reduced pressure. The crude product is purUied by recrystaUization from acetonitrUe to afford 0J0 gm of the title compound as a white soUd.
Physical characteristics are as foUows:
1H NMR (OMSO-d6) δ 10.2, 8.7, 8.2, 7.8, 7.7, 7.5, 7.4, 6.0, 4.5, 3.6, 2.3; MS (ESI+) m/z 584; HRMS (FAB) found 584.1 171 for C29H27CI2N3O4S+H.
EXAMPLE 103. N-(4-Chlorobenzyl)- l-([(4-chlorophenyl)suU'onyl]methyl)-6-(4- morpholinylmethyι)-4-oxo- 1 ,4-dihydro-3-quinolinecarboxamide
Figure imgf000153_0001
A solution of N-(4-chlorobenzyl)-l-([(4-chlorophenyl)suU'anyl]methyl)-6-(4- morphoUnylmethyl)-4-oxo-l,4-dUιydro-3-qu olinecarboxamide (0J 1 gm) from Example No. 101 in dichloromethane (2 mL) at 0 °C is treated with/?-toluenesuU"onic acid hydrate (0.04 gm) foUowed by m-chloroperoxybenzoic acid (-85%) (0.09 gm). The mixture is stirred for 0.75 hr. The reaction mixture is dUuted with dichloromethane, washed with saturated aqueous sodium suUite, saturated aqueous sodium bicarbonate, brine, dried (Na2SO ) and concentrated under reduced pressure. The crude product is purUied by recrystaUization from acetonitrUe to afford 0.09 gm of the title compound as a white soUd. Physical characteristics are as foUows: Η NMR (DMSO- δ 10J, 8.7, 8.2, 7.7, 7.6. 7.5, 7.4, 6.4, 4.5. 3.5, 2.3; MS (ESI+) m/z 600; HRMS (FAB) found 600.1121 for C29H27CI2N3O5S+H.
EXAMPLE 104. N-(4-Chlorobenzyl)-l-[(4-chlorophenoxy) methyl]-6-(4- morpholinylmethyl)-4-oxo- 1.4-dihydro-3-quinolinecarboxamide
Figure imgf000154_0001
A suspension of N-(4-chlorobenzyl)-4-hydroxy-6-(4-morpholinylmethyl)-3- quinoUnecarboxamide (0.21 gm) from Preparation No. 40 and cesium carbonate (0.33 gm) in DMF (2 mL) is treated with α.4-dichloroanisole (0J3 gm). The mixture is tightly capped and heated to 100 °C for 3 hrs. The reaction mixture is aUowed to cool to room temperature, dUuted with dichloromethane (50 mL) and washed with water. The aqueous phase is extracted with two additional portions of dichloromethane. The combined organic phase is washed with brine, dried (Na?SO4) and concentrated under reduced pressure. The crude product is purUied by flash column chromatography eluting with 1% to 4% methanol in dichloromethane and then by recrystaUization with acetonitrUe to afford 0.20 gm of the title compound as a white soUd.
Physical characteristics are as foUows: Η NMR (DMSO- 6) δ 10.2, 9.0, 8.2, 8.0, 7.8. 7.4. 7J , 6.5. 4.5. 3.6. 3.5. 2.4: MS
(ESI+) m/z 552: Anal. Found: C. 62.92; H, 4.94; N. 7.66.
EXAMPLE 105 N-(4-Chlorobenzyl)- l-[(2-methoxyethoxy)methyl]-6-(4- morpholinylmethyl)-4-oxo- 1.4-dihydro-3-quinolinecarboxamide
Figure imgf000154_0002
A suspension of'N-(4-chlorobenzyl)-4-hydroxy-6-(4-morpholinylmethyl)-3- quinoUnecarboxamide (0.21 gm) from Preparation No. 40 and cesium carbonate (0.34 gm) in DMF (2 mL) is treated with 2-methoxyethoxymethyl chloride (0.07 mL). The mixture is tightly capped and heated to 100 °C for 3 hrs. The reaction mixture is aUowed to cool to room temperature. dUuted with dichloromethane and washed with water. The aqueous phase is extracted with two additional portions of" dichloromethane. The combmed organic phase is washed with brine, dried (Na?SO4) and concentrated under reduced pressure. The crude product is purUied by flash column chromatography eluting with 1% to 5% methanol in dichloromethane and then by recrystaUization with acetonitrUe to afford 0.08 gm of the title compound as a white soUd.
Physical characteristics are as foUows:
Mp 150-152 °C: Η NMR DMSO-d6) δ 10.3, 9.0, 8.2, 7.9, 7.8, 7.4, 5.8, 4.5, 3.6, 3.4, 3J, 2.4; MS (ESI+) m/z 500; Anal. Found: C, 62.49; H, 6.03; N, 8.50.
EXAMPLE 106. 2-{ [3-{ [(4-Chlorobenzyl)amino]carbonyl}-6-(4-morphoUnyl- methyl)-4-oxo- 1 (4H)-quinoUnyl]methoxy }ethyl benzoate
Figure imgf000155_0001
A suspension of N-(4-chlorobenzyl)-4-hydroxy-6-(4-morpholinylmethyl)-3- quinolinecarboxamide (0.41 gm) from Preparation No. 40 and cesium carbonate (0.65 gm) in DMF (5 mL) is treated with benzoyloxyethylchloromethylether (-85%, 0.31 mL). The mixture is tightly capped and heated to 110 °C for 3 hrs. The reaction mixture is aUowed to cool to room temperature, dUuted with dichloromethane and washed with water (3x). The organic phase is washed with brine, dried (Na SO ) and concentrated under reduced pressure. The crude product is purUied by flash column chromatography elutmg with 2% to 6% methanol in dichloromethane and then by recrystaUization with acetonitrUe to afford 0.08 gm of the title compound as a white soUd.
Physical characteristics are as foUows:
Η NMR DMSO-d6) δ 10.3, 9.0, 8.2, 7.9, 7.7, 7.6, 7.4, 5.9, 4.6, 4.3, 3.9, 3.5, 3.3, 2.3; MS (ESI+) m/z 590; HRMS (FAB) found 590.2046 for C32H32CIN3O6+H. EXAMPLE 107. N-(4-Chlorobenzyl)-l-[(2-hydroxyethoxy)methyl]-6-(4- morpholinylmethyl)-4-oxo- 1 ,4-dihydro-3-quinolιnecarboxamide
Figure imgf000156_0001
A flask containing 2-{[3-{ [(4-chlorobenzyl)amino]carbonyl}-6-(4-morphoUnyl- methyl)-4-oxo-l(4H)-quinoUnyl]methoxy} ethyl benzoate (0J2 gm) from Example No. 106 is treated with methanol saturated with ammonia (5 mL). The mixture is tightly capped and stirred at room temperature for 3 days. The reaction mixture is concentrated under reduced pressure. The crude product is purUied by flash column chromatography eluting with 2% to 10% methanol in dichloromethane and then by recrystaUization with acetonitrUe to afford 0.07 gm of the title compound as a white soUd. Physical characteristics are as foUows: 1H NMR (OMSO-dβ) δ 10.3. 9.0, 8.2. 7.9, 7.8, 1.4. 5.8. 4.7. 4.5, 3.6. 3.5, 3.3. 2.4:
MS (ESI+) m/z 486; Anal. Found: C. 61.69: H, 5.85: N. 8.61.
EXAMPLE 108. N-(4-Chlorobenzyl)-6-(4-morphoUnylmethyl)-4-oxo- 1 -tetrahydro- 2H-pyran-4-yl-1.4-dihydro-3-quinolinecarboxamide (formula W-5: Z = O)
Figure imgf000156_0002
A flask containing 4-(4-aminobenzyl)morpholine from Preparation No. 22 (0.48 g) is treated with methanol (5 mL) and a few dozen dry molecular sieves (3A). The mixture is treated with acetic acid (1 mL) and terahydro-4H-pyran-4-one (0J4 mL). After 1 hour, the mixture is carefuUy treated with sodium cyanoboro hydride (0.6 g) and heated to reflux under an argon atmosphere. After 1 hour, the mixture is cooled to room temperature and fUtered with methanol washes. The filtrate is dUuted with diethyl ether and washed with aqueous sodium hydroxide (2N). The aqueous is back-extracted with dichloromethane. The combined organic layers are washed with brine, dried over sodium suU'ate, and concentrated under reduced pressure. The residue is flash column chromatographed on sUica eluting with 2% to 5% methanol in dichloromethane. The product-containing fractions are combined and evaporated to afford 0.34 g of" N-[4-(4-morphoUnylmethyl)phenyl]tetrahydro-2H-pyran- 4-amine as a white soUd.
A flask containing N-[4-(4-morpholinylmethyl)phenyl]tetrahydro-2H-pyran-4-amine (0.34 g) is treated with diethyl ethoxymethylenemalonate (030 mL) and pyridine (0.20 mL). The flask is tightly capped and heated to 140 υC for 2 hours. The reaction is cooled to room temperature and azeotroped under reduced pressure with toluene (3x). The residue is dissolved in dichloromethane and washed with water, brine, dried and concentrated under reduced pressure. The residue is chromatographed on sUica eluting with 2% to 6% methanol in dichloromethane. The product-containmg fractions are evaporated to give 0.41 g of diethyl 2-{[4-(4-morphoUnylmethyl)(tetrahydro-2H-pyran-4- yl)anUino]methylene}malonate as a tan oU.
A flask containing diethyl 2-{ [4-(4-morphoUnylmethyl)(tetrahydro-2H-pyran-4- yl)anilino] methylene} malonate (0.41 g) is treated with polyphosphoric acid (1.5 g). The reaction mixture is heated to 100 °C under a flow of nitrogen gas. After 1 hour the reaction is cooled to room temperature. The reaction mixture is carefuUy added to a vigorously stirred mixture of" dichloromethane and saturated aqueous bicarbonate. The layers are separated and the basic aqueous layer is extracted with three additional portions of dichloromethane. The combined organic layers are washed with water, brine, dried over sodium suU'ate and concentrated under reduced pressure. The residue is chromatographed on sUica eluting with 2% to 6% methanol in dichloromethane to afford 0.24 g of ethyl 6-(4- morpholinylmethyl)-4-oxo- 1 -tetrahydro-2H-pyran-4-yl- 1 ,4-dihydro-3-quinolinecarboxylate as a tan soUd.
A flask containing ethyl 6-(4-morpholinylmethyl)-4-oxo- l-tetrahydro-2H-pyran-4- yl-1.4-dihydro-3-quinolinecarboxylate (0J1 g) is treated with 4-chlorobenzylamine (2.0 mL). The reaction is tightly capped and heated to 190 υC for 1 hour. The reaction is cooled to room temperature, adsorbed onto siUca and chromatographed on sUica eluting with 2% to 6% methanol in dichloromethane and then by recrystaUization from ethyl acetate to afford 0J4 g of the title compound. Physical characteristics are as foUows:
1H NMR (DMSO-^ δ 10.4, 8.8, 8.3. 8J, 7.8. 7.4, 5.0, 4.5, 4.0, 3.7. 3.6, 3.5, 2.4, 2.0: MS (ESI+) m/z 496; Anal. Found: C, 65.20; H. 6.17: N, 8.23. EXAMPLE 109. N-(4-Chlorobenzyl)-l-(l-methyl-4-piperidinyl)-6-(4- morpholinylmethyl)-4-oxo- 1 ,4-dihydro-3-quinolinecarboxamide (formula W-5: Z = ΝMe)
Figure imgf000158_0001
A flask containing 4-(4-aminobenzyl)morphoUne from Preparation No. 22 (0.48 g) is treated with tetrhydrofuran (10 mL) and N-methyl-4-piperidone (0.37 mL) under an argon atmosphere. The solution is treated with acetic acid (0.20 mL) foUowed by sodium triacetoxyborohydride (0.80 g). After stirring overnight, the mixture is partitioned between diethyl ether and saturated aqueous sodium bicarbonate containing sodium hydroxide. The aqueous is back-extracted with additional portions of dichloromethane. The combined organic layer is washed with brine, dried over sodium suU'ate, and concentrated under reduced pressure. The residue is purUied by flash column chromatography on siUca gel eluting with 2% to 5% methanol saturated with ammonia in dichloromethane to afford 0.52 g of l-methyl-N-[4-(4-morpholinylmethyl)phenyl]-4-piperidinamine as a tan soUd.
A flask containing l-methyl-N-[4-(4-morpholinyknethyl)phenyl]-4-piperidinamine (0.52 g) is treated with diethyl ethoxymethylenemalonate (0.55 mL). The flask is tightly capped and heated to 150 °C for 1 hour. The reaction is cooled to room temperature. treated with diethyl ethoxymethylenemalonate (0.55 mL) and heated to 180 °C for 2 hours. The reaction is cooled to room temperature and flash column chromatographed on silica eluting with 5% to 20% methanol in dichloromethane. The product-containmg fractions are evaporated to give 0.75 g of diethyl 2-{[(l-methyl-4-piperidinyl)-4-(4- morphoUnylmethyl)anUino]methylene}malonate as tan soUd.
A flask containing diethyl 2-{ [(l-methyl-4-piperidinyl)-4-(4-morpholinylmethyl)- anilino]methylene}malonate (0.36 g) is treated with polyphosphoric acid (1.8 g). The reaction mixture is heated to 130 °C under a flow of nitrogen gas. After 4 hours the reaction is cooled to room temperature. The reaction mixture is carefuUy added to a vigorously stirred mixture of" dichloromethane and saturated aqueous bicarbonate. The layers are separated and the basic aqueous layer is extracted with three additional portions of dichloromethane. The combmed organic layers are washed with brine, dried over sodium suU'ate and concentrated under reduced pressure to afford 0.32 g of crude ethyl l-(l-methyl- 4-piperidinyl)-6-(4-morphoUnylmethyl)-4-oxo-l ,4-d ydro-3-quinoUnecarboxylate as a tan soUd.
A flask containing crude ethyl l-(l-methyl-4-piperidmyl)-6-(4-morphoUnylmethyl)-4- oxo- 1 ,4-dihydro-3-quinolinecarboxylate (0.31 g) is treated with 4-chlorobenzylamine (2.0 mL). The reaction is tightly capped and heated to 165 °C overnight. The reaction is cooled to room temperature, adsorbed onto sUica and chromatographed on sUica eluting with 2% to 10% methanol saturated with ammonia in dichloromethane and then by recrystaUization from ethyl acetate - hexanes to afford 0.1 1 g of the title compound.
Physical characteristics are as foUows: 1H NMR (OMSO-d6) δ 10.4, 8.8, 8.3, 8.0, 7.8, 7.4, 4.8, 4.5, 3.6, 3.5, 2.9, 2.4, 2.2,
2.0; MS (ESI+) m/z 509: Anal. Found: C, 65.71; H, 6.56; N, 10.85.
EXAMPLE 110. N-(4-Chlorobenzyl)-6-(4-morphoUnylmethyl)-4-oxo-l-(4- piperidinyl)-l,4-dUιydro-3-quinolinecarboxamide (formula W-5: Z = ΝH)
Figure imgf000159_0001
A flask containing 4-(4-aminobenzyl)morpholine from Preparation No. 22 (0.48 g) is treated with tetrahydrofuran (10 mL) and tert-butyl 4-oxo-l-piperidmecarboxylate (0.60 gm) under an argon atmosphere. The solution is treated with acetic acid (0J0 mL) foUowed by sodium triacetoxyborohydride (0.80 g). After stirring 3 days, the mixture is concentrated under reduced pressure. The residue is partitioned between dichloromethane and dUute aqueous sodium hydroxide. The aqueous is back-extracted with additional portions of dichloromethane. The combmed organic layer is washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue is flash column chromatographed on sUica gel elutmg with 2% to 6% methanol in dichloromethane to afford 0.96 g of tert-butyl 4-[4-(4-morpholinylmethyl)anilino]- l-piperidinecarboxylate as a tan soUd. A flask containing tert-butyl 4-[4-(4-morphoUnylmethyl)anUino]-l -piperidine- carboxylate (0.94 g) is treated with diethyl ethoxymethylenemalonate (1.0 mL). The flask is tightly capped and heated to 150 °C for 2 hours. The reaction is then heated to 175 °C for 2 hours. The reaction is cooled to room temperature and flash column chromatographed on siUca eluting with 2% to 5% methanol in dichloromethane. The product-containing fractions are evaporated to give 0.78 g of" diethyl 2-{ [[ l-(tert-butoxycarbonyl)-4-piperidinyl]-4-(4- morpholinylmethyl)anilino]methylene} malonate as tan soUd.
A flask containing a solution of diethyl 2-{ [[l-(tert-butoxycarbonyl)-4-piperidinyl]- 4-(4-morpholinytoιethyl)aniUno]methylene}malonate (0.36 g) in toluene (2 mL) is treated with polyphosphoric acid (2.1 g). The reaction mixture is heated to 120 °C under a flow of nitrogen gas. After 1 hour the reaction is cooled to room temperature. The reaction mixture is carefuUy added to a vigorously stirred mixture of dichloromethane and saturated aqueous bicarbonate. The layers are separated and the basic aqueous layer is extracted with three additional portions of dichloromethane. The combmed organic layers are washed with brine. dried over sodium suU'ate and concentrated under reduced pressure to afford 0J4 g of crude ethyl 6-(4-morpholinyUτιethyl)-4-oxo-l-(4-piperidinyl)-l J-dihydro-3-quinoUnecarboxylate as a tan oU.
A flask containing crude ethyl 6-(4-morphoUnylmethyl)-4-oxo- l-(4-piperidinyl)-1.4- dihydro-3-quinoUnecarboxylate (0J4 g) is treated with 4-chlorobenzylamine (1.0 mL). The reaction is tightly capped and heated to 180 °C for 2 hours. The reaction is cooled to room temperature and flash column chromatographed on silica eluting with 2% to 10% methanol saturated with ammonia in dichloromethane and then by recrystaUization from acetonitrUe to afford 0J0 g of the title compound as a white soUd. Physical characteristics are as foUows: Η NMR (OMSO-dβ) δ 10.4, 8.8, 8.3. 8J , 7.8. 1.4. 4.9. 4.5. 3.6. 3.5, 3J . 2.8, 2.4.
2.0. 1.8; MS (ESI+) m/z 495: Anal. Found: C, 65.1 1 : H, 6.38; N. 1 1.23. EXAMPLE 111. N-(4-Chlorobenzyl)-l-(lJ-dioxohexahydro-thiopyran-4-yl)-6-(4- morphoUnyknethyl)-4-oxo-l ,4-dihydro-3-quinoUnecarboxamide (formula W-5; Z = SO2)
on Λ
o o
A flask containing 4-(4-aminobenzyι)morpholine from Preparation No. 22 (0.48 g) is treated with tetrahydrofuran (10 mL) and terahydrothiopyran-4-one (0.35 gm) under an argon atmosphere. The solution is treated with acetic acid (0J0 mL) foUowed by sodium triacetoxyborohydride (0.80 g). After stirring overnight, the mixture is concentrated under reduced pressure. The residue is partitioned between dichloromethane and dUute aqueous sodium hydroxide. The aqueous is back-extracted with dichloromethane. The combined organic layers are washed with brine, dried over sodium suU'ate. and concentrated under reduced pressure. The residue is purUied by flash column chromatography on sUica eluting with 2% to 6% methanol in dichloromethane and then by recrystaUization from cyclohexane to afford 0.53 g of N-[4-(4-morpholinylmethyl)phenyl]tetrahydro-2H-thiopyran-4-amine as a tan soUd.
A flask containing N-[4-(4-morphoUnyUrιethyl)phenyl]tetrahydro-2H-thiopyran-4- amine (0.44 g) is treated with diethyl ethoxymethylenemalonate (0.35 mL). The flask is tightly capped and heated to 160 °C for 2 hours. The reaction is cooled to room temperature, treated with diethyl ethoxymethylenemalonate (0.35 mL) and pyridine (0.35 mL) and heated to 150 °C for 1 hour in a tightly sealed flask. The reaction is cooled to room temperature and azeotroped under reduced pressure with toluene (3x). The residue is flash column chromatographed on siUca gel eluting with ethyl acetate. The product-containing fractions are evaporated to give 0.59 g of diethyl 2-{[4-(4-morpholinylmethyl)(tetrahydro- 2H-thiopyran-4-yl)anUino]methylene}malonate as a tan soUd.
A solution of diethyl 2-{ [4-(4-morphoUnylmethyl)(tetrahydro-2H-thiopyran-4- yl)anilino]methylene}malonate (0.30 gm) in dichloromethane (5 mL) at 0 °C is treated with /7-toluenesuU'onic acid hydrate (0.57 gm) foUowed by /n-chloroperoxybenzoic acid (-85%) (0.32 gm). The mixture is stirred for 3 hr. The reaction mixture is dUuted with dichloromethane, washed with saturated aqueous sodium suUite. saturated aqueous sodium bicarbonate, brine, dried (Νa SO4) and concentrated under reduced pressure. The crude product is purUied by flash column chromatography on sUica gel eluting with 2% to 6% methanol in dichloromethane to afford 0J2 gm of 4-[4-(4-morpholinyl- methyl)anUino]tetrahydrothiopyran-lJ(2H)-dione as a white soUd.
A flask containing 4-[4-(4-morphoUnylmethyl)anilino]tetrahydro-thiopyran- l J (2H)- dione (0.1 1 g) is treated with diethyl ethoxymethylenemalonate (0J5 mL). The flask is tightly capped and heated to 155 υC for 2 hours. The reaction is cooled to room temperature, treated with diethyl ethoxymethylenemalonate (0J5 mL) and pyridine (0J5 mL) and heated to 120 °C for 2 hour in a tightly sealed flask. The reaction is cooled to room temperature and azeotroped under reduced pressure with toluene (3x). The residue is treated with diethyl ethoxymethylenemalonate (0.5 mL) and heated to 190 °C. After 2 hours, the reaction is cooled to room temperature and flash column chromatographed on siUca gel eluting with 2% to 6% methanol in dichloromethane. The product-containmg fractions are evaporated to give 0J 1 g of diethyl 2-{ [( l J-dioxohexahydrothiopyran-4-yl)-4- (4-morphoUnyUnethyl)anUino]methylene} malonate as a tan soUd. A flask containing a solution of diethyl 2- { [( 1 J -dioxohexahydro-thiopyran-4-yl)-4-
(4-morphoUnylmethyl)anUino] methylene} malonate (0J 1 g) in toluene (2 mL) is treated with polyphosphoric acid (1.5 g). The reaction mixture is heated to 120 υC under a flow of nitrogen gas. After 2 hours the reaction is cooled to room temperature. The reaction mixture is carefuUy added to a vigorously stirred mixture of dichloromethane and saturated aqueous bicarbonate. The layers are separated and the basic aqueous layer is extracted with two additional portions of dichloromethane. The combmed organic layers are washed with brine, dried over sodium suU'ate and concentrated under reduced pressure. The residue is purUied by flash column chromatography on siUca gel elutmg with 2% to 10% methanol in dichloromethane to afford 0.06 g of crude ethyl l-(l,l-dioxohexahydro-thiopyran-4-yl)-6- (4-morpholinylmethyl)-4-oxo- 1 ,4-dihydro-3-quinoUnecarboxylate as an off-white soUd. A flask containing ethyl l-(l, l-dioxohexahydro-thiopyran-4-yl)-6-(4- morpholinylmethyl)-4-oxo-l,4-dihydro-3-quinolinecarboxylate (0.06 g) is treated with 4- chlorobenzylamine (0.6 mL). The reaction is tightly capped and heated to 190 °C for 2 hours. The reaction is cooled to room temperature, adsorbed onto silica gel, flash column chromatographed on siUca elutmg with 2% to 10% methanol in dichloromethane. The product-containing fractions are concentrated under reduced pressure and triturated with diethyl ether. The resulting residue is dissolved in a smaU amount of dichloromethane and added dropwise to stirring diethyl ether (40 mL). The resulting precipitant is coUected by suction filtration to afford 0.05 g of the title compound as an off- white soUd.
Physical characteristics are as foUows:
1H NMR DMSO-d6) δ 10.3. 8.7. 8.3. 8.0, 7.8. 7.4. 5.3, 4.5, 3.6. 3.5, 3.3. 2.4; MS (ESI+) m/z 544; HRMS (FAB) found 544.1665 for C27H30C1N3O,S+H.
PREPARATION 53. 4-(3-bromo-4-fluorobenzyl)morpholine.
MorphoUne (0.96 mL) and acetic acid (0.57 mL) are added to a solution of 3-bromo- 4-fluorobenzaldehyde (2.03 g) in dichloroethane (40 mL). Sodium triacetoxyborohydride (3J8 g) is added in portions over an hour, and the reaction is stirred at room temperature for 18 hours. The reaction is quenched with a 1 N solution of NaOH ( 10 mL) and diluted with CH2Ch (100 mL). The organic layer is washed with 1 N NaOH (3 x 35 mL). The aqueous layers are back-extracted with CH2C12 (20 mL). The combmed organic layers are extracted with 0J N HCl (6 x 25 mL). The combined aqueous layers are basUied (pH = 12) with 2 N NaOH. and the product is extracted with CH2Ch (6 x 25 mL). The combined organic layers are washed with brine (20 mL) and dried (MgSO ). The solution is concentrated in vacuo to afford 2.23 g (82% ) of the title compound as a clear, colorless oU.
Physical characteristics are as foUows:
1H NMR (OMSO-d6) δ) 7.62. 7.35, 7.32, 3.57, 3.45, 2.34: HRMS (FAB) calcd for CnHI3BrFNO+H 274.0243. found 274.0243. Anal. Found for CπHπBrFNO: C, 48.15: H. 4.83: N. 5.10.
PREPARATION 54. 1 -[2-Fluoro-5-(4-morphoUnylmethyl)phenyl]- 1 -ethanone. A solution of 4-(3-bromo-4-tluorobenzyl)morpholine (35.5 g) of Preparation No. 53 in THF (400 mL) is cooled to -75 °C, and n-butyUithium is added via addition funnel maintaining the temperature below -65 °C. A solution of N-methyl-N-methoxyacetamide (16.0 g, prepared as described in Tetrahedron Lett. 1983, 24, 1857) in THF (50 mL) is added via addition funnel, again maintaining temperature below -65 °C. The reaction is stirred at -75 °C for 1 hour and then is allowed to warm to room temperature overnight. The reaction mixture is quenched with 1 Ν HCl (150 mL) and dUuted with ethyl acetate (400 mL). The layers are separated, and the aqueous layer is basUied with sat. sodium bicarbonate solution. The aqueous layer is extracted with ethyl acetate (2 x 100 mL). The combmed organic layers are washed with sat. sodium bicarbonate (2 x 100 mL) and brine (50 mL). The aqueous layers are back- extracted with ethyl acetate (100 mL). The combined organic layers are dried (Na SO4) and concentrated in vacuo to a yeUow oU. The oU is purified by fractional distillation at 135-140 °C/0.3 torr to afford 19.7 g (64%) of the title compound as a clear, colorless oU. Physical characteristics are as foUows:
1H NMR (DMSO-cfc) δ 1.12, 7.58. 7.31. 3.56. 3.48, 2.58. 234; IR (Uq.) 2421. 2259. 1996. 1979, 1919, 1688. 1612, 1492, 1417, 1361 , 1291. 1281. 1212, 11 18, 865 cm"1; MS (ESI+) m/z 238 (M+H)+. Anal. Found for C13H16FNO?: C, 65.43: H, 6.75: N, 5.84.
PREPARATION 55. Ethyl 3-[2-Fluoro-5-(4-morphoUnylmethyl)phenyl]-3- oxopropanoate.
A solution of l-[2-fluoro-5-(4-morpholinylmethyl)phenyl]- l-ethanone (19.6 g) of Preparation No. 54 in diethyl carbonate ( 150 mL) is cooled to 0 °C. and sodium hydride (60% dispersion. 6.6 g) is added slowly to the reaction mixture. The reaction is stirred at 0 °C for 3 hours, and then is aUowed to warm to room temperature overnight. The reaction mixture is quenched with acetic acid (10 mL), dUuted with water (200 mL) and then basUied with sat. sodium carbonate. The solution is then extracted with ether (3 x 200 mL). The combmed organic layers are washed with sat. sodium bicarbonate (100 mL) and brine (50 mL). The combmed aqueous layers are back-extracted with ether (50 mL). The combined organic layers are then dried (Na2SO4) and concentrated in vacuo to an orange oU. The crude product is purUied in 2 batches by column chromatography (heptane/IP A. 8/1 : 4/1) to afford 20.2 g (79%) of the title compound as a yeUow oU. Physical characteristics are as foUows: 1H NMR (DMSO-ύfe) δ 7.78. 7.62. 7.32. 4.21. 4.05. 3.57. 3.50, 2.34. 1 J6: IR (Uq.) 2419, 2261. 1996, 1979, 1744, 1689. 1626. 161 1 , 1493, 1331. 1260. 1215. 1147. 1117, 865. cm"1; MS (ESI+) m/z 310 (M+H)+: Anal. Calcd for C16H?oFNO4: C, 62.12: H. 6.52: N. 4.53. Found: C, 61.96; H, 6.67; N, 4.44. PREPARATION 56. Ethyl l-(4-Morphoϋnyl)-6-(4-morphoUnylmethyl)-4-oxo-l ,4- dihydro-3-quinolinecarboxylate.
Figure imgf000165_0001
Ethyl 3-[2-fluoro-5-(4-morpholinylmethyl)phenyl]-3-oxopropanoate (10.0 g) of Preparation No. 55, triethylorthoformate (10.8 mL) and acetic anhydride (10J mL) are combined in a flask equipped with a Dean-Stark trap and condenser. The reaction is heated to 150 °C for 3.5 hours. The excess acetic anhydride and triethylorthoformate are distUled off at 100 °C and 0.2 torr leaving a burgundy oU containing a mixture of E- and Z- isomers of ethyl-3-ethoxy-2-[2-tluoro-5-(4-morpholinylmethyl)benzoyl]-2-propenoate.
This crude mixture is dissolved in ethanol (50 mL), and 4-aminomorphoUne (4.1 mL) is added. The reaction mixture is stirred at room temperature for 2.5 hours and concentrated in vacuo. The resulting burgundy oU is purUied in two batches by column chromatography (MeOH/CH2Cl2: 1 %, 2% : 5%) to give ethyl (E)- and (Z)-2-[2-fluoro-5-(4- morphoUnylmethyl)benzoyl]-3-(4-morphoUnylamino)-2-propenoate as a yeUow oU.
The crude enamine is dissolved in THF. and sodium hydride is slowly added to the solution. After heating the mixture to 70 °C for 2 hours, the reaction is quenched with water (5 mL) and concentrated in vacuo to a burgundy slurry. More water (100 mL) is added, and the remaining THF removed in vacuo. The resulting yeUow precipitate suspended in an aqueous solution is fUtered on a fritted funnel and washed twice with water and once with ether to afford 5.9 g (55%) of the title compound as a powdery, yeUow soUd. Physical characteristics are as foUows:
Mp 209-21 1 °C; 1H NMR (DMSO-^) δ 8.87, 8.20, 8.1 1, 7.74, 4.23, 3.97, 3.78, 3.59, 3.57, 3.03, 2.37, 1.30; MS (ESI+) m/z. 402 (M+H)+; Anal. Found for C21H27N3O5: C, 62.83: H. 6.75: N. 10.44. EXAMPLE 112. N-(4-Chlorobenzyl)- 1 -(4-morphoUnyl)-6-(4-morphoUnylmethyl)- 4-oxo- 1 ,4-dihydro-3-quinolinecarboxamide
Figure imgf000166_0001
Ethyl 1 -(4-morpholinyl)-6-(4-morpholinylmethyl)-4-oxo- 1 ,4-di ydro-3- quinolinecarboxylate (5.0 g) from Preparation No. 56 and 4-chlorobenzylamine (7.6 mL) are combmed and heated to 190 °C for 7 hours. After cooling to room temperature, the mixture solidifies. The soUd is triturated with a 10: 1 mixture of EtOAc/MTBE (30 mL) and fUtered on a frit. The crude soUd is triturated again, this time with a hot mixture of 10: 1 EtOAc/MTBE (1 10 mL). The suspension is cooled to room temperature and fUtered on a frit to afford 4.9 g (79% ) of the title compound as a white soUd. Physical characteristics are as foUows:
Mp 195- 196 °C: Η NMR DMSO-d6) δ 10.30, 9J4. 8.28, 8.20, 7.81. 7.40, 4.56, 3.98, 3.80. 3.62. 3.57, 3.28, 3.08, 2.37; IR (muU) 2286, 1969, 1952, 1926, 1652. 1599, 1585, 1524, 1489, 1352, 1283, 1 1 1 1, 862, 808, 724 cm"1: MS (ESI+) for m/z 497 (M+H)J Anal. Found for C26H79CIN4O4: C, 62.69: H. 5.94; N, 1 1.22: Cl, 7.1 1.
EXAMPLE 113. /V-(4-Chlorobenzyl)- 1 -(4-methyl- 1 -piperazinyl)-6-(4- morpholinylmethyl)-4-oxo- 1 ,4-dihydro-3-quinolinecarboxamide
Figure imgf000166_0002
The title compound is prepared according to procedures analogous to those described in Preparation No. 56 employmg 1 -amino-4-methylpiperazine and Example No. 112. The crude product is purUied by recrystaUization in EtOH to afford 0.87g of the title compound as a white soUd. Physical characteristics are as foUows:
Mp 135-139 °C: Η NMR (OMSO-d6) δ 10.32, 8.97, 8J8, 7.80, 7.36, 4.54, 3.59, 3.55, 3.21, 3.05, 2.88, 2.36, 2.27: IR (drift) 2796. 2309, 1934, 1659, 1597, 1568, 1544, 1489, 1352, 1323, 1289, 1 1 15, 1008, 865, 809 cm"1: MS (ESI+) m/z 510 (M+H)+. HRMS (FAB) calcd for C27H32CLN5O3 +H 510.2272, found 510.2290. Anal. Found for C27H32CIN5O3: C, 63.59; H. 6.40; N, 13.33; Cl, 6.86.
EXAMPLE 114. N-(4-Chlorobenzyl)-6-(4-morphoUnylmethyl)-4-oxo- 1 Jl - piperidinyl)- 1 ,4-dihydro-3-quinoUnecarboxamide
Figure imgf000167_0001
The title compound is prepared according to procedures analogous to those described in Preparation No. 56 employing 1-aminopiperadine and Example No. 112. The crude product is purUied by recrystaUization in acetonitrUe to afford ()J3g of the title compound as a white soUd.
Physical characteristics are as foUows: Mp 161- 164 °C; 1H NMR (DMSO-d6) δ 1038, 9.07, 8.22. 8.20. 7.81. 7.40, 4.56,
3.61, 3.57, 3J0, 2.37, 1.81, 1.40: IR (drift) 2942, 2853. 1657. 1597. 1574, 1549, 1531, 1488, 1354, 1326, 1291 , 1 115, 807, 796. 680 cm"1: MS (ESI+) for m/z 495 (M+H)+; Anal. Calcd for C27H3,ClN4O3: C. 65.51 ; H. 6.31 ; N, 1132; Cl, 7J6. Found: C, 65.50; H, 6.23: N, 1 1.40; C1, 7J9.
EXAMPLE 115. N-(4-Chlorobenzyl)-6-(4-morphoUnylmethyl)-4-oxo-l-(l- pyrroUdinyl)- 1 ,4-dihydro-3-quinolinecarboxamide
Figure imgf000167_0002
The title compound is prepared according to procedures analogous to those described in Preparation No. 56 employing 1-aminopyrroUdine and Example No. 1 12. The crude product is purUied by recrystaUization in methanol to afford 0.39 g of the title compound as a white soUd.
Physical characteristics are as foUows:
Mp 21 1-214 °C; Η NMR (DMSO-d6) δ) 10.35, 9.08, 8J6, 8J3. 7.78, 7.36, 4.54. 3.59, 3.55, 3J4, 2.35, 2.05, 1.93; IR (drift) 2857, 2805, 1966, 1944, 1655, 1600, 1576, 1545, 1488, 1361 , 1324, 1 134. 1 113. 863, 809 cm"1: MS (ESI+) for m/z 481 (M+H)+: Anal. Found for C26H29CIN4O3: C. 64.57; H, 6J3; N, 1 1.53: Cl, 7J9.
EXAMPLE 116. N-(4-Chlorobenzyl)-l-[(2R)-2-(methoxymethyl)pyrroUdinyl]-6- (4-morphoUnylmethyl)-4-oxo- 1 ,4-dihydro-3-quinolinecarboxamide
Figure imgf000168_0001
The title compound is prepared according to procedures analogous to those described in Preparation No. 56 employing (R)-(+)-l-amino-2-(methoxymethyl)pyrrolidine and Example No. 1 12. The crude product is purUied by column chromatography (MeOH/CT Ck 0.5%, 1.5%, 2.5%) and trituration with ether to afford 0.79 g of the title compound as a white soUd. Physical characteristics are as foUows:
Mp 98-100 °C; !H NMR (OMSO-d6) δ) 10.35 , 9J5, 8.22, 8J8, 7.77, 7.39. 4.56, 3.61 , 3.57, 3.39, 3.25, 2.89, 2.37, 2.16, 2.01 , 1.70; IR (drift) 2350, 1663, 1597, 1580, 1549, 1488, 1351, 1325, 1203, 11 16, 1093, 867, 831 , 807. 800 cm"1; HRMS (FAB) calcd for C28H33CIN4O4+H 525.2268, found 525.2275.
EXAMPLE 117. N-(4-Chlorobenzyl)-l-(dimethylamino)-6-(4-morpholinylmethyl)- 4-oxo- 1 ,4-dihydro-3-quinolinecarboxamide
Figure imgf000168_0002
The title compound is prepared according to procedures analogous to those described in Preparation No. 56 employmg lJ-dimethylhydrazine and Example No. 1 12. The crude product is purUied by recrystaUization in methanol to afford OJ g of the title compound as a white soUd.
Physical characteristics are as foUows:
Mp 170-171 °C: Η NMR (OMSO-d6) δ 10.38. 9. 10, 8.20, 8J4, 7.82, 7.39, 4.57, 3.61 , 3.57, 2.92, 2.37: IR (drift) 1962, 1932, 1661, 1597, 1551, 1489, 1462, 1360, 1352, 1323, 1 1 13, 913, 866, 81 1, 804 cm"1; MS (ESI+) for m/z 455 (M+H)+; HRMS (FAB) calcd for C?4H27ClN4O3+H 455.1850, found 455.1857.
PREPARATION 57. 1 - Amino-N-(4-chlorobenzyl)-6-iodo-4-oxo- 1 ,4-dihydro-3- qumoUnecarboxamide.
Figure imgf000169_0001
A suspension of N-(4-chlorobenzyl)-4-hydroxy-6-iodo-3-quinolinecarboxamide (2.0 g) of Preparation No. 4 and of potassium carbonate (2.0 g) in DMF (40 mL) is stirred at room temperature for 5 hrs and then treated with of O-(mesitylsuU'onyl) hydroxylamine (1.5 g). After 24 hrs. the solvent is evaporated under reduced pressure and the residue is dUuted with water(150 mL). The resulting soUd is filtered and washed with water (3x) and ether (2x). RecrystaUization from hot acetic acid/water affords 1.35 g of" the title compound as a tan soUd.
Physical characteristics are as foUows:
Mp 230-235 °C (dec). 1H NMR (DMSO-40 δ 8.81, 8.54, 8J3, 7.89, 7.40-732, 6.69. 4.54.
EXAMPLE 118. l-Ammo-N-(4-chlorobenzyl)-6-(3-hydroxy- l-propynyl)-4-oxo- 1 ,4-dihydro-3-quinolinecarboxamide
Figure imgf000169_0002
1 - Ammo-N-(4-chlorobenzyl)-6-iodo-4-oxo- 1 J-dihydro-3-quinolinecarboxamide (0.25 g) from Preparation No. 57, copper (I) iodide (32 mg), and bis(triphenylphosphine)- paUadium (II) chloride (19 mg) are suspended in diethylamine (8 mL). Propargyl alcohol (39 μL) is added and the mixture is aUowed to stir at room temperature for 16 h. The mixture is dUuted with ethanol and then concentrated in vacuo. The crude soUd is triturated with dichloromethane and recrystaUized in acetic acid to affording 76 mg of the title compound as a beige soUd.
Physical properties are as foUows:
Mp 230-235 °C (dec); lH NMR (OMSO-d6) δ 10.25, 8.79, 8.22, 8.07. 7.85, 7.35, 6.70, 5.39, 4.52, 4.32: HRMS (FAB) calcd for C20H16CIN3O3+H 382.0958, found 382.0952;
EXAMPLE 119. l -Amino-N-(4-chlorobenzyl)-6-(3-hydroxypropyl)-4-oxo- l ,4- dihydro-3-quinolinecarboxamide
Figure imgf000170_0001
l -Amino-N-(4-chlorobenzyl)-6-(3-hydroxy-l-propynyl)-4-oxo- l ,4-dihydro-3- quinolinecarboxamide (0J1 g) from Example No. 1 18 is dissolved in a 1 : 1 mixture of methanol/DMF. To the solution is added 5% platinum on carbon (0.1 1 g) and acetic acid (0.5 mL). The reaction is shaken under a hydrogen atmosphere (35 psi) for 4.5 hours. The catalyst is removed by filtration through CeUte. The filtrate is concentrated in vacuo, and the resulting white soUd is triturated with dichloromethane. The crude product is then purUied by column chromatography (MeOH/CH2Cl2: 3%, 5%) yielding 0.10 g of the title compound as a white soUd. Physical properties are as foUows:
Mp 187-188 °C; Η NMR (DMSO- ) δ 10.44, 8.77, 8.06. 7.98, 7.71. 7.36. 6.67, 4.54, 4.50, 3.40, 2.77, 1.74; IR (drU't) 3272. 3183, 2941 , 1916, 1644. 1598, 1559. 1491 , 1433, 1242, 1093, 842, 805, 740, 724 cm"1: HRMS (FAB) calcd for C20H20CIN3O3+H 386.1271 , found 386.1282. PREPARATION 58. Butyl l-(Dimethylamino)-6-iodo-4-oxo- 1.4-dihydro-3- quinolinecarboxylate.
Figure imgf000171_0001
A solution of of the TBDMS ketene acetal of butyl acetate (8J g) and triethylamine (5.6 mL) in THF (20 mL) is added in one portion to a solution of" 2-chloro-5-iodobenzoyl chloride in THF (40 mL). The mixture is stirred 24 h and then the solvent was evaporated in a stream of" nitrogen. The residue is dUuted with ether (30 mL) and fUtered. The resulting filtrate is concentrated to afford 8.2 g of an oU which is dissolved in THF (100 mL) and treated with of 3 N hydrochloric acid (10 mL). After 5 h the volume of this mixture is reduced by two thirds by evaporation at reduced pressure. The residue is dUuted with dichloromethane (100 mL). The phases are separated and the organic layer dried over MgSO4. The mixture is fUtered and dissolved in toluene. The solvent was evaporated and the process was repeated untU TBDMS is no longer detectable in the mixture by Η NMR. The residual oU is purUied by column chromatography (gradient 30-45% dichloromethane hexanes) to afford 7.9 g of butyl 3-(2-chloro-5-iodophenyl)-3-oxopropanoate as an orange oU. A mixture of the above ketoester (3.3 g) and ethyl orthoformate (2.2 mL) in acetic anhydride (2 mL) is refluxed for 2 h. The excess triethyl orthoformate and acetic anhydride are removed by evaporation at reduced pressure foUowed by concentration from xylene (75 mL) to afford butyl 2-(2-chloro-5-iodobenzoyl)-3-ethoxy-2-propenoate as a crude oU.
Dimethylhydrazine (1 J mL) is added to a solution of the above crude enol ether (4.0 g) in ethanol (10 mL). The mixture is aUowed to stirr for 4 h. The reaction mixture is then concentrated to afford 4 g of butyl 2-(2-chloro-5-iodobenzoyl)-3-(2J-dimethylhydrazino)-2- propenoate as an amber oU.
The above hydrazide is dissolved in dioxane (50 mL) and treated with sodium hydride (0.6 g, 60% in mineral oU). The mixture is refluxed 2 hours, cooled to room temperature, and is fUtered washing with absolute ethanol (2 x 10 mL). The combined filtrate and washes are briefly refluxed with 5 g of DARCO, and the solution is fUtered through CeUte. The solvent was evaporated at reduced pressure, and the residue is purUied by column chromatography (gradient 5-15% ethyl acetate in dichloromethane) to afford 1.2 g of the title compound as a white soUd.
Physical characteristics are as foUows:
Η NMR (DMSO-^) δ 8.87, 8.43. 8.06. 7.86, 4J 8, 2.85, 1 JO- 1.55, 1.50-130, 0.91 ; MS (ESI+) m/z 415 (M+H+).
EXAMPLE 120. N-(4-Chlorobenzyl)-l-(dimethylamino)-6-(3-hydroxy-l- propynyl)-4-oxo- 1 ,4-dihydro-3-quinolinecarboxamide
Figure imgf000172_0001
Butyl l-(dimethylamino)-6-iodo-4-oxo-l ,4-dmydro-3-quinoUnecarboxylate (0.50 g) from Preparation No. 58 and 4-chlorobenzylamine (0J9 mL) are heated to 170 °C for 7 hours. The reaction is cooled to rt, and the crude soUd is recrystaUized in acetic acid yielding 0.54 g of the amide. The resulting amide (0J5g). copper (I) iodide (30 mg), and bis(triphenylphosphine)paUadium (II) chloride ( 18 mg) are suspended in diethylamine (8 mL). Propargyl alcohol (36 μL) is added and the mixture is aUowed to stir at room temperature for 16 h. The mixture is dUuted with ethanol and then concentrated in vacuo. The crude soUd is triturated with dichloromethane and purUied by column chromatography (2% MeOH CH Cl2), affording 9 mg of the title compound as a beige soUd. Physical properties are as foUows:
Mp 210-214 °C; Η NMR (DMSO- 6) δ 10.52, 9.34, 8.50, 839, 8.05, 7.62, 5.64, 4.83, 4.63, 3J9; IR (drift) 2225, 1928, 1912, 1646. 1592, 1572. 1549, 1486, 1462, 1357. 1346, 1032, 1026, 836, 806 cm"1; HRMS (FAB) calcd for C22H20CIN3O3+H 410.1271, found 410.1283.
PREPARATION 59. Ethyl l-(Dimethylamino)-4-oxo-l,4-dUιydro-3- quinolinecarboxylate.
Figure imgf000172_0002
Ethyl 3-(2-fluorophenyl)-3-oxopropanoate (15.0 g) is refluxed with triethylorthoformate (17.8 mL) in acetic anhydride (16.8 mL) for 4 hrs. The reaction mixture is dUuted with xylenes (75 mL) and is concentrated under reduced pressure to give 19J g of an amber oU. A solution of this oU (4.0 g) in ethanol (10 mL) is treated with 1 , 1 - dimethylhydrazine (1 J mL) and stirred for 1 min. The reaction mixture is concentrated and agitated with 4: 1 hexanes/ether. The solvent is decanted, and the final traces of solvent are removed at high vacuum to leave an amber oU of ethyl 3-(2,2-dimethylhydrazino)-2-(2- fluorobenzoyl)-2-propenoate.
The resulting hydrazide (4.0 g) is dissolved in dioxane (20 mL) and treated with 60% sodium hydride in oU (0.60 g). The mixture is refluxed under nitrogen for 2 hrs and then cooled to 25 °C. The reaction mixture is dUuted with ethanol (10 mL) and water (75 mL) and is then extracted with ethyl acetate (3 x 75 mL). The organic phases are combined, washed with brine, dried with calcium chloride and fUtered. The volume of the filtrate is reduced by evaporation at reduced pressure almost to dryness, and the residue is dUuted with diethyl ether (150 mL). The soUd is fUtered and washed with diethyl ether (2 x 20 mL) to afford 0.75 g of ethyl l-(dimethylamino)-^-oxo- 1.4-dihydro-3-qumolinecarboxylate as an orange soUd.
Physical characteristics are as foUows:
Mp 1 19-120 υC: 1H NMR (OMSO-d6) δ 8.89, 8J9. 8.09. 7.79. 7.47, 4.24, 3.30, 1.29: MS (ESI+) /z 283 (M+Na+): HRMS (FAB): calcd for C,4Hi7N2O3+H+: 261.1239. Found: 261.1234.
EXAMPLE 121. N-(4-Chlorobenzyl)-l-(dimethylammo)-4-oxo-l ,4-dihydro-3- quinolinecarboxamide
Figure imgf000173_0001
Ethyl l-(dmiethylamino)-4-oxo-l,4-dihydro-3-qu olinecarboxylate (0.21 g) of Preparation No. 59 and 4-chlorobenzylamine (1.2 mL) are heated to 180 °C for 10 hrs under nitrogen. The product is precipitated from the cooled reaction mixture by dUution with a mixture of toluene and hexanes. The crude product is then recrystaUized from aqueous acetic acid to give 0.030 g of the title compound. Physical characteristics are as foUows:
Mp 170-172 °C: 1H NMR DMSO-d6) δ 10.3, 9J , 8.3, 8.2, 7.9, 7.5, 7.4, 4.6, 2.9; MS (FAB) (M+H)+: calcd 356. H65, found 356.1 173.
PREPARATION 60. Ethyl l -(AUyloxy)-4-oxo- l ,4-dihydro-3-quinoline- carboxylate.
Figure imgf000174_0001
O-AUylhydroxylamine hydrate (1.52 g) is dissolved in ethanol (50 mL) and treated with 3 N aqueous sodium hydroxide untU a phenolphthaUen endpoint is achieved. Ethyl 3- ethoxy-2-(2-fluorobenzoyl)-2-propenoate (3.7 g, prepared from ethyl 3-(2-fluorophenyl)-3- oxopropanoate as in Preparation No. 59) is added, and the mixture is stirred for 3 h. The mixture is filtered and the resulting filtrate is concentrated. The crude enamine intemediate is treated with sodium hydride in refluxing dioxane according to the procedures analogous to those described in Preparation No. 58. The crude product is is purUied by column chromatography (30-40% ethyl acetate in dichloromethane). Fractions containing the major product are combined and concentrated at reduced pressure. The residue is dissolved in a minimum volume of ethyl acetate and stored at -15 °C overnight foUowed by the addition of ether (20 mL) and cyclohexane (20 mL). The soUd is coUected by filtration and washed with two portions of ether to afford 1.0 g of the title compound as a pale yeUow soUd. Physical characteristics are as foUows: Mp 98-100 °C. 1H NMR (DMSO-40 δ 8.89, 8.20, 7.85. 7.76, 7.51 , 6.3-6J , 5.50,
5.42, 4.88, 4.22, 1.28: MS (ESI+) m/z 296 (M + H+). Anal. Found for C15H15NO4: C, 65.80; H, 5.64; N, 5.09. EXAMPLE 122. l-(AUyloxy)-N-(4-chlorobenzyl)-4-oxo-1.4-dihydro-3- quinolinecarboxamide
Figure imgf000175_0001
Ethyl l-(aUyloxy)-4-oxo-l,4-dihydro-3-quinoUnecarboxylate (0.5g) of Preparation No. 60 is treated with sodium hydroxide (3 N, 2 mL) in ethanol (2 mL) and stirred for 30 min. The reaction mixture is neutraUzed with hydrochloric acid and fUtered. washing the filtrant with water (3x) and ether (lx). The crude carboxyUc acid is dried in a stream of au¬ to give 0.31 g of a white powder which is suspended in DMF (15 mL) and treated with 1 ,1'- carbonyldiimidazole (0.46 g). The reaction mixture is heated to 65 °C for 5 hrs. cooled and treated with H2O (0.03 mL). After 5 mmutes. 4-chlorobenzylamine (0J9 mL) is added. The mixture is stirred for 3 days. dUuted with water ( 15 mL) and fUtered to afforded 0J9 g of the title compound as a white solid.
Physical characteristics are as foUows:
Mp 113-1 14 °C; Η NMR (DMSO-^) δ 10.3. 9.0, 8.3. 7.9. 7.6. 7.4. 6.2. 5.5. 5.4, 4.9, 4.5: MS (FAB) (M+H)+: calcd 369.1006. found 369.1000.
EXAMPLE 123. N-(4-Chlorobenzyl)- l-methoxy-4-oxo-1.4-dihydro-3- quinoUnecarboxamide
Figure imgf000175_0002
Ethyl 3-ethoxy-2-(2-fluorobenzoyl)-2-propenoate (4.0 g. prepared from ethyl 3-(2- fluorophenyl)-3-oxopropanoate as in Preparation No. 59) and O-methylhydroxylamine ( 16 mmol, prepared by mixing 1 eq of sodium ethoxide with 1 eq of O-methylhydroxylamine hydrochloride in ethanol) are stirred in ethanol (20 mL) for 1 hour at rt. The mixture is concentrated, dUuted with dioxane (75 mL) and re-concentrated to remove any remaining ethanol. The resulting enamine is dUuted in dioxane (70 mL) and sodium hydride (60% dispersion, 0.64 g) is added. The mixture is heated to reflux for 2.5 hours, cooled to rt and concentrated in vacuo. The remaining residue is partiaUy dissolved in ethanol (100 mL) and fUtered. The filtrate is concentrated in vacuo and chromatographed (7% MeOH/CH2Cl2). The combined fractions are concentrated, leaving a residue which is recrystaUized in a 1 : 1 ether/hexanes mixture to afford 0.95 g of ethyl l-methoxy-4-oxo-1.4-dihydro-3- quinoUnecarboxylate (Mp 120-121 °C) as a white soUd.
The resulting carboxylate ester (0.48 g) is stirred with a solution of" 3 N NaOH (aqueous, 5 mL) in ethanol (6 mL) for 15 mmutes. The reaction mixture is neutraUzed with 3 N HCl, filtered, and washed with ethanol to give the carboxyUc acid as a white soUd. The carboxyhc acid (0J6 g) and N,N -carbonyldUmidazole (0J8 g) are dissolved in DMF (10 mL) and heated to 65 °C for 5 hours. The reaction mixture is cooled to 0 °C, quenched with water (0.01 mL) and stirred for 5 minutes. After warming to room temperature, 4- chlorobenzylamine (0.10 mL) is added. The reaction mixture is then stirred for 16 hours at room temperature. Water (15 mL) is added, and the precipitate is filtered off and washed with 1 :1 DMF/H2O (2 x 25 mL) and H2O (2 x 25 mL) to afford 50 mg of the title compound as a white soUd.
Physical properties are as foUows:
Mp 155-160 °C; 1H ΝMR (DMSO-^) δ 10.30, 9.08, 8.32, 7.91. 7.62, 7.39, 4.56. 4.21 ; IR (drU't) 1941 , 1920, 1650, 1603, 1549, 1489. 1463, 1350. 1221, 1013, 954, 840, 801, 751, 713 cm"1; HRMS (FAB) calcd for Cι8H15ClΝ?O3+H 343.0849, found 343.0867.
EXAMPLE 124. N-(4-Bromo benzyl)- 1 -(4-morpholinyl)-6-(4-morphoUnyknethyl)- 4-oxo- 1 ,4-dihydro-3-quinoUnecarboxamide
Figure imgf000176_0001
4-Bromobenzylamine hydrochloride (2J2 g) is suspended in water (5 mL) and neutraUzed with 2Ν aqueous NaOH (5 mL). The free amine is extracted with dichloromethane (2 x 25 mL). The organic layers are combmed, washed with brine (5 mL), and dried with Na2SO4. The solution is concentrated in vacuo to afford 1.48 g of a clear, colorless oU which is then combined with ethyl l-(4-morpholinyl)-6-(4-morphoUnylmethyl)- 4-oxo- l,4-dihydro-3-quinolinecarboxylate (0.48 g) from Preparation No. 56 and heated to 190°C for 3 hours. The reaction mixture is aUowed to cool to room temperature, and the resulting soUd is recrystaUized in ethyl acetate to afford 0.44 g of the title compound as a white soUd.
Physical properties are as foUows: Mp 200-202 °C. Η NMR (DMSO-d6) δ) 10.35, 9.03, 8.28, 8.21, 7.81 , 7.54, 7.31,
4.55, 3.96, 3.80, 3.62, 3.59, 3.28, 3.08, 2.37. IR (drift) 1966, 1926, 1652, 1597, 1585, 1549, 1522, 1487, 1359, 1351, 1283, 11 1 1 , 862, 807, 799 cm"1. MS (ESI+) m/z. 541 (M+H)+; HRMS (FAB) calcd for C26H29BRN4O4 +H 541.1451 , found 541.1447.
EXAMPLE 125. N-(4-Ruorobenzyl)-l-(4-morphoUnyl)-6-(4-morphoUnylmethyl)-
4-oxo- 1 ,4-dihydro-3-quinolinecarboxamide
Figure imgf000177_0001
Ethyl 1 -(4-morpholinyl)-6-(4-morphoUnylmethyl)-4-oxo- 1 ,4-dihydro-3- quinolinecarboxylate (0.33 g) from Preparation No. 56 and 4-fluorobenzylamine (0.55 mL) are combined and heated to 180 °C for 3 hours. The reaction is aUowed to cool to room temperature. The crude soUd is triturated with ether, fUtered, and recrystaUized in methanol to afford 0J4 g of the title compound as a white soUd.
Physical properties are as foUows:
Mp 165-167 °C. 1H NMR (DMSO-cfe) δ 10.33, 9.06, 8.27, 8.21, 7.81 , 7.39, 7J7, 5.76, 4.57, 3.97, 3.80, 3.62, 3.57, 3.08, 2.37. IR (drift) 1661 , 1598, 1549, 1510, 1488, 1355, 1324, 1288, 1269, 1223, 11 10, 864, 842, 829, 809 cm"1. MS (ESI+) /n z 481 (M+H)+; HRMS (FAB) calcd for C26H-29FN4O4 +H 481.2251. found 481.2245.
AU cited pubUcations, patents, and patent documents are incorporated by reference herein, as though individuaUy incorporated by reference. The invention has been described with reference to various specific and preferred embodiments and techniques. However, it should be understood that many variations and modUications may be made whUe remaining within the spirit and scope of the invention.

Claims

CLAIMS We claim:
1. A compound of" formula I,
Figure imgf000178_0001
I or a pharmaceuticaUy acceptable salt thereof wherein, X is a) O, or b) S:
W is a) R2: b) NR7R8. c) OR9, or d) SO,R9:
R' is a) Cl, b) F, c) Br. d) CN, or e) NO?;
R2 is a) (CH2CH2O)mR , 10 , b) het, wherein said het is bonded via a carbon atom. c) Ci-7 alkyl which may be partiaUy unsaturated and is optionaUy substituted by one or more substituents selected from a group consisting of" NR7R8, R11. CN, SO,R9. or OC?_4 alkyl which is further substituted by het, OR10, OC(=O)aryl, or NR7R8, or d) C3-8 cycloalkyl, which may be partiaUy unsaturated and is optionaUy substituted by R11, NR7R8, SO,R9, or Cι-7 alkyl optionaUy substituted by R11. NR7R8, or SO,R9;
R" is a) H. b) halo, or c) Cι-4 alkyl, optionaUy substituted by one to three halo;
4 is a) H, b) aryl. c) het. d) SO2NHR12. e) CONHR12, t) NR7R8, g) NHCOR12.
Figure imgf000179_0001
i) OC2-7 alkyl optionaUy substituted by -OH, j) SC2-7 alkyl optionaUy substituted by OH, or k) C]-8 alkyl which may be partiaUy unsaturated and is optionaUy substituted by one or more substituents selected from a group consisting of N3, OR10, NR7R8, halo, SO,R9. OR1? or Rπ: R5 is a) H. b) halo. c) C≡CR14. d) NR7R8. f) het. or g) Cj-7 alkyl, optionaUy substituted by OH:
R6 is a) H, b) halo. c) SC1.7 alkyl, e) Ci_7 aU oxy, optionaUy substituted by one or more halo or OH, or
1) Cι_7 alkyl, which may be partiaUy unsaturated and is optionaUy substituted by halo, NR10R10, (CH2)„OR13. R11, OC ,-7 alkyl which is further substituted with het, NR7R8, or SO.R9; R7 and R8 are independently a) H. b) aryl, c) Cι-7 alkyl which may be partiaUy unsaturated and is optionaUy substituted by one or more substituents selected from a group consisting of NR10R10. CONR10R10, R11. SO,R9. halo: or d) R7 and R8 together with the nitrogen to which they are attached to form a het; R9 is a) aryl, b) het, c) C .8cycloalkyl, or d) Cι_7alkyl which may be partiaUy unsaturated and optionaUy substituted by one or more OR10, Oaryl. het, aryl. NR10R10. CN. SH. SO,Cι_6 alkyl. SO, aryl. halo, or CONR10R10:
R10 is a) H, or b) Ci-7 alkyl. optionaUy substituted by OH;
R11 is a) OR10, b) Ohet, c) Oaryl, d) CO2R10. e) het, f) aryl, or g) CN;
R12 is a) H, b) het, c) aryl, d) C3-8 cycloalkyl, or e) Ci-7 alkyl optionaUy substituted by NR7R8, or R1 " :
R13 is a) (P=O)(OH)2, b) (P=O)(Cι.7 alkoxy)2, c) CO(CH2)nCON(CH3)(CH2)nSO3 "M+, d) an amino acid, e) C(=O)aryl. f) C(=O)Cι^alkyl, optionaUy substituted by NR10R10. or g) CO(CH2)nCO?H;
R14 is a) het, b) (CH2)nOR13. or c) Cι-7 alkyl substituted by one or more substituents selected from a group consisting of R11. OC ι_7 alkyl which is further substituted with het. NR7R8. or SO,R9: aryl is a phenyl radical or an ortho-fused bicycUc carbocyclic radical wherein at least one rmg is aromatic; het is a four- (4). five- (5). six- (6). or seven- (7) membered saturated or unsaturated heterocycUc ring having 1, 2. or 3 heteroatoms selected from the group consisting of oxygen, suUur, and nitrogen, which is optionaUy fused to a benzene ring, or any bicycUc heterocycle group; wherein any aryl is optionaUy substituted with one or more substituents selected from the group consisting of halo, OH, CF3, Cι_6alkoxy. and Cι-6 alkyl which maybe further substituted by one to three SR10. NR10R10. OR10, or CO2R10; wherein any het is optionaUy substituted with one or more substituents selected from the group consisting of halo, OH. CF3, d-6alkoxy. oxo. oxine. and Cι_6 alkyl which maybe further substituted by one to three SR10, NR10R10, OR10, or CO2R10; i is O, 1. or 2; m is 1. 2, or 3: n is 1, 2, 3, 4, 5, or 6: and
M is sodium, potassium, or Uthium;
With the proviso that R1 is not Cl, Br, F, or CN: when
X is O;
R2 is Cι.7 alkyl optionaUy substituted by R!J R3 is H, methyl, or halo;
R4 is H, CONH(C1-7alkyl), NR16R17, or C,_7 alkyl optionaUy substituted by OR10, CN.
COOH, or NR16R17:
R5 is H, halo. SO2NHR10. NR16R17, or C]-7 alkyl optionaUy substituted by OR10; R° is H, halo, C]-7 alkoxy. or Cι-7 alkyl optionaUy substituted by halo, OR10, CO R10 or
NR16R17;
R15 is NR16R17, OR10, CN. or CO2R10: and
R16 and R17 are independently H or d-7alkyl; or NR16R17 together with the nitrogen to which they are attached form a 5- or 6-membered ring such as pyrroUdine, piperidine. morphoUne, or piperazine.
2. A compound of claim 1 wherein R1 is Cl.
3. A compound of claim 1 wherein R is F.
4. A compound of claim 1 wherein R1 is CN, or NO2;
5. A compound of claim 1 wherein R2 is (CH2CH2O)mH. or (CH?CH2O)mC*-4 alkyl, wherein m is 2. or 3.
6. A compound of" claim 1 wherein R2 is d-8cycloalkyl optionally substituted by R11, NR7R8. SO,R9, or d-7 alkyl optionaUy substituted by R11, NR7R8, or SO,R9: wherein
R . R8, R9. R11 and i are the same as defined in claim 1.
7. A compound of claim 1 wherein R2 is cyclopropyl.
8. A compound of" claim 1 wherein R2 is het wherein said het is bonded via a carbon atom and is the same as defined in claim 1.
9. A compound of claim 8 wherein het is tetrahydro-2H-pyranyl. piperdinyl, 1 -methyl-piperidinyl, or 1 J -dioxo-tetrahydro-2H-thiopyran.
10. A compound of claim 1 wherein R2 is C2-7 alkyl which is partiaUy unsaturated and optionally substituted by NR7R8. R11, SO,R9, or OC2-4 alkyl which is further substituted by het. OR10, or OC(=O)aryl: wherein R7, R8, R9, R10 are the same as defined in claim 1.
1 1. A compound of claim 10 wherein R2 is (Z or E)-CH=CHR10, or -C-C≡CR10; wherem said R10 is H, or Cι-7 alkyl optionaUy substituted by OH.
12. A compound of claim 1 wherein R2 is d-7 alkyl substituted by NR7R8, R1 1, SO,R9, or OC2-4 alkyl which is further substituted by het, OR10, or OC(=O)aryl wherein R7, R8, R9, R10 and R11 are the same as defined in claim 1.
13. A compound of claim 1 wherem R2 is Cι-7 alkyl substituted by OC2.4 alkyl which is further substituted by het, OH, OC1-4 alkyl, or OC(=O)aryl.
14. A compound of" claim 1 wherein R2 is Cι_7 alkyl substituted by SO-R9 wherem R9 and I are the same as defined in claim 1.
15. A compound of claim 1 wherein R2 is Cι_7 alkyl substituted by SOjR9 ; wherein R9 is Ci_4 alkyl, optionaUy substituted by OH, or R9 is phenyl, optionaUy substituted by Cl; wherein i is 0, 1 , or 2.
16. A compound of claim 1 wherein R2 is methyl.
17. A compound of claim 1 wherem W is NR7R8, wherein R7 and R8 are the same as defined in claim 1.
18. A compound of claim 1 wherein W is NR7R8, wherein R7 and R8 together with the nitrogen to which they are attached to form a het, wherein said het is the same as defined in claim 1.
19. A compound of claim 18 wherein het is morphoUne, piperidine. pyrroUdine, piperazine, or 4-methyl-piperazine.
20. A compound of claim 1 wherein W is NR7R8, wherein R7 and R8 are mdependently H or C1.4 alkyl optionaUy substituted by OH.
21. A compound of claim 18 wherein het is morpholine.
22. A compound of claim 1 wherein W is OR9, or SO,R9 wherein R9 is Cι-6alkyl which may be partiaUy unsaturated and optionaUy substituted by OR10. Oaryl, het, aryl. NR10R10. CN, CONR10R10. or halo: wherein R10 is H or C,.4 alkyl .
23. A compound of claim 1 wherein R3 is H.
24. A compound of" claim 1 wherein R3 is CF3. or halo.
25. A compound of claim 1 wherein R4 is aryl or het.
26. A compound of claim 1 wherem R4 is SO?NHR12, CONHR12. NHCOR12. or NHSO2R12. wherein R12 is the same as defined in claim 1.
27. A compound of claim 1 wherein R4 is C2.8 alkyl which is partiaUy unsaturated and optionaUy substituted by OR10, NR7R8. halo. SO,R9, OR13 or R11. wherein R7, R8. R9. R10. R11 and R13 are the same as defined in claim 1.
28. A compound of claim 1 wherein R4 is (Z or E)-CH=CHCι. alkyl. optionaUy substituted by OH.
29. A compound of claim 1 wherein R4 is -C≡CCι-4 alkyl, optionaUy substituted by OH oorr OORR1133,, wwhheerreeimn RR1133 iiss ((PP==OO))((OOHH))22.. (P=O)(Cι-7 alkoxy)2. or CO(CH2)6CON(CH3)(CH2)„SO3 "M+.
30. A compound of claim 1 wherem R4 is d-8 alkyl substituted by OR13 wherein R13 is (P=O)(OH)2,
Figure imgf000184_0001
alkoxy)2, or CO(CH2)nCON(CH-,)(CH2)6SO3 "M+.
31. A compound of claim 1 wherein R4 is Cι_8 alkyl substituted by SO,R9. wherein R9 is the same as defined in cla n 1.
32. A compound of claim 1 wherein R4 is NR7R8. wherein R7 and R8 are the same as defined in claim 1.
33. A compound of claim 1 wherein R4 is d-s alkyl substituted by NR7R8. wherein R7 and R8 are the same as defined in claim 1.
34. A compound of claim 33 wherein R7 and R8 together with the nitrogen to which they are attached to form a het, wherein het is the same as defined in claim 1.
35. A compound of claim 33 wherein R7 and R8 are independently Cι_6 alkyl. optionaUy substituted by one or more substituents selected from a group consisting of OH, aryl, or CN wherein aryl is the same as defined in claim 1.
36. A compound of claim 1 wherein R4 is Cι-8 alkyl substituted by N3.
37. A compound of claim 1 wherein R4 is d-s alkyl substituted by het wherein het is the same as defined in clakn 1.
38. A compound of claim 1 wherem R4 is 4-morpholine methyl.
39. A compound of claim 1 wherein R4 is Cι-7 alkyl substituted by R11. wherein R11 is the same as defined in claim 1.
40. A compound of claim 1 wherein R1 is H or Cι-7 alkyl optionaUy substituted by OH.
41. A compound of claim 1 wherein R6 is OC,-? alkyl optionaUy substituted by one or more OH.
42. A compound of claim 1 wherein R6 is halo.
43. A compound of claim 1 wherein R6 is C≡Cd_7 alkyl substituted by one or more OH, or -7 alkoxy substituted by one or more OH.
44. A compound of claim 1 wherein R6 is H or Cι-7 alkyl. optionaUy substituted by halo. NR10R10, OH. CO2R10, or het; wherein R10 and het are the same as defined in claim 1.
45. A compound of" claim 1 wherein M is sodium, potassium, or Uthium.
46. A compound of claim 1 wherein X is S; W. R1, R2, R3. R4, R\ R° are the same as defined in claim 1.
47. A compound of claim 1 wherein X is O: R1, R3. R4, R\ R6 are the same as defined in claim 1 , W is NR7R8, OR9. SO,R9 or R2: wherein R2 is:
Figure imgf000186_0001
b) het, wherein said het is bonded via a carbon atom. c) Ci-7 alkyl which is partiaUy unsaturated and optionaUy substituted by OH, d) d- cycloalkyl, or e) Cι.7 alkyl which is optionaUy substituted by one or more substituents selected from a group consisting of Ohet. Oaryl. SO,R9, or O -4 alkyl which is further substituted by het, OR10, or OC(=O)aryl: wherein R7. R8. R9. R10 and n are the same as defined in claim 1.
48. A compound of claim 1 wherein X is O or S: R1 is Cl: R3 is H: Rs is H: R6 is H or F: R4 is 4-morpholinylmethyl: and R2 is: a) C1-4 alkyl substituted by SO,R9, or C alkoxy which is further substituted by OH. het. OC alkyl. or OC(=O)pheyl, b) (CH2CH2O)2d.4alkyl, c) Cι_6alkyl which is partiaUy unsaturated and optionaUy substituted by OH. d) cyclopropyl, e) tetrahydro-2H-pyranyl, 1) piperdkiyl. g) mopholinyl, h) 1 -methyl-piperidinyl, or i) 1 J -dioxo-tetrahydro-2H-thiopyran; wherein R9 is phenyl optionaUy substituted by Cl. or R9 is d-6alkyl optionaUy substituted by OH.
49. A compound of claim 1 wherein X is O or S; R1 is Cl; R3 is H: R5 is H: R6 is H or F; R4 is Cι_6alkyl which is partiaUy unsaturated and optionaUy substituted by OH or OR13: or R4 is C,.4alkyl substituted with OR13: W is NRI0R10. cyclopropyl, (O CHzO^OR10, or Cι-6 alkyl which may be partiaUy unsaturated and is optionaUy substituted by OH, mopholinyl,
NR10R10; C(=O)OC alkyl, wherein R10 is H or dialkyl; R13 is (P=O)(C,.7 alkoxy)2, CO(CH2)„CON(CH3)(CH2)„SO3"M+, or (P=O)(OH)?
50. A compound of claim 1 wherein X is O or S: R1 is Cl: R" is H; R3 is H: R6 is C≡Cd_4 alkyl optionaUy substituted by OH: R4 is H or C1- alkyl which may be partiaUy unsaturated and optionaUy substituted by OH. and W is C alkyl optionally substituted by OH.
51. A compound of claim 1 which is
Figure imgf000187_0001
or a pharmaceuticaUy acceptable salt.
52. A compound of" claim 1 which is
Figure imgf000187_0002
or a pharmaceuticaUy acceptable salt.
53. A compound of claim 1 which is
or a pharmaceuticaUy acceptable salt.
54. A compound of" claim 1 which is
Figure imgf000188_0002
or a pharmaceuticaUy acceptable salt.
55. A compound of" claim 1 which is
Figure imgf000188_0003
or a pharmaceuticaUy acceptable salt.
56. A compound of claim 1 which is
Figure imgf000188_0004
or a pharmaceuticaUy acceptable salt.
57. A compound of claim 1 which is
Figure imgf000189_0001
or a pharmaceuticaUy acceptable salt.
58. A compound claim 1 which is
Figure imgf000189_0002
or a pharmaceuticaUy acceptable salt.
59. A compound claim 1 which is
Figure imgf000189_0003
or a pharmaceuticaUy acceptable salt.
60 A compound of claim 1 wherein R2 is methyl, ethyl, propyl, isopropyl. butyl, tert- butyl, cyclopropyl, carboxymethyl, (Cι-7 alkoxy)carbonylmethyl, 2-hydroxyethyl. 2-(2-methoxyethoxy)ethyl, 3-(2-tetrahydropyranyloxy)propyl, 2-morpholinoethyl,
2-(diethylamino)ethyl, 2-(dimethylamino)ethyl, 2-piperidinoethyl, 3-piperidinopropyl. 2-( l methylpyrroUdin-2-yl)ethyl, 2-(diisopropylamino)ethyl, 2-pyrroUdin-l-ylethyl, 3- (dimethylamkιo)propyl, or vinyl.
61 A compound of claim 1 wherein R4 is 3-hydroxy-l -propynyl, 3-hydroxypropyl. hydro xymethyl, C/Λ-4- hydroxy- 1 -butenyl, tra/w-4-hydroxy- 1 -butenyl, (2-hydroxyethyl)(ethyl)amino, morphoUnomethyl, (CH2)2O(P=O)(OH)2, (CH2)3O(P=O)( (tert-butoxy)2, 3- [di(tert-butyl)phosphoryl] propyl, 3-phosphorylpropyl, Na+ OS(O)2CH?CH2N-CH3)C(=O)(CH2)6C(=O)O(CH2)3, or Na+ OS(O)2CH?CH?N(CH3)C(=O)-(CH2)6C(=O)OCH?C≡C-.
62. A compound of claim 1 which is:
( I ) N-(4-chlorobenzyl)-6-(3-hydroxy- 1 -propynyl)- 1 -isopropyl-4-oxo- 1 ,4-dihydro-3- quinoUnecarboxamide: (2) l-(sec-butyl)-N-(4-chlorobenzyl)-6-(3-hydroxy-l-propynyl)-4-oxo-l ,4-dihydro-3- quinolinecarboxamide:
(3) 1 -(sec-butyl)-N-(4-chlorobenzyl)-6-(3-hydroxy- 1 -propynyl)-8-methoxy-4-oxo- 1 ,4- dihydro-3-quinolinecarboxamide;
(4) N-(4-chlorobenzyl)-6-[3-hydroxy-l-propenyl]- l-[2-(4-morphoUnyl)ethyl]-4-oxo- 1 ,4-dihydro-3-quinolinecarboxamide:
(5) N-(4-chlorobenzyl)-8-lluoro-6-(3-hydroxy- 1 -propynyl)- 1 -methyl-4-oxo- 1 ,4- dihydro-3-quinolinecarboxamide:
(6) N-(4-chlorobenzyl)-8-fluoro-6-[(Z)-3-hydroxy- 1 -propenyl]- 1 -methyl-4-oxo- 1 ,4- dUιydro-3-quinolinecarboxamide; (7) N-(4-chlorobenzyl)-l-[2-(diethylammo)ethyl]-8-fluoro-6-(3-hydroxy-l-propynyl)-4- oxo- 1 ,4-dU ydro-3-quinolinecarboxamide;
(8) N-(4-chlorobenzyl)-6-(3-hydroxy- 1 -propynyl)-4-oxo- 1 -propyl- 1 ,4-dihydro-3- qukiolinecarboxamide:
(9) N-(4-chlorobenzyl)-l-[2-(diethylammo)ethyl]-6-(3-hydroxy- l-propynyl)-4-oxo-l,4- dUιydro-3-quinoUnecarboxamide;
(10) N-(4-chlorobenzyl)-l-[2-(dknethylamino)ethyl]-6-(3-hydroxy- l-propynyl)-4-oxo- 1.4-dihydro-3-quinolinecarboxamide hydrochloride;
(I I) N-(4-chlorobenzyl)-6-(3-hydroxy- l-propynyl)-4-oxo-l-[2-(l-piperidinyl)ethyl]- l ,4-dihydro-3-quinolinecarboxamide; (12) N-(4-chlorobenzyl)-6-(3-hydroxy- l-propynyl)-4-oxo-l-[3-(l-piperidinyl)propyl]-
1 ,4-dihydro-3-qukιolinecarboxamide;
( 13) N-(4-chlorobenzyl)-6-(3-hydroxy- 1 -propynyl)- 1 -[2-( 1 -methyl-2-pyrroUdinyl)ethyl] - 4-oxo- 1 ,4-dihydro-3-quinoUnecarboxamide;
(14) N-(4-chlorobenzyl)-l-[2-(dnsopropylamino)ethyl]-6-(3-hydroxy- l-propynyl)-4- oxo- 1 ,4-d ydro-3-qu olinecarboxamide;
( 15) N-(4-chlorobenzyl)-6-(3-hydroxy- 1 -propynyl)-4-oxo- 1 -[2-( 1 -pyrroUdinyl)ethyl]- 1 ,4-dihydro-3-qukιoUnecarboxamide; ( 16) N-(4-chlorobenzyl)-6-(3-hydroxy- 1 -propynyl)- 1 -[2-(4-morpholinyl)ethyl]-4-oxo-
1 ,4-dihydro-3-quinolinecarboxamide;
(17) N-(4-chlorobenzyl)-l -[3-(dimethylamino)propyl]-6-(3-hydroxy- l-propynyl)-4-oxo-
1.4-dUιydro-3-quinoUnecarboxamide: (18) N-(4-chlorobenzyl)-6-(3-hydroxy- 1 -propynyl)-4-oxo- 1 -vinyl- 1 ,4-dihydro-3- quinolinecarboxamide:
(19) N-(4-chlorobenzyl)-6-[(E)-3-hydroxy- l -propenyl]- l-methyl-4-oxo-l ,4-dihydro-3- quinoUnecarboxamide;
(20) N-(4-chlorobenzyl)-6-[(Z)-3-hydroxy- 1 -propenyl]- 1 -methyl-4-oxo- 1 ,4-dihydro-3- quinolinecarboxamide:
(21 ) N-(4-chlorobenzyl)- 1 -cyclopropyl-6-(3-hydroxy- 1 -propynyl)-4-oxo- 1.4-dihydro-3- quinolinecarboxamide:
(22) tert-butyl 2-[3-{ [(4-chlorobenzyl)aminoJcarbonyl}-6-(3-hydroxy-l-propynyl)-4- oxo- 1 (4H)-quinolinyl] acetate; (23) 2-[3-{ [(4-chlorobenzyl)amino]carbonyl}-6-(3-hydroxy- l-propynyl)-4-oxo- l (4H)- quinofinyl] acetic acid:
(24) N-(4-chlorobenzyl)- 1 -(2-hydroxyethyl)-6-(3-hydroxy- 1 -propynyl)-4-oxo- 1.4- dihydro-3-quinolinecarboxamide;
(25) N-(4-chlorobenzyl)-6-(3-hydroxy- 1 -propynyl)- 1 -methyl-4-oxo- 1.4-dihydro-3- quinolinecarboxamide:
(26) di(tert-butyl) 3-(3-{ [(4-chlorobenzyl)amino]carbonyl}- l-methyl-4-oxo- l ,4- dihydro-6-quinoUnyl)propyl phosphate;
(27) 3- (3-{ [(4-chlorobenzyl)amino] carbonyl }- l -methyl-4-oxo- 1.4-dmydro-6- quinoUnyl)propyl dihydrogen phosphate: (28) di(tert-butyl) 3-(3-{ [(4-chlorobenzyl)amino]carbonyl}-l -cyclopropyl-4-oxo- l ,4- dihydro-6-quinoUnyl)propyl phosphate;
(29) sodium 2-[{ 8-[3-(3-{ [(4-chlorobenzyl)amino]carbonyl}-l-cyclopropyl-4-oxo-l , 4- dihydro-6-quinolinyl)propoxy]-8-oxooctanoyl}(methyl)amino]- l -ethanesulfonate;
(30) sodium 2-[(8-{ [3-(3-{ [(4-chlorobenzyl)amino]carbonyl}-l-methyl-4-oxo- 1.4- dihydro-6-quinoUnyl)-2-propynyl]oxy}-8-oxooctanoyl)(methyl)amino]- 1 -ethanesuUonate;
(31) sodium 2-[(8-{ [3-(3-{ [(4-chlorobenzyl)amino]carbonyl}-l-methyl-4-oxo- 1.4- dmydro-6-quinolinyl)-2-propynyl]oxy}-8-oxooctanoyl)(methyl)amino]-l -ethanesuUonate; (32) sodium 2-[(8-{ [3-(3-{ [(4-chlorobenzyl)amino]carbonyl}-l-cyclopropyl-4-oxo-l ,4- dihydro-6-quinolinyl)-2-propynyl]oxy}-8-oxooctanoyl)(methyl)amino]-l -ethanesulfonate;
(33) 1 -(tert-butyl)-N-(4-chlorobenzyl)-6-(3-hydroxy- 1 -propynyl)-4-oxo- 1 ,4-dihydro-3- quinolinecarboxamide; (34) sodium 2-[{ 8-[3-(l-(tert-butyl)-3-{ [(4-chlorobenzyl)amino]-carbonyl}-4-oxo-l,4- dihydro-6-quinolinyl)propoxy]-8-oxooctanoyl}(methyl)amino]-l -ethanesulfonate;
(35) sodium 2-[(8-{ [3-(l-(tert-butyl)-3-{ [(4-chlorobenzyl)amino]-carbonyl}-4-oxo-l,4- dihydro-6-quinolinyl)-2-propynyl]oxy}-8-oxooctanoyl)(methyl)amino]- l -ethanesuUonate:
(36) N-(4-chlorobenzyl)-6-(3-hydroxy-l -propynyl)- l-[2-(2-methoxyethoxy)-ethyl]-4- oxo- 1 ,4-dihydro-3-quinolinecarboxamide:
(37) N-(4-cyanobenzyl)-6-(3-hydroxy- 1 -propynyl)- 1 -methyl-4-oxo- 1 ,4-dihydro-3- quinolinecarboxamide;
(38) N-(4-chlorobenzyl)- 1 -methyl-6-( 1 ,4-oxazepan-4-ylmethyl)-4-oxo- 1 ,4-dihydro-3- quinoUnecarboxamide; (39) N-(4-chlorobenzyl)- 1 -methyl-4-oxo-6-( 1 ,4-thiazepan-4-ylmethyl)- 1 ,4-dihydro-3- quinoUnecarboxamide;
(40) N-(4-chlorobenzyl)- l-methyl-6-(2-oxa-5-azabicyclo[2JJ]hept-5-ylmethyl)-4-oxo- l,4-dihydro-3-quinolinecarboxamide;
(41) N-(4-chlorobenzyl)-6-(2,3-dihydro-4H-l ,4-benzoxazin-4-ylmethyl)- l-methyl-4- oxo- 1 ,4-dihydro-3-quinoUnecarboxamide;
(42) 6-(azidomethyl)-N-(4-chlorobenzyl)- 1 -methyl-4-oxo- 1 ,4-dihydro-3-quinoline- carboxamide;
(43) N-(4-chlorobenzyl)- l-methyl-4-oxo-6-vinyl- 1 ,4-dmydro-3-quinoUne-carboxamide;
(44) N-(4-chlorobenzyl)-l-[2-(2-hydroxyethoxy)ethyl]-6-(3-hydroxy-l-propynyl)-4- oxo- 1 ,4-dihydro-3-quinoUnecarboxamide;
(45) N-(4-chlorobenzyl)-l-{2-[2-(2-methoxyethoxy)ethoxy]ethyl}-6-(4- morpholinylmethyl)-4-oxo- 1 ,4-dUιydro-3-qukιolinecarboxamide:
(46) N-(4-chlorobenzyl)-l-[2-(2-hydroxyethoxy)ethyl]-6-(4-morphoUnylmethyl)-4-oxo- 1 ,4-dihydro-3-quinolkιecarboxamide; (47) N-(4-chlorobenzyl)-l-[2-(2-ethoxyethoxy)ethyl]-6-(4-morphoUnyknethyl)-4-oxo-
1 ,4-dihydro-3-quinoUnecarboxamide;
(48) N-(4-chlorobenzyl)-6-(4-morpholinylmethyl)-4-oxo- 1 -(2-propynyl)- 1 ,4-dihydro-3- quinoUnecarboxamide; (49) N-(4-chlorobenzyl)- 1 -[2-(ethylsuU'anyl)ethyl]-6-(4-morphoUnyknethyl)-4-oxo- 1.4- dUιydro-3-quinoUnecarboxamide:
(50) N-(4-chlorobenzyl)-l-[3-(methylsuU'anyl)propyl]-6-(4-morphoUnylmethyl)-4-oxo- 1 ,4-dUιydro-3-quinolinecarboxamide; (51) N-(4-chlorobenzyl)-l-(4-hydroxy-2-butynyl)-6-(4-morphoUnyknethyl)-4-oxo-1.4- dihydro-3-quinolinecarboxamide;
(52) N-(4-chlorobenzyl)-6-{ [(2-hydroxy-2-phenylethyl)(methyl)amino]methyl}-l- methyl-4-oxo- 1 ,4-dihydro-3-quinolinecarboxamide:
(53) N-(4-chlorobenzyl)-l-[3-(methylsuUinyl)propyl]-6-(4-morphoUnylmethyl)-4-oxo- 1.4-dmydro-3-quinoUnecarboxamide;
(54) N-(4-chlorobenzyl)- l-{3-[(3-hydroxypropyl)suU'anyl]propyl}-6-(4- morphoUnyknethyl)-4-oxo- 1 ,4-dihydro-3-quinoUnecarboxamide;
(55) N-(4-chlorobenzyl)-l-[3-(methylsuU"onyl)propylJ-6-(4-morphoUnylmethyl)-4-oxo- l J-dinydro-3-quinolinecarboxamide; (56) N-(4-chlorobenzyl)- 1 -[2-(ethylsuUinyl)ethyl]-6-(4-morphohnylmethyl)-4-oxo- 1.4- dUιydro-3-quinoUnecarboxamide;
(57) N-(4-chlorobenzyl)-l-[2-(ethylsuUbnyl)ethyl]-6-(4-morpholinylmethyl)-4-oxo- 1.4- dmydro-3-quinolinecarboxamide;
(58) N-(4-chlorobenzyl)-l-{3-[(3-hydroxypropyl)suUinyl]propyl}-6-(4- morphoUnyknethyl)-4-oxo- 1.4-dihydro-3-quinoUnecarboxamide:
(59) N-(4-chlorobenzyl)-l-{3-[(3-hydroxypropyl)suU'onyl]propyl}-6-(4- morphoUnylmethyl)-4-oxo- 1.4-dmydro-3-quinolinecarboxamidc;
(60) N-(4-chlorobenzyl)-6-(4-morphoUnyknethyl)-4-oxo- 1 -[2-(phenylsuU'anyl)ethyl]- 1 J-dihydro-3-quinoUnecarboxamide;
(61) N-(4-chlorobenzyl)-l-[(methylsurfanyl)methyl]-6-(4-morphoUnyknethyl)-4-oxo-
1.4-dihydro-3-quinofinecarboxamide;
(62) N-(4-chlorobenzyl)-6-{ [[2-hydroxy-2-(4-hydroxyphenyl)ethyl](methyl)- amino]methyl}-l-methyl-4-oxo-l ,4-dmydro-3-quinolinccarboxamide;
(63) N-(4-chlorobenzyl)-6-[(3-hydroxy-l-azetidinyl)methyl]-l-methyl-4-oxo-1.4- dihydro-3-qukιolkιecarboxamide;
(64) N-(4-chlorobenzyl)-6-(4-morpholinylmethyl)-4-oxo- 1 -[(phenylsulfanyl)-methyl]- 1.4-dihydro-3-quinoUnecarboxamide;
(65) N-(4-chlorobenzyl)-6-{ [[2-hydroxy-2-(4-hydroxy-3-methoxyphenyl)ethyl]- (methyl)aminojmethyl}- l-methyl-4-oxo- 1 ,4-dihydro-3-quinolinecarboxamide;
(66) N-(4-chlorobenzyl)-6-[(3J-dmydroxy-l-azetidinyl)methyl]-l-methyl-4-oxo-l,4- dihydro-3-quinolinecarboxamide;
(67) N-(4-chlorobenzyl)-l-[(methylsuUinyl)methyl]-6-(4-morphoUnylmethyl)-4-oxo-l,4- dihydro-3-quinolinecarboxamide:
(68) N-(4-chlorobenzyl)-l-[(methylsuU"onyl)methyl]-6-(4-morpholkιylmethyl)-4-oxo- 1 ,4-dU ydro-3-quinoUnecarboxamide;
(69) N-(4-chlorobenzyl)-6-(4-morpholinylmethyl)-4-oxo- 1 -[(phenylsuUinyl)-methyl]- 1 ,4-dihydro-3-quinolinecarboxamide;
(70) N-(4-chlorobenzyl)-6-(4-morpholinylmethyl)-4-oxo- 1 -[(phenylsulfonyl)-methyl]- l,4-dihydro-3-quk olkιecarboxamide;
(71) N-(4-chlorobenzyl)-6-(3-hydroxypropyl)-l-[2-(2-methoxyethoxy)ethyl]-4-oxo-l,4- dihydro-3-quinolinecarboxamide;
(72) N-(4-chlorobenzyl)-l-[2-(2-methoxyethoxy)ethyl]-6-(4-morphoUnylmethyl)-4-oxo- l ,4-dihydro-3-quinoUnecarboxamide;
(73) N-(4-chlorobenzyl)- l-[2-(2-methoxyethoxy)ethyl]-4-oxo-6-[(4-oxo- l- piperidinyl)methyl]- 1 ,4-dihydro-3-quinoUnecarboxamide;
(74) N-(4-chlorobenzyl)-6-{ [(cyanomethyl)(methyl)amino]methyl}- 1-[2-(2- methoxyethoxy)ethyl]-4-oxo- 1 ,4-dihydro-3-quinolinecarboxamide:
(75) N-(4-chlorobenzyl)-6-{ [(3R)-3-hydroxypyrroUdinyl]methyl}- l-[2-(2- methoxyethoxy)ethyl]-4-oxo- 1.4-dihydro-3-quinolinecarboxamide;
(76) N-(4-chlorobenzyl)-l-[2-(2-methoxyethoxy)ethyl]-6-[(methylsuU'anyl)methyl]-4- oxo- 1 ,4-dmydro-3-quinoUnecarboxamide;
(77) N-(4-chlorobenzyl)-6-{ [[(lRJ5)-2-hydroxy- l-methyl-2-phenylethyl](methyl)- amino]methyl}-l-[2-(2-methoxyethoxy)ethyl]-4-oxo-l,4-dihydro-3-quinoUne-carboxamide;
(78) N-(4-chlorobenzyl)-6-{ [(2-hydroxy-2-phenylethyl)(methyl)amkιo]methyl}- 1 -[2-(2- methoxyethoxy)ethyl] -4-oxo- 1 ,4-dmydro-3-qumolinecarboxamide:
(79) N-(4-chlorobenzyl)-6-{ [[2-hydroxy-2-(4-hydroxyphenyl)ethyl](methyl)amino]- methyl}- l-[2-(2-methoxyethoxy)ethyl]-4-oxo-l,4-dmydro-3-quinoUnecarboxamide;
(80) l-{2-[2-(tert-butoxy)ethoxy]ethyl-N-(4-chlorobenzyl)-6-(4-morpho kιyl-methyl)-4- oxo-l ,4-dUιydro-3-quinolinecarboxamide;
(81) 1 - { 2-[2-(tert-butoxy)ethoxy]ethyl-N-(4-chlorobenzyl)-6- { [[2-hydroxy-2-(4- hydroxyphenyl)ethyl](methyl)amino]methyl-4-oxo-1.4-dihydro-3-qukιoline-carboxamide:
(82) N-(4-chlorobenzyl)-6-(3-hydroxy- 1 -propynyl)- 1 -methyl-4-oxo- 1 ,4-dihydro-3- quinoUnecarbothioamide:
(83) N-(4-chlorobenzyl)-8-(3-hydroxy-l -propynyl)- l-methyl-4-oxo-1.4-dihydro-3- quinolinecarboxamide;
(84) N-(4-chlorobenzyl)-8-(4-hydroxy- 1 -butynyl)- 1 -methyl-4-oxo- 1 ,4-dihydro-3- quinolinecarboxamide;
(85) N-(4-chlorobenzyl)-6-{ [3-(hydroxyimino)-l-azetidinyl]methyl}-l-methy]-4-oxo- 1 ,4-dihydro-3-quinolinecarboxamide;
(86) N-(4-chlorobenzyl)-l-{2-[2-(4-morphoUnyl)ethoxy]ethyl}-6-(4- morpholinylmethyl)-4-oxo- 1.4-dihydro-3-quinoUnecarboxamide:
(87) N-(4-chlorobenzyl)- 1 -([(4-chlorophenyl)suU'anylJmethyl)- 6-(4- morpholinylmethyl)-4-oxo- 1.4-dU ydro-3-quinoUnecarboxamide:
(88) N-(4-chlorobenzyl)- l-([(4-chlorophenyl)suUinyl]methyl)-6-(4-morpholkιylmethyl)-
4-oxo- 1.4-dihydro-3-quinohnecarboxamide:
(89) N-(4-chlorobenzyl)- 1 -([(4-chlorophenyl)suU"onyl]methyl)-6-(4-morphoUnylmethyl)- 4-oxo- 1 ,4-dUιydro-3-quinoUnecarboxamide;
(90) N-(4-chlorobenzyl)- l-[(4-chlorophenoxy)methyl]-6-(4-morphoUnyknethyl)-4-oxo- 1 ,4-dUιydro-3-quinoUnecarboxamide;
(91) N-(4-chlorobenzyl)-l-[(2-methoxyethoxy)methyl]-6-(4-morphoUnyknethyl)-4-oxo- l,4-dihydro-3-quinolinecarboxamide;
(92) 2-{ f3-{ [(4-chlorobenzyl)amino]carbonyl}-6-(4-morpholkiylmethyl)-4-oxo- 1 (4H)- quinoUnylJmethoxy} ethyl benzoate:
(93) N-(4-chlorobenzyl)- 1 -[(2-hydroxyethoxy)methyl]-6-(4-morphoUιιylmethyl)-4-oxo-
1 ,4-dmydro-3-quinolinecarboxamide;
(94) N-(4-chlorobenzyl)-6-(4-morpholinylmethyl)-4-oxo-l-tetrahydro-2H-pyran-4-yl- 1 ,4-dihydro-3-quinolinecarboxamide;
(95) N-(4-chlorobenzyl)- l-(l-methyl-4-piperidmyl)-6-(4-morpholinylmethyl)-4-oxo-l,4- dUιydro-3-qukιolinecarboxamide;
(96) N-(4-chlorobenzyl)-6-(4-morpholinylmethyl)-4-oxo- 1 -(4-piperidinyl)- 1.4-dUιydro- 3-quinoUnecarboxamide:
(97) N-(4-chlorobenzyl)- 1 -( 1 J -dioxohexahydrothiopyran-4-yl)-6-(4- morpholinylmethyl)-4-oxo- 1 ,4-dihydro-3-quinoUnecarboxamide:
(98) N-(4-chlorobenzyl)-l-(4-morpholinyl)-6-(4-morpholinylmethyl)-4-oxo-l,4- dihydro-3-quinolinecarboxamide;
(99) N-(4-chlorobenzyl)- 1 -(4-methyl- 1 -piperazinyl)-6-(4-morpholinylrnethyl)-4-oxo-
1 ,4-dihydro-3-quinolinecarboxamide;
(100) N-(4-chlorobenzyl)-6-(4-morpholinylmethyl)-4-oxo-l-(l -piperidinyl)- 1 ,4-dihydro- 3-quinolinecarboxamide:
(101) N-(4-chlorobenzyl)-6-(4-morpholinylmethyl)-4-oxo- 1 -( 1 -pyrroUdinyl)- 1 ,4- dihydro-3-quinolkιecarboxamide:
(102) N-(4-chlorobenzyl)-l-[(2R)-2-(methoxymethyl)pyrroUdinylJ-6-(4- morphoUnyknethyl)-4-oxo-1.4-dihydro-3-qukιolinecarboxamide:
(103) N-(4-chlorobenzyl)-l-(dimethylamino)-6-(4-morphoUnyknethyl)-4-oxo- 1.4- dihydro-3-quinoUnecarboxamide;
(104) l-Amino-N-(4-chlorobenzyl)-6-(3-hydroxy-l -propynyl)-4-oxo- 1.4-dihydro-3- quinolinecarboxamide:
(105) l-Amino-N-(4-chlorobenzyl)-6-(3-hydroxypropyl)-4-oxo- l ,4-dihydro-3- quinolinecarboxamide;
( 106) N-(4-chlorobenzyl)- 1 -(dimethylamino)-6-(3-hydroxy- 1 -propynyl)-4-oxo- 1 ,4- dihydro-3-quinolinecarboxamide;
(107) N-(4-chlorobenzyl)- l-(dimethylamino)-4-oxo- 1.4-dihydro-3- quinolinecarboxamide;
(108) l-(allyloxy)-N-(4-chlorobenzyl)-4-oxo-1.4-dihydro-3-quinolinecarboxamide;
(109) N-(4-chlorobenzyl)-l-methoxy-4-oxo- 1 J-dihydro-3-quinolkιecarboxamide:
(110) N-(4-bromobenzyl)-l-(4-morphoUnyl)-6-(4-morpholinylmethyl)-4-oxo-l,4- dihydro-3-quinolkiecarboxamide;
(111) N-(4-fluorobenzyl)- 1 -(4-morphoUnyl)-6-(4-morphoUnyknethyl)-4-oxo- 1.4- dUιydro-3-quinolinecarboxamide;
(112) N-(4-chlorobenzyl)-l-{ [2-(4-morpholinyl)ethoxylmethyl}-6-(4- morphoUnylmethyl)-4-oxo- 1 ,4-dmydro-3-quinoUnecarboxamide:
(113) N-(4-chlorobenzyl)-l-{ [2-(dimethylamino)ethoxy]methyl}-6-(4- morphoUnyknethyl)-4-oxo- 1 ,4-dmydro-3-qukιoUnecarboxamide:
(1 14) N-(4-chlorobenzyl)- 1 -{ [2-(4-methyl- 1 -piperazinyl)ethoxy]methyl}-6-(4- morphoUnylmethyl)-4-oxo- 1 ,4-dihydro-3-quinolinecarboxamide;
(115) N-(4-chlorobenzyl)-6-(4-morphoUnylmethyl)-4-oxo-l-{ [2-(l- piperidinyl)ethoxy]methyl}- 1.4-dmydro-3-quinoUnecarboxamide: (116) N-(4-chlorobenzyl)-6-(4-morpholinylmethyl)-4-oxo-l-{ [2-(l- pyrroUdinyl)ethoxy]methyl}-1.4-dihydro-3-quinoUnecarboxamide: or a pharmaceuticaUy acceptable salt thereof.
63. A compound of claim 1 which is: ( 1 ) 1 -(sec-butyl)-N-(4-chlorobenzyl)-6-(3-hydroxy- 1 -propynyl)-4-oxo- 1.4-dihydro-3- quinolinecarboxamide:
(2) l-(sec-butyl)-N-(4-chlorobenzyl)-6-(3-hydroxy-l-propynyl)-8-methoxy-4-oxo-l ,4- dihydro-3-quinolinecarboxamide:
(3) N-(4-chlorobenzyl)-6-[3-hydroxy-l-propcnylJ-l-[2-(4-morphoUnyl)ethyl]-4-oxo- 1.4-dUιydro-3-quinoUnecarboxamide;
(4) N-(4-chlorobenzyl)-8-lluoro-6-(3-hydroxy- 1 -propynyl)- 1 -methyl-4-oxo- 1.4- dihydro-3-qukιoUnecarboxamide;
(5) N-(4-chlorobenzyl)-8-fluoro-6-[(Z)-3-hydroxy- 1 -propenyl]- 1 -methyl-4-oxo- 1 ,4- dihydro-3-quk olinecarboxamide: (6) N-(4-chlorobenzyl)-l-[2-(diethylamino)ethyl]-6-(3-hydroxy- l-propynyl)-4-oxo-1.4- dihydro-3-quinoUnecarboxamide;
(7) N-(4-chlorobenzyl)-l-[2-(dknethylamino)ethyl]-6-(3-hydroxy- l-propynyl)-4-oxo- 1 J-dihydro-3-quinolkιecarboxamide hydrochloride;
(8) N-(4-chlorobenzyl)-6-(3-hydroxy- 1 -propynyl)-4-oxo- 1 -[2-( 1 -piperidinyl)ethyl]- 1.4- dihydro-3-quinoUnecarboxamide;
(9) N-(4-chlorobenzyl)-6-(3-hydroxy-l-propynyl)-4-oxo-l-[3-( l-piperidinyl)propyl]- 1.4-dihydro-3-quinolinecarboxamide:
(10) N-(4-chlorobenzyl)-6-(3-hydroxy- l -propynyl)- l-[2-(l -methyl-2-pyrroUdinyl)ethyl]- 4-oxo- 1.4-dihydro-3-quinolinecarboxamide: (1 1) N-(4-chlorobenzyl)-l-[2-(dUsopropylamino)ethyl]-6-(3-hydroxy-l-propynyl)-4- oxo- 1 ,4-dihydro-3-quinolinecarboxamide;
(12) N-(4-chlorobenzyl)-6-(3-hydroxy-l-propynyl)-4-oxo-l-[2-(l -pyrroUdinyl)ethylj- lJ-dmydro-3-quinoUnecarboxamide; (13) N-(4-chlorobenzyl)-6-(3-hydroxy-l -propynyl)- 1 -[2-(4-morpholinyl)ethyl]-4-oxo- l,4-dihydro-3-quinoUnecarboxamide:
(14) N-(4-chlorobenzyl)-l-[3-(dimethylamino)propyl]-6-(3-hydroxy-l-propynyl)-4-oxo- l,4-dUιydro-3-quinolinecarboxamide: (15) N-(4-chlorobenzyl)-6-(3-hydroxy- 1 -propynyl)-4-oxo- 1 -vinyl- 1 ,4-dihydro-3- quinolinecarboxamide :
(16) N-(4-chlorobenzyl)-6-[(E)-3-hydroxy-l-propenyl]-l-methyl-4-oxo-1.4-dihydro-3- quinolinecarboxamide:
(17) N-(4-chlorobenzyl)-6-[(Z)-3-hydroxy- 1 -propenyl]- 1 -methyl-4-oxo- 1 ,4-dihydro-3- quinoUnecarboxamide:
(18) N-(4-chlorobenzyl)- 1 -cyclopropyl-6-(3-hydroxy- 1 -propynyl)-4-oxo- 1.4-dihydro-3- quinolinecarboxamide:
(19) tert-butyl 2-[3-{ [(4-chlorobenzyl)amino]carbonyl}-6-(3-hydroxy-l-propynyl)-4- oxo- 1 (4H)-quinolinyl] acetate; (20) N-(4-chlorobenzyl)- 1 -(2-hydroxyethyl)-6-(3-hydroxy- 1 -propynyl)-4-oxo- 1 ,4- dihydro-3-quinoUnecarboxamide;
(21 ) N-(4-chlorobenzyl)-6-(3-hydroxy- 1 -propynyl)- 1 -methyl-4-oxo- 1 J-dihydro-3- quinoUnecarboxamide:
(22) 3-(3-{ [(4-chlorobenzyl)aminoJcarbonyl}- l-methyl-4-oxo- 1.4-dmydro-6- quinolinyOpropyl dkiydrogen phosphate;
(23) di(tert-butyl) 3-(3- { [(4-chlorobenzyl)amino]carbonyl } - 1 -cyclopropyl-4-oxo- 1.4- dUιydro-6-quinolinyl)propyl phosphate;
(24) sodium 2-[{ 8-[3-(3-{ [(4-chlorobenzyl)amino]carbonyl}-l-cyclopropyl-4-oxo- 1 ,4- dihydro-6-quinoUnyl)propoxy]-8-oxooctanoyl} (methyl)amino]- 1 -ethanesuUonate: (25) sodium 2-[(8-{ [3-(3-{ [(4-chlorobenzyl)amino]carbonyl}-l-methyl-4-oxo-l,4- dihydro-6-quinoUnyl)-2-propynyl]oxy}-8-oxooctanoyl)(methyl)aminoJ-l -ethanesuUonate:
(26) N-(4-chlorobenzyl)-6-(3-hydroxy- l -propynyl)- l-[2-(2-methoxyethoxy)-ethylJ-4- oxo- 1 ,4-dUιydro-3-quinolinecarboxamide;
(27) N-(4-cyanobenzyl)-6-(3-hydroxy-l-propynyl)-l-methyl-4-oxo- l ,4-dihydro-3- quinoUnecarboxamide:
(28) N-(4-chlorobenzyl)-6-(3-hydroxy-l-propynyl)-4-oxo- 1 -propyl- 1 ,4-dihydro-3- quinolinecarboxamide: (29) N-(4-chlorobenzyl)- 1 -methyl-6-( 1 ,4-oxazepan-4-ylmethyl)-4-oxo- 1 ,4-dihydro-3- quino Unecar bo xamide :
(30) N-(4-chlorobenzyl)- 1 -methyl-4-oxo-6-( 1.4-thiazepan-4-ylmethyl)- 1 ,4-dihydro-3- quinolkiecarboxamide: (31) 6-(azidomethyl)-Ν-(4-chlorobenzyl)- 1 -methyl-4-oxo- 1.4-dihydro-3- quinolinecarboxamide;
(32) N-(4-chlorobenzyl)-6-[(4,4-dUluoro-l -piperidinyl)methyl]- l-methyl-4-oxo-l,4- dihydro-3-quinoUnecarboxamide;
(33) N-(4-chlorobenzyl)-4-hydroxy-6-iodo-3-quinoUnecarbothioamide; (34) N-(4-chlorobenzyl)-6-(2.3-dmydro-4H- 1 ,4-benzoxazin-4-yknethyl)- 1 -methyl-4- oxo- 1 ,4-dihydro-3-quinolkιecarboxamide.
(35) N-(4-chlorobenzyl)- 1 -methyl-4-oxo-6-vinyl- 1 ,4-dihydro-3-quinoline-carboxamide:
(36) N-(4-chlorobenzyl)- l-[2-(2-hydroxyethoxy)ethyl]-6-(3-hydroxy- l -propynyl)-4- oxo- 1.4-dihydro-3-quinoUnecarboxamide; (37) N-(4-chlorobenzyl)-l-{ 2-[2-(2-methoxyethoxy)ethoxy]ethyl}-6-(4- morpholinylmethyl)-4-oxo- 1 ,4-dihydro-3-quinolinecarboxamide:
(38) N-(4-chlorobenzyl)- 1 -[2-(2-hydroxyethoxy)ethyl]-6-(4-morpholinylmethyl)-4-oxo- 1.4-dU ydro-3-quinoUnecarboxamide:
(39) N-(4-chloro benzyl)- 1 -[2-(2-ethoxyethoxy)ethyl]-6-(4-morphoUnylmethyl)-4-oxo- 1 ,4-dUιydro-3-quinoUnecarboxamide:
(40) N-(4-chlorobenzyl)- l-[2-(ethylsuU'anyl)ethyl]-6-(4-morphoUnylmethyl)-4-oxo- 1 ,4- dihydro-3-quinolinecarboxamide;
(41) N-(4-chlorobenzyl)- l-[3-(methylsuU"anyl)propyl]-6-(4-morphoUnylmethyl)-4-oxo- l ,4-dihydro-3-quinoUnecarboxamide: (42) N-(4-chlorobenzyl)- l-(4-hydroxy-2-butynyl)-6-(4-morphoUnylmethyl)-4-oxo- 1.4- dihydro-3-quinolinecarboxamide:
(43) N-(4-chlorobenzyl)-6-{ [(2-hydroxy-2-phenylethyl)(methyl)amino]methyl}- 1 - methyl-4-oxo- 1 ,4-dihydro-3-quinolkιecarboxamide:
(44) N-(4-chlorobenzyl)- 1 -[3-(methylsuUinyl)propyl]-6-(4-morpho kιylmethyl)-4-oxo- 1 ,4-dihydro-3-quinolkιecarboxamide;
(45) N-(4-chlorobenzyl)-l-{3-[(3-hydroxypropyl)suU'anyl]propyl}-6-(4- morpholinylmethyl)-4-oxo- 1 ,4-dihydro-3-quinolinecarboxamide: (46) N-(4-chlorobenzyl)-l-[3-(methylsuU'onyl)propyl]-6-(4-morphoUnylmethyl)-4-oxo- l ,4-dihydro-3-quinolinecarboxamide;
(47) N-(4-chlorobenzyl)- 1 -[2-(ethylsuUinyl)ethyl]-6-(4-morphoUnylmethyl)-4-oxo- 1 ,4- dU ydro-3-quinolinecarboxamide; (48) N-(4-chlorobenzyl)-l-[2-(ethylsuU"onyl)ethyl]-6-(4-morphoUnyknethyl)-4-oxo-l ,4- dihydro-3-quinolkιecarboxamide;
(49) N-(4-chlorobenzyl)-l-{3-[(3-hydroxypropyl)suUinyl]propyl}-6-(4- morpholinylmethyl)-4-oxo- 1 ,4-dihydro-3-quinolinecarboxamide;
(50) N-(4-chlorobenzyl)-l-{3-[(3-hydroxypropyl)suU'onylJpropyl}-6-(4- morphoUnyknethyl)-4-oxo- 1 ,4-dU ydro-3-qukιolkιecarboxamide;
(51) N-(4-chlorobenzyl)-6-(4-morphoUnylmethy])-4-oxo- 1 -[2-(phenylsuU"anyl)ethylJ- 1.4-dihydro-3-quinolinecarboxamide:
(52) N-(4-chlorobenzyl)- 1 -[(methylsuU"anyl)methyl]-6-(4-morphoUnylmethyl)-4-oxo- l ,4-dUιydro-3-quinorinecarboxamide; (53) N-(4-chlorobenzyl)-6-{ [[2-hydroxy-2-(4-hydroxyphenyl)ethyl](methyl)- amino]methyl}-l-methyl-4-oxo-l,4-dkιydro-3-quinolmecarboxamide;
(54) N-(4-chlorobenzyl)-6-f (3-hydroxy- 1 -azetidinyl)methyl]- 1 -methyl-4-oxo- 1 ,4- dihydro-3-quinolinecarboxamide;
(55) N-(4-chlorobenzyl)-6-(4-morphoUnylmethyl)-4-oxo- 1 -[(phenylsuU'anyl)-methyl]- 1 ,4-dihydro-3-quinoUnecarboxamide
(56) N-(4-chlorobenzyl)-6-{ [[2-hydroxy-2-(4-hydroxy-3-methoxyphenyl)ethyl]- (methyl)amkιo]methyl}-l-methyl-4-oxo- l,4-dmydro-3-quinolinecarboxamide;
(57) N-(4-chlorobenzyl)-6-[(3,3-dihydroxy- 1 -azetidinyl)methyl]- 1 -methyl-4-oxo- 1 ,4- dihydro-3-quinolinecarboxamide; (58) N-(4-chlorobenzyl)-l-[(methylsuUinyl)methylJ-6-(4-morpholkιyknethyl)-4-oxo-l,4- dUιydro-3-quinolinecarboxamide;
(59) N-(4-chlorobenzyl)- 1 -[(methylsuU"onyl)methyl]-6-(4-morphoUnyknethyl)-4-oxo- 1 ,4-dihydro-3-quinolinecarboxamide;
(60) N-(4-chlorobenzyl)-6-(4-morphoUnyknethyl)-4-oxo- 1 -[(phenylsuUinyl)-methyl]- 1 ,4-dUiydro-3-quinolinecarboxamide;
(61 ) N-(4-chlorobenzyl)-6-(4-morphoUnyknethyl)-4-oxo- 1 -[(phenylsuU'onyl)-methyl]- 1 ,4-dmydro-3-quinoUnecarboxamide; (62) N-(4-chlorobenzyl)-6-(3-hydroxypropyl)- l-[2-(2-methoxyethoxy)ethyl]-4-oxo- 1.4- dihydro-3-quinoUnecarboxamide:
(63) N-(4-chlorobenzyl)- 1 -[2-(2-methoxyethoxy)ethyl]-6-(4-morpholinylmethyl)-4-oxo- l ,4-dihydro-3-quinoUnecarboxamide; (64) N-(4-chlorobenzyl)-l-[2-(2-methoxyethoxy)ethyl]-4-oxo-6-[(4-oxo-l - piperidinyl)methyl]- 1.4-dihydro-3-quinoiinecarboxamide:
(65) N-(4-chlorobenzyl)-6-{ [(3R)-3-hydroxypyrroUdinyl]methyl}- 1-[2-(2- methoxyethoxy)ethylJ -4-oxo- 1 ,4-dihydro-3-quinolinecarboxamide;
(66) N-(4-chlorobenzyl)-6-{ [[(lRJ5)-2-hydroxy- l-methyl-2-phenylethyl](methyl)- amkiojmethyl}- l-[2-(2-methoxyethoxy)ethyl]-4-oxo- 1.4-dihydro-3-quinoUne-carboxamide:
(67) N-(4-chlorobenzyl)-6-{ [[2-hydroxy-2-(4-hydroxyphenyl)ethyl](methyl)aminoj- methyl}-l-[2-(2-methoxyethoxy)ethyl]-4-oxo- 1.4-dmydro-3-quinoUnecarboxamide:
(68) l-{ 2-[2-(t^rt-butoxy)ethoxy]ethyl-N-(4-chlorobenzyl)-6-(4-morphoUnyl-methyl)-4- oxo- 1.4-dUιydro-3-quinoUnecarboxamide: (69) l-{ 2-[2-(tert-butoxy)ethoxy]ethyl-N-(4-chlorobenzyl)-6-{ [[2-hydroxy-2-(4- hydroxyphenyl)ethyl](methyl)amino]methyl-4-oxo- 1.4-dmydro-3-qumoUne-carboxamide;
(70) N-(4-chlorobenzyl)-6-(3-hydroxy- 1 -propynyl)- 1 -methyl-4-oxo- 1.4-dihydro-3- quinoUnecarbothio amide ;
(71 ) N-(4-chlorobenzyl)-8-(3-hydroxy- 1 -propynyl)- 1 -methyl-4-oxo- 1 J-dihydro-3- quinoUnecarboxamide:
(72) N-(4-chlorobenzyl)-8-(4-hydroxy- l-butynyl)- l-methyl-4-oxo- 1.4-dihydro-3- quinoUnecarboxamide:
(73) N-(4-chlorobenzyl)-6-{ [3-(hydroxyimkιo)- l-azetidinyl]methyl}-l-methyl-4-oxo- 1 ,4-dihydro-3-quinolkιecarboxamide; (74) N-(4-chlorobenzyl)-l-{ 2-[2-(4-morphoUnyl)ethoxylethyl}-6-(4- morpholkιyUτιethyl)-4-oxo- 1 ,4-dihydro-3-quinolinecarboxamide:
(75) N-(4-chlorobenzyl)-l-([(4-chlorophenyl)suU'anyl]methyl)- 6-(4- morphork yknethyl)-4-oxo- 1 ,4-dmydro-3-quinoUnecarboxamide:
(76) N-(4-chlorobenzyl)- 1 -([(4-chlorophenyl)suUmyl]methyl)-6-(4-morpholinylmethyl)- 4-oxo- 1 ,4-dmydro-3-quinolkιecarboxamide:
(77) N-(4-chlorobenzyl)- 1 -([(4-chlorophenyl)suU'onyl]methyl)-6-(4-morphoUnylmethyl)- 4-oxo- 1 ,4-dUιydro-3-quinolkιecarboxamide: (78) N-(4-chlorobenzyl)-l-[(4-chlorophenoxy) methyl]-6-(4-morpholinylmethyl)-4-oxo- 1 ,4-dihydro-3-quinoUnecarboxamide;
(79) N-(4-chlorobenzyl)-l-[(2-methoxyethoxy)methyl]-6-(4-morphoUnylmethyl)-4-oxo- 1 ,4-dihydro-3-quinolinecarboxamide; (80) 2-{ [3-{ [(4-chlorobenzyl)amino]carbonyl}-6-(4-morphohnylmethyl)-4-oxo-l (4H)- quinoUnyl]methoxy} ethyl benzoate;
(81) N-(4-chlorobenzyl)-l-[(2-hydroxyethoxy)methyl]-6-(4-morpholinylmethyl)-4-oxo- 1 ,4-dUιydro-3-quinolkιecarboxamide;
(82) N-(4-chlorobenzyl)-6-(4-morpholinylmethyl)-4-oxo- 1 -tetrahydro-2H-pyran-4-yl- 1 ,4-dihydro-3-quinolinecarboxamide;
(83) N-(4-chlorobenzyl)- 1 -( 1 -methyl-4-piperidinyl)-6-(4-morpholinylmethyl)-4-oxo- 1 ,4- dU ydro-3-quinoUnecarboxamide:
(84) N-(4-chlorobenzyl)-6-(4-morphoUnylmethyl)-4-oxo- 1 -(4-piperidinyl)- 1 ,4-dihydro- 3-quinolinecarboxamide; (85) N-(4-chlorobenzyl)- 1 -( 1 , 1 -dioxohexahydrothiopyran-4-yl)-6-(4- morphoUnylmethyl)-4-oxo- 1 ,4-dihydro-3-quinoUnecarboxamide;
(86) N-(4-chlorobenzyl)-l-(4-morpholinyl)-6-(4-morphoUnylmethyl)-4-oxo- 1.4- dihydro-3-quk oUnecarboxamide;
(87) N-(4-chlorobenzyl)- 1 -(4-methyl- 1 -piperazinyl)-6-(4-morphoUnylmethyl)-4-oxo- 1 ,4-dihydro-3-quinolinecarboxamide;
(88) N-(4-chlorobenzyl)-6-(4-morpholinylmethyl)-4-oxo- 1 -( 1 -piperidinyl)- 1.4-dihydro- 3-quinolinecarboxamide;
(89) N-(4-chlorobenzyl)-6-(4-morpholinylmethyl)-4-oxo-l-(l-pyrroUdinyl)- l,4-dihydro- 3-quinolkιecarboxamide: (90) N-(4-chlorobenzyl)- 1 -[(2R)-2-(methoxymethyl)pyrroUdinyl]-6-(4- morphoUnyknethyl)-4-oxo- 1.4-dihydro-3-quinoUnecarboxamide;
(91 ) N-(4-chlorobenzyl)- 1 -(dimethylamino)-6-(4-morphoUnylmethyl)-4-oxo- 1.4- dihydro-3-quinoUnecarboxamide;
(92) l-amino-N-(4-chlorobenzyl)-6-(3-hydroxy-l-propynyl)-4-oxo-l ,4-dihydro-3- quinoUnecarboxamide;
(93) 1 -amino-N-(4-chlorobenzyl)-6-(3-hydroxypropyl)-4-oxo- 1 ,4-dihydro-3- quinolkiecarboxamide; (94) N-(4-chlorobenzyl)- 1 -(dimethylamino)-6-(3-hydroxy- 1 -propynyl)-4-oxo- 1 ,4- dihydro-3-quinolinecarboxamide;
(95) l-(allyloxy)-N-(4-chlorobenzyl)-4-oxo-l ,4-dihydro-3-quinoUnecarboxamide; or a pharmaceuticaUy acceptable salt thereof.
64. A compound of claim 1 which is:
( 1 ) 1 -(sec-butyl)-N-(4-chlorobenzyl)-6-(3-hydroxy- 1 -propynyl)-4-oxo- 1 ,4-dihydro-3- quinolinecarboxamide;
(2) 1 -(sec-butyl)-N-(4-chlorobenzyl)-6-(3-hydroxy- 1 -propynyl)-8-methoxy-4-oxo- 1 ,4- dihydro-3-quinolkιecarboxamide;
(3) N-(4-chlorobenzyl)-6-[3-hydroxy-l-propenyl]-l-[2-(4-morpholinyl)ethyl]-4-oxo- l,4-dihydro-3-quinolinecarboxamide;
(4) N-(4-chlorobenzyl)-8-fluoro-6-(3-hydroxy- l -propynyl)- l-methyl-4-oxo- 1,4- dihydro-3-quinoUnecarboxamide; (5) N-(4-chlorobenzyl)-8-lluoro-6-[(Z)-3-hydroxy-l-propenyl]-l-methyl-4-oxo-1.4- dUiydro-3-quinolinecarboxamide;
(6) N-(4-chlorobenzyl)- l-[2-(dimethylamino)ethyl]-6-(3-hydroxy- l-propynyl)-4-oxo- 1 ,4-dU ydro-3-quinoUnecarboxamide hydrochloride;
(7) N-(4-chlorobenzyl)-6-(3-hydroxy-l-propynyl)-4-oxo- l-[2-(l-piperidinyl)ethyl]- 1.4- dihydro-3-quinoUnecarboxamide;
(8) N-(4-chlorobenzyl)-6-(3-hydroxy-l-propynyl)-4-oxo-l-[3-(l-piperidinyl)propylJ- l,4-dihydro-3-quinolinecarboxamide;
(9) N-(4-chlorobenzyl)-6-(3-hydroxy- 1 -propynyl)- l-[2-(l -methyl-2-pyrroUdinyl)ethyl]- 4-oxo- 1 ,4-dihydro-3-quinolkιecarboxamide; (10) N-(4-chlorobenzyl)-l-[2-(dUsopropylamino)ethyl]-6-(3-hydroxy-l-propynyl)-4- oxo- 1 ,4-dihydro-3-quinolinecarboxamide;
(11) N-(4-chlorobenzyl)-6-(3-hydroxy- 1 -propynyl)-4-oxo- 1 -[2-( 1 -pyrroUdinyl)ethyι]- l,4-dihydro-3-quinolinecarboxamide;
(12) N-(4-chlorobenzyl)-6-(3-hydroxy-l -propynyl)- l-[2-(4-morphoUnyl)ethyl]-4-oxo- 1 ,4-dUiydro-3-quinolinecarboxamide;
(13) N-(4-chlorobenzyl)-l-[3-(dimethylamrno)propyl]-6-(3-hydroxy-l-propynyl)-4-oxo- 1 ,4-dihydro-3-quinoUnecarboxamide; (14) N-(4-chlorobenzyl)-6-(3-hydroxy-l-propynyl)-4-oxo-l -vinyl- 1 ,4-dihydro-3- quinolinecarboxamide ;
(15) N-(4-chlorobenzyl)-6-[(E)-3-hydroxy- 1 -propenyl]- 1 -methyl-4-oxo- 1 ,4-dihydro-3- quinolinecarboxamide; (16) N-(4-chlorobenzyl)-6-[(Z)-3-hydroxy- 1 -propenyl]- 1 -methyl-4-oxo- 1 ,4-dihydro-3- quinohnecarboxamide:
(17) N-(4-chlorobenzyl)- 1 -cyclopropyl-6-(3-hydroxy- 1 -propynyl)-4-oxo- 1 ,4-dihydro-3- quinolkiecarboxamide:
(18) tert-butyl 2-[3-{ [(4-chlorobenzyl)amino]carbonyl}-6-(3-hydroxy-l-propynyl)-4- oxo- l(4H)-quinolkiyl]acetate;
( 19) N-(4-chlorobenzyl)- 1 -(2-hydroxyethyl)-6-(3-hydroxy- 1 -propynyl)-4-oxo- 1 ,4- dihydro-3-quinoUnecarboxamide:
(20) N-(4-chlorobenzyl)-6-(3-hydroxy- 1 -propynyl)- 1 -methyl-4-oxo- 1 ,4-dihydro-3- quinoUnecarboxamide: (21) 3-(3-{ [(4-chlorobenzyl)amino]carbonyl}- l-methyl-4-oxo- 1 ,4-dihydro-6- quinolinyl)propyl dihydrogen phosphate:
(22) di(tert-butyl) 3-(3-{ [(4-chlorobenzyl)amino]carbonyl}- l-cyc opropyl-4-oxo- 1,4- dihydro-6-qukιolinyl)propyl phosphate;
(23) sodium 2-[{ 8-[3-(3- { [(4-chlorobenzyl)amino]carbonyl }- 1 -cyclopropyl-4-oxo- 1 ,4- dUιydro-6-qukιoUnyl)propoxy]-8-oxooctanoyl}(methyl)amino]- l -ethanesuUonate;
(24) sodium 2-[(8-{ [3-(3-{ [(4-chlorobenzyl)amino]carbonyl}-l-methyl-4-oxo-l,4- dihydro-6-quinoUnyl)-2-propynyl]oxy}-8-oxooctanoyl)(methyl)amino]-l -ethanesulfonate:
(25) N-(4-chlorobenzyl)-6-(3-hydroxy-l -propynyl)- l-[2-(2-methoxyethoxy)ethyl]-4- oxo- 1 ,4-dihydro-3-quinolinecarboxamide: (26) N-(4-cyanobenzyl)-6-(3-hydroxy- 1 -propynyl)- 1 -methyl-4-oxo- 1 ,4-dihydro-3- quinoUnecarboxamide ;
(27) N-(4-chlorobenzyl)-6-(3-hydroxy- l-propynyl)-4-oxo- 1 -propyl- 1.4-dihydro-3- quinolinecarboxamide;
(28) 6-(azidomethyl)-N-(4-chlorobenzyl)- 1 -methyl-4-oxo- 1 ,4-dihydro-3- quinoUnecarboxamide;
(29) N-(4-chlorobenzyl)-6-(2J-dihydro-4H-l ,4-benzoxazin-4-ylmethyl)-l-methyl-4- oxo- 1 ,4-dihydro-3-qukιolinecarboxamide;
(30) N-(4-chlorobenzyl)- 1 -methyl-4-oxo-6-vinyl- 1.4-dihydro-3-quinoUne-carboxamide; (31) N-(4-chlorobenzyl)-l-[2-(2-hydroxyethoxy)ethyl]-6-(3-hydroxy-l-propynyl)-4- oxo- 1 ,4-dihydro-3-quinoUnecarboxamide;
(32) N-(4-chlorobenzyl)- 1 - { 2-[2-(2-methoxyethoxy)ethoxy]ethyl } -6-(4- morphoUnylmethyl)-4-oxo- 1 ,4-dihydro-3-quinoUnecarboxamide: (33) N-(4-chlorobenzyl)-l-[2-(2-hydroxyethoxy)ethyl]-6-(4-morphoUnyknethyl)-4-oxo-
1.4-dihydro-3-quinolinecarboxamide:
(34) N-(4-chlorobenzyl)-l-[2-(2-ethoxyethoxy)ethyl]-6-(4-morphoUnyknethyl)-4-oxo- 1.4-dihydro-3-quinolinecarboxamide;
(35) N-(4-chlorobenzyl)-l-[2-(ethylsuU'anyl)ethyl]-6-(4-morphoUnylmethyl)-4-oxo-1.4- dihydro-3-quinolinecarboxamide;
(36) N-(4-chlorobenzyl)-l-[3-(methylsuU'anyl)propyl]-6-(4-morpholinylmethyl)-4-oxo- 1.4-dmydro-3-qukiofinecarboxamide;
(37) N-(4-chlorobenzyl)- l-(4-hydroxy-2-butyny])-6-(4-morphoUnyknethyl)-4-oxo- 1.4- dihydro-3-quinolinecarboxamide: (38) N-(4-chlorobenzyl)- 1 -[3-(methylsuUinyl)propyl]-6-(4-morphoUnyknethyl)-4-oxo-
1.4-dmydro-3-quinoUnecarboxamide:
(39) /V-(4-chlorobenzyl)-l-{3-[(3-hydroxypropyl)suU'anylJpropyl}-6-(4- morpholinylmethyl)-4-oxo- 1.4-dihydro-3-quinoUnecarboxamide;
(40) N-(4-chlorobenzyl)- 1 -[3-(methylsuU'onyl)propyl]-6-(4-morphoUnymιethyl)-4-oxo- 1.4-dmydro-3-qumolinecarboxamide:
(41) N-(4-chlorobenzyl)-l-[2-(ethylsuUinyl)ethyl]-6-(4-morphoUnyknethyl)-4-oxo-1.4- dmydro-3-quinoUnecarboxamide:
(42) N-(4-chlorobenzyl)- 1 -[2-(ethylsuU"onyl)ethyl]-6-(4-morpholinyUnethyl)-4-oxo- 1 ,4- dU ydro-3-quinolinecarboxamide: (43) N-(4-chlorobenzyl)- l-{3-[(3-hydroxypropyl)suUinyl]propyl}-6-(4- morpholinylmethyl)-4-oxo- 1.4-dmydro-3-quinoUnecarboxamide:
(44) N-(4-chlorobenzyl)-l-{3-[(3-hydroxypropyl)suU'onyl]propyl}-6-(4- morphoUnylmethyl)-4-oxo- 1.4-dmydro-3-qukιofkιecarboxamide:
(45) N-(4-chlorobenzyl)-6-(4-morpholkιyUnethyl)-4-oxo- l-[2-(phenylsuk"anyl)ethyl]- 1.4-dmydro-3-quinolinecarboxamide;
(46) N-(4-chlorobenzyl)- 1 -[(methylsuUanyl)methyl]-6-(4-morphoUnyknethyl)-4-oxo- 1.4-dUιydro-3-quinoUnecarboxamide; (47) N-(4-chlorobenzyl)-6-{ [[2-hydroxy-2-(4-hydroxyphenyl)ethyl](methyl)- amino]methyl}-l-methyl-4-oxo-l,4-dihydro-3-quinolk ecarboxamide;
(48) N-(4-chlorobenzyl)-6-[(3-hydroxy- l-azetidinyl)methyl]-l-methyl-4-oxo-l,4- dihydro- 3 -quinolinecarboxamide ; (49) N-(4-chlorobenzyl)-6-(4-morphoUnylmethyl)-4-oxo-l-[(phenylsuU'anyl)-methyl]- l,4-dihydro-3-quinolinecarboxamide;
(50) N-(4-chlorobenzyl)-6-{ [[2-hydroxy-2-(4-hydroxy-3-methoxyphenyl)ethylJ- (methyl)amino]methyl}-l-methyl-4-oxo-l ,4-dmydro-3-qumolinecarboxamide:
(51 ) N-(4-chlorobenzyl)-6-[(3.3-dihydroxy- 1 -azetidinyl)methyl]- 1 -methyl-4-oxo- 1 ,4- dihydro-3-quinolinecarboxamide:
(52) N-(4-chlorobenzyl)-l-[(methylsuUinyl)methyl]-6-(4-morphoUnyknethyl)-4-oxo-1.4- dihydro-3-quinoUnecarboxamide;
(53) N-(4-chlorobenzyl)- 1 -[(methylsuU'onyl)methyl]-6-(4-morphoUnyknethyl)-4-oxo- l,4-dmydro-3-qurnoUnecarboxamide: (54) N-(4-chlorobenzyl)-6-(4-morphoUnyUnethyl)-4-oxo- l-[(phenylsuUinyl)-methyl]-
1.4-dmydro-3-quinoUnecarboxamide;
(55) N-(4-chlorobenzyl)-6-(4-morphoUnylmethyl)-4-oxo-l-[(phenylsuUOnyl)-methyl]- 1 ,4-dihydro-3-quinoUnecarboxamide;
(56) N-(4-chlorobenzyl)-6-(3-hydroxypropyl)- 1 -[2-(2-methoxyethoxy)ethyl]-4-oxo- 1.4- dihydro-3-qukιoUnecarboxamide;
(57) N-(4-chlorobenzyl)- l-[2-(2-methoxyethoxy)ethyl]-6-(4-morphoUnylmethyl)-4-oxo- 1.4-dihydro-3-quinolinecarboxamide:
(58) V-(4-chlorobenzyl)-l-[2-(2-methoxyethoxy)ethyl]-4-oxo-6-[(4-oxo- l- piperidmyl)methyl]- 1.4-dihydro-3-quinolkιecarboxamide: (59) N-(4-chlorobenzyl)-6-{ [(3R)-3-hydroxypyrroUdinyl]methyl}- 1-[2-(2- methoxyethoxy)ethyl] -4-oxo- 1 ,4-dihydro-3-quinolinecarboxamide:
(60) N-(4-chlorobenzyl)-6-{[[2-hydroxy-2-(4-hydroxyphenyl)ethyl](methyl)amino]- methyl}-l-[2-(2-methoxyethoxy)ethyl]-4-oxo-1.4-dihydro-3-quinoUnecarboxamide:
(61) l-{2-[2-(tert-butoxy)ethoxy]ethyl-N-(4-chlorobenzyl)-6-(4-morphoUnyl-methyl)-4- oxo- 1 ,4-dihydro-3-quinoUnecarboxamide:
(62) l-{2-[2-(tert-butoxy)ethoxy]ethyl-N-(4-chlorobenzyl)-6-{ [[2-hydroxy-2-(4- hydroxyphenyl)ethyl](methyl)amino]methyl-4-oxo-l ,4-dihydro-3-quinoUne-carboxamide: (63) N-(4-chlorobenzyl)-6-(3-hydroxy-l -propynyl)- l-methyl-4-oxo- 1 ,4-dihydro-3- quinolinecarbothio amide;
(64) N-(4-chlorobenzyl)-8-(3-hydroxy-l-propynyl)- l-methyl-4-oxo-l,4-dmydro-3- quinoUnecarboxamide: (65) N-(4-chlorobenzyl)-8-(4- hydroxy- 1 -butynyl)- 1 -methyl-4-oxo- 1 ,4-dihydro-3- qumolinecarboxamide;
(66) N-(4-chlorobenzyl)-6- { [3-(hydroxyimino)- 1 - azetidinyl] methyl }- 1 -methyl-4-oxo- 1 ,4-dihydro-3-quinoUnecarboxamide;
(67) N-(4-chlorobenzyl)-l-{2-[2-(4-morphoUnyl)ethoxy]ethyl}-6-(4- morphoUnylmethyl)-4-oxo- 1.4-dihydro-3-quinolinecarboxamide;
(68) N-(4-chlorobenzyl)-l-([(4-chlorophenyl)suU"anylJmethyl)- 6-(4- morphoUnyknethyl)-4-oxo- 1 ,4-dihydro-3-quinoUnecarboxamide;
(69) N-(4-chlorobenzyl)- 1 -([(4-chlorophenyl)sulfmyl]methyl)-6-(4-morphoUnylmethyl)- 4-oxo- 1 ,4-dihydro-3-quinolinecarboxamide; (70) N-(4-chlorobenzyl)-l-([(4-chlorophenyl)suU'onylJmethyl)-6-(4-morphoUnyknethyl)-
4-oxo- 1 ,4-dihydro-3-quinolinecarboxamide:
(71) N-(4-chlorobenzyl)-l-[(2-methoxyethoxy)methyl]-6-(4-morphoUnyknethyl)-4-oxo- l ,4-dihydro-3-quinoUnecarboxamide;
(72) 2-{ [3-{ [(4-chlorobenzyl)aminoJcarbonyl}-6-(4-morpholinyknethyl)-4-oxo-l (4H)- qukiolinyfjmethoxy} ethyl benzoate:
(73) /V-(4-chlorobenzyl)-l -[(2-hydroxyethoxy)methyl]-6-(4-morpholinylmethyl)-4-oxo-
1 ,4-dihydro-3-quinoUnecarboxamide;
(74) N-(4-chlorobenzyl)-6-(4-morphoUnylmethyl)-4-oxo-l-tetrahydro-2H-pyran-4-yl- 1 ,4-dihydro-3-quinoUnecarboxamide; (75) N-(4-chlorobenzyl)-l-(l-methyl-4-piperidinyl)-6-(4-morphoUnylmethyl)-4-oxo-l ,4- dihydro-3-quinolinecarboxamide;
(76) N-(4-chlorobenzyl)-6-(4-morphoUnylmethyl)-4-oxo- 1 -(4-piperidinyl)- 1 ,4-dihydro- 3-quinolinecarboxamide;
(77) N-(4-chlorobenzyl)- 1 -( 1 J -dioxohexahydrothiopyran-4-yl)-6-(4- morphoUnylmethyl)-4-oxo-l ,4-dmydro-3-quinoUnecarboxamide;
(78) N-(4-chlorobenzyl)-l-(4-morpholkιyl)-6-(4-morphoUnylmethyl)-4-oxo- l,4- dihydro-3-quinoUnecarboxamide; (89) N-(4-chlorobenzyl)- 1 -(4-methyl- 1 -piperazinyl)-6-(4-morphoUnylmethyl)-4-oxo- l ,4-dihydro-3-quinolιnecarboxamide;
(80) N-(4-chlorobenzyl)-6-(4-morphoUnylmethyl)-4-oxo- 1 -( 1 -piperidinyl)- 1 ,4-dihydro- 3-quinoUnecarboxamide: (81) N-(4-chlorobenzyl)- 1 -(dimethylamino)-6-(4-morpholinylmethyl)-4-oxo- 1 ,4- dUιydro-3-quinoUnecarboxamide;
(82) l-amino-N-(4-chlorobenzyl)-6-(3-hydroxy-l-propynyl)-4-oxo-l,4-dihydro-3- quinolinecarboxamide:
(83) 1 -amino-N-(4-chlorobenzyl)-6-(3-hydroxypropyl)-4-oxo- 1.4-dihydro-3- quinoUnecarboxamide: or a pharmaceuticaUy acceptable salt thereof.
65. A compound of claim 1 which is
( I) N-(4-chlorobenzyl)-8-fluoro-6-[(Z)-3-hydroxy- 1 -propenyl]- l-methyl-4-oxo- 1.4- dihydro-3-quinolinecarboxamide; (2) N-(4-chlorobenzyl)-6-(3-hydroxy- l -propynyl)- l-[2-(4-morpholinyl)ethyl]-4-oxo-
1.4-dihydro-3-quinolinecarboxamide;
(3) N-(4-chlorobenzyl)-6-(3-hydroxy- 1 -propynyl)-4-oxo- 1 -vinyl- 1.4-dihydro-3- quinoUnecarboxamide:
(4) N-(4-chlorobenzyl)-6-[(Z)-3-hydroxy-l-propenyl]- l-methyl-4-oxo- 1 ,4-dihydro-3- qumoUnecarboxamide:
(5) N-(4-chlorobenzyl)- 1 -cyclopropyl-6-(3-hydroxy- 1 -propynyl)-4-oxo- 1.4-dihydro-3- quinoUnecarboxamide;
(6) N-(4-chlorobenzyl)- 1 -(2-hydroxyethyl)-6-(3-hydroxy- 1 -propynyl)-4-oxo- 1 ,4- dihydro-3-quinolinecarboxamide; (7) N-(4-chlorobenzyl)-6-(3-hydroxy- 1 -propynyl)- 1 -methyl-4-oxo- 1 ,4-dihydro-3- qumolkiecarboxamide:
(8) 3-(3-{ [(4-chlorobenzyl)amkιo]carbonyl}- l-methyl-4-oxo-l,4-dmydro-6- quinoUnyl)propyl dihydrogen phosphate;
(9) sodium 2-[(8-{ [3-(3-{ [(4-chlorobenzyl)amino]carbonyl}- l-methyl-4-oxo-l .4- dUiydro-6-quinolinyl)-2-propynyl]oxy}-8-oxooctanoyl)(methyl)amino]-l -ethanesuUonate:
(10) N-(4-chlorobenzyl)-6-(3-hydroxy-l-propynyl)-l-[2-(2-methoxyethoxy)-ethyl]-4- oxo- 1 ,4-dihydro-3-quinoUnecarboxamide;
(I I) Ν-(4-chlorobenzyl)-l-methyl-4-oxo-6-vinyl-1.4-dmydro-3-quinoUne-carboxamide; ( 12) N-(4-chlorobenzyl)- 1 -[2-(2-hydroxyethoxy)ethyl]-6-(3-hydroxy- 1 -propynyl)-4- oxo- 1 ,4-dihydro-3-quinolinecarboxamide:
(13) N-(4-chlorobenzyl)-l-[2-(2-hydroxyethoxy)ethyl]-6-(4-morphoUnylmethyl)-4-oxo- l,4-dihydro-3-quinoUnecarboxamide: (14) N-(4-chlorobenzyl)-l-[2-(2-ethoxyethoxy)ethyl]-6-(4-morphobnylmethyl)-4-oxo-
1.4-dihydro-3-quinoUnecarboxamide;
( 15) N-(4-chlorobenzyl)- 1 -[2-(ethylsulfanyl)ethyl]-6-(4-morpholinylmethyl)-4-oxo- 1 ,4- dihydro-3-quinolkιecarboxamide;
(16) N-(4-chlorobenzyl)- 1 -[3-(methylsuU'anyl)propylJ-6-(4-morpholkιylmethyl)-4-oxo- 1 ,4-dihydro-3-quinolinecarboxamide:
( 17) N-(4-chlorobenzyl)- 1 -(4-hydroxy-2-butynyl)-6-(4-morpholinylmethyl)-4-oxo- 1 ,4- dihydro-3-quinolinecarboxamide:
(18) N-(4-chlorobenzyl)-l-[3-(methylsuUinyl)propyl]-6-(4-morpholinylmethyl)-4-oxo-
1.4-dihydro-3-quinoUnecarboxamide; (19) N-(4-chlorobenzyl)-l-{3-[(3-hydroxypropyl)suU'anyl]propyl}-6-(4- morpholinylmethyl)-4-oxo- 1 ,4-dihydro-3-quinolinecarboxamide:
(20) N-(4-chlorobenzyl)-l-f3-(methylsuU'onyl)propyl]-6-(4-morphoUnylmethyl)-4-oxo- l,4-dihydro-3-quinolinecarboxamide:
(21) N-(4-chlorobenzyl)-l-[2-(ethylsuUinyl)ethyl]-6-(4-morphoUnylmethyl)-4-oxo-1.4- dihydro-3-quinoUnecarboxamide;
(22) N-(4-chlorobenzyl)-l-[2-(ethylsuU'onyl)ethyl]-6-(4-morphoUnylmethyl)-4-oxo-1.4- dihydro-3-quinoUnecarboxamide:
(23) N-(4-chlorobenzyl)-l-{3-[(3-hydroxypropyl)sulfonyl]propyl}-6-(4- morpholinyknethyl)-4-oxo- 1.4-dihydro-3-quinolinecarboxamide: (24) N-(4-chlorobenzyl)-6-(4-morpholk yknethyl)-4-oxo- l-[2-(phenylsuU"anyl)ethyl]- l,4-dUιydro-3-quinoUnecarboxamide;
(25) N-(4-chlorobenzyl)-l-[(methylsuU'anyl)methyl]-6-(4-morpholkιylmethyl)-4-oxo- 1 ,4-dUιydro-3-quk olinecarboxamide;
(26) N-(4-chlorobenzyl)-6-{ [[2-hydroxy-2-(4-hydroxyphenyl)ethyl](mcthyl)- amino] methyl}- l-methyl-4-oxo- 1.4-dihydro-3-quinoUnecarboxamide:
(27) N-(4-chlorobenzyl)-6-(4-morphoUnylmethyl)-4-oxo- 1 -[(phenylsulfanyl)-methyl]- 1 ,4-dihydro-3-quinoUnecarboxamide; (28) N-(4-chlorobenzyl)-6-{ [[2-hydroxy-2-(4-hydroxy-3-methoxyphenyl)ethyl]- (methyl)amino]methyl}-l-methyl-4-oxo-1.4-dihydro-3-quinolinecarboxamide:
(29) N-(4-chlorobenzyl)-6-[(3J-dihydroxy-l-azetidinyl)methyl]-l-methyl-4-oxo-l,4- dkiydro-3-quinoUnecarboxamide; (30) N-(4-chlorobenzyl)- 1 -[(methylsulfinyl)methyl]-6-(4-morphoUnylmethyl)-4-oxo- 1 ,4- dihydro-3-quinolinecarboxamide;
(31 ) N-(4-chlorobenzyl)- 1 -[(methylsuU'onyl)methyl]-6-(4-morphoUnylmethyl)-4-oxo- l,4-dihydro-3-quinohnecarboxamide;
(32) N-(4-chlorobenzyl)-6-(4-morpholinylmethyl)-4-oxo- l-[(phenylsuUinyl)-methyl]- 1.4-dihydro-3-quinoUnecarboxamide;
(33) N-(4-chlorobenzyl)-6-(4-morpholinylmethyl)-4-oxo-l-[(phenylsuUOnyl)-methyl]- 1.4-dihydro-3-quinolinecarboxamide;
(34) N-(4-chlorobenzyl)-6-(3-hydroxypropyl)- 1 -[2-(2-methoxyethoxy)ethyl]-4-oxo- 1.4- dihydro-3-quinoUnecarboxamide; (35) N-(4-chlorobenzyl)- l-[2-(2-methoxyethoxy)ethyl]-6-(4-morpholinylmethyl)-4-oxo-
1.4-dihydro-3-qumolinecarboxamide;
(36) l-{2-[2-(tert-butoxy)ethoxy]ethyl-/V-(4-chlorobenzyl)-6-(4-morphoUnyl-methyl)-4- oxo- 1 ,4-dihydro-3-quinolinecarboxamide:
(37) N-(4-chlorobenzyl)-6-(3-hydroxy- 1 -propynyl)- 1 -methyl-4-oxo- 1.4-dihydro-3- quinolinecarbothioamide:
(38) N-(4-chlorobenzyl)-8-(3-hydroxy- 1 -propynyl)- 1 -methyl-4-oxo- 1.4-dihydro-3- quinoUnecarboxamide;
(39) N-(4-chlorobenzyl)-8-(4-hydroxy- 1 -butynyl)- 1 -methyl-4-oxo- 1 ,4-dihydro-3- quinoUnecarboxamide: (40) N-(4-chlorobenzyl)-l-([(4-chlorophenyl)suU'anyl]methyl)- 6-(4- morphoUnylmethyl)-4-oxo- 1 ,4-dihydro-3-quinoUnecarboxamide;
(41) N-(4-chlorobenzyl)-l-([(4-chlorophenyl)sulfinyl]methyl)-6-(4-morphoUnylmethyl)- 4-oxo- 1.4-dihydro-3-qumoUnecarboxamide;
(42) N-(4-chlorobenzyl)-l-[(2-methoxyethoxy)methyl]-6-(4-morphofinylmethyl)-4-oxo- 1.4-dUιydro-3-qumoUnecarboxamide;
(43) 2-{ [3-{ [(4-chlorobenzyl)amino]carbonyl}-6-(4-morphorinyknethyl)-4-oxo-l(4H)- quinoUnyl]methoxy} ethyl benzoate; (44) N-(4-chlorobenzyl)-l-[(2-hydroxyethoxy)methyl]-6-(4-morpholinylmethyl)-4-oxo- 1 ,4-dihydro-3-quinolinecarboxamide;
(45) N-(4-chlorobenzyl)-6-(4-morpholinylmethyl)-4-oxo- 1 -tetrahydro-2H-pyran-4-yl- 1 ,4-dUιydro-3-quinolkιecarboxamide; (46) N-(4-chlorobenzyl)-l-(l-methyl-4-piperidinyl)-6-(4-morphoUnyknethyl)-4-oxo- 1 ,4- dihydro-3-quinoUnecarboxamide;
(47) N-(4-chlorobenzyl)-6-(4-morpholinylmethyl)-4-oxo- 1 -(4-piperidinyl)- 1 ,4-dihydro- 3-quinolinecarboxamide;
(48) N-(4-chlorobenzyl)- 1 -( 1 J -dioxohexahydrothiopyran-4-yl)-6-(4- morphoUnylmethyl)-4-oxo- 1 ,4-dihydro-3-quinoUnecarboxamide:
(49) N-(4-chlorobenzyl)- 1 -(4-morpholinyl)-6-(4-morphohnylmethyl)-4-oxo- 1 ,4- dihydro-3-quinolinecarboxamide;
(50) l-amino-N-(4-chlorobenzyl)-6-(3-hydroxy- l-propynyl)-4-oxo-l,4-dihydro-3- qukiolinecarboxamide; (51) 1 -amino-N-(4-chlorobenzy])-6-(3-hydroxypropyl)-4-oxo- 1 ,4-dihydro-3- quinolinecarboxamide; or a pharmaceuticaUy acceptable salt thereof.
66. A compound claim 1 which is
(5) Ν-(4-chlorobenzyl)-l-methyl-4-oxo-6-(tetrahydro-2H-pyran-4-ylmethyl)-l ,4- dihydro-3-quinoUnecarboxamide:
(5) N-(4-chlorobenzyl)-l-methyl-6-(4-morpholinylmethyl)-4-oxo-l,4-dihydro-3- quinoUnecarbothioamide; (5) N-(4-chlorobenzyl)-8-(2-hydroxyethoxy)-6-(3-hydroxypropyl)-l-methyl-4-oxo-l,4- dihydro-3-quinoUnecarboxamide; (5) N-(4-chlorobenzyl)- 1 -cyclopropyl-6-(3-hydroxypropyl)-4-oxo- 1 ,4-dihydro-3- qukiolinecarboxamid; (5) l-{2-[bis(2-hydroxyethyl)amino]ethyl}-N-(4-chlorobenzyl)-6-(4-morphoUnyl- methyl)-4-oxo-l,4-dmydro-3-quinolinecarboxamide; or a pharmaceuticaUy acceptable salt thereof.
67. A compound of claim 1 which is:
(1) N-(4-chlorobenzyl)-8-[2-hydroxy-l-(hydroxymethyl)ethoxy]-6-(3-hydroxypropyl)- l-methyl-4-oxo-l,4-dihydro-3-quinolkiecarboxamide; (2) N-(4-chlorobenzyl)-8-lluoro-6-(hydroxymethyl)-4-oxo-l-[3-(tetrahydro-2H-pyran-2- yloxy)propyl]- 1 ,4-dihydro-3-quinolinecarboxamide:
(3) N-(4-chlorobenzyl)-6-[ethyl(2-hydroxyethyl)amino]-l-methyl-4-oxo 1 ,4-dihydro-3- quinolinecarboxamide ; (4) N-(4-chlorobenzyl)- 1 -cyclopropyl-6-(4-morphoϋnyknethyl)-4-oxo- 1 ,4-dihydro-3- qukiolkiecarboxamide;
(5) 6-{ [bis(2-hydroxyethyl)amino]methyl}-N-(4-chlorobenzyl)-l-methyl-4-oxo-l,4- dU ydro-3-quinoUnecarboxamide;
(6) N-(4-chlorobenzyl)-6-{ [(2-hydroxyethyl)(methyl)amino]methyl}- l-methyl-4-oxo- 1 ,4-dϋιydro-3-quinolkιecarboxamide;
(7) 6-((benzyl(2-hydroxyethyl)amino)methyl)-N-(4-chlorobenzyl)-l-methyl-4-oxo-l,4- dihydro-3-quinolinecarboxamide;
(8) N-(4-chlorobenzyl)-6-[(4,4-dUluoro- 1 -piperidinyl)methyl]- l-methyl-4-oxo- 1.4- dUιydro-3-quinoUnecarboxamide; (9) N-(4-chlorobenzyl)-6-{ [4-iluoro-3,6-dihydro-l (2H)-pyridmyl]methyl}- l-methyl-4- oxo- l,4-dihydro-3-quinolinecarboxamide: or a pharmaceuticaUy acceptable salt thereof.
68. A compound of claim 1 which is:
(1) N-(4-chlorobenzyl)-l-[2-(2-hydroxyethoxy)ethyl]-6-(3-hydroxy- l-propynyl)-4-oxo- 1 ,4-dihydro-3-quinoUnecarboxamide;
(2) N-(4-chlorobenzyl)-6-{ [[2-hydroxy-2-(4-hydroxyphenyl)ethyl] (methyl) amino] methyl } - 1 -methyl-4-oxo- 1 ,4-dihydro-3-quinoUnecarboxamide;
(3) N-(4-chlorobenzyl)-6-{ [[2-hydroxy-2-(4-hydroxy-3-methoxyphenyl) ethyl] (methyl)amino]methyl}-l-methyl-4-oxo-l,4-dihydro-3-quinoUnecarboxamide: (4) N-(4-chlorobenzyl)-6-[(3J-dihydroxy-l-azetidinyl)methyl]- l-methyl-4-oxo-l,4- dihydro-3-quinolinecarboxamide;
(5) N-(4-chlorobenzyl)-8-fluoro-6-[(Z)-3-hydroxy- 1 -propenyl]- 1 -methyl-4-oxo- 1 ,4- dihydro-3-quinofkiecarboxamide;
(6) N-(4-chlorobenzyl)-6-(3-hydroxy-l-propynyl)-l-[2-(4-morphoUnyl)ethyl]-4-oxo- 1 ,4-dmydro-3-quinoUnecarboxamide;
(7) N-(4-chlorobenzyl)-6-[(Z)-3-hydroxy- 1-propenyl]- 1 -methyl-4-oxo- 1 ,4-dihydro-3- quinoUnecarboxamide ; (8) N-(4-chlorobenzyl)- 1 -cyclopropyl-6-(3-hydroxy- 1 -propynyl)-4-oxo- 1 ,4-dihydro-3- quinoUnecarboxamide;
(9) N-(4-chlorobenzyl)-l-(2-hydroxyethyl)-6-(3-hydroxy-l-propynyl)-4-oxo-l,4- dkiydro-3-quinoUnecarboxamide; (10) N-(4-chlorobenzyl)-6-(3-hydroxy- 1 -propynyl)- 1 -methyl-4-oxo- 1 ,4-dihydro-3- qukiolinecarboxamide;
(1 1) N-(4-chlorobenzyl)-6-(3-hydroxy-l-propynyl)-l-[2-(2-methoxyethoxy)ethyl]-4- oxo-1 ,4-dihydro-3-quinoUnecarboxamide;
( 12) N-(4-chlorobenzyl)-6-(3-hydroxy- 1 -propynyl)- 1 -methyl-4-oxo- 1 ,4-dihydro-3- quinoUnecarbothioamide:
( 13) N-(4-chlorobenzyl)-8-(3-hydroxy- 1-propynyl)- 1 -methyl-4-oxo- 1 ,4-dihydro-3- quinolinecarboxamide;
( 14) N-(4-chlorobenzyl)-8-(4-hydroxy- 1 -butynyl)- 1 -methyl-4-oxo- 1 ,4-dihydro-3- quinoUnecarboxamide; (15) N-(4-chlorobenzyl)-l-methyl-4-oxo-6-(tetrahydro-2H-pyran-4-ylmethyl)-l,4- dihydro-3-quinoUnecarboxamide; or a pharmaceuticaUy acceptable salt thereof.
69. The compound of claim 1 which is:
( 1 ) N-(4-chlorobenzyl)- 1 -(4-morpholinyl)-6-(4-morpholinylmethyl)-4-oxo- 1 ,4-dihydro- 3-quinolinecarboxamide:
(2) l-amino-N-(4-chlorobenzyl)-6-(3-hydroxy-l-propynyl)-4-oxo-l,4-dihydro-3- quinolinecarboxamide;
(3) 1 -amino-N-(4-chlorobenzyl)-6-(3-hydroxypropyl)-4-oxo- 1 ,4-dihydro-3- quinoUnecarboxamide: (4) N-(4-bromobenzyl)- 1 -(4-morpholinyl)-6-(4-morpholinylmethyl)-4-oxo- 1 ,4-dihydro-
3-quinolinecarboxamide;
(5) N-(4-fluorobenzyl)-l-(4-morpholinyl)-6-(4-morpholinylmethyl)-4-oxo- 1 ,4-dihydro- 3-quinoUnecarboxamide: or a pharmaceuticaUy acceptable salt thereof.
70. The compound of claim 1 which is:
(1) N-(4-chlorobenzyl)-l-{ [(4-chlorophenyl)sulfanyl]methyl}-6-(4-morpholinylmethyl)- 4-oxo-l ,4-dUιydro-3-quinolkιecarboxamide; (2) N-(4-chlorobenzyl)-l-{ [(4-chlorophenyl)suUinyl]methyl}-6-(4-morphoUnylmethyl)- 4-oxo- 1 ,4-dUιydro-3-quinoUnecarboxamide:
(3) N-(4-chlorobenzyl)-l-[(2-methoxyethoxy)methyl]-6-(4-mo hoUnylmethyl)-4-oxo- 1 ,4-dihydro-3-quinolinecarboxamide; (4) 2-{ [3-{[(4-chlorobenzyl)amino]carbonyl}-6-(4-morpho inylmethyl)-4-oxo-l(4H)- qukιolinyl]methoxy} ethyl benzoate;
(5) N-(4-chlorobenzyl)-l-[(2-hydroxyethoxy)methyl]-6-(4-morphoUnyknethyl)-4-oxo- 1 ,4-dihydro-3-quinolinecarboxamide;
(6) N-(4-chlorobenzyl)-6-(4-morpholinyknethyl)-4-oxo- 1 -tetrahydro-2H-pyran-4-yl- 1 ,4-dUiydro-3-quinolinecarboxamide;
(7) N-(4-chlorobenzyl)- l-(l-methyl-4-piperidinyl)-6-(4-morphoUnylmethyl)-4-oxo-l,4- dihydro-3-quinoUnecarboxamide;
(8) N-(4-chlorobenzyl)-6-(4-morphoUnyknethyl)-4-oxo- 1 -(4-piperidinyl)- 1.4-dihydro-3- quinoUnecarboxamide; (9) N-(4-chlorobenzyl)-l-(lJ-dioxohexahydro-Uambda~6— thiopyran-4-yl)-6-(4- morpholkιylmethyl)-4-oxo- 1 ,4-dihydro-3-quinolinecarboxamide:
( 1 ) N- (4- chlorobenzyl)- 1 -(4-morpholkιyl)-6-(4-morphorkιyknethyl)-4-oxo- 1.4- dihydro-3-quinoUnecarboxamide:
(1 1) /V-(4-chlorobenzyl)-l-[2-(2-hydroxyethoxy)ethyl]-6-(4-morphoUnylmethyl)-4-oxo- 1 ,4-dihydro-3-quinoUnecarboxamide:
(12) N-(4-chlorobenzyl)-l-[2-(2-ethoxyethoxy)ethyl]-6-(4-morpholinylmethyl)-4-oxo- 1.4-dmydro-3-quino necarboxamide:
( 13) N-(4-chlorobenzyl)- 1 -[2-(ethylsuU"anyl)ethyl]-6-(4-morpholinylmethyl)-4-oxo- 1 ,4- dihydro-3-quinoUnecarboxamide: (14) N-(4-chlorobenzyl)-l-[3-(methylsuU'anyl)propyl]-6-(4-morphoUnyknethyl)-4-oxo- l,4-dUiydro-3-quinolinecarboxamide;
( 15) N-(4-chlorobenzyl)- 1 -(4-hydroxy-2-butynyl)-6-(4-morphoUnylmethyl)-4-oxo- 1 ,4- dihydro-3-quinoUnecarboxamide;
(16) 1 - { 2- [bis(2-hydroxyethyl)amk o]ethyl } -N-(4-chlorobenzyl)-6-(4- morpholinylmethyl)-4-oxo- 1.4-dihydro-3-qumoUnecarboxamide:
(17) N-(4-chlorobenzyl)-l-[3-(methylsuUinyl)propyl]-6-(4-morpholinyknethyl)-4-oxo- 1 ,4-dmydro-3-qumolinecarboxamide; (18) N-(4-chlorobenzyl)-l-{3-[(3-hydroxypropyl)suU'anyl]propyl}-6-(4- morphoUnylmethyl)-4-oxo- 1 ,4-dihydro-3-quinoUnecarboxamide;
(19) N-(4-chlorobenzyl)-l-[3-(methylsulfonyl)propyl]-6-(4-morpholinylmethyl)-4-oxo- 1 ,4-dUιydro-3-quinoUnecarboxamide: (20) N-(4-chlorobenzyl)- 1 -[2-(ethylsuUinyl)ethyl]-6-(4-morpholinylmethyl)-4-oxo- 1 ,4- dihydro-3-quinolinecarboxamide;
(21 ) N-(4-chlorobenzyl)- 1 -[2-(ethylsulfonyl)ethyl]-6-(4-morpholinylmethyl)-4-oxo- 1 ,4- dkiydro - 3 -quinoUnecarbo xamide ;
(22) N-(4-chlorobenzyl)-l-{3-[(3-hydroxypropyl)suU"onyl]propyl}-6-(4- morpholinylmethyl)-4-oxo- 1 ,4-dihydro-3-quinolinecarboxamide:
(23) N-(4-chlorobenzyl)-6-(4-morpholinylmethyl)-4-oxo-l-[2-(phenylsulfanyl)ethylJ- l ,4-dihydro-3-quinoUnecarboxamide:
(24) N-(4-chlorobenzyl)- 1 -[(methylsulfanyl)methyl]-6-(4-morpholinylmethyl)-4-oxo- l,4-dihydro-3-quinoUnecarboxamide: (25) N-(4-chlorobenzyl)-6-(4-morphoUnylmethyl)-4-oxo-l-[(phenylsuU"anyl)methyl]-
1 ,4-dmydro-3-quinoUnecarboxamide:
(26) N-(4-chlorobenzyl)- 1 -[(methylsulfinyl)methyll-6-(4-morphoUnylmethyl)-4-oxo- 1.4- dUιydro-3-quinolinecarboxamide;
(27) N-(4-chlorobenzyl)-l-[(methylsuU'onyl)methyl]-6-(4-morphoUnyknethyl)-4-oxo- 1 ,4-dU ydro-3-quinolinecarboxamide;
(28) N-(4-chlorobenzyl)-6-(4-morphoUnylmethyl)-4-oxo- 1 -[(phenylsuUinyl)methyl]- 1.4- dUiydro-3-quinoUnecarboxamide;
(29) N-(4-chlorobenzyl)-6-(4-morphoUnyknethyl)-4-oxo- l-[(phenylsuU'onyl)methyl]- 1 ,4-dihydro-3-quinolinecarboxamide; (30) N-(4-chlorobenzyl)- l-[2-(2-methoxyethoxy)ethyl]-6-(4-morphoUnylmethyl)-4-oxo-
1 ,4-dihydro-3-quinolinecarboxamide;
(31) l-{2-[2-(tert-butoxy)ethoxy]ethyl}-N-(4-chlorobenzyl)-6-(4-morpholinylmethyl)-4- oxo- 1 ,4-dmydro-3-quinolinecarboxamide;
(32) N-(4-chlorobenzyl)- 1 -cyclopropyl-6-(4-morpholinylmethyl)-4-oxo- 1 ,4-dihydro-3- quinolinecarboxamide ; or a pharmaceuticaUy acceptable salt thereof.
71. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceuticaUy acceptable carrier
72. A method for inhibiting a vkal DNA polymerase, comprising contacting the polymerase with an effective inhibitory amount of a compound of claim 1.
73. The method of claim 72 wherein the polymerase and the compound are contacted in vitro.
74. The method of claim 72 wherein the polymerase and the compound are contacted in vivo.
75. A method of treating infections from herpesvkuses which comprises administering to a patient in need thereof an effective amount of a compound of" formula I as shown in claim
1 .
76. The method of claim 75 wherein said herpesvkuses is herpes sknplex vkus types 1 , herpes simplex vkus types 2, variceUa zoster vkus, cytomegalovkus, Epstein-Barr vkus, human herpes vkuses 6, human herpes vkuses 7 or human herpes vkuses.
77. The method of claim 75 wherein said herpesvkuses is herpes simplex vkus types 1 , herpes simplex vkus types 2, variceUa zoster vkus, cytomegalovkus, Epstein-Barr vkus, human herpes vkuses 7 or human herpes vkuses.
78. The method of claim 75 wherein said herpesvkuses is human cytomegalovkus.
79. The method of claim 75 wherein the effective amount of a compound of claim 1 is administered oraUy, parenteraUy or topicaUy.
80. The method of claim 75 wherein the effective amount of" a compound of" claim 1 is in an amount of" from about 0.1 to about 300 mg/kg of body weight.
81. The method of claim 75 wherein the effective amount of a compound of claim 1 is in an amount of from about 1 to about 30 mg/kg of body weight.
PCT/US1999/027960 1999-01-08 1999-12-22 Quinolinecarboxamides as antiviral agents WO2000040561A1 (en)

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EA200100757A EA003945B1 (en) 1999-01-08 1999-12-22 Quinolinecarboxamides as antiviral agents
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KR1020017008629A KR20010101421A (en) 1999-01-08 1999-12-22 Quinolinecarboxamides as Antiviral Agents
JP2000592270A JP2002534416A (en) 1999-01-08 1999-12-22 Quinolinecarboxamide as an antiviral agent
EP99967145A EP1140850A1 (en) 1999-01-08 1999-12-22 Quinolinecarboxamides as antiviral agents
SK830-2001A SK8302001A3 (en) 1999-01-08 1999-12-22 Quinolinecarboxamides as antiviral agents
AU23486/00A AU760207B2 (en) 1999-01-08 1999-12-22 Quinolinecarboxamides as antiviral agents
CA002353636A CA2353636A1 (en) 1999-01-08 1999-12-22 Quinolinecarboxamides as antiviral agents
NZ512824A NZ512824A (en) 1999-01-08 1999-12-22 Quinolinecarboxamides as antiviral agents
IL14417199A IL144171A0 (en) 1999-01-08 1999-12-22 Quinolinecarboxamides as antiviral agents
NO20013383A NO20013383L (en) 1999-01-08 2001-07-06 Quinoline carboxamides as antiviral agents
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IL144171A0 (en) 2002-05-23
CN1333753A (en) 2002-01-30
ID29550A (en) 2001-09-06
BR9916772A (en) 2004-06-15
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CN1161336C (en) 2004-08-11
EP1140850A1 (en) 2001-10-10
CZ20012454A3 (en) 2002-03-13
TR200101906T2 (en) 2001-12-21
NZ512824A (en) 2003-09-26
EA200100757A1 (en) 2001-12-24
NO20013383L (en) 2001-09-07
HUP0200308A2 (en) 2002-06-29
EA003945B1 (en) 2003-10-30
US6248739B1 (en) 2001-06-19
SK8302001A3 (en) 2002-04-04

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