WO2011045084A1 - Quinolinyloxyphenylsulfonamides - Google Patents

Quinolinyloxyphenylsulfonamides Download PDF

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WO2011045084A1
WO2011045084A1 PCT/EP2010/006525 EP2010006525W WO2011045084A1 WO 2011045084 A1 WO2011045084 A1 WO 2011045084A1 EP 2010006525 W EP2010006525 W EP 2010006525W WO 2011045084 A1 WO2011045084 A1 WO 2011045084A1
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Prior art keywords
methoxy
quinolin
yloxy
phenyl
propoxy
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PCT/EP2010/006525
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French (fr)
Inventor
Axel Ullrich
Robert Torka
Yixiang Zhang
György Kéri
László ÖRFI
István Szabadkai
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MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V.
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Priority to EP10776309.6A priority Critical patent/EP2462117B1/en
Priority to US13/500,761 priority patent/US8685971B2/en
Priority to ES10776309.6T priority patent/ES2644083T3/en
Priority to CN201080046094.6A priority patent/CN102574804B/en
Priority to AU2010306003A priority patent/AU2010306003B2/en
Publication of WO2011045084A1 publication Critical patent/WO2011045084A1/en
Priority to HK12111861.9A priority patent/HK1171017A1/en
Priority to US14/202,951 priority patent/US9169241B2/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • 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
    • 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
    • C07D401/12—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 chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D405/12—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 chain containing hetero atoms as chain links
    • 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
    • C07D409/12—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 linked by a chain containing hetero atoms as chain links
    • 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
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to quinolinyloxyphenylsulfonamides and stereoisomeric forms, solvates, hydrates and/or pharmaceutically acceptable salts of these quinolinyloxyphenylsulfonamide compounds as well as pharmaceutical compositions containing at least one of these compounds together with at least one pharmaceutically acceptable carrier, excipient and/or diluent.
  • Said quinolinyloxyphenylsulfonamides are useful for prophylaxsis, treatment and/or after-treatment of hyperproliferative disorders, such as cancer, tumors and particularly cancer metastases.
  • PCT/EP2009/002798 refers to similar compounds which are inhibitors of receptor tyrosine kinases of the AXL receptor family. These compounds are suitable for the treatment or prevention of disorders associated with, accompanied by or caused by hyperfunction of a receptor of the AXL family.
  • the compounds of PCT/EP2009/002798 are suitable for the treatment of hyperproliferative disorders, such as cancer and particularly cancer metastases.
  • -R 3 , -R 4 , -R 5 , -R 6 are independently of each other selected from hydrogen, halogen, nitro, C-i- 6 alkyl, C 3 -Cio-cycloalkyl, d- 6 alkoxy, wherein the C-i- 6 alkyl, C 3 - Cio-cycloalkyl or C-i -6 alkoxy groups are optionally mono- or polysubstituted by hydroxyl, halogen, Ci -4 alkyl and/or Ci -4 alkoxy, wherein the C- M alkyl and/or Ci -4 alkoxy groups are optionally mono- or polysubstituted by hydroxyl and/or halogen.
  • -R 7 represents
  • a saturated or unsaturated three- to twelve-membered carbocyclic or heterocyclic ring system which is optionally mono- or polysubstituted by hydroxy, C-i- 6 alkyl, C 3 -Cio-cycloalkyl, C2- 6 alkenyl, C 2-6 alkynyl, Ci -6 alkoxy, a halogen atom, or a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group
  • the C-i -6 alkyl, C 3 -Ci 0 -cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, and Ci -6 alkoxy groups are optionally substituted by a halogen atom or a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group
  • C-i-6 alkyl or C-i-6 alkoxy which is unsubstituted or substituted by a saturated or unsaturated three- to twelve-membered carbocyclic or heterocyclic ring system which is optionally mono- or polysubstituted by hydroxy, C-i-6 alkyl, C 2- 6 alkenyl, C 2- 6 alkynyl, C 1-6 alkoxy, a halogen atom, or a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group, and the C-i-6 alkyl, C 2- 6 alkenyl, C 2- 6 alkynyl, and Ci_6 alkoxy groups are optionally substituted by a halogen atom or a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group,
  • a nitrogen atom substituted with a saturated or unsaturated three- to twelve- membered or heterocyclic ring system which is optionally mono- or polysubstituted by hydroxy, C -6 alkyl, C 2- 6 alkenyl, C 2- 6 alkynyl, d-6 alkoxy, a halogen atom, or a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group
  • the C 1-6 alkyl, C 2- 6 alkenyl, C 2- 6 alkynyl, and Ci -6 alkoxy groups are optionally substituted by a halogen atom or a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group
  • -R 8 represents hydrogen, hydroxyl, halogen, Ci -6 alkoxy, C-i-6 alkylcarbonyl, carboxyl, C3-Ci 0 -cycloalkyl, Ci-6 alkoxycarbonyl, a heterocyclic group, a heterocycloalkyl group with one or two heteroatoms selected from O, N, S and 2 to 6 carbon atoms, C 1-6 -alkyl, -NH-CO-NR 9 R 10 , -CO-NR 9 R 10 , -NR 9 R 10 ;
  • -R 9 and -R 10 are independently of each other selected from hydrogen, C3-C6- cycloalkyl, C-i -6 alkyl optionally substituted by hydroxyl, halogen and/or C- alkoxy or
  • -R 9 and -R 10 may combine with the nitrogen atom attached thereto to form a saturated or unsaturated five- or six-membered heterocyclic group, wherein the heterocyclic group is optionally substituted by hydroxyl, amino, halogen, -COOH, C-i-6 alkyl, C 2- 6 alkenyl, C 2-6 alkynyl, Ci-6 alkoxy, C-i-6 alkoxycarbonyl, C -6 alkylcarbonyl, C-i-6 acyloxy, a saturated or unsaturated three- to twelve-membered carbocyclic or heterocyclic ring system,
  • Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, Ci-6 alkoxy, C-i -6 alkoxycarbonyl, C-i-6 alkylcarbonyl and/or C -6 acyloxy groups are optionally substituted by hydroxyl, d-6 alkoxy, or a saturated or unsaturated three- to twelve-membered carbocyclic or heterocyclic ring system;
  • one or both hydrogen atoms on said amino group are optionally substituted by C-i-6 alkyl or a saturated or unsaturated three- to twelve- membered carbocyclic or heterocyclic ring system, and the C-i-6 alkyl group is optionally substituted by hydroxyl, C-i-6 alkoxy, or a saturated or unsaturated three- to twelve-membered carbocyclic or heterocyclic ring system;
  • saturated or unsaturated three- to twelve-membered carbocyclic or heterocyclic ring system is optionally substituted by hydroxyl, Ci -6 alkyl, C 2- 6 alkenyl, C 2 -6 alkynyl, C-i -6 alkoxy, C-i -6 alkoxycarbonyl, or a saturated or unsaturated three- to twelve-membered carbocyclic or heterocyclic ring system, wherein the C-i -6 alkyl, C 2- 6 alkenyl, and C 2- 6 alkynyl groups are optionally substituted by hydroxyl, C-i-6 alkoxy, or a saturated or unsaturated three- to twelve- membered carbocyclic or heterocyclic ring system; when the carbocyclic or heterocyclic group is substituted by two C-i-6 alkyl groups, the two alkyl groups may combine together to form an alkylene chain; and the carbocyclic or heterocyclic group may be condensed with another saturated or unsaturated five- to
  • -R 9 is selected from hydrogen, d-6-alkyl which is optionally substituted by hydroxyl, halogen and/or Ci -4 -alkoxy and -R 10 is selected from C-i-6-alkyl which is optionally substituted by hydroxyl, halogen and/or Ci -4 -alkoxy.
  • R 11 - R 22 represent independently of each other linear or branched, substituted or unsubstituted C C 2 o-alkyl, -H, -OH, -OCH 3 , -OC 2 H 5 , -OC 3 H 7 , -O-cyclo- C 3 H 5 , -OCH(CH 3 ) 2 , -OC(CH 3 ) 3 , -OC 4 H 9 , -OPh, -OCH 2 -Ph, -OCPh 3 , -SH, -SCH 3 , -SC 2 H 5 , -SC 3 H 7 , -S-cyclo-C 3 H 5 , -SCH(CH 3 ) 2 , -SC(CH 3 ) 3 , -NO 2 , -F, -CI, -Br, -I, -N 3 , -CN, -OCN, -NCO, -SCN, -NCS, -CHO, -
  • Ci-C 6 -alkyl refers to -CH 3 , -C 2 H 5 , -C 3 H 7 , -CH(CH 3 ) 2 , -C4H9, -CH 2 -CH(CH 3 ) 2 , -CH(CH 3 )-C 2 H 5 , -C(CH 3 ) 3 , -CH(CH 3 )-C 3 H 7 , -CH;>-CH(CH 3 )-C 2 H5, -CH(CH 3 )-CH(CH 3 ) 2 , -CsHu, -C(CH 3 ) 2 -C 2 H 5 , -CH2-C(CH 3 ) 3 , -CH(C 2 H 5 ) 2 , -C 2 H 4 -CH(CH 3 ) 2 , -C 6 H 13 , -C 3 H6-CH(CH 3 ) 2
  • C 3 -Cio-cycloalkyl or “carbocyclic group” refers to
  • -CH(C ⁇ CH)-C ⁇ C-CH 3 Preferred are -C ⁇ CH and -C ⁇ C-CH 3 .
  • aryl or “carbocyclic group” refers to phenyl, indenyl, indanyl, naphthyl, 1 ,2-dihydro-naphthyl, 2,3-dihydronaphthyl, 1 ,2,3,4- tetrahydronaphthyl (tetralinyl), fluorenyl, anthryl (anthracenyl), 9,10-dihydroanthryl, 1 ,2,3,4-tetrahydro-anthryl, 1 ,2,3,4,5,6,7,8-octahydro-anthryl, azulenyl, diphenylmethyl, benzyl, triphenylmethyl (trityl), styryl, naphthoquinonyl, acenaphthyl, anthraquinonyl, phenanthryl (phenanthrenyl) and especially to a mono- or bi
  • heteroaryl or “heterocyclic ring” or “heterocyclic group” refers to heteroaromatic groups which have from 5 to 10 ring atoms, from 1 to 4 of which are selected from O, N and/or S. Preferred groups have 1 or 2 heteroatoms in a 5- or 6-membered aromatic ring. Mono and bicyclic ring systems are included.
  • Typical heteroaryl groups which are at least partially aromatic include pyridyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, pyridazinyl, pyrimidyl, pyrazinyl, 1 ,3,5-triazinyl, ,2,3-triazolyl, 1 ,3,4-thiadiazolyl, indolizinyl, indolyl, isoindolyl, benzo[b]furyl, thiophenyl, benzo[b]thienyl, indazolyl, benzimidazolyl, benzthiazolyl, thiazolyl, purinyl, quinolizinyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, 1 ,8-naph
  • Said herteroaryl groups may further be substituted by one, two, three, four, five or more substituents selected from the group consisting of R 18 - R 30 , linear or branched C -C6-alkyl, C3-C6-cycloalkyl, linear or branched C2-C 6 -alkenyl, linear or branched C2 -alkynyl and aryl.
  • Preferred heterocyclic groups from which also R 7 can be selected are:
  • R to >27 are independently of each other selected from the substituents mentioned below.
  • Preferred heterocnch -NR 9 R 10 groups are:
  • Said preferred herteroaryl groups and heterocyclic groups may further be substituted by one, two, three, four, five or more substituents selected from the group consisting of R 23 - R 35 , linear or branched C-i-Ce-alkyl, C3-Cio-cycloalkyl, linear or branched C 2 -C6-alkenyl, linear or branched C 2 -C6-alkynyl and aryl.
  • heterocyclic group or “heterocyclic ring” or “heterocyclic ring system” or “heterocyclyl” refers to carbocycles having at least one heteroatom in the ring such as oxygen, nitrogen, or sulfur. Such heterocycles may be saturated or partially unsaturated but not aromatic.
  • heterocyclic residues are 1 ,3-dioxolane, benzo[1 ,3]dioxolyl, pyrazolinyl, pyranyl, thiomorpholinyl, pyrazolidinyl, piperidyl, piperazinyl, 1 ,4-dioxanyl, imidazolinyl, pyrrolinyl, imidazolidinyl, morpholinyl, 1 ,4-dithianyl, pyrrolidinyl, oxozolinyl, oxazolidinyl, isoxazolinyl, isoxazolidinyl, thiazolinyl, thiazolidinyl, isothiazolinyl, isothiazolidinyl, dihydropyranl, pyrrolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl.
  • Aryl refers to phenyl, substituted phenyl and heteroaryl, wherein substituted phenyl and heteroaryl have the meanings as defined above.
  • Ci-C 6 alkyloxy or "Ci-C 6 alkoxy” refers to the residue -O-C-i-C-6-alkyl, wherein C-i-C6-alkyl has the meanings as defined above.
  • the following C C6 alkoxy groups are preferred -O-CH 3) -O-C 2 H 5 , -O-C3H7, -0-CH(CH 3 ) 2 , -O-C 4 H 9) -0-CH 2 -CH(CH 3 ) 2 , -0-CH(CH 3 )-C 2 H 5 , -O-C(CH 3 ) 3 , and -0-C 5 Hn .
  • C-i-C 6 alkyloxycarbonyl or "C1-C6 alkoxycarbonyl” refers to the residue -CO-0-C-i-C 6 -alkyl, wherein CrC6-alkyl has the meanings as defined above.
  • Preferred C-i-C 6 alkoxycarbony groups are -CO-OCH 3 , -CO-OC2H5, -CO-OQ3H7, -CO-OCH(CH 3 ) 2 , -CO-OC 4 H 9 ,
  • Ci-C 6 alkylcarbonyl or "Ci-C 6 alkanoyl” or “Ci-C 6 acyl” refers to the residue -CO-Ci-C6-alkyl, wherein CrC 6 -alkyl has the meanings as defined above.
  • Preferred C-i-C 6 acyl groups are -CO-CH 3 , -CO-C 2 H 5 , -CO-C 3 H 7 , -CO-CH(CH 3 ) 2 , -CO-C 4 H 9 , -CO-CH 2 -CH(CH 3 ) 2 ,
  • C1-C6 alkylcarbonyloxy or "C1-C6 alkanoyloxy” or "Ci-C 6 acyloxy" refers to the residue -0-CO-Ci-C6-alkyl, wherein d-C6-alkyl has the meanings as defined above.
  • Preferred C1-C6 acyloxy groups are -O-CO-CH3, -O-CO-C2H5, -O-CO-C3H7, -O-CO-CH(CH 3 ) 2 , -O-CO-C 4 H 9 ,
  • substituted or "substituted alkyl”, “substituted cycloalkyl”, “substituted heterocyclyl”, “substituted aryl”, “substituted heteroaryl”, “substituted heterocyclic group”, “substituted carboicyclic group” respectively shall refer to the addressed residue such as “alkyl”, “cycloalkyl”, “heterocyclyl", “aryl”, or “heteroaryl” bearing one, two, three, four, five or more, preferably one or two substituents R 23 to R 35 independently selected from the following group:
  • Preferred residues R -X-O- are selected from:
  • the substituent -R 22 refers to the residues disclosed above and preferably to phenyl, benzyl, Ci-C 6 -alkyl, pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, -OH, -CH2-OH, -C2H4-OH, -OCH 3> -CH2-OCH3 or -C2H4-OCH3.
  • one of -R 1 and -R 2 represents -O-X-R 8 ;
  • -R 1 and -R 2 represents -H, -OH, -OCH 3 , -OCF3, -OC2H5, -OC3H7, -OCH2CH2-OCH3, -OCH 2 CH2-OC 2 H 5 ;
  • -X- represents -CR 11 R 12 -, -CR 11 R 12 -CR 13 R 14 -, -CR 11 R 12 -CR 13 R 14 -CR 15 R 16 - -CR 11 R 12 -CR 3 R 14 -CR 15 R 16 -CR 17 R 18 -, -CR 11 R 2 -CR 13 R 14 -CR 15 R 16 -CR 17 R 18 -, -CR 11 R 2 -CR 13 R 14 -CR 15 R 16 -CR 17 R 18 - CR 19 R 20_ I _ (C
  • -R 3 , -R 4 , -R 5 , -R 6 are independently of each other selected from -H, halogen, nitro, C-i-zralkyl, C 3 -C5-cycloalkyl, Ci -6 -alkoxy;
  • -R represents -H, -OH, -F, -CI, -Br, -I, -OCH 3 , -OC 2 H 5 , -OC 3 H 7 , -O- cyclo-C 3 H 5 , -OCH(CH 3 ) 2 , -OC(CH 3 ) 3 , -OC 4 H 9> -CHO, -COCH 3 , -COC 2 H 5 , -COC 3 H 7 , -CO-cyclo-C 3 H 5 , -COCH(CH 3 ) 2 , -COC(CH 3 ) 3 , -COOH, -cyclo- C 3 H 5) -cyclo
  • -R 9 and -R 10 are independently of each other selected from -H, -CH 2 F -CHF 2 , -CF 3 , -CH2CI, -CH 2 Br, -CH 2 -CH 2 F, -CH 2 -CH 2 CI, -CH 2 -CH 2 Br, -CH 3 , -C 2 H5, -C3H7, -CH(CH3) 2 , -C(CH3)3, -C4H9, -C5H11, -CH 2 -CH(CH 3 ) 2 , -CH(CH 3 )-C 2 H 5 , -C(CH 3 ) 3 , -cyclo-C 3 H 5l -cyclo-C 4 H 7 , -cyclo-C 5 H 9 , -cyclo-C 6 Hn;
  • R 1 - R 27 represent independently of each other -H, -OH, -OCH 3 , -OC 2 H 5 , -OC3H7, -O-cyclo-C 3 H 5 , -OCH(CH 3 ) 2 , -OC(CH 3 ) 3 , -OC 4 H 9 , -OCH 2 Ph, -OPh, -SH, -SCH 3 , -SC2H5, -NO2, -F, -CI, -Br, -I, -CN, -CHO, -COCH 3 , -COC2H5, -COC 3 H 7 , -CO-cyclo-C 3 H 5 , -COCH(CH 3 ) 2 , -COOH, -COOCH 3 , -COOC 2 H 5 , -COOC 3 H 7) -COO-cyclo-C 3 H 5) -COOCH(CH 3 ) 2 , -OOC-CH 3)
  • -R 1 is -O-X-R 8
  • -R 2 is preferably -H, -OCH 3 , -OCF 3 , -OC 2 H 5 and if -R 2 is -O-X-R 8 , than -R 1 is preferably -H, -OCH 3 , -OCF 3 , -OC 2 H 5 .
  • -R 3 , -R 4 , -R 5 , -R 6 are independently of each -OCH 3 , -OC 2 H 5 , -OC 3 H 7) -OCF 3 , -F, -CI, -Br, -I, -CH 3 , -C 2 H 5 , -C 3 H 7 , -cyclo-C 3 H 5 , -CH(CH 3 ) 2 , and more preferably -OCH 3 , -OC 2 H 5 , -OCF 3 , -F, -CI, -Br, -CH 3 , -C 2 H 5 .
  • At least one of -R 3 , -R 4 and -R 5 are selected from -F or -CI. It is also preferred if at least one of -R 3 and -R 4 is -F and preferably -R 3 is -F.
  • -R 7 is one of the following groups -CH 3 , -C 2 H 5 , -C 3 H 7 , -C 4 Hg, -C 5 Hn , Compounds wherein R 1 and R 2 are a methoxy group are excluded from the present application. Such compounds having the substitution pattern of the compounds disclosed herein have shown moderate to low activity or no activity and are consequently not preferred. Also compounds of general formula (I), wherein both groups R 1 and R 2 are ethoxy groups are still not preferred and could also be excluded from the present invention. However compounds wherein both of R 1 and R 2 represent propoxy, butoxy, pentoxy etc. have shown activity and belong to the compounds of the present invention and are consequently not excluded from the scope of protection.
  • Biphenyl-3-sulfonic acid (3-fluoro-4- ⁇ 6-methoxy-7-[3-(4-methyl-piperazin-1 -yl)- propoxy]-quinolin-4-yloxy ⁇ -phenyl)-amide
  • Butane-1 -sulfonic acid ⁇ 3-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)- quinolin-4-yloxy]-phenyl ⁇ -amide
  • the present invention also comprises pharmaceutically acceptable salts of the compounds according to the general formula (I), all stereoisomeric forms of the compounds according to the general formula (I) as well as solvates, especially hydrates or prodrugs thereof.
  • a prodrug is commonly described as an inactive or protected derivative of an active ingredient or a drug, which is converted to the active ingredient or drug in the body.
  • the inventive compounds bear basic and/or acidic substituents, they may form salts with organic or inorganic acids or bases.
  • suitable acids for such acid addition salt formation are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, oxalic acid, malonic acid, salicylic acid, p-aminosalicylic acid, malic acid, fumaric acid, succinic acid, ascorbic acid, maleic acid, sulfonic acid, phosphonic acid, perchloric acid, nitric acid, formic acid, propionic acid, gluconic acid, lactic acid, tartaric acid, hydroxymaleic acid, pyruvic acid, phenylacetic acid, benzoic acid, p-aminobenzoic acid, p-hydroxybenzoic acid, methanesulfonic acid, ethanesulfonic acid, nitrous acid, hydroxyethanesulfonic acid, ethylenesulfonic acid
  • the salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt in the conventional manner.
  • suitable inorganic or organic bases are, for example, NaOH, KOH, NH 4 OH, tetraalkylammonium hydroxide, lysine or arginine and the like.
  • Salts may be prepared in a conventional manner using methods well known in the art, for example by treatment of a solution of the compound of the general formula (I) with a solution of an acid, selected out of the group mentioned above.
  • Some of the compounds of the present invention may be crystallised or recrystallised from solvents such as aqueous and organic solvents. In such cases solvates may be formed.
  • This invention includes within its scope stoichiometric solvates including hydrates as well as compounds containing variable amounts of water that may be produced by processes such as lyophilisation.
  • Certain compounds of the general formula (I) may exist in the form of optical isomers, e.g. diastereoisomers and mixtures of isomers in all ratios, e.g. racemic mixtures.
  • the invention includes all such forms, in particular the pure isomeric forms.
  • the different isomeric forms may be separated or resolved one from the
  • ULA-P03071WO21 Application other by conventional methods, or any given isomer may be obtained by conventional synthetic methods or by stereospecific or asymmetric syntheses.
  • a compound according to the general formula (I) contains an alkene moiety, the alkene can be presented as a cis or trans isomer or a mixture thereof.
  • an isomeric form of a compound of the invention is provided substantially free of other isomers, it will preferably contain less than 5% w/w, more preferably less than 2% w/w and especially less than 1 % w/w of the other isomers.
  • Another aspect of the present invention relates to the use of the inventive quinolinyloxyphenylsulfonamide derivatives as drugs, i.d. as pharmaceutically active agents applicable in medicine.
  • the inventive quinolinyloxyphenylsulfonamides are useful for the treatment and/or prevention of AXL receptor tyrosine kinase induced disorders, wherein the AXL receptor tyrosine kinase induced disorders are selected from the group comprising hyperproliferative disorders, breast, colon, prostate, lung, gastric, ovarian, endometrial, renal, hepatocellular, thyroid, uterine cancer, esophageal carcinoma, squamous cell carcinoma, leukemia, osteosarcoma, melanoma, glioblastoma, and neuroblastoma.
  • the inventive quinolinyloxyphenylsulfonamides are useful for the preparation of a pharmaceutical formulation for prophylaxis, treatment and after- treatment cancer, tumors and cancer metastases.
  • the quinolinyloxyphenylsulfonamide compounds of the present invention can be used for prophylaxis and treatment of various cancer types and especially of cancer metastases.
  • the compounds of the present invention are useful for the treatment and after-treatment of various cancer types such as adenocarcinoma, choroidal melanoma, acute leukemia, acoustic neurinoma, ampullary carcinoma, anal carcinoma, astrocytoma, basal cell carcinoma, pancreatic cancer, desmoid tumor, bladder cancer, bronchial carcinoma, breast cancer, Burkitt's lymphoma, corpus cancer, CUP-syndrome (carcinoma of unknown primary), colorectal cancer, small intestine cancer, small intestinal tumors, ovarian cancer, endometrial carcinoma, ependymoma, epithelial cancer types, Ewing's tumors, gastrointestinal tumors, gastric cancer, gallbladder cancer, gall bladder carcinomas, uterine cancer, cervical cancer, cervix, glioblastomas, gynecologic tumors, ear, nose and throat tumors, hematologic neoplasias
  • ULA-P03071WO21 Application hypophysis tumor, carcinoids, Kaposi's sarcoma, laryngeal cancer, germ cell tumor, bone cancer, colorectal carcinoma, head and neck tumors (tumors of the ear, nose and throat area), colon carcinoma, craniopharyngiomas, oral cancer (cancer in the mouth area and on lips), cancer of the central nervous system, liver cancer, liver metastases, leukemia, eyelid tumor, lung cancer, lymph node cancer (Hodgkin's/Non-Hodgkin's), lymphomas, stomach cancer, malignant melanoma, malignant neoplasia, malignant tumors gastrointestinal tract, breast carcinoma, rectal cancer, medulloblastomas, melanoma, meningiomas, Hodgkin's disease, mycosis fungoides, nasal cancer, neurinoma, neuroblastoma, kidney cancer, renal cell carcinomas, non-Hodgkin's lymphomas
  • lung cancer lymph node cancer (Hodgkin's/Non-Hodgkin's), head and neck tumors (tumors of the ear, nose and throat area), breast cancer, ovarian cancer, gastric cancer, gastrointestinal tumors, intestinal tumors.
  • Another aspect of the present invention is directed to the use of at least one quinolinyloxyphenylsulfonamide compound and/or pharmaceutically acceptable salts thereof for the preparation of a pharmaceutical formulation for prophylaxis, treatment and/or after-treatment of cancer, tumors and especially cancer metastases.
  • Still another aspect of the present invention is directed to pharmaceutical compositions comprising at least one quinolinyloxyphenylsulfonamide compound of the present invention as active ingredient, together with at least one pharmaceutically acceptable carrier, excipient and/or diluents.
  • the pharmaceutical compositions of the present invention can be prepared in a conventional solid or liquid carrier or diluent and a conventional pharmaceutically- made adjuvant at suitable dosage level in a known way.
  • the preferred preparations are adapted for oral application.
  • These administration forms include, for example, pills, tablets, film tablets, coated tablets, capsules, powders and deposits.
  • the present invention also includes pharmaceutical preparations for parenteral application, including dermal, intradermal, intragastral, intracutan, intravasal, intravenous, intramuscular, intraperitoneal, intranasal, intravaginal, intrabuccal, percutan, rectal, subcutaneous, sublingual, topical, or transdermal application, which preparations in addition to typical vehicles and/or diluents contain at least one compound according to the present invention and/or a pharmaceutical acceptable salt thereof as active ingredient.
  • compositions according to the present invention containing at least one compound according to the present invention, and/or a pharmaceutical acceptable salt thereof as active ingredient will typically be administered together with suitable carrier materials selected with respect to the intended form of administration, i.e. for oral administration in the form of tablets, capsules (either solid filled, semi-solid filled or liquid filled), powders for constitution, extrudates, deposits, gels, elixirs, dispersable granules, syrups, suspensions, and the like, and consistent with conventional pharmaceutical practices.
  • suitable carrier materials selected with respect to the intended form of administration, i.e. for oral administration in the form of tablets, capsules (either solid filled, semi-solid filled or liquid filled), powders for constitution, extrudates, deposits, gels, elixirs, dispersable granules, syrups, suspensions, and the like, and consistent with conventional pharmaceutical practices.
  • the active drug component may be combined with any oral non-toxic pharmaceutically acceptable carrier, preferably with an inert carrier like lactose, starch, sucrose, cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, talc, mannitol, ethyl alcohol (liquid filled capsules) and the like.
  • suitable binders, lubricants, disintegrating agents and coloring agents may also be incorporated into the tablet or capsule.
  • Powders and tablets may contain about 5 to about 95 weight % of the quinolinyloxyphenylsulfonamide compound and/or the respective pharmaceutically active salt as active ingredient.
  • Suitable binders include starch, gelatin, natural sugars, corn sweeteners, natural and synthetic gums such as acacia, sodium alginate, carboxymethylcellulose, polyethylene glycol and waxes.
  • suitable lubricants there may be mentioned boric acid, sodium benzoate, sodium acetate, sodium chloride, and the like.
  • Suitable disintegrants include starch, methylcellulose, guar gum, and the like. Sweetening and flavoring agents as well as preservatives may also be included, where appropriate. The disintegrants, diluents, lubricants, binders etc. are discussed in more detail below.
  • compositions of the present invention may be formulated in sustained release form to provide the rate controlled release of any one or more of the components or active ingredients to optimise the therapeutic effect(s), e.g. antihistaminic activity and the like.
  • Suitable dosage forms for sustained release include tablets having layers of varying disintegration rates or controlled release polymeric matrices impregnated with the active components and shaped in tablet form or capsules containing such impregnated or encapsulated porous polymeric matrices.
  • Liquid form preparations include solutions, suspensions, and emulsions.
  • Liquid form preparations may also include solutions for intranasal administration.
  • Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be present in combination with a pharmaceutically acceptable carrier such as an inert, compressed gas, e.g. nitrogen.
  • a pharmaceutically acceptable carrier such as an inert, compressed gas, e.g. nitrogen.
  • a low melting fat or wax such as a mixture of fatty acid glycerides like cocoa butter is melted first, and the active ingredient is then dispersed homogeneously therein e.g. by stirring. The molten, homogeneous mixture is then poured into conveniently sized moulds, allowed to cool, and thereby solidified.
  • solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration.
  • liquid forms include solutions, suspensions, and emulsions.
  • the compounds according to the present invention may also be delivered transdermally.
  • the transdermal compositions may have the form of a cream, a lotion, an aerosol and/or an emulsion and may be included in a transdermal patch of the matrix or reservoir type as is known in the art for this purpose.
  • capsule refers to a specific container or enclosure made e.g. of methyl cellulose, polyvinyl alcohols, or denatured gelatins or starch for holding or containing compositions comprising the active ingredient(s).
  • Capsules with hard shells are typically made of blended of relatively high gel strength gelatins from bones or pork skin.
  • the capsule itself may contain small amounts of dyes, opaquing agents, plasticisers and/or preservatives.
  • Under tablet a compressed or moulded solid dosage form is understood which comprises the active ingredients with suitable diluents.
  • the tablet may be prepared by compression of mixtures or granulations obtained by wet granulation, dry granulation, or by compaction well known to a person of ordinary skill in the art.
  • Oral gels refer to the active ingredients dispersed or solubilised in a hydrophilic semi-solid matrix.
  • Powders for constitution refers to powder blends containing the active ingredients and suitable diluents which can be suspended e.g. in water or in juice.
  • Suitable diluents are substances that usually make up the major portion of the composition or dosage form. Suitable diluents include sugars such as lactose, sucrose, mannitol, and sorbitol, starches derived from wheat, corn rice, and potato, and celluloses such as microcrystalline cellulose.
  • the amount of diluent in the composition can range from about 5 to about 95 % by weight of the total composition, preferably from about 25 to about 75 weight %, and more preferably from about 30 to about 60 weight %.
  • disintegrants refers to materials added to the composition to support break apart (disintegrate) and release the pharmaceutically active ingredients of a medicament.
  • Suitable disintegrants include starches, "cold water soluble" modified starches such as sodium carboxymethyl starch, natural and synthetic gums such as locust bean, karaya, guar, tragacanth and agar, cellulose derivatives such as methylcellulose and sodium carboxymethylcellulose, microcrystalline celluloses, and cross-linked microcrystalline celluloses such as sodium croscaramellose, alginates such as alginic acid and sodium alginate, clays such as bentonites, and effervescent mixtures.
  • the amount of disintegrant in the composition may range from about 2 to about 20 weight % of the composition, more preferably from about 5 to about 10 weight %.
  • Binders are substances which bind or "glue” together powder particles and make them cohesive by forming granules, thus serving as the "adhesive" in the formulation. Binders add cohesive strength already available in the diluent or bulking agent. Suitable binders include sugars such as sucrose, starches derived from wheat corn rice and potato, natural gums such as acacia, gelatin and tragacanth, derivatives of seaweed such as alginic acid, sodium alginate and ammonium calcium alginate, cellulose materials such as methylcellulose, sodium carboxymethylcellulose and hydroxypropylmethylcellulose, polyvinylpyrrolidone, and inorganic compounds such as magnesium aluminum silicate. The amount of binder in the composition may range from about 2 to about 20 weight % of the composition, preferably from about 3 to about 10 weight %, and more preferably from about 3 to about 6 weight %.
  • Lubricants refer to a class of substances which are added to the dosage form to enable the tablet granules etc. after being compressed to release from the mould
  • Suitable lubricants include metallic stearates such as magnesium stearate, calcium stearate, or potassium stearate, stearic acid, high melting point waxes, and other water soluble lubricants such as sodium chloride, sodium benzoate, sodium acetate, sodium oleate, polyethylene glycols and D,L-leucine. Lubricants are usually added at the very last step before compression, since they must be present at the surface of the granules.
  • the amount of lubricant in the composition may range from about 0.2 to about 5 weight % of the composition, preferably from about 0.5 to about 2 weight %, and more preferably from about 0.3 to about 1.5 weight % of the composition.
  • Glidents are materials that prevent caking of the components of the pharmaceutical composition and improve the flow characteristics of granulate so that flow is smooth and uniform.
  • Suitable glidents include silicon dioxide and talc.
  • the amount of glident in the composition may range from about 0.1 to about 5 weight % of the final composition, preferably from about 0.5 to about 2 weight %.
  • Coloring agents are excipients that provide coloration to the composition or the dosage form. Such excipients can include food grade dyes adsorbed onto a suitable adsorbent such as clay or aluminum oxide.
  • the amount of the coloring agent may vary from about 0.1 to about 5 weight % of the composition, preferably from about 0.1 to about 1 weight %.
  • Method B Waters X Waters XBridge C18 (5cm x 4.6mm, 3.5um), gradient 0-95% B (0.00 min 5 % B, 0.50 min 5 % B, 5.50 min 95 % B, 6.00 min 95 %
  • Mass spectra were obtained using Waters SQD MS detector (Ionization: ES7ES " , Source block temp: 1 10 C, Desolvation temp: 250 °C, Desolvation Gas: 500 L/h, Cone Gas: 80 L/h, Capillary: 3000 V, Cone: 30 V, Extractor: 6 V, Rf Lens: 0.1 V, Scan: 80 to 1000 m/z in 1 sec, Inter-scan delay: 0.1 s).
  • TLC Thin-layer chromatography
  • R 2 has the meanings as disclosed herein and is, for instance, -OCH 3 .
  • R 1 has the meanings as disclosed herein and is, for instance, -OCH 3 .
  • the D' compound can be prepared in the similar manner as described patent US 2005/0029264, Example 13 (Atsushi Miwa et al.).
  • General Method 2 Starting from aniline derivatives
  • R 2 has the meanings as disclosed herein and is, for instance, -OCH 3 .
  • compounds, showed in Reaction Scheme can be prepared according to the described literature.
  • R 2 is a hydrogen atom
  • Example 1 Lidstrom Kyle et al.
  • benzyloxy group is at the position 6 in the quinoline ring and can be prepared in the similar manner [WO 2005/032484, Example 2 (Lindstrom Kyle et al.)]:
  • Butane-1 -sulfonic acid ⁇ 3-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)- quinolin-4-yloxy]-phenyl ⁇ -amide

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Abstract

The present invention relates to quinolinyloxyphenylsulfonamides and stereoisomeric forms, solvates, hydrates and/or pharmaceutically acceptable salts of these quinolinyloxyphenylsulfonamide compounds as well as pharmaceutical compositions containing at least one of these compounds together with at least one pharmaceutically acceptable carrier, excipient and/or diluent. Said quinolinyloxyphenylsulfonamides are useful for prophylaxsis, treatment and/or after-treatment of hyperproliferative disorders, such as cancer, tumors and particularly cancer metastases.

Description

Quinolinyloxyphenylsulfonamides
Specification
The present invention relates to quinolinyloxyphenylsulfonamides and stereoisomeric forms, solvates, hydrates and/or pharmaceutically acceptable salts of these quinolinyloxyphenylsulfonamide compounds as well as pharmaceutical compositions containing at least one of these compounds together with at least one pharmaceutically acceptable carrier, excipient and/or diluent. Said quinolinyloxyphenylsulfonamides are useful for prophylaxsis, treatment and/or after-treatment of hyperproliferative disorders, such as cancer, tumors and particularly cancer metastases.
Background of the invention
The international patent application PCT/EP2009/002798 refers to similar compounds which are inhibitors of receptor tyrosine kinases of the AXL receptor family. These compounds are suitable for the treatment or prevention of disorders associated with, accompanied by or caused by hyperfunction of a receptor of the AXL family. The compounds of PCT/EP2009/002798 are suitable for the treatment of hyperproliferative disorders, such as cancer and particularly cancer metastases.
It is object of the present invention to provide further compounds and pharmaceutically acceptable salts thereof which can be used as pharmaceutically active agents, especially for prophylaxis, treatment and after-treatment of cancer, tumors and particularly cancer metastases.
The object of the present invention is solved by the teaching of the independent claims. Further advantageous features, aspects and details of the invention are evident from the dependent claims, the description, and the examples of the present application.
The novel quinolinyloxyphenylsulfonamides according to the present invention are represented by the following general formula (I)
Figure imgf000003_0001
if -R1 represents -O-X-R8 than -R2 represents -H, -OH, -OCH3,
-OCF3, -OC2H5, -OC3H7, -OCH2CH2-OCH3, -OCH2CH2-OC2H5;
if -R2 represents -O-X-R8 than -R1 represents -H, -OH, -OCH3,
-OCF3, -OC2H5, -OC3H7, -OCH2CH2-OCH3, -OCH2CH2-OC2H5; -X- represents -CR1 R12-, -CR11R12-CR 3R14-, -CR11R12-CR13R14-CR15R16- -CR11R12-CR13R14-CR15R16-CR17R18-, -CR1 R12-CR 3R14-CR15R16-CR 7R18- CRi9R20_j _CR R12-CR13R14-CR15R 6-CR17R18-CR19R20-CR21R22-, -(CH2)n- NH-, -CO-, -(CH2)n-CO-, -(CH2)n-NH-CO-NH- -(CH2)n-NH-CO-, -(CH2)n-NH-CO-O-, -(CH2)n-CO-NH-, -(CH2)n-O-CO-NH-, -(CH2)n-O-CO- -(CH2)n-O-, -(CH2)n-; n is an integer selected from 1 , 2, 3, 4, 5 and 6;
-R3, -R4, -R5, -R6 are independently of each other selected from hydrogen, halogen, nitro, C-i-6 alkyl, C3-Cio-cycloalkyl, d-6 alkoxy, wherein the C-i-6 alkyl, C3- Cio-cycloalkyl or C-i-6 alkoxy groups are optionally mono- or polysubstituted by hydroxyl, halogen, Ci-4 alkyl and/or Ci-4 alkoxy, wherein the C-M alkyl and/or Ci-4 alkoxy groups are optionally mono- or polysubstituted by hydroxyl and/or halogen. -R7 represents
(i) a saturated or unsaturated three- to twelve-membered carbocyclic or heterocyclic ring system which is optionally mono- or polysubstituted by hydroxy, C-i-6 alkyl, C3-Cio-cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 alkoxy, a halogen atom, or a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group, and the C-i-6 alkyl, C3-Ci0-cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, and Ci-6 alkoxy groups are optionally substituted by a halogen atom or a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group,
(ii) C-i-6 alkyl or C-i-6 alkoxy which is unsubstituted or substituted by a saturated or unsaturated three- to twelve-membered carbocyclic or heterocyclic ring system which is optionally mono- or polysubstituted by hydroxy, C-i-6 alkyl, C2-6 alkenyl, C2- 6 alkynyl, C1-6 alkoxy, a halogen atom, or a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group, and the C-i-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and Ci_6 alkoxy groups are optionally substituted by a halogen atom or a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group,
(iii) a nitrogen atom substituted with a saturated or unsaturated three- to twelve- membered or heterocyclic ring system which is optionally mono- or polysubstituted by hydroxy, C -6 alkyl, C2-6 alkenyl, C2-6 alkynyl, d-6 alkoxy, a halogen atom, or a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group, and the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and Ci-6 alkoxy groups are optionally substituted by a halogen atom or a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group,
-R8 represents hydrogen, hydroxyl, halogen, Ci-6 alkoxy, C-i-6 alkylcarbonyl, carboxyl, C3-Ci0-cycloalkyl, Ci-6 alkoxycarbonyl, a heterocyclic group, a heterocycloalkyl group with one or two heteroatoms selected from O, N, S and 2 to 6 carbon atoms, C1-6-alkyl, -NH-CO-NR9R10, -CO-NR9R10, -NR9R10;
-R9 and -R10 are independently of each other selected from hydrogen, C3-C6- cycloalkyl, C-i-6 alkyl optionally substituted by hydroxyl, halogen and/or C- alkoxy or
-R9 and -R10 may combine with the nitrogen atom attached thereto to form a saturated or unsaturated five- or six-membered heterocyclic group, wherein the heterocyclic group is optionally substituted by hydroxyl, amino, halogen, -COOH, C-i-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 alkoxy, C-i-6 alkoxycarbonyl, C -6 alkylcarbonyl, C-i-6 acyloxy, a saturated or unsaturated three- to twelve-membered carbocyclic or heterocyclic ring system,
wherein the Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 alkoxy, C-i-6 alkoxycarbonyl, C-i-6 alkylcarbonyl and/or C -6 acyloxy groups are optionally substituted by hydroxyl, d-6 alkoxy, or a saturated or unsaturated three- to twelve-membered carbocyclic or heterocyclic ring system;
wherein in the amino group one or both hydrogen atoms on said amino group are optionally substituted by C-i-6 alkyl or a saturated or unsaturated three- to twelve- membered carbocyclic or heterocyclic ring system, and the C-i-6 alkyl group is optionally substituted by hydroxyl, C-i-6 alkoxy, or a saturated or unsaturated three- to twelve-membered carbocyclic or heterocyclic ring system;
wherein the saturated or unsaturated three- to twelve-membered carbocyclic or heterocyclic ring system is optionally substituted by hydroxyl, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C-i-6 alkoxy, C-i-6 alkoxycarbonyl, or a saturated or unsaturated three- to twelve-membered carbocyclic or heterocyclic ring system, wherein the C-i-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl groups are optionally substituted by hydroxyl, C-i-6 alkoxy, or a saturated or unsaturated three- to twelve- membered carbocyclic or heterocyclic ring system; when the carbocyclic or heterocyclic group is substituted by two C-i-6 alkyl groups, the two alkyl groups may combine together to form an alkylene chain; and the carbocyclic or heterocyclic group may be condensed with another saturated or unsaturated five- to seven- membered carbocyclic or heterocyclic group to form a bicyclic group.
Preferably -R9 is selected from hydrogen, d-6-alkyl which is optionally substituted by hydroxyl, halogen and/or Ci-4-alkoxy and -R10 is selected from C-i-6-alkyl which is optionally substituted by hydroxyl, halogen and/or Ci-4-alkoxy. R11 - R22 represent independently of each other linear or branched, substituted or unsubstituted C C2o-alkyl, -H, -OH, -OCH3, -OC2H5, -OC3H7, -O-cyclo- C3H5, -OCH(CH3)2, -OC(CH3)3, -OC4H9, -OPh, -OCH2-Ph, -OCPh3, -SH, -SCH3, -SC2H5, -SC3H7, -S-cyclo-C3H5, -SCH(CH3)2, -SC(CH3)3, -NO2, -F, -CI, -Br, -I, -N3, -CN, -OCN, -NCO, -SCN, -NCS, -CHO, -COCH3, -COC2H5, -COC3H7, -CO-cyclo-C3H5, -COCH(CH3)2, -COC(CH3)3, -COOH, -COCN, -COOCH3, -COOC2H5, -COOC3H7, -COO-cyclo-C3H5, -COOCH(CH3)2, -COOC(CH3)3, -OOC-CH3, -OOC-C2H5, -OOC-C3H7, -OOC-cyclo-C3H5, -OOC-CH(CH3)2, -OOC-C(CH3)3> -CONH2, -CONHCH3, -CONHC2H5, -CONHC3H7, -CONH-cyclo-C3H5, -CONH[CH(CH3)2], -CONH[C(CH3)3], -CON(CH3)2, -CON(C2H5)2, -CON(C3H7)2,
-CON(cyclo-C3H5)2, -CON[CH(CH3)2]2, -CON[C(CH3)3]2, -NH2, -NHCH3, -NHC2H5, -NHC3H7, -NH-cyclo-C3H5, -NHCH(CH3)2, -NHC(CH3)3, -N(CH3)2, -N(C2H5)2, -N(C3H7)2, -N(cyclo-C3H5)2, -N[CH(CH3)2]2, -N[C(CH3)3]2, -SOCH3, -SOC2H5, -SOC3H7, -SO-cyclo-C3H5, -SOCH(CH3)2, -SOC(CH3)3l -SO2CH3, -SO2C2H5, -SO2C3H7, -SO2-cyclo-C3H5, -SO2CH(CH3)2, -SO2C(CH3)3, -SO3H, -SO3CH3, -OCHF2, -SO3C2H5, -SO3C3H7, -SO3-cyclo-C3H5, -SO3CH(CH3)2, -SO3C(CH3)3, -OCF3, -OC2F5, -O-COOCH3, -O-COOC2H5, -O-COOC3H7, -O-COO-cyclo-C3H5,
ULA-P03071WO21 Application -0-COOCH(CH3)2, -0-COOC(CH3)3, -NH-CO-NH2, -NH-CO-NHCH3, -NH-CO-NHC2H5, -NH-CO-NHC3H7( -NH-CO-NH-cyclo-C3H5,
-NH-CO-NH[CH(CH3)2], -NH-CO-NH[C(CH3)3], -NH-CO-N(CH3)2>
-NH-CO-N(C2H5)2, -NH-CO-N(C3H7)2, -NH-CO-N(cyclo-C3H5)2, -NH-CO-N[CH(CH3)2]2) -NH-CO-N[C(CH3)3]2, -NH-CS-NH2,
-NH-CS-NH-cyclo-C3H5, -NH-CS-NHC3H7> -NH-CS-NH[CH(CH3)2], -NH-CS-NH[C(CH3)3], -NH-CS-N(CH3)2, -NH-CS-N(C2H5)2,
-NH-CS-N(C3H7)2, -NH-CS-N(cyclo-C3H5)2, -NH-CS-N[CH(CH3)2]2, -NH-CS-N[C(CH3)3]2, -NH-C(=NH)-NH2, -NH-C(=NH)-NHCH3, -NH-C(=NH)-NHC2H5, -NH-CS-NHC2H5, -NH-C(=NH)-NHC3H7,
_NH-C(=NH)-NH-cyclo-C3H5, -NH-C(=NH)-NH[CH(CH3)2], _NH-C(=NH)-NH[C(CH3)3]I -NH-CS-NHCH3, -NH-C(=NH)-N(CH3)2, -NH-C(=NH)-N(C2H5)2) -NH-C(=NH)-N(C3H7)2, -NH-C(=NH)-N(cyclo-C3H5)2, -NH-C(=NH)-N[CH(CH3)2]2l -NH-C(=NH)-N[C(CH3)3]2, -O-CO-NH2, -0-CO-NHCH3, -O-CO-NHC2H5, -O-CO-NHC3H7, -O-CO-NH-cyclo-C3H5, -O-CO-NH[CH(CH3)2], -0-CO-NH[C(CH3)3], -0-CO-N(CH3)2,
-0-CO-N(C2H5)2, -O-CO-N(C3H7)2) -O-CO-N(cyclo-C3H5)2,
-0-CO-N[CH(CH3)2]2, -0-CO-N[C(CH3)3]2, -O-CO-OCH3, -O-CO-OC2H5, -O-CO-OC3H7, -0-CO-0-cyclo-C3H5, -O-CO-OCH(CH3)2) -0-CO-OC(CH3)3, -CH2F -CHF2) -CF3, -CH2CI, -CHCI2, -CCI3, -CH2Br -CHBr2) -CBr3l -CH2I -CHI2) -Cl3, -CH2-CH2F -CH2-CHF2, -CH2-CF3, -CH2-CH2CI, -CH2-CHCI2, -CH2-CCI3, -CH2-CH2Br -CH2-CHBr2, -CH2-CBr3, -CH2-CH2I, -CH2-CHI2, -CH2-CI3, -CH3, -C2H5) -C3H7, -cyclo-C3H5, -CH(CH3)2, -C(CH3)3, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -Ph, -CH2-Ph, -CPh3, -CH=CH2, -CH2-CH=CH2, -C(CH3)=CH2, -CH=CH-CH3, -C2H4-CH=CH2, -CH=C(CH3)2, -C≡CH, -C≡C-CH3, -CH2-C≡CH, -Si(CH3)3) and stereoisomeric forms, solvates, hydrates and/or pharmaceutically acceptable salts thereof. As used herein, the term "C1-6 alkyl" or "linear or branched Ci-C6-alkyl" refers to -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -CH(CH3)-C3H7, -CH;>-CH(CH3)-C2H5, -CH(CH3)-CH(CH3)2, -CsHu, -C(CH3)2-C2H5, -CH2-C(CH3)3, -CH(C2H5)2, -C2H4-CH(CH3)2, -C6H13, -C3H6-CH(CH3)2, -C2H4-CH(CH3)-C2H5, -CH(CH3)-C4H9, -CH2-CH(CH3)-C3H7, -CH(CH3)-CH2-CH(CH3)2, -CH(CH3)-CH(CH3)-C2H5j -CH2-CH(CH3)-CH(CH3)2, -CH2-C(CH3)2-C2H5, -C(CH3)2-C3H7,
-C{CH3)2-CH{CH3)2, -C2H4-C(CH3)3, and -CH(CH3)-C(CH3)3, wherein in the afore-mentioned groups one or more hydrogen atoms can be replaced by -OH, -OCH3, -OC2H5, -SH, -SCH3, -SC2H5, -NO2, -F, -CI, -Br, -I, -N3, -COCH3, -COC2H5, -COOCH3, -COOC2H5, -OOC-CH3, -OOC-C2H5, -COOH, -CONH2, -CON(CH3)2, -CON(C2H5)2, -NH2, -NHCH3, -NHC2H5, -N(CH3)2, -N(C2H5)2, -SOCH3, -SOC2H5, -SO3H, -OCF3, -CF3, -C≡CH. Preferred are -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5i -C(CH3)3, and -C5Hn. Especially preferred are -CH3, -C2H5, -C3H7.
As used herein, the term "C3-Cio-cycloalkyl" or "carbocyclic group" refers to
Figure imgf000007_0001
Prefferred are the following cycloalkyls:
Figure imgf000007_0002
As used herein, the term "C2-6 alkenyl" or "linear or branched C2-C6-alkenyl" refers to -CH=CH2, -CH2-CH=CH2, -CH=CH-CH3, -C2H4-CH=CH2, -CH=CH-C2H5 -CH2-C(CH3)=CH2, -CH(CH3)-CH=CH, -CH=C(CH3)2, -C(CH3)=CH-CH3 — CH=CH— CH=CH2,— C3H6- CH=CH2, — C2H4— CH=CH— CH3, — CH^ CH=CH— C2Hs
■CH— CH— C3H7, 2— CH— CH— CH— CH2, -CH=CH-CH=CH-CH3 CH=CH-CH2-CH=CH2 -C(CH3)=CH-CH=CH2, -CH=C(CH3)-CH=CH2 ■CH=CH-C(CH3)=CH2, -C2H4-C(CH3)=CH2, -CH2-CH(CH3)-CH=CH2 ■CH(CH3)-CH2-CH=CH -CH2-CH=C(CH3)2, -CH2-C(CH3)=CH-CH3 •CH(CH3)-CH=CH-CH3 -CH=CH-CH(CH3)2, -CH=C(CH3)-C2H5 •C(CH3)=CH-C2H5, -C(CH3)=C(CH3)2, -C(CH3)2-CH=CH2 CH(CH3)-C(CH3)=CH2, -C(CH3)=CH-CH=CH2, -CH=C(CH3)-CH=CH2 CH=CH-C(CH3)=CH2, — C4H8_ CH=CH2, — C3H(5— CH=CH— CH3 •C2H4— CH=CH— C2H5, — CH2— CH=CH— C3H7, — CH=CH— C4Hg
-C3H6-C(CH3)=CH2, -C2H4-CH(CH3)-CH=CH2, -CH2-CH(CH3)-CH2-CH=CH2 -CH2-CH=CH-CH3) -CH(CH3)-C2H4-CH=CH2, -C2H4-CH=C(CH3)2
-C2H4-C(CH3)=CH-CH3, -CH2-CH(CH3)-CH=CH-CH3 -CH(CH3)-CH2-CH=CH-CH3, -C(CH3)=CH2, -CH2-CH=CH-CH(CH3)2 -CH2-CH=C(CH3)-C2H5, -CH2-C(CH3)=CH-C2H5, -CH(CH3)-CH=CH-C2H5 -CH=CH-CH2-CH(CH3)2, -CH=CH-CH(CH3)-C2H5, -CH=C(CH3)-C3H7 -C(CH3)=CH-C3H7, -CH2-CH(CH3)-C(CH3)=CH2) -CH(CH3)-CH2-C(CH3)=CH2 -CH(CH3)-CH(CH3)-CH=CH2, -CH2-C(CH3)2-CH=CH2, -C(CH3)2-CH2-CH=CH2 -CH2-C(CH3)=C(CH3)2, -CH(CH3)-CH=C(CH3)2, -C(CH3)2-CH=CH-CH3 -CH(CH3)-C(CH3)=CH-CH3, -CH=C(CH3)-CH(CH3)2, -C(CH3)=CH-CH(CH3)2 -C(CH3)=C(CH3)-C2H5, -C(CH3)2-C(CH3)=CH2, -CH(C2H5)-C(CH3)=CH2 -C(CH3)(C2H5)-CH=CH2, -CH(CH3)-C(C2H5)=CH2, -CH2-C(C2H5)=CH-CH3 -C[CH2-CH(CH3)2]=CH2, -C2H4-CH=CH-CH=CH2 -CH2-CH=CH-CH2-CH=CH2, -CH=CH-C2H4-CH=CH2, -CH=CH-C(CH3)3 -CH2-CH=CH-CH=CH-CH3, -CH=CH-CH2-CH=CH-CH3 -C[CH(CH3)(C2H5)]=CH2) -CH=CH-CH=CH-C2H5, -CH2-CH=CH-C(CH3)=CH2 -C(C2H5)=CH-C2H5l -CH2-CH=C(CH3)-CH=CH2, -CH2-C(CH3)=CH-CH=CH2 -C(C2H5)=C(CH3)2, -CH(CH3)-CH=CH-CH=CH2, -CH=CH-CH2-C(CH3)=CH2 -C(C4H9)=CH2) -CH=CH-CH(CH3)-CH=CH2, -CH=C(CH3)-CH2-CH=CH2 -C[C(CH3)3]=CH2, -CH=C(CH3)-CH=CH-CH3, -C(CH3)=CH-CH2-CH=CH2 -CH(C2H5)-CH=CH-CH3, -CH=CH-C(CH3)=CH-CH3, -CH=CH-CH=C(CH3)2 -C(C3H7)=CH-CH3, -C(CH3)=CH-CH=CH-CH3, -CH=C(CH3)-C(CH3)=CH2 -CH2-C(C3H7)=CH2, -C(CH3)=CH-C(CH3)=CH2, -C(CH3)=C(CH3)-CH=CH2 and -CH=CH-CH=CH-CH=CH2. Preferred are -CH=CH2, -CH2-CH=CH2, -C(CH3)=CH2, -CH=CH-CH3l -C2H4-CH=CH2, -CH2-CH=CH-CH3. Especially preferred are -CH=CH2 — CH2— CH=CH2. As used herein, the term "C2-6 alkynyl" or "linear or branched C2-C6-alkynyl" refers to -C≡CH, -C≡C-CH3, -CH2-C≡CH, -C2H4-C≡CH, -CH2-C≡C-CH3, -C≡C-C2H5, — C3H6— C=CH, — C2H4— C=C— CH3, — CH2— C=C— C2H5, — C=C— C3H7, -CHiCHaJ-CsCH, -CH2-CH(CH3)-C≡CH, -CH(CH3)-CH2-C≡CH,
— CH(CH3)— C=C— CH3, — C4Hg— C=CH, — 03Ηβ— C=C— CH3, — C2H4— C=C— C2H5, -CH2-C≡C-C3H7, -C2H4-CH(CH3)-C≡CH, -CH2-CH(CH3)-CH2-C≡CH,
Figure imgf000009_0001
-CH(CH3)-C≡C-C2H5l -CH2-C≡C-CH(CH3)2, -C≡C-CH(CH3)-C2H5,
-C≡C-CH2-CH(CH3)2, -C≡C-C4H9> -C≡C-C(CH3)3, -CH(C2H5)-C≡C-CH3, -C(CH3)2-C≡C-CH3, -CH(C2H5)-CH2-C≡CH, -CH2-CH(C2H5)-C≡CH, -C(CH3)2-CH2-C≡CH, -CH2-C(CH3)2-C≡CH, -CH(CH3)-CH(CH3)-C≡CH, -CH(C3H7)-C≡CH, -C(CH3)(C2H5)-C≡CH, -C≡C-C≡CH, -CH2-C≡C-C≡CH, -C≡C-C≡C-CH3, -CH(C≡CH)2, -C2H4-C≡C-C≡CH, -CH2-C≡C-CH2-C≡CH, -C≡C-C2H4-C≡CH, -CH2-C≡C-C≡C-CH3, -C≡C-CH2-C≡C-CH3,
-C≡C-C≡C-C2H5, -C≡C-CH(CH3)-C≡CH, -CH(CH3)-C≡C-C≡CH, -CH(C≡CH)-CH2-C≡CH, -C(C≡CH)2-CH3, -CH2-CH(C≡CH)2,
-CH(C≡CH)-C≡C-CH3. Preferred are -C≡CH and -C≡C-CH3.
As used herein, the term "aryl" or "carbocyclic group" refers to phenyl, indenyl, indanyl, naphthyl, 1 ,2-dihydro-naphthyl, 2,3-dihydronaphthyl, 1 ,2,3,4- tetrahydronaphthyl (tetralinyl), fluorenyl, anthryl (anthracenyl), 9,10-dihydroanthryl, 1 ,2,3,4-tetrahydro-anthryl, 1 ,2,3,4,5,6,7,8-octahydro-anthryl, azulenyl, diphenylmethyl, benzyl, triphenylmethyl (trityl), styryl, naphthoquinonyl, acenaphthyl, anthraquinonyl, phenanthryl (phenanthrenyl) and especially to a mono- or bicyclic 6 to 10 membered ring system, preferably phenyl or napthyl.
As used herein, the term "heteroaryl" or "heterocyclic ring" or "heterocyclic group" refers to heteroaromatic groups which have from 5 to 10 ring atoms, from 1 to 4 of which are selected from O, N and/or S. Preferred groups have 1 or 2 heteroatoms in a 5- or 6-membered aromatic ring. Mono and bicyclic ring systems are included. Typical heteroaryl groups which are at least partially aromatic include pyridyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, pyridazinyl, pyrimidyl, pyrazinyl, 1 ,3,5-triazinyl, ,2,3-triazolyl, 1 ,3,4-thiadiazolyl, indolizinyl, indolyl, isoindolyl, benzo[b]furyl, thiophenyl, benzo[b]thienyl, indazolyl, benzimidazolyl, benzthiazolyl, thiazolyl, purinyl, quinolizinyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, 1 ,8-naphthyridinyl, tetrahydroquinolyl, benzooxazolyl, chrom-2- onyl, indazolyl, indenyl. Said herteroaryl groups may further be substituted by one, two, three, four, five or more substituents selected from the group consisting of R18 - R30, linear or branched C -C6-alkyl, C3-C6-cycloalkyl, linear or branched C2-C6-alkenyl, linear or branched C2 -alkynyl and aryl.
Preferred heterocyclic groups from which also R7 can be selected are:
Figure imgf000010_0001
ULA-P03071WO21 Application
Figure imgf000011_0001
Figure imgf000012_0001
ULA-P03071WO21 Application
Figure imgf000013_0001
ULA-P03071WO21 Application
Figure imgf000014_0001
Figure imgf000015_0001
wherein R to >27 are independently of each other selected from the substituents mentioned below.
Preferred heteroc clic -NR9R10 groups are:
Figure imgf000015_0002
Said preferred herteroaryl groups and heterocyclic groups may further be substituted by one, two, three, four, five or more substituents selected from the group consisting of R23 - R35, linear or branched C-i-Ce-alkyl, C3-Cio-cycloalkyl, linear or branched C2-C6-alkenyl, linear or branched C2-C6-alkynyl and aryl.
As used herein, the term "heterocyclic group" or "heterocyclic ring" or "heterocyclic ring system" or "heterocyclyl" refers to carbocycles having at least one heteroatom in the ring such as oxygen, nitrogen, or sulfur. Such heterocycles may be saturated or partially unsaturated but not aromatic. Examples for heterocyclic residues are 1 ,3-dioxolane, benzo[1 ,3]dioxolyl, pyrazolinyl, pyranyl, thiomorpholinyl, pyrazolidinyl, piperidyl, piperazinyl, 1 ,4-dioxanyl, imidazolinyl, pyrrolinyl, imidazolidinyl, morpholinyl, 1 ,4-dithianyl, pyrrolidinyl, oxozolinyl, oxazolidinyl, isoxazolinyl, isoxazolidinyl, thiazolinyl, thiazolidinyl, isothiazolinyl, isothiazolidinyl, dihydropyranl, pyrrolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl.
Aryl refers to phenyl, substituted phenyl and heteroaryl, wherein substituted phenyl and heteroaryl have the meanings as defined above.
As used herein, the term "Ci-C6 alkyloxy" or "Ci-C6 alkoxy" refers to the residue -O-C-i-C-6-alkyl, wherein C-i-C6-alkyl has the meanings as defined above. The following C C6 alkoxy groups are preferred -O-CH3) -O-C2H5, -O-C3H7, -0-CH(CH3)2, -O-C4H9) -0-CH2-CH(CH3)2, -0-CH(CH3)-C2H5, -O-C(CH3)3, and -0-C5Hn . Most preferred are -0-CH3, -0-C2H5 and -O-C3H. As used herein, the term "Ci-C6 alkyloxycarbonyl" or "C1-C6 alkoxycarbonyl" refers to the residue -CO-0-C-i-C6-alkyl, wherein CrC6-alkyl has the meanings as defined above. Preferred C-i-C6 alkoxycarbony groups are -CO-OCH3, -CO-OC2H5, -CO-OQ3H7, -CO-OCH(CH3)2, -CO-OC4H9,
-CO-OCH2-CH(CH3)2, -CO-OCH(CH3)-C2H5, -CO-OC(CH3)3, and -CO-OCsHn . Most preferred are -CO-OCH3, -CO-OC2H5, -CO-OC3H7.
As used herein, the term "Ci-C6 alkylcarbonyl" or "Ci-C6 alkanoyl" or "Ci-C6 acyl" refers to the residue -CO-Ci-C6-alkyl, wherein CrC6-alkyl has the meanings as defined above. Preferred C-i-C6 acyl groups are -CO-CH3, -CO-C2H5, -CO-C3H7, -CO-CH(CH3)2, -CO-C4H9, -CO-CH2-CH(CH3)2,
-CO-CH(CH3)-C2H5, -CO-C(CH3)3, and -CO-C5Hn . Most preferred are -CO-CH3, -CO-C2H5, -CO-C3H7. As used herein, the term "C1-C6 alkylcarbonyloxy" or "C1-C6 alkanoyloxy" or "Ci-C6 acyloxy " refers to the residue -0-CO-Ci-C6-alkyl, wherein d-C6-alkyl has the meanings as defined above. Preferred C1-C6 acyloxy groups are -O-CO-CH3, -O-CO-C2H5, -O-CO-C3H7, -O-CO-CH(CH3)2, -O-CO-C4H9,
-O-CO-CH2-CH(CH3)2, -0-CO-CH(CH3)-C2H5, -O-CO-C(CH3)3, and -O-CO-CsHn. Most preferred are -0-CO-CH3, -O-CO-C2H5, -0-CO-C3H7.
The term "substituted" or "substituted alkyl", "substituted cycloalkyl", "substituted heterocyclyl", "substituted aryl", "substituted heteroaryl", "substituted heterocyclic group", "substituted carboicyclic group" respectively shall refer to the addressed residue such as "alkyl", "cycloalkyl", "heterocyclyl", "aryl", or "heteroaryl" bearing one, two, three, four, five or more, preferably one or two substituents R23 to R35 independently selected from the following group:
Figure imgf000017_0001
-OH, -OCH3, -OC2H5, -OC3H7) -O-cyclo-C3H5, -OCH(CH3)2, -OC(CH3)3, -OC4H9, -OPh, -OCH2-Ph, -OCPh3, -SH, -SCH3, -SC2H5, -SC3H7, -S-cyclo-C3H5) -SCH(CH3)2, -SC(CH3)3, -NO2, -F, -CI, -Br, -I, -N3, -CN, -OCN, -NCO, -SCN, -NCS, -CHO, -COCH3, -COC2H5, -COC3H7, -CO-cyclo-C3H5, -COCH(CH3)2, -COC(CH3)3, -COOH, -COCN, -COOCH3, -COOC2H5> -COOC3H7, -COO-cyclo-C3H5, -COOCH(CH3)2, -COOC(CH3)3l -OOC-CH3, -OOC-C2H5, -OOC-C3H7, -OOC-cyclo-C3H5, -OOC-CH(CH3)2, -OOC-C(CH3)3, -OCHF2, -CONH2, -CONHCH3, -CONHC2H5, -CONHC3H7, -CONH-cyclo-C3H5, -CONH[CH(CH3)2], -CONH[C(CH3)3], -CON(CH3)2, -CON(C2H5)2, -CON(C3H7)2, -CON(cyclo-C3H5)2, -CON[CH(CH3)2]2, -CON[C(CH3)3]2> -NH2, -NHCH3, -NHC2H5, -NHC3H7, -NH-cyclo-C3H5, -NHCH(CH3)2, -NHC(CH3)3, -N(CH3)2, -N(C2H5)2, -N(C3H7)2, -N(cyclo-C3H5)2, -N[CH(CH3)2]2, -N[C(CH3)3]2, -SOCH3, -SOC2H5,
ULA-P03071WO21 Application -SOC3H7, -SO-cyclo-C3H5, -SOCH(CH3)2, -SOC(CH3)3, -S02CH3l -SO2C2H5, -S02C3H7, -SO2-cyclo-C3H5> -SO2CH(CH3)2, -S02C(CH3)3, -SO3H, -SO3CH3, -S03C2H5, -S03C3H7) -S03-cyclo-C3H5, -S03CH(CH3)2l -SO3C(CH3)3, -OCF3, -OC2F5, -0-COOCH3, -0-COOC2H5, -0-COOC3H7, -0-COO-cyclo-C3H5, -O-COOCH(CH3)2, -0-COOC(CH3)3) -NH-CO-NH2, -NH-CO-NHCH3, -Si(CH3)3, -NH-CO-NHC2H5, -NH-CO-NHC3H7) -NH-CO-NH-cyclo-C3H5, -0-CO-NH2, -0-CO-NHCH3, -0-CO-NHC2H5> -0-CO-NHC3H7) -O-CO-NH-cyclo-C3H5, -O-CO-NH[CH(CH3)2],
-0-CO-NH[C(CH3)3], -O-CO-N(CH3)2, -O-CO-N(C2H5)2, -O-CO-N(C3H7)2, -0-CO-N(cyclo-C3H5)2, -0-CO-N[CH(CH3)2]2, -O-CO-N[C(CH3)3]2l
-0-CO-OCH3, -O-CO-OC2H5> -O-CO-OC3H7, -O-CO-0-cyclo-C3H5, -O-CO-OCH(CH3)2, -0-CO-OC(CH3)3, -CH2F -CHF2, -CF3, -CH2CI, -CHCI2, -CCI3) -CH2Br -CHBr2, -CBr3, -CH2I -CHI2, -Cl3, -CH2-CH2F — CH2— CHF2, — CH2— CF3, — CH2— CH2CI, — CH2— CHCI2, — CH2— CCI3, — CH2— CH2Br -CH2-CHBr2, -CH2-CBr3, -CH2-CH2I, -CH2-CHI2, -CH2-CI3) -cyclo-C3H5, -Ph, -CH2-Ph, -CPh3, -CH=CH2, -CH2-CH=CH2) -C(CH3)=CH2, -CH=CH-CH3, -C2H4-CH=CH2, -CH=C(CH3)2, -C≡CH, -C≡C-CH3, -CH2-C≡CH, -CH3) — C2H5, — C3H7, — CH(CH3)2, — C4Hg, — CH2— CH(CH3)2, — CH(CH3)— C2Hsi -C(CH3)3, -CH(CH3)-C3H7, -CH2-CH(CH3)-C2H5, -CH(CH3)-CH(CH3)2, -CsHu, -C(CH3)2-C2H5l -CH2-C(CH3)3, -CH(C2H5)2, -C2H4-CH(CH3)2, -CeHi3, — C3H6— CH(CH3)2, — C2H4— CH(CH3)— C2Hs, — CH(CH3)— C4Hg, -CH2-CH(CH3)-C3H7, -CH(CH3)-CH2-CH(CH3)2, -CH(CH3)-CH(CH3)-C2H5, — CH2— CH(CH3)— CH(CH3)2, — CH^ C(CH3)2— C2Hs, — C(CH3)2— C3H7,
-C(CH3)2-CH(CH3)2, -C2H4-C(CH3)3, and -CH(CH3)-C(CH3)3.
Preferred residues R -X-O- are selected from:
Figure imgf000018_0001
Figure imgf000019_0001
wherein
the substituent -R13 has the meanings as defined herein;
the substituent -R22 refers to the residues disclosed above and preferably to phenyl, benzyl, Ci-C6-alkyl, pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, -OH, -CH2-OH, -C2H4-OH, -OCH3> -CH2-OCH3 or -C2H4-OCH3.
Further preferred compounds of the present invention are such compounds wherein 8-X-O- is selected from:
Figure imgf000019_0002
wherein
the substituents -R9, -R 0, -R13 and CrC6-alkyl have the meanings as defined herein.
ULA-P03071WO21 Application Another group of preferred compounds has residues R -X-O- selected from the following groups :
Figure imgf000020_0001
wherein
the substituent -R13 has the meanings as defined above. Preferred are also compounds of the general formula (I)
Figure imgf000020_0002
wherein
one of -R1 and -R2 represents -O-X-R8;
and the other one of -R1 and -R2 represents -H, -OH, -OCH3, -OCF3, -OC2H5, -OC3H7, -OCH2CH2-OCH3, -OCH2CH2-OC2H5; -X- represents -CR11R12-, -CR11R12-CR13R14-, -CR11 R12-CR13R14-CR15R16- -CR11R12-CR 3R14-CR15R16-CR17R18-, -CR11R 2-CR13R14-CR15R16-CR17R18- CR19R20_I _(C|_|2)n_NH_ -CO-, -(CH2)n-CO-, -(CH2)n-NH-CO-NH-, -(CH2)n-NH-CO-, -(CH2)n-NH-CO-O- -(CH2)n-CO-NR9-, -(CH2)n-O-CO- NH-, -(CH2)n-O-CO-, -(CH2)n-O- -(CH2)n-; n is an integer selected from 1 , 2, 3, 4, 5 and 6;
-R3, -R4, -R5, -R6 are independently of each other selected from -H, halogen, nitro, C-i-zralkyl, C3-C5-cycloalkyl, Ci-6-alkoxy; -R represents -H, -OH, -F, -CI, -Br, -I, -OCH3, -OC2H5, -OC3H7, -O- cyclo-C3H5, -OCH(CH3)2, -OC(CH3)3, -OC4H9> -CHO, -COCH3, -COC2H5, -COC3H7, -CO-cyclo-C3H5, -COCH(CH3)2, -COC(CH3)3, -COOH, -cyclo- C3H5) -cyclo-C4H7, -cyclo-C5H9, -cyclo-C6Hn, -COOCH3, -COOC2H5, -COOC3H7, -COO-cyclo-C3H5, -COOCH(CH3)2l -COOC(CH3)3, -CONH2, -CONHCH3, -CONHC2H5> -CONHC3H7, -CONH-cyclo-C3H5,
-CONH[CH(CH3)2], -CONH[C(CH3)3], -CON(CH3)2) -CON(C2H5)2, -CON(C3H7)2, -CON(cyclo-C3H5)2, -CON[CH(CH3)2]2, -CON[C(CH3)3]2, -NH2, -NHCH3l -NHC2H5, -NHC3H7, -NH-cyclo-C3H5, -NHCH(CH3)2, -NHC(CH3)3, -N(CH3)2, -N(C2H5)2, -N(C3H7)2, -N(cyclo-C3H5)2, -N[CH(CH3)2]2, -N[C(CH3)3]2, -OOC-CH3, -OOC-C2H5) -OOC-C3H7, -OOC-cyclo-C3H5, -OOC-CH(CH3)2, -OOC-C(CH3)3, -NH-CO-NH2, -NH-CO-NHCH3, -NH-CO-NHC2H5, -NH-CO-NHC3H7, -NH-CO-NH- cyclo-C3H5, -NH-CO-NH[CH(CH3)2], -NH-CO-NH[C(CH3)3], -NH-CO-N(CH3)2, -NH-CO-N(C2H5)2, -NH-CO-N(C3H7)2, -NH-CO-N(cyclo-C3H5)2,
-NH-CO-N[CH(CH3)2]2, -NH-CO-N[C(CH3)3]2, -NH-COOCH3, -NH- COOC2H5l -NH-COOC3H7, -NH-COO-cyclo-C3H5, -NH-COOCH(CH3)2, -NH-COOC(CH3)3, -O-CO-NH2, -O-CO-NHCH3, -O-CO-NHC2H5, -O-CO-NHC3H7, -O-CO-NH-cyclo-C3H5, -O-CO-NH[CH(CH3)2], -O-CO- NH[C(CH3)3], -O-CO-N(CH3)2, -O-CO-N(C2H5)2) -O-CO-N(C3H7)2, -O- CO-N(cyclo-C3H5)2, -O-CO-N[CH(CH3)2]2, -O-CO-N[C(CH3)3]2l -NH-CO- NR9R10, -CO-NR9R10, -NR9R10, -CH2F -CHF2) -CF3, -CH2CI, -CH2Br, -CH2-CH2F, -CH2-CH2CI, -CH2-CH2Br, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C(CH3)3, -C4H9, -CsHu, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -Ph, -CH2-Ph, -CH=CH2, -CH2-CH=CH2, -C≡CH,
Figure imgf000021_0001
Figure imgf000022_0001
-R9 and -R10 are independently of each other selected from -H, -CH2F -CHF2, -CF3, -CH2CI, -CH2Br, -CH2-CH2F, -CH2-CH2CI, -CH2-CH2Br, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C(CH3)3, -C4H9, -C5H11, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -cyclo-C3H5l -cyclo-C4H7, -cyclo-C5H9, -cyclo-C6Hn;
Figure imgf000022_0002
ULA-P03071WO21 Application
Figure imgf000023_0001
Figure imgf000024_0001
ULA-P03071WO21 Application
Figure imgf000025_0001
ULA-P03071WO21 Application
Figure imgf000026_0001
Figure imgf000027_0001
R1 - R27 represent independently of each other -H, -OH, -OCH3, -OC2H5, -OC3H7, -O-cyclo-C3H5, -OCH(CH3)2, -OC(CH3)3, -OC4H9, -OCH2Ph, -OPh, -SH, -SCH3, -SC2H5, -NO2, -F, -CI, -Br, -I, -CN, -CHO, -COCH3, -COC2H5, -COC3H7, -CO-cyclo-C3H5, -COCH(CH3)2, -COOH, -COOCH3, -COOC2H5, -COOC3H7) -COO-cyclo-C3H5) -COOCH(CH3)2, -OOC-CH3) -OOC-C2H5, -OOC-C3H7, -OOC-cyclo-C3H5, -OOC-CH(CH3)2, -CONH2, -CONHCH3, -CONHC2H5, -CONHC3H7, -CONH-cyclo-C3H5, -CONH[CH(CH3)2], -CON(CH3)2, -CON(C2H5)2, -CON(C3H7)2) -CON(cyclo- C3H5)2, -NH-OC-CH3, -NH-OC-C2H5, -NH-OC-C3H7, -NH-OC-cyclo- C3H5, -NH-OC-CH(CH3)2, -NH-OC-C(CH3)3, -NH2, -NHCH3, -NHC2H5, -NHC3H7, -NH-cyclo-C3H5, -NHCH(CH3)2, -N(CH3)2, -N(C2H5)2, -N(C3H7)2, -N(cyclo-C3H5)2, -N[CH(CH3)2]2, -SOCH3, -SOC2H5, -SO2CH3, -SO2C2H5, -SO3H, -SO3CH3, -SO3C2H5, -SO3C3H7, -OCF3, -OC2F5, -OCH2F -OCHF2, -CH2F -CHF2, -CF3, -CH2CI, -CH2Br, -CH2-CH2F, -CH2-CH2CI, -CH3, -C2H5, -C3H7, -cyclo-C3H5, -CH(CH3)2, -C(CH3)3, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -CH=CH2> -CH2-CH=CH2, -CH=CH-CH3, -C≡CH, -C≡C-CH3, -CH2-C≡CH, -Ph, -CH2-Ph, -CH=CH-Ph;
and stereoisomeric forms, solvates, hydrates and/or pharmaceutically acceptable salts thereof.
If -R1 is -O-X-R8, -R2 is preferably -H, -OCH3, -OCF3, -OC2H5 and if -R2 is -O-X-R8, than -R1 is preferably -H, -OCH3, -OCF3, -OC2H5. Preferably -R3, -R4, -R5, -R6 are independently of each -OCH3, -OC2H5, -OC3H7) -OCF3, -F, -CI, -Br, -I, -CH3, -C2H5, -C3H7, -cyclo-C3H5, -CH(CH3)2, and more preferably -OCH3, -OC2H5, -OCF3, -F, -CI, -Br, -CH3, -C2H5. Moreover it is preferred if at least one of -R3, -R4 and -R5 are selected from -F or -CI. It is also preferred if at least one of -R3 and -R4 is -F and preferably -R3 is -F.
Preferably -R7 is one of the following groups -CH3, -C2H5, -C3H7, -C4Hg, -C5Hn ,
Figure imgf000028_0001
Figure imgf000029_0001
Compounds wherein R1 and R2 are a methoxy group are excluded from the present application. Such compounds having the substitution pattern of the compounds disclosed herein have shown moderate to low activity or no activity and are consequently not preferred. Also compounds of general formula (I), wherein both groups R1 and R2 are ethoxy groups are still not preferred and could also be excluded from the present invention. However compounds wherein both of R1 and R2 represent propoxy, butoxy, pentoxy etc. have shown activity and belong to the compounds of the present invention and are consequently not excluded from the scope of protection.
Excluded from this application and excluded from the patent claims and excluded from the general formula (I) are the following compounds which are excluded by the following disclaimer:
N'-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N-methyl-N-(2- phenylethyl)sulfamide,
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-1- phenylmethanesulfonamide,
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-2- phenylethanesulfonamide,
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-3-phenylpropane-1- sulfonamide.
The following specific compounds are also preferred which are selected from the group comprising or consisting of:
1 ) 2,5-Difluoro-N-{3-fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4- yloxy]-phenyl}-benzenesulfonamide,
2) 2-Fluoro-N-{3-fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4- yloxy]-phenyl}-benzenesulfonamide,
3) 4-Chloro-2-fluoro-N-{3-fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)- quinolin-4-yloxy]-phenyl}-benzenesulfonamide,
4) N-{3-Fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4-yloxy]- phenyl}-2-trifluoromethyl-benzenesulfonamide,
5) N-{3-Fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4-yloxy]- phenyl}-3-trifluoromethyl-benzenesulfonamide,
6) 2,6-Dichloro-N-{3-fluoro-4-[6-methoxy-7-(3-piperidin-1 -yl-propoxy)-quinolin-4- yloxy]-phenyl}-benzenesulfonamide,
7) N-{3-Fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin4-yloxy]- phenyl}-2-nitro-benzenesulfonamide, Biphenyl-3-sulfonic acid {3-fluoro-4-[6-methoxy-7-(3-piperidin-1 -yl-propoxy)- quinolin-4-loxy]-phenyl}-amide,
3- Difluoromethoxy-N-{3-fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)- quinolin-4-yloxy]-phenyl}-benzenesulfonamide,
N-{3-Fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4-yloxy]- phenyl}-3-phenoxy-benzenesulfonamide,
2,6-Difluoro-N-{3-fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4- yloxy]-phenyl}-benzenesulfonamide,
2,5-Difluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]- quinolin-4-yloxy}-phenyl)-benzenesulfonamide,
Biphenyl-3-sulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1 -yl)- propoxy]-quinolin-4-yloxy}-phenyl)-amide,
N-(3-Fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4- yloxy}-phenyl)-3-phenoxy-benzenesulfonamide,
2-Cyano-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]- quinolin-4-yloxy}-phenyl)-benzenesulfonamide,
2.4- Difluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]- quinolin-4-yloxy}-phenyl)-benzenesulfonamide,
2,3,4-Trifluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)- propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide,
4- Fluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]- quinolin-4-yloxy}-phenyl)-3-methoxy-benzenesulfonamide,
2- Bromo-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]- quinolin-4-yloxy}-phenyl)-benzenesulfonamide,
2.5- Dichloro-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)- propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide,
N-(3-Fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4- yloxy}-phenyl)-2-nitro-benzenesulfonamide,
3- Fluoro-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]- quinolin-4-yloxy}-phenyl)-benzenesulfonamide,
3-Chloro-4-fluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)- propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide,
N-(3-Fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4- yloxy}-phenyl)-2-trifluoromethyl-benzenesulfonamide,
N-(3-Fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4- yloxy}-phenyl)-2-trifluoromethoxy-benzenesulfonamide,
2-Fluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]- quinolin-4-yloxy}-phenyl)-benzenesulfonamide, 4-Chloro-2-fluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)- propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide,
N-(3-Fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4- yloxy}-phenyl)-2-methyl-benzenesulfonamide,
2- Chloro-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]- quinolin-4-yloxy}-phenyl)-benzenesulfonamide,
3- Difluoromethoxy-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)- propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide,
Thiophene-2-sulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1 - yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide,
2>6-Dichloro-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)- propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide,
N-(3-Fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4- yloxy}-phenyl)-2-methoxy-benzenesulfonamide,
3,5-Dichloro-N-{3-fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4- yloxy]-phenyl}-2-methoxy-benzenesulfonamide,
3,5-Dichloro-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)- propoxy]- quinolin-4-yloxy}-phenyl)-2-methoxy-benzenesulfonamide.
N-(3-Fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4- yloxy}-phenyl)-benzenesulfonamide,
3-Fluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]- quinolin-4-yloxy}-phenyl)-benzenesulfonamide,
2- Chloro-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]- quinolin-4-yloxy}-phenyl)-benzenesulfonamide
'N-iS-Fluoro^-ie-methoxy^-p-iS-methyl-piperidin-l-ylJ-propoxyj-quinolin^- yloxy}-phenyl)-3-trifluoromethyl-benzenesulfonamide
N-(3-Fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4- yloxy}-phenyl)-2-nitro-benzenesulfonamide
3- Cyano-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]- quinolin-4-yloxy}-phenyl)-benzenesulfonamide,
N-(3-Fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4- yloxy}-phenyl)-3-methoxy-benzenesulfonamide,
3-Difluoromethoxy-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)- propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide,
N-(3-Fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4- yloxy}-phenyl)-2-methyl-benzenesulfonamide,
N-(3-Fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4- yloxy}-phenyl)-2-trifluoromethoxy-benzenesulfonamide, 46 N-(3-Fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4- yloxy}-phenyl)-3-trifIuoromethoxy-benzenesulfonamide,
47 2,4-Difluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]- quinolin-4-yloxy}-phenyl)-benzenesulfonamide,
48 3.4- Difluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]- quinolin-4-yloxy}-phenyl)-benzenesulfonamide,
49 2,3,4-Trifluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)- propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide,
50 2.5- Dichloro-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin1-yl)-propoxy]- quinolin-4-yloxy}-phenyl)-benzenesulfonamide,
51 2.6- Dichloro-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]- quinolin-4-yloxy}-phenyl)-benzenesulfonamide,
52 3.4- Dichloro-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]- quinolin-4-yloxy}-phenyl)-benzenesulfonamide,
53 3.5- Dichloro-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]- quinolin-4-yloxy}-phenyl)-benzenesulfonamide,
54 3-Chloro-2-fluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)- propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide,
55 2- Fluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]- quinolin-4-yloxy}-phenyl)-5-methyl-benzenesulfonamide,
56 3- Fluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]- quinolin-4-yloxy}-phenyl)-4-methyl-benzenesulfonamide,
57 3-Chloro-4-fluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)- propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide,
58 Naphthalene-1 -sulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin- 1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide,
59 N-(3-Fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4- yloxy}-phenyl)-3-phenoxy-benzenesulfonamide,
60 Cyclopropanesulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1 - yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide,
61 1-Methyl-1 H-pyrazole-3-sulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(3-methyl- piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide,
62 5-Methyl-thiophene-2-sulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(3-methyl- piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide,
63 5-Chloro-thiophene-2-sulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(3-methyl- piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide,
64 2,4-Dichloro-thiophene-3-sulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(3-methyl- piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide,
ULA-P03071WO21 Application Thiophene-3-sulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1 - yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide,
3-(3-Fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4- yloxy}-phenylsulfamoyl)-thiophene-2-carboxylic acid methyl ester,
Benzo[b]thiophene-3-sulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(3-methyl- piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide,
1 -Ethyl-1 H-pyrazole-4-sulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(3-methyl- piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide,
3-Chloro-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]- quinolin-4-yloxy}-phenyl)-benzenesulfonamide,
N-(3-Fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4- yloxy}-phenyl)-3-methyl-benzenesulfonamide,
N-(3-Fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4- yloxy}-phenyl)-2-methoxy-benzenesulfonamide,
3- Cyano-4-fluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)- propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide,
2-Phenyl-ethenesulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-
1- yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide,
Quinoline-8-sulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1 - yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide,
3,5-Dichloro-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]- quinolin-4-yloxy}-phenyl)-2-methoxy-benzenesulfonamide,
3.5- Dichloro-N-{3-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-
4- yloxy]-phenyl}-2-methoxy-benzenesulfonamide,
2.6- Difluoro-N-{3-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin- 4-yloxy]-phenyl}-benzenesulfonamide,
N-{3-Fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4-yloxy]- phenyl}-2-trifluoromethoxy-benzenesulfonamide,
Butane-1 -sulfonic acid {3-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)- quinolin-4-yloxy]-phenyl}-amide,
2.5- Difluoro-N-{3-fluoro-4-[6-methoxy-7-(piperidin-3-ylmethoxy)-quinolin-4- yloxy]-phenyl}-benzenesulfonamide,
2- Fluoro-N-{3-fluoro-4-[6-methoxy-7-(2-morpholin-4-yl-ethoxy)-quinolin-4- yloxy]-phenyl}-benzenesulfonamide,
2.6- Difluoro-N-{3-fluoro-4-[6-methoxy-7-(2-morpholin-4-yl-ethoxy)-quinolin-4- yloxy]-phenyl}-benzenesulfonamide,
2,5-Difluoro-N-{3-fluoro-4-[6-methoxy-7-(4-morpholin-4-yl-butoxy)-quinolin-4- yloxy]-phenyl}-benzenesulfonamide, 84) 2,5-Difluoro-N-{3-fluoro-4-[7-(4-morpholin-4-yl-butoxy)-quinolin-4-yloxy]- phenylj-benzenesulfonamide,
85) N-(3-Fluoro-4-{6-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}- phenyl)-2-trifluoromethyl-benzenesulfonamide,
86) N-(3-Fluoro-4-{7-methoxy-6-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinoiin-4- yloxy}-phenyl)-2-trifluoromethyl-benzenesulfonamide,
87) N-(3-Chloro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4- yloxy}-phenyl)-2-trifluoromethyl-benzenesulfonamide,
88) N-(3,5-Dichloro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]- quinolin-4-yloxy}-phenyl)-2,6-difluoro-benzenesulfonamide,
89) N-(4-{6-Methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-3- methyl-phenyl)-2-trifluoromethyl-benzenesulfonamide,
90) 2,5-Difluoro-N-(3-methoxy-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)- propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide,
91 ) N-{4-[6,7-Bis-(2-methoxy-ethoxy)-quinolin-4-yloxy]-3-fluoro-phenyl}-2,6- difluoro-benzenesulfonamide,
92) {4-[2-Fluoro-4-(2-fluoro-benzenesulfonylamino)-phenoxy]-6-methoxy-quinolin- 7-yloxy}-acetic acid ethyl ester,
93) 2-{4-[2-Fluoro-4-(2-trifluoromethyl-benzenesulfonylamino)-phenoxy]-6- methoxy-quinolin-7-yloxy}-N,N-dimethyl-acetamide,
94) Cyclohexanecarboxylic acid 4-[4-(2,5-difluoro-benzenesulfonylamino)-2- fluoro-phenoxy]-6-methoxy-quinolin-7-yl ester,
95) N-(3-Fluoro-4-{6-methoxy-7-[3-(tetrahydro-pyran-4-ylamino)-propoxy]- quinolin-4-yloxy}-phenyl)-2-trifluoromethyl-benzenesulfonamide,
96) N-{4-[7-(3-Cyclopropylamino-propoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro- phenyl}-2-trifluoromethyl-benzenesulfonamide,
97) N-{4-[7-(3-Cyclobutylamino-propoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro- phenyl}-2-trifluoromethyl-benzenesulfonamide,
98) N-(4-{7-[3-(3-tert-Butyl-ureido)-propoxy]-6-methoxy-quinolin-4-yloxy}-3-fluoro- phenyl)-2-trifluoromethyl-benzenesulfonamide,
99) N-(3-Fluoro-4-{6-methoxy-7-[3-(2-methyl-piperidin-1-yl)-propoxy]-quinolin-4- yloxy}-phenyl)-2-trifluoromethyl-benzenesulfonamide,
100) N-{4-[7-(3-Dimethylamino-propoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro- phenyl}-2-trifluoromethyl-benzenesulfonamide,
101 ) N-{4-[7-(3-Diethylamino-propoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro- phenyl}-2-trifluoromethyl-benzenesulfonamide,
102) N-(3-{6-Methoxy-7-[3-(4-methyl-piperazin-1 -yl)-propoxy]-quinolin-4-yloxy}- phenyl)-2-trifluoromethyl-benzenesulfonamide. 103) N-{3-Fluoro-4-[6-methoxy-7-(2-morpholin-4-yl-ethoxy)-quinolin-4-yloxy]- phenyl}-2-methoxy-benzenesulfonamide
104) 2,6-Dichloro-N-{3-fluoro-4-[6-methoxy-7-(2-morpholin-4-yl-ethoxy)-quinolin-4- yloxy]-phenyl}-benzenesulfonamide
105) Thiophene-2-sulfonic acid {3-fluoro-4-[6-methoxy-7-(2-morpholin-4-yl-ethoxy)- quinolin-4-yloxy]-phenyl}-amide
106) 2,5-Dichloro-N-{3-fluoro-4-[6-methoxy-7-(2-morpholin-4-yl-ethoxy)-quinolin-4- yloxy]-phenyl}-benzenesulfonamide
107) 1-Methyl-1 H-pyrazole-3-sulfonic acid {3-fluoro-4-[6-methoxy-7-(2-morpholin- 4-yl-ethoxy)-quinolin-4-yloxy]-phenyl}-amide
108) 2-Chloro-N-{3-fIuoro-4-[6-methoxy-7-(2-morpholin-4-yl-ethoxy)-quinolin-4- yloxy]-phenyl}-benzenesulfonamide
109) N-{3-Fluoro-4-[6-methoxy-7-(2-morpholin-4-yl-ethoxy)-quinolin-4-yloxy]- phenyl}-2-nitro-benzenesulfonamide
110) 2,6-Difluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1 -yl)-propoxy]- quinolin-4-yloxy}-phenyl)-benzenesulfonamide
111 ) N-(3-Chloro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4- yloxy}-phenyl)-2-fluoro-benzenesulfonamide
112) N-(3-Chloro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1 -yl)-propoxy]-quinolin-4- yloxy}-phenyl)-2,5-difluoro-benzenesulfonamide
113) Benzo[b]thiophene-3-sulfonic acid {3-fluoro-4-[6-methoxy-7-(3-piperidin-1-yl- propoxy)-quinolin-4-yloxy]-phenyl}-amide
114) Benzo[b]thiophene-3-sulfonic acid {3-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl- propoxy)-quinolin-4-yloxy]-phenyl}-amide
115) Benzo[b]thiophene-3-sulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(4-methyl- piperidin-1-yl)-propoxy]-quinolin-4-loxy}-phenyl)-amide
116) Benzo[b]thiophene-3-sulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(4-methyl- piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide
117) Benzo[b]thiophene-3-sulfonic acid (3-chloro-4-{6-methoxy-7-[3-(4-methyl- piperazin-1 -yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide
118) N-(3-Chloro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1 -yl)-propoxy]-quinolin-4- yloxy}-phenyl)-2,6-difluoro-benzenesulfonamide
119) 2,6-Dichloro-N-(3-chloro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1 -yl)- propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide
120) (3-{4-[2-Fluoro-4-(2-trifluoromethyl-benzenesulfonylamino)-phenoxy]-6- methoxy-quinolin-7-yloxy}-propyl)-carbamic acid tert-butyl ester
121 ) (3-{4-[4-(2,5-Difluoro-benzenesulfonylamino)-2-fluoro-phenoxy]-6-methoxy- quinolin-7-yloxy}-propyl)-carbamic acid tert-butyl ester
ULA-P03071WO21 Application 122) N-{4-[7-(3-Amino-propoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro-phenyl}-2,5- difluoro-benzenesulfonamide hydrochloride
123) 2,5-Difluoro-N-(3-{6-methoxy-7-[3-(4-methyl-piperazin-1 -yl)-propoxy]-quinolin- 4-yloxy}-phenyl)-benzenesulfonamide
124) 2,5-Dichloro-N-(3-chloro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1 -yl)- propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide
125) 2,6-Difluoro-N-(3-{6-methoxy-7-[3-(4-methyl-piperazin-1 -yl)-propoxy]-quinolin- 4-yloxy}-phenyl)-benzenesulfonamide
126) N-(3-{6-Methoxy-7-[3-(4-methyl-piperazin-1 -yl)-propoxy]-quinolin-4-yloxy}- phenyl)-2-trifluoromethoxy-benzenesulfonamide
127) 2,5-Dichloro-N-(3-{6-methoxy-7-[3-(4-methyl-piperazin-1 -yl)-propoxy]- quinolin-4-yloxy}-phenyl)-benzenesulfonamide
128) 2,6-Dichloro-N-(3-{6-methoxy-7-[3-(4-methyl-piperazin-1 -yl)-propoxy]- quinolin-4-yloxy}-phenyl)-benzenesulfonamide
129) Thiophene-2-sulfonic acid (3-{6-methoxy-7-[3-(4-methyl-piperazin-1 -yl)- propoxy]-quinolin-4-yloxy}-phenyl)-amide
130) 5-Chloro-thiophene-2-sulfonic acid (3-{6-methoxy-7-[3-(4-methyl-piperazin-1- yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide
131 ) 5-Methyl-thiophene-2-sulfonic acid (3-{6-methoxy-7-[3-(4-methyl-piperazin-1- yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide
132) N-[5-(3-{6-Methoxy-7-[3-(4-methyl-piperazin-1 -yl)-propoxy]-quinolin-4-yloxy}- phenylsulfamoyl)-4-methyl-thiazol-2-yl]-acetamide
133) Thiophene-3-sulfonic acid (3-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)- propoxy]-quinolin-4-yloxy}-phenyl)-amide
134) 2,5-Dichloro-thiophene-3-sulfonic acid (3-{6-methoxy-7-[3-(4-methyl- piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide
35) 3-(3-{6-Methoxy-7-[3-(4-methyl-piperazin-1 -yl)-propoxy]-quinolin-4-yloxy}- phenylsulfamoyl)-thiophene-2-carboxylic acid methyl ester
136) Benzo[b]thiophene-3-sulfonic acid (3-{6-methoxy-7-[3-(4-methyl-piperazin-1- yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide
137) Furan-2-sulfonic acid (3-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]- quinolin-4-yloxy}-phenyl)-amide
138) 3,5-Dimethyl-isoxazole-4-sulfonic acid (3-{6-methoxy-7-[3-(4-methyl- piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide
139) 1 -Methyl-1 H-pyrazole-3-sulfonic acid (3-{6-methoxy-7-[3-(4-methyl-piperazin- 1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide
140) 1-Ethyl-1 H-pyrazole-4-sulfonic acid (3-{6-methoxy-7-[3-(4-methyl-piperazin-1- yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide
ULA-P03071WO21 Application 141 ) 2-Methyl-1 H-imidazole-4-sulfonic acid (3-{6-methoxy-7-[3-(4-methyl- piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide
142) Cyclopropanesulfonic acid (3-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)- propoxy]-quinolin-4-yloxy}-phenyl)-amide
143) 2-Phenyl-ethenesulfonic acid (3-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)- propoxy]-quinolin-4-yloxy}-phenyl)-amide
144) Thiophene-2-sulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(2-methyl-piperidin-1- yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide
145) 5-Chloro-thiophene-2-sulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(2-methyl- piperidin-1 -yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide
146) 2,4-Dichloro-thiophene-3-sulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(2-methyl- piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide
147) Benzo[b]thiophene-3-sulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(2-methyl- piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide
148) Furan-2-sulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(2-methyl-piperidin-1-yl)- propoxy]-quinolin-4-yloxy}-phenyl)-amide
149) 2-Methyl-1 H-imidazole-4-sulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(2-methyl- piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide
150) 1-Methyl-1 H-pyrazole-3-sulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(2-methyl- piperidin-1 -yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide
151 ) 2,5-Difluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(2-methyl-piperidin-1 -yl)-propoxy]- quinolin-4-yloxy}-phenyl)-benzenesulfonamide
152) 2,6-Difluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(2-methyl-piperidin-1 -yl)-propoxy]- quinolin-4-yloxy}-phenyl)-benzenesulfonamide
153) N-(3-Fluoro-4-{6-methoxy-7-[3-(2-methyl-piperidin-1-yl)-propoxy]-quinolin-4- yloxy}-phenyl)-2-trifluoromethoxy-benzenesulfonamide
154) 2,5-Dichloro-N-(3-fluoro-4-{6-methoxy-7-[3-(2-methyl-piperidin-1 -yl)-propoxy]- quinolin-4-yloxy}-phenyl)-benzenesulfonamide
155) 3-{3-Fluoro-4-[6-methoxy-7-(3-piperidin-1 -yl-propoxy)-quinolin-4-yloxy]- phenylsulfamoyl}-thiophene-2-carboxylic acid methyl ester
156) 3-(3-Fluoro-4-{6-methoxy-7-[3-(4-methyl-piperidin-1 -yl)-propoxy]-quinolin-4- yloxy}-phenylsulfamoyl)-thiophene-2-carboxylic acid methyl ester
157) 3-{3-Fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]- phenylsulfamoyl}-thiophene-2-carboxylic acid methyl ester
158) 3-(3-Fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1 -yl)-propoxy]-quinolin-4- yloxy}-phenylsulfamoyl)-thiophene-2-carboxylic acid methyl ester
159) 1 ,3,5-Trimethyl-1 H-pyrazole-4-sulfonic acid {3-fluoro-4-[6-methoxy-7-(3- piperidin-1-yl-propoxy)-quinolin-4-yloxy]-phenyl}-amide )) 1 ,3,5-Trimethyl-1 H-pyrazole-4-sulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(4- methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide
I ) 1 ,3,5-Trimethyl-1 H-pyrazole-4-sulfonic acid {3-fluoro-4-[6-methoxy-7-(3- morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenyl}-amide
I) 1 ,3,5-Trimethyl-1 H-pyrazole-4-sulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(4- methyl-piperazin-1 -yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide
J) 1-Methyl-1 H-pyrazole-3-sulfonic acid {3-fluoro-4-[6-methoxy-7-(3-piperidin-1 - yl-propoxy)-quinolin-4-yloxy]-phenyl}-amide
I·) 1 -Methyl-1 H-pyrazole-3-sulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(4-methyl- piperidin-1 -yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide
)) 1-Methyl-1 H-pyrazole-3-sulfonic acid {3-fluoro-4-[6-methoxy-7-(3-morpholin-
4-yl-propoxy)-quinolin-4-yloxy]-phenyl}-amide
)) 1 -Methyl-1 H-pyrazole-3-sulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(4-methyl- piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide
') 2-Methyl-3H-imidazole-4-sulfonic acid {3-fluoro-4-[6-methoxy-7-(3-piperidin-1- yl-propoxy)-quinolin-4-yloxy]-phenyl}-amide
}) 2-Methyl-3H-imidazole-4-sulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(4-methyl- piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide
)) 2-Methyl-3H-imidazole-4-sulfonic acid {3-fluoro-4-[6-methoxy-7-(3-morpholin-
4-yl-propoxy)-quinolin-4-yloxy]-phenyl}-amide
)) 2-Methyl-3H-imidazole-4-sulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(4-methyl- piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide
I ) 2,5-Difluoro-N-(4-{6-methoxy-7-[3-(4-methyl-piperidin-1 -yl)-propoxy]-quinolin-
4-yloxy}-3-methyl-phenyl)-benzenesulfonamide
) 2,6-Difluoro-N-(4-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-
4-yloxy}-3-methyl-phenyl)-benzenesulfonamide
2,6-Difluoro-N-(3-methoxy-4-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)- propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide
I) N-(4-{6-Methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-3- methyl-phenyl)-2-trifluoromethoxy-benzenesulfonamide
>) 2,5-Dichloro-N-(4-{6-methoxy-7-[3-(4-methyl-piperidin-1 -yl)-propoxy]-quinolin-
4-yloxy}-3-methyl-phenyl)-benzenesulfonamide
>) 2,6-Dichloro-N-(4-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-
4-yloxy}-3-methyl-phenyl)-benzenesulfonamide
r) N-{4-[7-(3-Dimethylamino-propoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro- phenyl}-2,5-difluoro-benzenesulfonamide
5) N-{4-[7-(3-Dimethylamino-propoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro- phenyl}-2,6-difluoro-benzenesulfonamide 179) N-{4-[7-(3-Dimethylamino-propoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro- phenyl}-2-trifluoromethoxy-benzenesulfonamide
180) 2,5-Dichloro-N-{4-[7-(3-dimethylamino-propoxy)-6-methoxy-quinolin-4-yloxy]- 3-fluoro-phenyl}-benzenesulfonamide
181 ) 2,6-Dichloro-N-{4-[7-(3-dimethylamino-propoxy)-6-methoxy-quinolin-4-yloxy]- 3-fluoro-phenyl}-benzenesulfonamide
182) 5-Chloro-thiophene-2-sulfonic acid {4-[7-(3-dimethylamino-propoxy)-6- methoxy-quinolin-4-yloxy]-3-fluoro-phenyl}-amide
183) N-(5-{4-[7-(3-Dimethylamino-propoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro- phenylsulfamoyl}-4-methyl-thiazol-2-yl)-acetamide
184) 3-{4-[7-(3-Dimethylamino-propoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro- phenylsulfamoyl}-thiophene-2-carboxylic acid methyl ester
185) Furan-2-sulfonic acid {4-[7-(3-dimethylamino-propoxy)-6-methoxy-quinolin-4- yloxy]-3-fluoro-phenyl}-amide
186) Thiophene-2-sulfonic acid {4-[7-(3-dimethylamino-propoxy)-6-methoxy- quinolin-4-yloxy]-3-fluoro-phenyl}-amide
187) 2,5-Difluoro-N-(4-fluoro-3-{6-methoxy-7-[3-(4-methyl-piperidin-1 -yl)-propoxy]- quinolin-4-yloxy}-phenyl)-benzenesulfonamide
188) 2,6-Difluoro-N-(4-fluoro-3-{6-methoxy-7-[3-(4-methyl-piperidin-1 -yl)-propoxy]- quinolin-4-yloxy}-phenyl)-benzenesulfonamide
189) N-(4-Fluoro-3-{6-methoxy-7-[3-(4-methyl-piperidin-1 -yl)-propoxy]-quinolin-4- yloxy}-phenyl)-2-trifluoromethyl-benzenesulfonamide
190) N-(4-Fluoro-3-{6-methoxy-7-[3-(4-methyl-piperidin-1 -yl)-propoxy]-quinolin-4- yloxy}-phenyl)-2-trifluoromethoxy-benzenesulfonamide
191 ) 2,5-Dichloro-N-(4-fluoro-3-{6-methoxy-7-[3-(4-methyl-piperidin-1 -yl)-propoxy]- quinolin-4-yloxy}-phenyl)-benzenesulfonamide
192) 2,6-Dichloro-N-(4-fluoro-3-{6-methoxy-7-[3-(4-methyl-piperidin-1 -yl)-propoxy]- quinolin-4-yloxy}-phenyl)-benzenesulfonamide
193) N-(2-Chloro-5-{6-methoxy-7-[3-(4-methyl-piperidin-1 -yl)-propoxy]-quinolin-4- yloxy}-phenyl)-2,5-difluoro-benzenesulfonamide
194) N-(2-Chloro-5-{6-methoxy-7-[3-(4-methyl-piperidin-1 -yl)-propoxy]-quinolin-4- yloxy}-phenyl)-2,6-difluoro-benzenesulfonamide
195) N-(2-Chloro-5-{6-methoxy-7-[3-(4-methyl-piperidin-1 -yl)-propoxy]-quinolin-4- yloxy}-phenyl)-2-trifluoromethyl-benzenesulfonamide
196) N-(2-Chloro-5-{6-methoxy-7-[3-(4-methyl-piperidin-1 -yl)-propoxy]-quinolin-4- yloxy}-phenyl)-2-trifluoromethoxy-benzenesulfonamide
197) 2,5-Dichloro-N-(2-chloro-5-{6-methoxy-7-[3-(4-methyl-piperidin-1 -yl)- propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide
ULA-P03071WO21 Application 198) 2,6-Dichloro-N-(2-chloro-5-{6-methoxy-7-[3-(4-methyl-piperidin-1 -yl)- propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide
199) 2,5-Difluoro-N-[3-fluoro-4-(6-methoxy-quinolin-4-yloxy)-phenyl]- benzenesulfonamide
200) 2,6-Difluoro-N-[3-fluoro-4-(6-methoxy-quinolin-4-yloxy)-phenyl]- benzenesulfonamide
201 ) N-[3-Fluoro-4-(6-methoxy-quinolin-4-yloxy)-phenyl]-2-trifluoromethyl- benzenesulfonamide
202) N-[3-Fluoro-4-(6-methoxy-quinolin-4-yloxy)-phenyl]-2-trifluoromethoxy- benzenesulfonamide
203) 2,5-Dichloro-N-[3-fluoro-4-(6-methoxy-quinolin-4-yloxy)-phenyl]- benzenesulfonamide
204) 2,6-Dichloro-N-[3-fluoro-4-(6-methoxy-quinolin-4-yloxy)-phenyl]- benzenesulfonamide
205) Naphthalene-2-sulfonic acid [3-fluoro-4-(6-methoxy-quinolin-4-yloxy)-phenyl]- amide
206) Cyclopropanesulfonic acid [3-fluoro-4-(6-methoxy-quinolin-4-yloxy)-phenyl]- amide
207) 2,5-Difluoro-N-(3-methoxy-4-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)- propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide
208) N-(3-Methoxy-4-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin- 4-yloxy}-phenyl)-2-trifluoromethyl-benzenesulfonamide
209) N-(3,5-Dichloro-4-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin- 4-yloxy}-phenyl)-2,6-difluoro-benzenesulfonamide
210) N-(3,5-Dichloro-4-{6-methoxy-7-[3-(4-methyl-piperidin-1 -yl)-propoxy]-quinolin- 4-yloxy}-phenyl)-2-trifluoromethyl-benzenesulfonamide
211 ) Acetic acid 4-{4-[4-(2,5-difluoro-benzenesulfonylamino)-2-fluoro-phenoxy]-6- methoxy-quinolin-7-yloxy}-butyl ester
212) Acetic acid 4-{4-[2-fluoro-4-(2-trifluoromethyl-benzenesulfonylamino)- phenoxy]-6-methoxy-quinolin-7-yloxy}-butyl ester
213) N-{2-Fluoro-4-[6-methoxy-7-(3-pyrrolidin-1-yl-propoxy)-quinolin-4-yloxy]- phenyl}-2-trifluoromethyl-benzenesulfonamide
214) N-{3-Fluoro-4-[6-methoxy-7-(4-morpholin-4-yl-butoxy)-quinolin-4-yloxy]- phenyl}-2-trifluoromethyl-benzenesulfonamide
215) N-(2-Fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1 -yl)-propoxy]-quinolin-4- yloxy}-phenyl)-2-trifluoromethyl-benzenesulfonamide
ULA-P03071WO21 Application The present invention also comprises pharmaceutically acceptable salts of the compounds according to the general formula (I), all stereoisomeric forms of the compounds according to the general formula (I) as well as solvates, especially hydrates or prodrugs thereof. A prodrug is commonly described as an inactive or protected derivative of an active ingredient or a drug, which is converted to the active ingredient or drug in the body.
In case, the inventive compounds bear basic and/or acidic substituents, they may form salts with organic or inorganic acids or bases. Examples of suitable acids for such acid addition salt formation are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, oxalic acid, malonic acid, salicylic acid, p-aminosalicylic acid, malic acid, fumaric acid, succinic acid, ascorbic acid, maleic acid, sulfonic acid, phosphonic acid, perchloric acid, nitric acid, formic acid, propionic acid, gluconic acid, lactic acid, tartaric acid, hydroxymaleic acid, pyruvic acid, phenylacetic acid, benzoic acid, p-aminobenzoic acid, p-hydroxybenzoic acid, methanesulfonic acid, ethanesulfonic acid, nitrous acid, hydroxyethanesulfonic acid, ethylenesulfonic acid, p-toluenesulfonic acid, naphthylsulfonic acid, sulfanilic acid, camphorsulfonic acid, china acid, mandelic acid, o-methylmandelic acid, hydrogen-benzenesulfonic acid, picric acid, adipic acid, d-o-tolyltartaric acid, tartronic acid, (o, m, p)-toluic acid, naphthylamine sulfonic acid, and other mineral or carboxylic acids well known to those skilled in the art. The salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt in the conventional manner. Examples for suitable inorganic or organic bases are, for example, NaOH, KOH, NH4OH, tetraalkylammonium hydroxide, lysine or arginine and the like. Salts may be prepared in a conventional manner using methods well known in the art, for example by treatment of a solution of the compound of the general formula (I) with a solution of an acid, selected out of the group mentioned above. Some of the compounds of the present invention may be crystallised or recrystallised from solvents such as aqueous and organic solvents. In such cases solvates may be formed. This invention includes within its scope stoichiometric solvates including hydrates as well as compounds containing variable amounts of water that may be produced by processes such as lyophilisation.
Certain compounds of the general formula (I) may exist in the form of optical isomers, e.g. diastereoisomers and mixtures of isomers in all ratios, e.g. racemic mixtures. The invention includes all such forms, in particular the pure isomeric forms. The different isomeric forms may be separated or resolved one from the
ULA-P03071WO21 Application other by conventional methods, or any given isomer may be obtained by conventional synthetic methods or by stereospecific or asymmetric syntheses. Where a compound according to the general formula (I) contains an alkene moiety, the alkene can be presented as a cis or trans isomer or a mixture thereof. When an isomeric form of a compound of the invention is provided substantially free of other isomers, it will preferably contain less than 5% w/w, more preferably less than 2% w/w and especially less than 1 % w/w of the other isomers.
Another aspect of the present invention relates to the use of the inventive quinolinyloxyphenylsulfonamide derivatives as drugs, i.d. as pharmaceutically active agents applicable in medicine.
The inventive quinolinyloxyphenylsulfonamides are useful for the treatment and/or prevention of AXL receptor tyrosine kinase induced disorders, wherein the AXL receptor tyrosine kinase induced disorders are selected from the group comprising hyperproliferative disorders, breast, colon, prostate, lung, gastric, ovarian, endometrial, renal, hepatocellular, thyroid, uterine cancer, esophageal carcinoma, squamous cell carcinoma, leukemia, osteosarcoma, melanoma, glioblastoma, and neuroblastoma.
Moreover the inventive quinolinyloxyphenylsulfonamides are useful for the preparation of a pharmaceutical formulation for prophylaxis, treatment and after- treatment cancer, tumors and cancer metastases. Thus, the quinolinyloxyphenylsulfonamide compounds of the present invention can be used for prophylaxis and treatment of various cancer types and especially of cancer metastases.
Furthermore, the compounds of the present invention are useful for the treatment and after-treatment of various cancer types such as adenocarcinoma, choroidal melanoma, acute leukemia, acoustic neurinoma, ampullary carcinoma, anal carcinoma, astrocytoma, basal cell carcinoma, pancreatic cancer, desmoid tumor, bladder cancer, bronchial carcinoma, breast cancer, Burkitt's lymphoma, corpus cancer, CUP-syndrome (carcinoma of unknown primary), colorectal cancer, small intestine cancer, small intestinal tumors, ovarian cancer, endometrial carcinoma, ependymoma, epithelial cancer types, Ewing's tumors, gastrointestinal tumors, gastric cancer, gallbladder cancer, gall bladder carcinomas, uterine cancer, cervical cancer, cervix, glioblastomas, gynecologic tumors, ear, nose and throat tumors, hematologic neoplasias, hairy cell leukemia, urethral cancer, skin cancer, skin testis cancer, brain tumors (gliomas), brain metastases, testicle cancer,
ULA-P03071WO21 Application hypophysis tumor, carcinoids, Kaposi's sarcoma, laryngeal cancer, germ cell tumor, bone cancer, colorectal carcinoma, head and neck tumors (tumors of the ear, nose and throat area), colon carcinoma, craniopharyngiomas, oral cancer (cancer in the mouth area and on lips), cancer of the central nervous system, liver cancer, liver metastases, leukemia, eyelid tumor, lung cancer, lymph node cancer (Hodgkin's/Non-Hodgkin's), lymphomas, stomach cancer, malignant melanoma, malignant neoplasia, malignant tumors gastrointestinal tract, breast carcinoma, rectal cancer, medulloblastomas, melanoma, meningiomas, Hodgkin's disease, mycosis fungoides, nasal cancer, neurinoma, neuroblastoma, kidney cancer, renal cell carcinomas, non-Hodgkin's lymphomas, oligodendroglioma, esophageal carcinoma, osteolytic carcinomas and osteoplastic carcinomas, osteosarcomas, ovarial carcinoma, pancreatic carcinoma, penile cancer, plasmocytoma, prostate cancer, pharyngeal cancer, rectal carcinoma, retinoblastoma, vaginal cancer, thyroid carcinoma, Schneeberger disease, esophageal cancer, spinalioms, T-cell lymphoma (mycosis fungoides), thymoma, tube carcinoma, eye tumors, urethral cancer, urologic tumors, urothelial carcinoma, vulva cancer, wart appearance, soft tissue tumors, soft tissue sarcoma, Wilm's tumor, cervical carcinoma and tongue cancer. Most active are the inventive compounds on lung cancer, lymph node cancer (Hodgkin's/Non-Hodgkin's), head and neck tumors (tumors of the ear, nose and throat area), breast cancer, ovarian cancer, gastric cancer, gastrointestinal tumors, intestinal tumors. Another aspect of the present invention is directed to the use of at least one quinolinyloxyphenylsulfonamide compound and/or pharmaceutically acceptable salts thereof for the preparation of a pharmaceutical formulation for prophylaxis, treatment and/or after-treatment of cancer, tumors and especially cancer metastases.
Still another aspect of the present invention is directed to pharmaceutical compositions comprising at least one quinolinyloxyphenylsulfonamide compound of the present invention as active ingredient, together with at least one pharmaceutically acceptable carrier, excipient and/or diluents. The pharmaceutical compositions of the present invention can be prepared in a conventional solid or liquid carrier or diluent and a conventional pharmaceutically- made adjuvant at suitable dosage level in a known way. The preferred preparations are adapted for oral application. These administration forms include, for example, pills, tablets, film tablets, coated tablets, capsules, powders and deposits.
Furthermore, the present invention also includes pharmaceutical preparations for parenteral application, including dermal, intradermal, intragastral, intracutan, intravasal, intravenous, intramuscular, intraperitoneal, intranasal, intravaginal, intrabuccal, percutan, rectal, subcutaneous, sublingual, topical, or transdermal application, which preparations in addition to typical vehicles and/or diluents contain at least one compound according to the present invention and/or a pharmaceutical acceptable salt thereof as active ingredient.
The pharmaceutical compositions according to the present invention containing at least one compound according to the present invention, and/or a pharmaceutical acceptable salt thereof as active ingredient will typically be administered together with suitable carrier materials selected with respect to the intended form of administration, i.e. for oral administration in the form of tablets, capsules (either solid filled, semi-solid filled or liquid filled), powders for constitution, extrudates, deposits, gels, elixirs, dispersable granules, syrups, suspensions, and the like, and consistent with conventional pharmaceutical practices. For example, for oral administration in the form of tablets or capsules, the active drug component may be combined with any oral non-toxic pharmaceutically acceptable carrier, preferably with an inert carrier like lactose, starch, sucrose, cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, talc, mannitol, ethyl alcohol (liquid filled capsules) and the like. Moreover, suitable binders, lubricants, disintegrating agents and coloring agents may also be incorporated into the tablet or capsule. Powders and tablets may contain about 5 to about 95 weight % of the quinolinyloxyphenylsulfonamide compound and/or the respective pharmaceutically active salt as active ingredient. Suitable binders include starch, gelatin, natural sugars, corn sweeteners, natural and synthetic gums such as acacia, sodium alginate, carboxymethylcellulose, polyethylene glycol and waxes. Among suitable lubricants there may be mentioned boric acid, sodium benzoate, sodium acetate, sodium chloride, and the like. Suitable disintegrants include starch, methylcellulose, guar gum, and the like. Sweetening and flavoring agents as well as preservatives may also be included, where appropriate. The disintegrants, diluents, lubricants, binders etc. are discussed in more detail below.
ULA-P03071WO21 Application Moreover, the pharmaceutical compositions of the present invention may be formulated in sustained release form to provide the rate controlled release of any one or more of the components or active ingredients to optimise the therapeutic effect(s), e.g. antihistaminic activity and the like. Suitable dosage forms for sustained release include tablets having layers of varying disintegration rates or controlled release polymeric matrices impregnated with the active components and shaped in tablet form or capsules containing such impregnated or encapsulated porous polymeric matrices. Liquid form preparations include solutions, suspensions, and emulsions. As an example, there may be mentioned water or water/propylene glycol solutions for parenteral injections or addition of sweeteners and opacifiers for oral solutions, suspensions, and emulsions. Liquid form preparations may also include solutions for intranasal administration. Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be present in combination with a pharmaceutically acceptable carrier such as an inert, compressed gas, e.g. nitrogen. For preparing suppositories, a low melting fat or wax, such as a mixture of fatty acid glycerides like cocoa butter is melted first, and the active ingredient is then dispersed homogeneously therein e.g. by stirring. The molten, homogeneous mixture is then poured into conveniently sized moulds, allowed to cool, and thereby solidified.
Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions, and emulsions.
The compounds according to the present invention may also be delivered transdermally. The transdermal compositions may have the form of a cream, a lotion, an aerosol and/or an emulsion and may be included in a transdermal patch of the matrix or reservoir type as is known in the art for this purpose.
The term capsule as recited herein refers to a specific container or enclosure made e.g. of methyl cellulose, polyvinyl alcohols, or denatured gelatins or starch for holding or containing compositions comprising the active ingredient(s). Capsules with hard shells are typically made of blended of relatively high gel strength gelatins from bones or pork skin. The capsule itself may contain small amounts of dyes, opaquing agents, plasticisers and/or preservatives. Under tablet a compressed or moulded solid dosage form is understood which comprises the active ingredients with suitable diluents. The tablet may be prepared by compression of mixtures or granulations obtained by wet granulation, dry granulation, or by compaction well known to a person of ordinary skill in the art. Oral gels refer to the active ingredients dispersed or solubilised in a hydrophilic semi-solid matrix. Powders for constitution refers to powder blends containing the active ingredients and suitable diluents which can be suspended e.g. in water or in juice.
Suitable diluents are substances that usually make up the major portion of the composition or dosage form. Suitable diluents include sugars such as lactose, sucrose, mannitol, and sorbitol, starches derived from wheat, corn rice, and potato, and celluloses such as microcrystalline cellulose. The amount of diluent in the composition can range from about 5 to about 95 % by weight of the total composition, preferably from about 25 to about 75 weight %, and more preferably from about 30 to about 60 weight %.
The term disintegrants refers to materials added to the composition to support break apart (disintegrate) and release the pharmaceutically active ingredients of a medicament. Suitable disintegrants include starches, "cold water soluble" modified starches such as sodium carboxymethyl starch, natural and synthetic gums such as locust bean, karaya, guar, tragacanth and agar, cellulose derivatives such as methylcellulose and sodium carboxymethylcellulose, microcrystalline celluloses, and cross-linked microcrystalline celluloses such as sodium croscaramellose, alginates such as alginic acid and sodium alginate, clays such as bentonites, and effervescent mixtures. The amount of disintegrant in the composition may range from about 2 to about 20 weight % of the composition, more preferably from about 5 to about 10 weight %.
Binders are substances which bind or "glue" together powder particles and make them cohesive by forming granules, thus serving as the "adhesive" in the formulation. Binders add cohesive strength already available in the diluent or bulking agent. Suitable binders include sugars such as sucrose, starches derived from wheat corn rice and potato, natural gums such as acacia, gelatin and tragacanth, derivatives of seaweed such as alginic acid, sodium alginate and ammonium calcium alginate, cellulose materials such as methylcellulose, sodium carboxymethylcellulose and hydroxypropylmethylcellulose, polyvinylpyrrolidone, and inorganic compounds such as magnesium aluminum silicate. The amount of binder in the composition may range from about 2 to about 20 weight % of the composition, preferably from about 3 to about 10 weight %, and more preferably from about 3 to about 6 weight %.
Lubricants refer to a class of substances which are added to the dosage form to enable the tablet granules etc. after being compressed to release from the mould
ULA-P03071WO21 Application or die by reducing friction or wear. Suitable lubricants include metallic stearates such as magnesium stearate, calcium stearate, or potassium stearate, stearic acid, high melting point waxes, and other water soluble lubricants such as sodium chloride, sodium benzoate, sodium acetate, sodium oleate, polyethylene glycols and D,L-leucine. Lubricants are usually added at the very last step before compression, since they must be present at the surface of the granules. The amount of lubricant in the composition may range from about 0.2 to about 5 weight % of the composition, preferably from about 0.5 to about 2 weight %, and more preferably from about 0.3 to about 1.5 weight % of the composition.
Glidents are materials that prevent caking of the components of the pharmaceutical composition and improve the flow characteristics of granulate so that flow is smooth and uniform. Suitable glidents include silicon dioxide and talc. The amount of glident in the composition may range from about 0.1 to about 5 weight % of the final composition, preferably from about 0.5 to about 2 weight %.
Coloring agents are excipients that provide coloration to the composition or the dosage form. Such excipients can include food grade dyes adsorbed onto a suitable adsorbent such as clay or aluminum oxide. The amount of the coloring agent may vary from about 0.1 to about 5 weight % of the composition, preferably from about 0.1 to about 1 weight %.
ULA-P03071WO21 Application EXPERIMENTAL PART
Examples 1 ) Analytical Methods (HPLC, NMR, TLC and melting point)
Analytical HPLC/MS was performed on an Waters HPLC/MS system using reverse phase
Method A: Waters XTerra MS C18 (5cm x 4.6mm, 5um), gradient 0-95% B (0.00 min 5 % B, 0.50 min 5 % B, 5.50 min 95 % B, 6.00 min 95 %B, 6.50 min 5 % B, 7.00 min 5 % B), Solvent A: Water/ 0.05% HCOOH, Solvent B: AcCN/ 0.05% HCOOH over 7.00 min, flow = 2.0 ml/min. Separation module was Waters Alliance 2795.
Method B: Waters X Waters XBridge C18 (5cm x 4.6mm, 3.5um), gradient 0-95% B (0.00 min 5 % B, 0.50 min 5 % B, 5.50 min 95 % B, 6.00 min 95 %
B, 6.50 min 5 % B, 7.00 min 5 % B), Solvent A: 5mM NH4HCO3, Solvent B: AcCN over 7.00 min, flow = 2.0 ml/min. Separation module was Waters Alliance 2795. UV spectra were recorded using a Waters 996 DAD UV detector. Mass spectra were obtained using Waters SQD MS detector (Ionization: ES7ES", Source block temp: 1 10 C, Desolvation temp: 250 °C, Desolvation Gas: 500 L/h, Cone Gas: 80 L/h, Capillary: 3000 V, Cone: 30 V, Extractor: 6 V, Rf Lens: 0.1 V, Scan: 80 to 1000 m/z in 1 sec, Inter-scan delay: 0.1 s).
1H NMR spectra were recorded on a Bruker Avanve 300 MHz AV spectrometer in deuterated solvents (DMSO-d6). Chemical shifts□ are in parts per million (ppm).
Thin-layer chromatography (TLC) analysis was performed with Kieselgel 60 F254 (Merck) plates and visualized using UV light.
Melting point measurement was Biichi melting Point B-54 instrument.
SYNTHESIS OF COMPOUNDS
First of all general methods will be presented for the synthesis of basic building blocks. In subsequent reactions these basic building blocks can be functionalized
ULA-P03071WO21 Application via common methods of organic syntheses to obtain the desired target compounds.
General Method 1 : Starting from 4-hydroxy-acetophenone derivatives
Figure imgf000050_0001
R2 has the meanings as disclosed herein and is, for instance, -OCH3.
Synthesis of 1-(4-Benzyloxy-3-methoxy-phenyl)-ethanone [A]
The mixture of 31.62 g (190 mmol) 1-(4-hydroxy-3-methoxy-phenyl)-ethanone, 16.36g (118mmol) potassium carbonate, 0.5g potassium iodide, 400ml acetone and 33.15 g (190 mmol) ml benzyl bromide were refluxed for 2 days. The solvent
ULA-P03071WO21 Application was evaporated, the residue was taken up in 400 ml of water. The precipitate was filtered, washed with 100 ml of sodium carbonate saturated aqueous solution and 2 x100 ml of water, then dried on air to give 47.8 g of product [A]. Yield 98%. Synthesis of 1-(4-Benzyloxy-5-methoxy-2-nitro-phenyl)-ethanone [B].
1-(4-Benzyloxy-3-methoxy-phenyl)-ethanone (24.61 g, 96 mmol) was dissolved in acetic acid (100 ml) and the mixture was cooled to 10°C. Nitric acid fuming (Fluka ID 84392, 100%, 10 ml, 240 mmol) was added dropwise to the cooled solution over 2 hours. The reaction mixture was allowed to come to room temperature and stirred for 16 hours. The reaction mixture was poured into water (400 ml). The precipitate was filtered, washed with water, then taken up in sodium hydrogencarbonate saturated aqueous solution (300 ml) and stirred for 2 hours. The precipitate was filtered, washed with water and dried. The raw product was recrystallized from ethyl alcohol (1000 ml) to give 18.25 g of product [B]. Yield 65%.
Synthesis of 1-(2-amino-4-benzyloxy-5-methoxv-phenvl)-ethanone [C].
A mixture of 1-(4-Benzyloxy-5-methoxy-2-nitro-phenyl)-ethanone (11.94 g 39.6 mmol), ammonium chloride (13.48 g, 250mmol), zinc powder (65.39 g, 1000 mmol), ethyl alcohol (720 ml) and water (70 ml) was refluxed until completion (5 hours). The mixture was filtered through celite and washed with hot ethyl alcohol. The filtrate was evaporated in vacuum. The residue was taken up in the mixture of chloroform (200 ml), water (200 ml) and the pH of this mixture was set to 8 by adding sodium hydroxide solutuion. The two layers were separated, the aqueous layer was extracted with chloroform (2 x 50 ml). The organic layers were combined, washed with water and over Na2SO4, and concentrated to give 9.25 product [C]. Yield 86%.
Synthesis of 7-benzyloxy-6-methoxy-1 H-quinolin-4-one [D].
A mixture of sodium methylate (270 mmol, 14.75 g, favorable prepared from sodium metal and methanol before use), 1 ,2-dimeythoxyethane (122 ml) and 1-(2- amino-4-benzyloxy-5-methoxv-phenvl)-ethanone (6.68 g 24 mmol) was stirred at 0°C for 1 hour. Ethyl formate (10.7 ml, 9.81 g, 132 mmol) was added to the reaction mixture, that was allowed to come to room temperature and stirred for further 4 hours. The mixture was diluted with water (50 ml) and acidified to pH 1 by adding hydrochloric acid (1 N, 185 ml). The precipitate was filtered, washed with water and dried to give 6.51 g of product [D]. Yield: 94%.
ULA-P03071WO21 Application Synthesis of 7-benzyloxy-4-chloro-6-methoxy-quinoline [E]
A mixture of 7-benzyloxy-6-methoxy-4-quinolone (9.72 g 34.5 mmol) and phosphorus oxychloride (130 ml) was stirred at 110 °C for 3 hours. The stirred mixture was concentrated at atmospheric pressure. The residue was dissolved in chloroform (150 ml), then ice and water was added to the solution. The mixture was rendered weakly alkaline by the addition of saturated sodium carbonate solution. The two phases were separated, the aqueous layer was extracted with chloroform. The extract was washed with water, dried over sodium sulfate, and the solvent was removed by evaporation under the reduced pressure. The residue was solidified under diisopropyl ether to give 9.82 g of product [E]. Yield: 94%.
Synthesis of 7-benzyloxy-4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-quinoline [F]. A mixture of 7-benzyloxy-4-chloro-6-methoxy-quinoline (2.04 g, 6.8 mmol), 2- fluoro-4-nitrophenol (2.34g 14.9 mmol) and chlorobenzene (40 ml) was stirred at reflux temperature for 2 days. The reaction mixture was cooled, diluted with saturated sodium carbonate solution (30ml) and stirred for 3 hours. The precipitate was filtered and the filtrate was separated. The aqueous layer was extracted with chloroform (3x30 ml). The organic layers were combined, washed with water and dried over sodium sulfate. The solvent was removed by evaporation under the reduced pressure. The residue was purified by column chromatography. The pure product was solidified under diisopropyl ether to give 1.11 g of product [F]. Yield: 39%. Synthesis of 4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-quinolin-7-ol [G]
7-Benzyloxy-4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-quinoline (2.75 g, 6.54 mmol) was added slowly in portion into hydrobromic acid solution (33% in acetic acid, 45 ml). The mixture was stirred at room temperature for 2 hours, then poured into diethyl ether (300 ml). The precipitate was filtered and washed with diethyl ether. The solid hydrobromide salt was stirred in the mixture of sodium acetate aqueous solution (10%, 60 ml) and ethyl acetate (15 ml) for 1 day. The precipitate was filtered, washed with water and dried to give 1.82 g of product [G]. Yield: 86%
The free hydroxy group of compound [G] was substituted with the residue R8-X- by an etherification reaction or a nucleophilic substitution to result in compound [H]. For the coupling, for reagent could be used chloroalkyl- (Cl-X-R8), bromoalkyl (Br-X-R8) or mesylate (MeS02-X-R8) derivatives as well.
ULA-P03071WO21 Application Alternatively, the preparation of compound H can be prepared with an another method. Some potential intermediate - H-1 , H-2, H-3 - are described in the literature that can be used for preparing the corresponding H compound, see J. Med. Chem. 2008, 51 (18), 5766-5779 (Noel D. Angelo et. Al.).
Figure imgf000053_0001
The nitro group of compound [H] was reduced to the amino group as described above for compound [C]. The preparation of the sulfonamide group is described below.
ULA-P03071WO21 Application General Method: Starting from 3-hydroxy-acetophenone derivatives
Figure imgf000054_0001
[ Η' ]
R1 has the meanings as disclosed herein and is, for instance, -OCH3.
The D' compound can be prepared in the similar manner as described patent US 2005/0029264, Example 13 (Atsushi Miwa et al.). General Method 2: Starting from aniline derivatives
Figure imgf000055_0001
R2 has the meanings as disclosed herein and is, for instance, -OCH3.
For some embodiments, compounds, showed in Reaction Scheme can be prepared according to the described literature. For example the preparation of compound D (where R2 is a hydrogen atom) is described in the patent WO 2005/032484, Example 1 (Lindstrom Kyle et al.).
In certain embodiments, benzyloxy group is at the position 6 in the quinoline ring and can be prepared in the similar manner [WO 2005/032484, Example 2 (Lindstrom Kyle et al.)]:
Figure imgf000055_0002
ULA-P03071WO21 Application General procedure for sulfonamide compounds
Figure imgf000056_0001
0.31 mmol appropriately substituted sulfonylchloride and 0.3 mmol appropriately substituted 4-(4-amino-phenoxy)quinoline derivative was dissolved 3 ml abs. pyridine and stirred while the starting amine disappears according to the TLC (at room temperature 1-21 days or at 60°C for 24 hours). The reaction mixture was poured into 50 ml of water and extracted with 3x30 ml of chloroform. The organic phase was washed with water, dried over anhydrous sodium sulfate, filtrated and evaporated. The residue was purified on TLC plate (saturated with vapour of NH4OH, eluent chloroform-methanol 9:1 ). The pure product was solidified under diisopropyl ether.
General procedure for modification of sulfonamide compounds
There are some other possibilities to modify the sulfonamide derivatives. For example using a protected aminoalkyl reagent we could prepare the protected derivative [G+3]. After removing the protective group the free amine [G+4] can be prepared, which is convenient material for produce further derivatives, e.g. react with isocyanate or with aldehyde or ketone (reductive alkylation).
Figure imgf000057_0001
The synthesis is equivalent to the above reaction scheme for these inventive compounds wherein R2 represents R8-X-. The general reaction scheme is shown below. The single reaction protocols are the same as disclosed above.
Example 1
2,5-Difluoro-N-{3-fluoro-4-[6-methoxy-7-(3-pipehdin-1-yl-propoxy)-quinolin-4- yloxy]-phenyl}-benzenesulfonamide
Figure imgf000057_0002
C3oH3oF3N305S Mw. 601 .65
LC/MS purity: 99 %, m/z 600 [M-H]", 602 [M+H]+ Rt. 3.12 min.(Method B)
1H NMR (300 MHz, DMSO-d6): 9.0 (bs, 1 H), 8.41 (d, 1 H), 7.61-7.03 (m, 8H), 6.30 (d, 1 H), 4.26 (t, 2H), 3.97 (s, 3H), 3.40 (bs, 2H), 3.33 (bs, 2H), 2.45 (bs, 2H), 2.1 1 (bs, 6H), 1.63 (bs, 2H).
Melting point: 206-208 °C.
Yield: 46 % Example 2
2-Fluoro-N-{3-fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4-yloxy]- phenylj-benzenesul
Figure imgf000058_0001
C30H31 F2N3O5S Mw. 583.66
LC/MS purity: 99 %, m/z 582 [M-H]" , 584 [M+H]+ Rt. 3.18 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 9.2 (bs, 1 H), 8.43 (d, 1 H), 7.84 (t, 1 H), 7.60 (d, 1 H), 7.47 (s, 1 H), 7.32 (m, 3H), 7.18 (t, 1 H), 6.99 (d, 1 H), 6.87 (d, 1 H), 6.33 (d, 1 H), 4.18 (t, 2H), 3.92 (s, 3H), 2.43 (bs, 6H), 1.96 (t, 2H), 1.52 (bs, 4H), 1 .40 (bs, 2H).
Melting point: 214-216 °C.
Yield: 38 %
Example 3
4-Chloro-2-fluoro-N-{3-fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4- yloxy]-phenyl}-ben
Figure imgf000058_0002
ULA-P03071WO21 Application C30H30CIF2N3O5S Mw.618.10
LC/MS purity: 100 %, m/z 616 [M-H]", 618 [M+H]+ Rt.3.32 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 9.8 (bs, 1H), 8.43 (d, 1H), 7.82 (t, 1H), 7.56 (dd, 1H), 7.49 (s, 1H), 7.39 (m, 2H), 7.15 (t, 1H), 6.96 (dd, 1H), 6.82 (d, 1H), 6.35 (d, 1H), 4.19 (t, 2H), 3.92 (s, 3H), 2.58 (m, 6H), 2.02 (m, 2H), 1.56 (m, 4H), 1.43 (m, 2H).
Melting point: 122-124 °C.
Yield: 36 % Example 4
N-{3-Fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4-yloxy]-phenyl}-2- trifluoromethyl-ben
Figure imgf000059_0001
C31H31F4N3O5S Mw.633.67
LC/MS purity: 100 %, m/z 632 [M-H]" , 634 [M+H]+ Rt.3.36 min. (Method B)
H NMR (300 MHz, DMSO-d6): 10.0 (bs, 1H), 8.45 (d, 1H), 8.14 (d, 1H), 7.93 (d, 1H), 7.78 (m, 2H), 7.48 (s, 1H), 7.38 (s, 1H), 7.21 (t, 1H), 7.00 (dd, 1H), 6.88 (d, 1H), 6.36 (d, 1H), 4.19 (t, 2H), 3.64 (s, 3H), 2.62 (m, 6H), 2.03 (m, 2H), 1.59 (m, 4H), 1.44 (m, 2H).
Melting point: 173-175 °C.
Yield: 48%
Example 5
N-{3-Fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4-yloxy]-phenyl}-3- trifluoromethyl-benzenesulfonamide
Figure imgf000059_0002
C31H31F4N3O5S Mw.633.67 LC/MS purity: 100 %, m/z 632 [M-H]", 634 [M+H]+ Rt. 3.34 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 9.8 (bs, 1 H), 8.43 (d, 1 H), 8.00 (m, 3H), 7.78 (t, 2H), 7.48 (s, 1 H), 7.38 (s, 1 H), 7.22 (t, 1 H), 7.04 (dd, 1 H), 6.89 (d, 1 H), 6.32 (d, 1 H), 4.19 (t, 1 H), 3.92 (s, 3H), 2.64 (m, 6H), 2.02 (m, 2H), 1.56 (m, 4H), 1.44 (m, 2H).
Melting point: 123-126 °C.
Yield: 61 %
Example 6
2,6-Dichloro-N-{3-fluoro-4-[6-methoxy-7-(3-pipehdin-1 -yl-propoxy)-quinolin-4- yloxy]-phenyl}-benzenesulfonamide
Figure imgf000060_0001
C30H30CI2FN3O5S Mw. 634.56
LC/MS purity: 99 %, m/z 632 [M-H]', 634 [M+H]+ Rt. 3.31 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 9.8 (bs, 1 H), 8.42 (d, 1 H), 7.48 (m, 3H), 7.37 (m, 2H), 7.08 (t, 1 H), 6.90 (d, 1 H), 6.73 (d, 1 H), 6.33 (d, 1 H), 4.18 (t, 2H), 3.92 (s, 3H), 2.52 (m, 6H), 1.99 (m, 2H), 1.53 (m, 4H), 1.41 (m, 2H).
Melting point: 206-208 °C.
Yield: 35 %
Example 7
N-{3-Fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin4-yloxy]-phenyl}-2- nitro-benzenesulfonamide
Figure imgf000060_0002
C30H31FN4O7S Mw. 610.67
LC/MS purity: 100 %, m/z 609 [M-H]', 611 [M+H]+ Rt. 2.99 min. (Method B) 1H NMR (300 MHz, DMSO-d6): 11 (bs, 1 H), 8.43 (d, 1 H), 7.93 (t, 1 H), 7.65 (m, 3H), 7.49 (s, 1 H), 7.38 (s, 1 H), 7.06 (t, 1 H), 6.84 (dd, 1 H), 6.72 (d, 1 H), 6.35 (d, 1 H), 4.20 (t, 2H), 3.93 (s, 3H), 2.71 (bs, 6H), 2.07 (m, 2H), 1.60 (bs, 4H), 1.46 (bs, 2H).
Melting point: 113-116 °C.
Yield: 41 %
Example 8
Biphenyl-3-sulfonic acid {3-fluoro-4-[6-methoxy-7-(3-piperidin-1 -yl-propoxy)- quinolin-4-loxy]-phenyl}-amide
Figure imgf000061_0001
C36H36FN3O5S Mw. 641.77
LC/MS purity: 100 %, m/z 640 [M-H]" f 642 [M+H]+ Rt. 3.95 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 10.6 (bs, 1 H), 8.37 (d, 1 H), 8.03 (s, 1 H), 7.95 (d, 1 H), 7.79 (d, 1 H), 7.68 (m, 3H), 7.49 (m, 4H), 7.37 (s, 1 H), 7.32 (t, 1 H), 7.16 (dd, 1 H), 7.00 (d, 1 H), 6.28 (d, 1 H), 4.17 (t, 2H), 3.90 (s, 3H), 2.44 (bs, 6H), 1.97 (m, 2H), 1.53 (bs, 4H), 1.39 (m, 2H).
Melting point: 113-115 °C.
Yield: 47 %
Example 9
3- Difluoromethoxy-N-{3-fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-
4- yloxy]-phenyl}-benzenesulfonamide
Figure imgf000061_0002
C3iH32F3N3O6S Mw. 631.68
LC/MS purity: 100 %, m/z 630 [M-H]", 632 [M+H]+ Rt. 3.44 min. (Method B) 1H NMR (300 MHz, DMSO-d6): 10.2 (bs, 1 H), 8.43 (d, 1 H), 8.66-7.21 (m, 7H), 7.05 (d, 1 H), 6.91 (d, 1 H), 6.33 (d, 1 H), 4.18 (t, 2H), 3.92 (s, 3H), 3.59 (m,1 H), 2.52 (bs, 6H), 1.99 (m, 2H), 1.52 (bs, 4H), 1.41 (m, 2H).
Melting point: 105-106 °C.
Yield: 77 %
Example 10
N-{3-Fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4-yloxy]-phenyl}-3- phenoxy-benzenesulfonamide
Figure imgf000062_0001
CaeHseFNaOsS Mw. 657.77
LC/MS purity: 97 %, m/z 656 [M-H]", 658 [M+H]+ Rt. 3.93 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 10.4 (bs, 1 H), 8.43 (d, 1 H), 7.58-7.24 (m, 10H), 7.07-6.90 (m, 4H), 6.35 (d, 1 H), 4.18 (t, 2H), 3.93 (s, 3H), 2.49 (bs, 6H), 1.99 (bs, 2H), 1.53 (bs, 4H), 1.41 (bs, 2H).
Melting point: 146-147 °C.
Yield: 38 %
Example 11
2,6-Difluoro-N-{3-fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4- yloxy]-phenyl}-ben
Figure imgf000062_0002
C30H30F3N3O5S Mw. 601.65
LC/MS purity: 98 %, m/z 600 [M-H]", 602 [M+H]+ Rt. 2.99 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 10.2 (bs, 1 H), 8.44 (d, 1 H), 7.59 (t, 1 H), 7.49 (s, 1 H), 7.39 (s, 1 H), 7.20 (m, 3H), 7.04 (d, 1 H), 6.89 (d, 1 H), 6.35 (d, 1 H), 4.20 (t, 2H), 3.92 (s, 3H), 2.70 (bs, 6H), 2.06 (bs, 2H), 1.45 (bs, 4H), 1.24 (bs, 2H). Melting point: 242-244 °C.
Yield: 27 %
Example 12
2,5-Difluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]- quinolin-4-yloxy}-ph
Figure imgf000063_0001
C30H31 F3N4O5S Mw. 616.66
LC/MS purity: 99 %, m/z 615 [M-H]", 617 [M+H]+ Rt. 2.91 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 10.3 (bs, 1 H), 8.43 (d, 1 H), 7.60 (m, 1 H), 7.42 (m, 4H), 7.19 (t, 1 H), 7.02 (dd, 1 H), 6.88 (d, 1 H), 6.35 (d, 1 H), 4.18 (t, 2H), 4.01 (bs, 4H), 3.92 (s, 3H), 3.35 (bs, 6H), 2.26 (s, 3H), 1.95 (m, 2H).
Melting point: 124-126 °C.
Yield: 24 %
Example 13
Biphenyl-3-sulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1 -yl)- propoxy]-quinolin-4
Figure imgf000063_0002
C36H37FN4O5S Mw. 656.78
LC/MS purity: 97 %, m/z 655 [M-H]", 657 [M+H]+ Rt. 3.71 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 10.5 (bs, 1 H), 8.36 (d, 1 H), 8.03 (d, 1 H), 7.96 (t,
1 H), 7.79 (d, 1 H), 7.67 (m, 3H), 7.52-7.12 (m, 6H), 7.04 (dd, 1 H), 6.90 (d, 1 H),
6.28 (d, 1 H), 4.17 (t, 2H), 3.93 (s, 3H), 2.40 (bs, 10H), 2.19 (s, 3H), 1.96 (t, 2H).
Melting point: 190-191 °C.
Yield: 40 % Example 14
N-(3-Fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1 -yl)-propoxy]-quinolin-4- yloxy}-phenyl)-3-ph
Figure imgf000064_0001
C36H37FN4O6S Mw. 672.78
LC/MS purity: 97 %, m/z 671 [M-H]", 673 [M+H]+ Rt. 3.68 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 1 1 (bs, 1 H), 8.43 (s, 1 H), 7.62-7.23 (m, 10H), 7.10-6.92 (m, 4H), 6.35 (d, 1 H), 4.18 (t, 2H), 3.93 (s, 3H), 2.47 (m, 4H), 2.40 (m, 6H), 2.19 (s, 3H), 1 .96 (t, 2H).
Melting point: 140-141 °C.
Yield: 24 %
Example 15
2-Cyano-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]- quinolin-4-yloxy}-ph
Figure imgf000064_0002
C-3iH32FN505S Mw. 605.69
LC/MS purity: 99 %, m/z 604 [M-H]\ 606 [M+H]+ Rt. 2.73 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 10.6 (bs, 1 H), 8.44 (d, 1 H), 7.50 (m, 3H), 7.37 (m, 3H), 7.28 (t, 1 H), 7.10 (d, 1 H), 6.96 (d, 1 H), 6.34 (d, 1 H), 4.17 (t, 2H), 3.92 (s, 3H), 2.44 (m, 4H), 2.36 (m, 6H), 2.16 (s, 3H), 1.94 (m, 2H).
Melting point: 109-1 1 1 °C.
Yield: 22 % Example 16
2,4-Difluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]- quinolin-4-yloxy}-phenyl)-benzenesulfonamide
Figure imgf000065_0001
C3oH3i F3N4O5S Mw. 616.66
LC/MS purity: 99 %, m/z 615 [M-H]", 617 [M+H]+ Rt. 2.93 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 10 (bs, 1 H), 8.43 (d, 1 H), 7.93 (t, 1 H), 7.47 (m, 2H), 7.36 (s, 1 H), 7.22 (m, 2H), 7.08 (dd, 1 H), 6.92 (dd, 1 H), 6.34 (d, 1 H), 4.18 (t, 2H), 3.92 (s, 3H), 2.44 (m, 4H), 2.36 (m, 6H), 2.18 (s, 3H), 1.96 (t, 2H).
Melting point: 99-102 °C.
Yield: 42 %
Example 17
2,3,4-Trifluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]- quinolin-4-yloxy}-phenyl)-benzenesulfonamide
Figure imgf000065_0002
C3oH3oF4N405S Mw. 634.65
LC/MS purity: 98 %, m/z 633 [M-H]\ 635 [M+H]+ Rt. 2.98 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 10.2 (bs, 1 H), 8.44 (d, 1 H), 7.92 (d, 1 H), 7.80 (d, 1 H), 7.77 (t, 1 H), 7.48 (s, 1 H), 7.38 (s, 1 H), 7.26 (t, 1 H), 7.02 (d, 1 H), 6.36 (d, 1 H), 4.21 (t, 2H), 3.98 (s, 3H), 2.45 (m, 4H), 2.36 (m, 6H), 2.18 (s, 3H), 1.95 (t, 2H). Melting point: 88-90 °C.
Yield: 45 %
Example 18
4-Fluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin- 4-yloxy}-phenyl)-3-methoxy-benzenesulfonamide
ULA-P03071WO21 Application
Figure imgf000066_0001
C31H34F2N4O6S Mw. 628.70
LC/MS purity: 99 %, m/z 627 [M-H]", 629 [M+H]+ Rt. 3.19 min. (Method B)
H NMR (300 MHz, DMSO-d6): 10.9 (bs, 1 H), 8.44 (d, 1 H), 7.52-7.28 (m, 6H), 7.10 (d, 1 H), 6.94 (dd, 1 H), 6.34 (d, 1 H), 4.17 (t, 2H), 3.92 (s, 3H), 3.88 (s, 3H), 2.44 (m, 4H), 2.37 (m, 6H), 2.19 (s, 3H), 1.94 (t, 2H).
Melting point: 167-169 °C.
Yield: 60 %
Example 19
2-Bromo-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]- quinolin-4-yloxy}-phenyl)-benzenesulfonamide
Figure imgf000066_0002
C3oH32BrFN4O5S Mw. 659.58
LC/MS purity: 98 %, m/z 657 [M-H]", 659 [M+H]+ Rt. 3.17 min. (Method B)
H NMR (300 MHz, DMSO-d6): 10.5 (bs, 1 H), 8.43 (d, 1 H), 8.11 (d, 1 H), 7.81 (d, 1 H), 7.57-7.46 (m, 3H), 7.36 (s, 1 H), 7.26 (t, 1 H), 7.05 (d, 1 H), 6.94 (d, 1 H), 6.34 (d, 1 H), 4.17 (t, 2H), 3.91 (s, 3H), 2.45 (bs, 10H), 2.20 (s, 3H), 1.95 (t, 2H).
Melting point: 98-101 °C.
Yield: 40 %
Example 20
2,5-Dichloro-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]- quinolin-4-yloxy}-phenyl)-benzenesulfonamide
ULA-P03071WO21 Application
Figure imgf000067_0001
C3oH3iCl2FN4O5S Mw. 649.57
LC/MS purity: 98 %, m/z 647 [M-H]", 649 [M+H]+ Rt. 3.20 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 11 (bs, 1 H), 8.42 (d, 1 H), 7.98 (bs, 1 H), 7.60 (bs, 2H), 7.48 (bs, 1 H), 7.38 (bs, 1 H), 7.18 (t, 1 H), 6.98 (d, 1 H), 6.85 (d, 1 H), 6.34 (d, 1 H), 4.18 (t, 2H), 3.92 (s, 3H), 2.50 (bs, 10H), 2.28 (s, 3H), 1.78 (m, 2H).
Melting point: 134-136 °C.
Yield: 38 %
Example 21
N-(3-Fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4- yloxy}-phenyl)-2-nitro-benzenesulfonamide
Figure imgf000067_0002
C3oH32FN5O7S Mw. 625.68
LC/MS purity: 99 %, m/z 624 [M-H]", 626 [M+H]+ Rt. 2.81 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 10.4 (bs, 1 H), 8.43 (d, 1 H), 7.96 (m, 1 H), 7.77 (m, 1 H), 7.70 (m, 2H), 7.48 (s, 1 H), 7.37 (s, 1 H), 7.15 (t, 1 H), 6.94 (d, 1 H), 6.79 (d, 1 H), 6.35 (d, 1 H), 4.18 (t, 2H), 3.92 (s, 3H), 2.73 (m, 4H), 2.54 (m, 6H), 2.35 (s, 3H), 1.98 (m, 2H).
Melting point: 125-128 °C.
Yield: 29 %
Example 22
3-Fluoro-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4- yloxy}-phenyl)-benzenesulfonamide
Figure imgf000068_0001
C30H32F2N4O5S Mw. 598.67
LC/MS purity: 99 %, m/z 597 [M-H]", 599 [M+H]+ Rt. 3.07 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 10.9 (bs, 1 H), 8.44 (d, 1 H), 7.63-7.47 (m, 5H), 7.37 (s, 1 H), 7.29 (t, 1 H), 7.00 (dd, 1 H), 6.94 (d, 1 H), 6.35 (d, 1 H), 4.17 (t, 2H), 3.92 (s, 3H), 2.45 (m, 10H), 2.20 (s, 3H), 1.96 (m, 2H).
Melting point: 82-84 °C.
Yield: 48 %
Example 23
3-Chloro-4-fluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)- propoxy]-quinolin-4
C30H31CIF2N4O5S Mw. 633.12
LC/MS purity: 98 %, m/z 631 [M-H]", 633 [M+H]+ Rt. 3.24 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 10.5 (bs, 1 H), 8.44 (d, 1 H), 7.91 (dd, 1 H), 7.77 (m, 1 H), 7.59 (t, 1 H), 7.48 (s, 1 H), 7.37 (s, 1 H), 7.25 (t, 1 H), 7.06 (d, 1 H), 6.90 (d, 1 H), 6.36 (d, 1 H), 4.18 (t, 2H), 3.92 (s, 3H), 2.46 (bs, 10H), 2.22 (s, 3H), 1.96 (m, 2H). Melting point: 108-110 °C.
Yield: 57 %
Example 24
N-(3-Fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4- yloxy}-phenyl)-2-trifluoromethyl-benzenesulfonamide
Figure imgf000069_0001
C3iH32F4N405S Mw. 648.68
LC/MS purity: 99 %, m/z 647 [M-H]", 649 [M+H]+ Rt. 3.11 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 11 (bs, 1 H), 8.44 (d, 1 H), 8.14 (d, 1 H), 7.95 (d, 1 H), 7.80 (m, 2H), 7.47 (s, 1 H), 7.36 (s, 1 H), 7.24 (t, 1 H), 7.02 (dd, 1 H), 6.90 (d, 1 H), 6.35 (d, 1 H), 4.17 (t, 2H), 3.91 (s, 3H), 2.45 (bs, 10H), 2.23 (s, 3H), 1.96 (m, 2H).
Melting point: 102-106 °C.
Yield: 26 %
Example 25
N-(3-Fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4- yloxy}-phenyl)-2-trifl
Figure imgf000069_0002
C31H32F4N4O6S Mw. 664.68
LC/MS purity: 100 %, m/z 663 [M-H]-, 665 [M+H]+ Rt. 3.26 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 9.8 (bs, 1 H), 8.44 (d, 1 H), 8.01 (d, 1 H), 7.73 (t, 1 H), 7.52 (m, 2H), 7.47 (s, 1 H), 7.36 (s, 1 H), 7.26 (t, 1 H), 7.07 (d, 1 H), 6.91 (d, 1 H), 6.33 (d, 1 H), 4.18 (t, 2H), 3.91 (s, 3H), 2.44 (bs, 10H), 2.23 (s, 3H), 1.96 (m, 2H).
Melting point: 86-90 °C.
Yield: 23 %
Example 26
2-Fluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin- 4-yloxy}-phenyl)-benzenesulfonamide
ULA-P03071WO21 Application
Figure imgf000070_0001
C30H32F2N4O5S Mw. 598.67
LC/MS purity: 100 %, m/z 597 [M-H]", 599 [M+H]+ Rt. 2.85 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 11.5 (bs, 1 H), 8.43 (d, 1 H), 7.88 (t, 1 H), 7.68 (d, 1 H), 7.47-7.28 (m, 5H), 7.09 (d, 1 H), 6.96 (d, 1 H), 6.33 (d, 1 H), 4.17 (t, 2H), 3.91 (s, 3H), 2.43 (bs, 10H), 2.20 (s, 3H), 1.96 (m, 2H).
Melting point: 185-186 °C.
Yield: 28 %
Example 27
4-Chloro-2-fluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)- propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide
Figure imgf000070_0002
C3oH3iCIF2N405S Mw. 633.12
LC/MS purity: 100 %, m/z 631 [M-H]", 633 [M+H]+ Rt. 3.05 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 10 (bs, 1 H), 8.44 (d, 1 H), 7.85 (t, 1 H), 7.63 (d, 1 H), 7.48 (s, 1 H), 7.43 (d, 1 H), 7.37 (s, 1 H), 7.22 (t, 1 H), 7.04 (d, 1 H), 6.89 (d, 1 H), 6.35 (d, 1 H), 4.18 (t, 2H), 3.92 (s, 3H), 2.50 (bs, 10H), 2.25 (s, 3H), 1.98 (m, 2H).
Melting point: 106-110 °C.
Yield: 26 %
Example 28
N-(3-Fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4- yloxy}-phenyl)-2-methyl-benzenesulfonamide
ULA-P03071WO21 Application
Figure imgf000071_0001
C31H35FN4O5S Mw.594.71
LC/MS purity: 99 %, m/z 593 [M-H]", 595 [M+H]+ Rt.3.28 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 11 (bs, 1H), 8.43 (d, 1H), 7.91 (t, 1H), 7.53-7.24 (m, 6H), 7.05 (d, 1H), 6.94 (d, 1H), 6.32 (d, 1H), 4.17 (t, 2H), 3.91 (s, 3H), 2.62 (s, 3H), 2.40 (m, 10H), 2.16 (s, 3H), 1.95 (m, 2H).
Melting point: 73-75 °C.
Yield: 35 % Example 29
2-Chloro-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]- quinolin-4-yloxy}-ph
Figure imgf000071_0002
C3oH32CIFN405S Mw.615.13
LC/MS purity: 99 %, m/z 613 [M-H]", 615 [M+H]+ Rt.3.09 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 11.2 (bs, 1H), 8.43 (d, 1H), 8.08 (d, 1H), 7.62 (m, 2H), 7.52 (m, 1H), 7.46(s, 1H), 7.36 (s, 1H), 7.26 (t, 1H), 7.06 (dd, 1H), 6.94 (d, 1H), 6.32 (d, 1H), 4.17 (t, 2H), 3.91 (s, 3H), 2.43 (m, 10H), 2.19 (s, 3H), 1.96 (m, 2H).
Melting point: 96-98 °C.
Yield: 36 %
Example 30
3-Difluoromethoxy-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)- propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide
Figure imgf000072_0001
C31H33F3N4O6S Mw. 646.69
LC/MS purity: 100 %, m/z 645 [M-H]", 647 [M+H]+ Rt. 3.15 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 10.4 (bs, 1 H), 7.65-7.26 (m, 8H), 7.09 (d, 1 H), 6.95 (d, 1 H), 6.33 (d, 1 H), 4.17 (t, 2H), 3.92 (s, 3H), 3.51 (m, 1 H), 2.43 (m, 10H), 2.20 (s, 3H), 1.96 (m, 2H).
Melting point: 95-97 °C.
Yield: 41 % Example 31
Thiophene-2-sulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1 -yl)- propoxy]-quinolin-4
Figure imgf000072_0002
C28H3i FN405S2 Mw. 586.71
LC/MS purity: 99 %, m/z 585 [M-H]", 587 [M+H]+ Rt. 2.81 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 10.1 (bs, 1 H), 8.45 (d, 1 H), 7.88 (d, 1 H), 7.56 (d, 1 H), 7.49 (s, 1 H), 7.38(s, 1 H), 7.32 (t, 1 H), 7.13 (m, 2H), 7.00 (d, 1 H), 6.36 (d, 1 H), 4.18 (t, 2H), 3.93 (s, 3H), 2.43 (m, 10H), 2.21 (s, 3H), 1.96 (m, 2H).
Melting point: 201-202 °C.
Yield: 46 %
Example 32
2,6-Dichloro-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]- quinolin-4-yloxy}-phenyl)-benzenesulfonamide
ULA-P03071WO21 Application
Figure imgf000073_0001
C30H31CI2FN4O5S Mw. 649.57
LC/MS purity: 99 %, m/z 647 [M-H]", 649 [M+H]+ Rt. 3.03 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 10.4 (bs, 1 H), 8.43 (d, 1 H), 7.59 (m, 2H), 7.48 (m, 2H), 7.36 (s, 1 H), 7.25 (t, 1 H), 7.05 (d, 1 H), 6.90 (d, 1 H), 6.33 (d, 1 H), 4.18 (t, 2H), 3.91 (s, 3H), 2.50 (bs, 10H), 2.20 (s, 3H), 1.97 (m, 2H).
Melting point: 1 13-1 16 °C.
Yield: 38 % Example 33
N-(3-Fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1 -yl)-propoxy]-quinolin-4- yloxy}-phenyl)-2-m
Figure imgf000073_0002
C31H35FN4O6S Mw. 610.71
LC/MS purity: 97 %, m/z 609 [M-H]", 61 1 [M+H]+ Rt. 3.33 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 10.3 (bs, 1 H), 8.42 (d, 1 H), 7.82 (d, 1 H), 7.62 (t, 1 H), 7.45 (s, 1 H), 7.36(s, 1 H), 7.31 (s, 1 H), 7.21 (d, 1 H), 7.14-6.99 (m, 3H), 6.28 (d, 1 H), 4.17 (t, 2H), 3.90 (s, 6H), 2.39 (m, 10H), 2.15 (s, 3H), 1.94 (m, 2H).
Melting point: 168-170 °C.
Yield: 36 %
Example 34
3,5-Dichloro-N-{3-fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4- yloxy]-phenyl}-2-methoxy-benzenesulfonamide
ULA-P03071WO21 Application
Figure imgf000074_0001
C31H32CI2FN3O6S Mw. 664.59
LC/MS purity: 97 %, m/z 662 [M-H]", 664 [M+H]+ Rt. 3.91 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 10.5 (bs, 1 H), 8.44 (d, 1 H), 7.88 (bs, 1 H), 7.76 (bs, 1 H), 7.49 (s, 1 H), 7.38 (s, 1 H), 7.20 (t, 1 H), 7.02 (d, H), 6.87 (d, 1 H), 6.36 (d, 1 H), 4.19 (t, 2H), 3.92 (s, 6H), 2.61 (bs, 6H), 2.03 (bs, 2H), 1 .90 (bs, 4H), 1 .80 (bs, 2H). Melting point: 173-175 °C.
Yield: 27 % Example 35
3,5-Dichloro-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]- quinolin-4-yloxy}-phenyl)-2-methoxy-benzenesulfonamide
Figure imgf000074_0002
C31 H33CI2FN4O6S Mw. 679.60
LC/MS purity: 98 %, m/z 677 [M-H]", 679 [M+H]+ Rt. 3.79 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 10.4 (bs, 1 H), 8.44 (d, 1 H), 7.93 (d, 1 H), 7.76 (d, 1 H), 7.48 (s, 1 H), 7.37 (s, 1 H), 7.25 (t, 1 H), 7.05 (dd, 1 H), 6.91 (d, 1 H), 6.36 (d, 1 H), 4.18 (t, 2H), 3.92 (s, 6H), 2.50 (bs, 10H), 2.25 (s, 3H), 1 .97 (m, 2H).
Melting point: 183-185 °C.
Yield: 36 %
Example 36
N-(3-Fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}- phenyl)-benzenesulfonamide
ULA-P03071WO21 Application
Figure imgf000075_0001
C31H34FN3O5S Mw. 579.70
LC/MS purity: 99 %, m/z 578 [M-H]", 580 [M+H]+ Rt. 3.70 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 10.6 (bs, 1 H), 8.44 (d, 1 H), 7.80 (d, 2H), 7.58 (m, 3H), 7.47 (s, 1 H), 7.37 (s, 1 H), 7.28 (t, 1 H), 7.09 (d, 1 H), 6.95 (d, 1 H), 6.33 (d, 1 H), 4.17 (t, 2H), 3.91 (s, 3H), 2.80 (m, 2H), 2.45 (m, 2H), 1.96 (m, 2H), 1.90 (m, 1 H), 1.58 (m, 4H), 1.38 (m, 1 H), 0.86 (m, 1 H), 0.84 (d, 3H)
Melting point: 160-161 °C.
Yield: 32 %
Example 37
3- Fluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-
4- yloxy}-phenyl)-benzenesulfonamide
Figure imgf000075_0002
C31 H33F2N305S Mw. 597.69
LC/MS purity: 99 %, m/z 596 [M-H]", 598 [M+H]+ Rt. 3.55 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 10.6 (bs, 1 H), 8.44 (d, 1 H), 7.62 (bs, 2H), 7.57 (t, 1 H), 7.45 (m, 2H), 7.37 (s, 1 H), 7.25 (t, 1 H), 7.07 (dd, 1 H), 6.92 (d, 1 H), 6.35 (d, 1 H), 4.18 (t, 2H), 3.92 (s, 3H), 2.86 (m, 2H), 2.53 (m, 2H), 1.98 (m, 3H), 1.65 (m, 4H), 1.50 (m, 1 H), 0.88 (m, 1 H), 0.84 (d, 3H)
Melting point: 113-115 °C.
Yield: 26 %
Example 38
2-Chloro-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin- 4-yloxy}-phenyl)-benzenesulfonamide
ULA-P03071WO21 Application 5
Figure imgf000076_0001
C31H33CIFN3O5S Mw. 614.14
LC/MS purity: 98 %, m/z 612 [M-H]", 614 [M+H]+ Rt. 3.67 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 10.8 (bs, 1 H), 8.43 (d, 1 H), 8.08 (d, 1 H), 7.62 (bs, 2H), 7.52 (m, 1 H), 7.46 (s, 1 H), 7.37 (s, 1 H), 7.26 (t, 1 H), 7.06 (d, 1 H), 6.97 (d, 1 H), 6.33 (d, 1 H), 4.18 (t, 2H), 3.91 (s, 3H), 2.87 (m, 2H), 2.55 (m, 2H), 1.98 (m, 3H), 1.69 (m, 4H), 1.49 (m, 1 H), 0.89 (m, 1 H), 0.84 (d, 3H)
Melting point: 115-118 °C.
Yield: 22 %
Example 39
'N-(3-Fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}- phenyl)-3-trifluoromethyl-benzenesulfonamide
Figure imgf000076_0002
C32H33F4N3O5S Mw. 647.69
LC/MS purity: 99 %, m/z 646 [M-H]-, 648 [M+H]+ Rt. 3.01 min. (Method A)
H NMR (300 MHz, DMSO-d6): 10 (bs, 1 H), 8.43 (d, 1 H), 8.02 (m, 3H), 7.80 (t, 1 H), 7.48 (s, 1 H), 7.38 (s, 1 H), 7.25 (t, 1 H), 7.07 (dd, 1 H), 6.91 (d, 1 H), 6.32 (d, 1 H), 4.19 (t, 2H), 3.92 (s, 3H), 2.96 (m, 2H), 2.63 (m, 2H), 2.55 (m, 3H), 1.82 (m, 1 H), 1.66 (m, 3H), 1.52 (m, 1 H), 0.92 (m, 1 H), 0.84 (d, 3H)
Melting point: 128-130 °C.
Yield: 41 %
Example 40
N-(3-Fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}- phenyl)-2-nitro-benzenesulfonamide
Figure imgf000077_0001
C31H33FN4O7S Mw.624.69
LC/MS purity: 100 %, m/z 623 [M-H]", 625 [M+H]+ Rt.3.26 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 10.5 (bs, 1H), 8.43 (d, 1H), 7.94 (m, 1H), 7.73 (m, 1H), 7.50 (s, 1H), 7.39 (s, 1H), 7.10 (t, 1H), 6.89 (dd, 1H), 6.76 (d, 1H), 6.36 (d, 1H), 4.21 (t, 2H), 3.93 (s, 3H), 3.09 (m, 2H), 2.80 (m, 2H), 2.22 (m, 1H), 2.09 (m, 3H), 1.68 (m, 3H), 1.56 (m, 1H), 0.96 (m, 1H), 0.87 (d, 3H)
Melting point: 136-138 °C.
Yield: 19 %
Example 41
3- Cyano-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-
4- yloxy}-phenyl)-be
Figure imgf000077_0002
C32H33FN4O5S Mw.604.71
LC/MS purity: 99 %, m/z 603 [M-H]", 605 [M+H]+ Rt.3.29 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 10.5 (bs, 1H), 8.44 (d, 1H), 8.14 (s, 1H), 8.05 (t, 2H), 7.75 (t, 1H), 7.49 (s, 1H), 7.38 (s, 1H), 7.22 (t, 1H), 7.04 (dd, 1H), 6.32 (d, 1H), 6.35 (d, 1H), 4.20 (t, 2H), 3.92 (s, 3H), 2.96 (m, 2H), 2.64 (m, 2H), 2.05 (m, 3H), 1.85 (m, 1 H), 1.66 (m, 3H), 1.56 (m, 1 H), 0.92 (m, 1 H), 0.86 (d, 3H)
Melting point:125-127 °C.
Yield: 26 %
Example 42
N-(3-Fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}- phenyl)-3-methoxy-benzenesulfonamide
Figure imgf000078_0001
C32H36FN3O6S Mw. 609.72
LC/MS purity: 98 %, m/z 608 [M-H]", 610 [M+H]+ Rt. 3.75 min. (Method B)
H NMR (300 MHz, DMSO-d6): 10.6 (bs, 1 H), 8.44 (d, 1 H), 7.49 (m, 2H), 7.36 (m, 2H), 7.30 (m, 2H), 7.20 (d, 1 H), 7.14 (d, 1 H), 6.99 (d, 1 H), 6.35 (d, 1 H), 4.18 (t, 2H), 3.91 (s, 3H), 3.80 (s, 3H), 2.82 (m, 2H), 2.48 (m, 2H), 1.97 (m, 2H), 1.90 (m, 1 H), 1.62 (m, 4H), 1.49 (m, 1 H), 0.92 (m, 1 H), 0.84 (d, 3H)
Melting point: 172-174 °C.
Yield: 35 %
Example 43
3-Difluoromethoxy-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)- propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide
Figure imgf000078_0002
C32H34F3N3O6S Mw. 645.70
LC/MS purity: 99 %, m/z 644 [M-H]", 646 [M+H]+ Rt. 3.70 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 10.5 (bs, 1 H), 8.44 (bs, 1 H), 7.65-7.32 (m, 7H), 7.09 (d, 1 H), 6.96 (d, 1 H), 6.34 (bs, 1 H), 4.18 (bs, 2H), 3.92 (s, 3H), 3.57 (m, 1 H), 2.89 (bs, 2H), 2.55 (bs, 2H), 2.00 (bs, 3H), 1.63 (bs, 4H), 1.51 (m, 1 H), 0.88 (m, 1 H), 0.86 (d, 3H)
Melting point: 99-100 °C.
Yield: 25 %
Example 44
N-(3-Fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}- phenyl)-2-methyl-benzenesulfonamide
Figure imgf000079_0001
C32H36FN3O5S Mw. 593.72
LC/MS purity: 99 %, m/z 592 [M-H]', 594 [M+H]+ Rt. 3.89 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 10.7 (bs, 1 H), 8.43 (d, 1 H), 7.92 (d, 1 H), 7.51-7.25 (m, 6H), 7.05 (d, 1 H), 6.94 (d, 1 H), 6.32 (d, 1 H), 4.17 (t, 2H), 3.91 (s, 3H), 2.80 (m, 2H), 2.62 (s, 3H), 2.52 (m, 2H), 1.96 (m, 2H), 1.88 (m, 1 H), 1.61 (m, 4H), 1.48 (m, 1 H), 0.90 (m, 1 H), 0.84 (d, 3H)
Melting point: 99-100 °C.
Yield: 26 %
Example 45
N-(3-Fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}- phenyl)-2-trifluoromethoxy-benzenesulfonamide
Figure imgf000079_0002
C32H33F4N3O6S Mw. 663.69
LC/MS purity: %, m/z 642 [M-H]", 644 [M+H]+ Rt. 3.84 min. (Method B)
H NMR (300 MHz, DMSO-d6): 10.4 (bs, 1 H), 8.43 (d, 1 H), 7.98 (d, 1 H), 7.67 (t, 1 H), 7.48 (bs, 3H), 7.37 (s, 1 H), 7.18 (t, 1 H), 7.00 (d, 1 H), 6.84 (d, 1 H), 6.33 (d, 1 H), 4.18 (t, 2H), 3.92 (s, 3H), 2.83 (m, 2H), 2.56 (m, 2H), 1.99 (m, 3H), 1.63 (m, 4H), 1.51 (m, 1 H), 0.89 (m, 1 H), 0.84 (d, 3H)
Melting point: 128-130°C.
Yield: 21 %
Example 46
N-(3-Fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}- phenyl)-3-trifluoromethoxy-benzenesulfonamide
ULA-P03071WO21 Application
Figure imgf000080_0001
C32H33F4N3O6S Mw. 663.69
LC/MS purity: 99 %, m/z 662 [M-H]", 664 [M+H]+ Rt. 3.87 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 10 (bs, 1 H), 8.42 (d, 1 H), 7.79 (d, 1 H), 7.66 (m, 2H), 7.56 (d, 1 H), 7.48 (s, 1 H), 7.37 (s, 1 H), 7.19 (t, 1 H), 7.01 (dd, 1 H), 6.86 (d, 1 H), 6.32 (d, 1 H), 4.18 (t, 2H), 3.92 (s, 3H), 2.87 (m, 2H), 2.54 (m, 2H), 1.98 (m, 3H), 1.65 (m, 4H), 1.51 (m, 1 H), 0.88 (m, 1 H), 0.84 (d, 3H)
Melting point: 102-104 °C.
Yield: 21 %
Example 47
2,4-Difluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]- quinolin-4-yloxy}-phenyl)-benzenesulfonamide
Figure imgf000080_0002
C31H32F3N3O5S Mw. 615.68
LC/MS purity: 99 %, m/z 614 [M-H]', 616 [M+H]+ Rt. 3.48 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 10.5 (bs, 1 H), 8.44 (d, 1 H), 7.92 (m, 1 H), 7.48 (s, 2H), 7.44 (d, 1 H), 7.38 (s, 1 H), 7.25 (m, 2H), 7.05 (dd, 1 H), 6.91 (d, 1 H), 6.35 (d, 1 H), 4.19 (t, 2H), 3.92 (s, 3H), 2.92 (m, 2H), 2.60 (m, 2H), 2.03 (m, 3H), 1.78 (m, 1 H), 1.65 (m, 3H), 1.54 (m, 1 H), 0.92 (m, 1 H), 0.85 (d, 3H)
Melting point: 118-120 °C.
Yield: 18 %
Example 48
3,4-Difluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]- quinolin-4-yloxy}-phenyl)-benzenesulfonamide
Figure imgf000081_0001
C31H32F3N3O5S Mw. 615.68
LC/MS purity: 99 %, m/z 614 [M-H]", 616 [M+H]+ Rt. 3.59 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 10.5 (bs, 1 H), 8.43 (d, 1 H), 7.78 (t, 1 H), 7.59 (m, 2H), 7.48 (s, 1 H), 7.37 (s, 1 H), 7.21 (t, 2H), 7.04 (d, 1 H), 6.88 (d, 1 H), 6.36 (d, 1 H), 4.18 (t, 2H), 3.92 (s, 3H), 2.98 (m, 2H), 2.55 (m, 2H), 2.00 (m, 3H), 1.70 (m, 3H), 1.51 (m, 1 H), 0.90 (m, 1 H), 0.84 (d, 3H)
Melting point: 120-122 °C.
Yield: 34 %
Example 49
2,3,4-Trifluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1 -yl)-propoxy]- quinolin-4-yloxy}-phenyl)-benzenesulfonamide
Figure imgf000081_0002
C31 H31 F4N3O5S Mw. 633.67
LC/MS purity: 100 %, m/z 632 [M-H]", 634 [M+H]+ Rt. 3.46 min. (Method B)
LC/MS purity: 100 %, m/z 632 [M-H]", 634 [M+H]+ Rt. 3.46 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 10.2 (bs, 1 H), 8.44 (d, 1 H), 7.64 (m, 1 H), 7.50 (s, 1 H), 7.39 (m, 2H), 7.16 (t, 1 H), 6.98 (dd, 1 H), 6.84 (d, 1 H), 6.37 (d, 1 H), 4.21 (t, 2H), 3.93 (s, 3H), 3.1 1 (m, 2H), 2.81 (m, 2H), 2.16 (m, 4H), 1 .69 (m, 3H), 1 .58 (m, 1 H), 0.96 (m, 1 H), 0.88 (d, 3H)
Melting point: 134-136 °C.
Yield: 28 % Example 50
2,5-Dichloro-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin1 -yl)-propoxy]- quinolin-4-yloxy}-phenyl)-benzenesulfonamide
Figure imgf000082_0001
C3iH32Cl2FN3O5S Mw. 648.59
LC/MS purity: 99 %, m/z 646 [M-H]", 648 [M+H]+ Rt. 3.03 min. (Method A)
1H NMR (300 MHz, DMSO-d6): 10.4 (bs, 1 H), 8.44 (d, 1 H), 7.98 (s, 1 H), 7.60 (bs, 2H), 7.48 (s, 1 H), 7.39 (s, 1 H), 7.18 (t, 1 H), 6.98 (d, 1 H), 6.86 (d, 1 H), 6.35 (d, 1 H), 4.18 (t, 2H), 3.92 (s, 3H), 3.04 (m, 2H), 2.74 (m, 2H), 2.23 (m, 1 H), 2.07 (m, 2H), 1.95 (m, 1 H), 1.68 (m, 3H), 1.56 (m, 1 H), 0.95 (m, 1 H), 0.87 (d, 3H)
Melting point: 127-129 °C.
Yield: 29 %
Example 51
2,6-Dichloro-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]- quinolin-4-yloxy}-p
Figure imgf000082_0002
C3i H32CI2FN305S Mw. 648.59
LC/MS purity: 99 %, m/z 646 [M-H]\ 648 [M+H]+ Rt. 3.59 min. (Method B)
H NMR (300 MHz, DMSO-d6): 10.6 (bs, 1 H), 8.43 (d, 1 H), 7.58 (d, 1 H), 7.57 (s, 1 H), 7.48 (m, 2H), 7.38 (s, 1 H), 7.22 (t, 1 H), 7.02 (dd, 1 H), 6.88 (d, 1 H), 6.34 (d, 1 H), 4.20 (t, 2H), 3.92 (s, 3H), 3.01 (m, 2H), 2.70 (m, 2H), 2.16 (m, 1 H), 2.05 (m, 2H), 1.91 (m, 1 H), 1.68 (m, 3H), 1.55 (m, 1 H), 0.98 (m, 1 H), 0.86 (d, 3H)
Melting point: 119-121 °C.
Yield: 16 %
Example 52
3,4-Dichloro-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]- quinolin-4-yloxy}-phenyl)-benzenesulfonamide
Figure imgf000083_0001
C31H32CI2FN3O5S Mw.648.59
LC/MS purity: 99 %, m/z 646 [M-H]", 648 [M+H]+ Rt.3.11 min. (Method A)
1H NMR (300 MHz, DMSO-d6): 10.4 (bs, 1H), 8.44 (d, 1H), 7.92 (d, 1H), 7.80 (d, 1H), 7.71 (dd, 1H), 7.49 (s, 1H), 7.39 (s, 1H), 7.23 (t, 1H), 7.05 (dd, 1H), 6.89 (d, 1H), 6.36 (d, 1H), 4.20 (t, 2H), 3.93 (s, 3H), 2.98 (m, 2H), 2.67 (m, 2H), 2.13 (m, 1H), 2.03 (m, 2H), 1.86 (m, 1H), 1.67 (m, 3H), 1.57 (m, 1H), 0.92 (m, 1H), 0.86 (d, 3H)
Melting point: 123-124 °C.
Yield: 15%
Example 53
3,5-Dichloro-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]- quinolin-4-yloxy}-phenyl)-benzenesulfonamide
Figure imgf000083_0002
C31H32CI2FN3O5S Mw.648.59
LC/MS purity: 98 %, m/z 646 [M-H]", 648 [M+H]+ Rt.3.13 min. (Method A)
1H NMR (300 MHz, DMSO-d6): 10.3 (bs, 1H), 8.44 (d, 1H), 7.81 (d, 1H), 7.69 (s, 1H), 7.68 (s, 1H), 7.50 (s, 1H), 7.39 (s, 1H), 7.20 (t, 1H), 7.01 (dd, 1H), 6.86 (d, 1H), 6.36 (d, 1H), 4.21 (t, 2H), 3.93 (s, 3H), 3.06 (m, 2H), 2.76 (m, 2H), 2.23 (m, 1H), 2.06 (m, 2H), 1.97 (m, 1H), 1.69 (m, 3H), 1.57 (m, 1H), 0.92 (m, 1H), 0.87 (d, 3H)
Melting point: 126-128 °C.
Yield: 19 %
Example 54
ULA-P03071WO21 Application 3-Chloro-2-fluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]- quinolin-4-yloxy}-phenyl)-benzenesulfonamide
Figure imgf000084_0001
C31H32CIF2N3O5S Mw.632.13
LC/MS purity: 98 %, m/z 630 [M-H]", 632 [M+H]+ Rt.3.50 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 10.3 (bs, 1H), 8.43 (d, 1H), 7.81 (d, 1H), 7.76 (d, 1H), 7.49 (s, 1H), 7.39 (s, 1H), 7.33 (t, 1H), 7.19 (t, 1H), 7.02 (dd, 1H), 6.87 (d, 1H), 6.36 (d, 1H), 4.20 (t, 2H), 3.93 (s, 3H), 3.03 (m, 2H), 2.73 (m, 2H), 2.20 (m, 1H), 2.06 (m, 2H), 1.94 (m, 1H), 1.68 (m, 3H), 1.56 (m, 1H), 0.93 (m, 1H), 0.86 (d, 3H)
Melting point: 125-127 °C.
Yield: 18 %
Example 55
2-Fluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin- 4-yloxy}-phenyl)-5-
Figure imgf000084_0002
C32H35F2N3O5S Mw.611.71
LC/MS purity: 99 %, m/z 610 [M-H]-, 612 [M+H]+ Rt.3.73 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 10.2 (bs, 1H), 8.44 (d, 1H), 7.69 (d, 1H), 7.49 (d, 1H), 7.47 (s, 1H), 7.38 (s, 1H), 7.30 (td, 2H), 7.12 (dd, 1H), 6.99 (d, 1H), 6.34 (d, 1H), 4.19 (t, 2H), 3.92 (s, 3H), 2.90 (m, 2H), 2.57 (s, 2H), 2.34 (s, 3H), 2.01 (m, 3H), 1.74 (m, 1H), 1.61 (m, 3H), 1.52 (m, 1H), 0.90 (m, 1H), 0.85 (d, 3H)
Melting point: 149-151 °C.
Yield: 23 %
ULA-P03071WO21 Application Example 56
3- Fluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-
4- yloxy}-phenyl)-4-
Figure imgf000085_0001
C32H35F2N3O5S Mw. 611.71
LC/MS purity: 99 %, m/z 610 [M-H]', 612 [M+H]+ Rt. 3.85 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 10.5 (bs, 1 H), 8.44 (d, 1 H), 7.52 (m, 4H), 7.38 (s, 1 H), 7.31 (t, 1 H), 7.13 (dd, 1 H), 6.98 (d, 1 H), 6.36 (d, 1 H), 4.19 (t, 2H), 3.92 (s, 3H), 2.88 (m, 2H), 2.54 (m, 2H), 2.29 (m, 3H), 1.99 (m, 3H), 1.63 (m, 4H), 1.54 (m, 1 H), 0.89 (m, 1 H), 0.84 (d, 3H)
Melting point: 174-176 °C.
Yield: 19 %
Example 57
3-Chloro-4-fluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1 -yl)-propoxy]- quinolin-4-yloxy}-p
Figure imgf000085_0002
C31H32CIF2N3O5S Mw. 632.13
LC/MS purity: 96 %, m/z 630 [M-H]', 632 [M+H]+ Rt. 2.97 min. (Method A)
1H NMR (300 MHz, DMSO-d6): 10.6 (bs, 1 H), 8.44 (d, 1 H), 7.91 (dd, 1 H), 7.77 (m, 1 H), 7.58 (t, 1 H), 7.48 (s, 1 H), 7.38 (s, 1 H), 7.24 (t, 1 H), 7.06 (dd, 1 H), 6.89 (d, 1 H), 6.36 (d, 1 H), 4.19 (t, 2H), 3.92 (s, 3H), 2.83 (m, 2H), 2.61 (s, 2H), 2.03 (m, 3H), 1.78 (m, 1 H), 1.63 (m, 3H), 1.52 (m, 1 H), 0.91 (m, 1 H), 0.85 (d, 3H)
Melting point: 124-126 °C.
Yield: 30 % Example 58
Naphthalene-1 -sulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin propoxy]-quinolin
Figure imgf000086_0001
C35H36FN3O5S Mw. 629.76
LC/MS purity: 99 %, m/z 628 [M-H]", 630 [M+H]+ Rt. 2.95 min. (Method A)
1H NMR (300 MHz, DMSO-d6): 10.4 (bs, 1 H), 8.82 (d, 1 H), 8.39 (d, 1 H), 8.20 (m, 2H), 8.06 (d, 1 H), 7.65 (m, 3H), 7.42 (s, 1 H), 7.35 (s, 1 H), 7.16 (t, 1 H), 6.99 (d, 1 H), 6.85 (d, 1 H), 6.26 (d, 1 H), 4.16 (t, 2H), 3.89 (s, 3H), 2.83 (m, 2H), 2.48 (m, 2H), 1.96 (m, 3H), 1.62 (m, 4H), 1.49 (m, 1 H), 0.89 (m, 1 H), 0.84 (d, 3H)
Melting point: 131-133 °C.
Yield: 21 %
Example 59
N-(3-Fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1 -yl)-propoxy]-quinolin-4-yloxy}- phenyl)-3-phenoxy-benzenesulfonamide
Figure imgf000086_0002
C37H38FN3O6S Mw. 671.79
LC/MS purity: 98 %, m/z 670 [M-H]", 672 [M+H]+ Rt. 3.18 min. (Method A)
1H NMR (300 MHz, DMSO-d6): 10.4 (bs, 1 H), 8.44 (d, 1 H), 7.62-7.22 (m, 10H),
7.04 (m, 3H), 6.93 (d, 1 H), 6.35 (d, 1 H), 4.19 (t, 2H), 3.93 (s, 3H), 2.86 (m, 2H),
2.48 (m, 2H), 1.99 (m, 3H), 1.65 (m, 4H), 1.51 (m, 1 H), 0.88 (m, 1 H), 0.84 (d, 3H)
Melting point:146-147 °C.
Yield: 24 %
ULA-P03071WO21 Application Example 60
Cyclopropanesulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin propoxy]-quinolin-4
Figure imgf000087_0001
C28H34FN3O5S Mw.543.66
LC/MS purity: 96 %, m/z 542 [M-H]', 544 [M+H]+ Rt.3.65 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 10.3 (bs, 1H), 8.47 (d, 1H), 7.52 (s, 1H), 7.45 (d, 1H), 7.39 (s, 1H), 7.28 (d, 1H), 7.17 (d, 1H), 6.45 (d, 1H), 4.19 (t, 2H), 3.94 (s, 3H), 3.17 (m, 1H), 2.77 (m, 3H), 2.44 (m, 2H), 1.96 (m, 2H), 1.84 (m, 1H), 1.61 (m, 3H), 1.48 (m, 1H), 0.99 (m, 2H), 0.97 (m, 2H), 0.88 (m, 1H), 0.84 (d, 3H)
Melting point: 158-160 °C.
Yield: 11 %
Example 61
1-Methyl-1H-pyrazole-3-sulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(3-methyl- piperidin-1-yl)-prop
Figure imgf000087_0002
C29H34FN505S Mw.583.69
LC/MS purity: 97 %, m/z 582 [M-H]-, 584 [M+H]+ Rt.3.09 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 10.2 (bs, 1H), 8.45 (d, 1H), 7.84 (d, 1H), 7.49 (s, 1H), 7.37 (s, 1H), 7.30 (t, 1H), 7.15 (dd, 1H), 7.00 (d, 1H), 6.63 (d, 1H), 6.38 (d, 1H), 4.18 (t, 2H), 3.93 (s, 3H), 3.90 (s, 3H), 2.78 (m, 2H), 2.44 (m, 2H), 1.96 (m, 2H), 1.85 (m, 1H), 1.58 (m, 4H), 1.46 (m, 1H), 0.85 (m, 1H), 0.83 (d, 3H)
Melting point: 164-166 °C.
Yield: 31 % Example 62
5-Methyl-thiophene-2-sulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin- 1-yl)-propoxy]-quin
Figure imgf000088_0001
C3oH34FN3O5S2 Mw.599.75
LC/MS purity: 99 %, m/z 598 [M-H]", 600 [M+H]+ Rt.3.62 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 10.5 (bs, 1H), 8.45 (d, 1H), 7.49 (s, 1H), 7.38 (s, 1H), 7.36 (s, 1H), 7.30 (t, 1H), 7.12 (dd, 1H), 6.98 (d, 1H), 6.83 (d, 1H), 6.38 (d, 1H), 4.18 (t, 2H), 3.93 (s, 3H), 2.85 (m, 2H), 2.54 (m, 2H), 2.46 (s, 3H), 1.97 (m, 3H), 1.63 (m, 4H), 1.50 (m, 1 H), 0.88 (m, 1 H), 0.84 (d, 3H)
Melting point: 99-101 °C.
Yield: 29 %
Example 63
5-Chloro-thiophene-2-sulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin- 1-yl)-propoxy]-quin
Figure imgf000088_0002
C29H31CIFN3O5S2MW.620.17
LC/MS purity: 99 %, m/z 618 [M-H]\ 620 [M+H]+ Rt.3.50 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 10.8 (bs, 1H), 8.46 (d, 1H), 7.51 (s, 1H), 7.40 (s,
1H), 7.33 (s, 1H), 7.23 (t, 1H), 7.12 (d, 1H), 7.04 (d, 1H), 6.91 (d, 1H), 6.39 (d, 1H),
4.21 (t, 2H), 3.93 (s, 3H), 3.16 (m, 2H), 2.79 (m, 2H), 2.28 (s, 1H), 2.09 (m, 3H),
1.68 (m, 3H), 1.58 (m, 1H), 0.96 (m, 1H), 0.88 (d, 3H)
Melting point: 100-103 °C.
Yield: 19%
ULA-P03071WO21 Application Example 64
2,4-Dichloro-thiophene-3-sulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(3-methyl- piperidin-1-yl)-prop
Figure imgf000089_0001
C29H30CI2FN3O5S2 Mw.654.61
LC/MS purity: 98 %, m/z 652 [M-H]", 654 [M+H]+ Rt.3.03 min. (Method A)
1H NMR (300 MHz, DMSO-d6): 10.5 (bs, 1H), 8.45 (d, 1H), 7.51 (s, 1H), 7.38 (s, 1H), 7.18 (s, 1H), 7.16 (t, 1H), 6.97 (d, 1H), 6.82 (d, 1H), 6.39 (d, 1H), 4.20 (t, 2H), 3.93 (s, 3H), 3.17 (m, 2H), 2.68 (m, 2H), 2.18 (m, 1H), 2.06 (m, 2H), 1.88 (m, 1H), 1.67 (m, 3H), 1.53 (m, 1H), 0.93 (m, 1H), 0.86 (d, 3H)
Melting point: 119-121 °C.
Yield: 39 %
Example 65
Thiophene-3-sulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)- propoxy]-quinolin-4
Figure imgf000089_0002
C29H32FN3O5S2 Mw.585.72
LC/MS purity: 99 %, m/z 584 [M-H]", 586 [M+H]+ Rt.3.49 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 10.4 (bs, 1H), 8.44 (d, 1H), 8.19 (d, 1H), 7.71 (m, 1H), 7.48 (s, 1H), 7.37 (s, 1H), 7.30 (m, 2H), 7.13 (dd, 1H), 6.99 (d, 1H), 6.36 (d, 1H), 4.18 (t, 2H), 3.92 (s, 3H), 2.80 (m, 2H), 2.46 (m, 2H), 1.95 (m, 2H), 1.87 (m, 1H), 1.66 (m, 1H), 1.60 (m, 3H), 1.48 (m, 1H), 0.92 (m, 1H), 0.84 (d, 3H)
Melting point: 174-176 °C.
Yield: 28 % Example 66
3-(3-Fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}- phenylsulfamoyl)-t
Figure imgf000090_0001
C31H34FN3O7S2 Mw.643.76
LC/MS purity: 98 %, m/z 642 [M-H]', 644 [M+H]+ Rt.3.78 min. (Method B)
H NMR (300 MHz, DMSO-d6): 10.4 (bs, 1H), 8.45 (d, 1H), 7.94 (d, 1H), 7.48 (s, 1H), 7.47 (s, 1H), 7.37 (s, 1H), 7.30 (t, 1H), 7.13 (dd, 1H), 6.98 (d, 1H), 6.36 (d, 1H), 4.18 (t, 2H), 3.92 (s, 3H), 3.88 (m, 3H), 2.85 (m, 2H), 2.54 (s, 2H), 1.96 (m, 3H), 1.65 (m, 4H), 1.47 (m, 1H), 0.92 (d, 1H), 0.92 (d, 3H)
Melting point: 132-134 °C.
Yield: 9 %
Example 67
Benzo[b]thiophene-3-sulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin- 1-yl)-propoxy]-quin
Figure imgf000090_0002
C33H34FN3O5S2 Mw.635.78
LC/MS purity: 99 %, m/z 634 [M-H]-, 636 [M+H]+ Rt.3.86 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 10.4 (bs, 1H), 8.57 (s, 1H), 8.41 (d, 1H), 8.25 (d, 1H), 8.09 (d, 1H), 7.54 (m, 2H), 7.45 (s, 1H), 7.36 (s, 1H), 7.22 (t, 1H), 7.09 (d, 1H), 6.93 (d, 1H), 6.29 (d, 1H), 4.16 (t, 2H), 3.90 (s, 3H), 2.85 (m, 2H), 2.51 (m, 2H), 1.96 (m, 3H), 1.65 (m, 4H), 1.49 (m, 1H), 0.92 (m, 1H), 0.84 (d, 3H)
Melting point: 126-128 °C.
Yield: 26 % Example 68
1 -Ethyl-1 H-pyrazole-4-sulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(3-methyl- piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide
Figure imgf000091_0001
C3oH36FN5O5S Mw.597.71
LC/MS purity: 99 %, m/z 596 [M-H]", 598 [M+H]+ Rt.3.35 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 10.4 (bs, 1H), 8.45 (d, 1H), 8.33 (s, 1H), 7.75 (s, 1H), 7.49 (s, 1H), 7.38 (s, 1H), 7.36 (t, 1H), 7.16 (d, 1H), 7.03 (d, 1H), 6.38 (d, 1H), 4.16 (m, 4H), 3.93 (s, 3H), 2.80 (m, 2H), 2.45 (m, 2H), 1.96 (m, 2H), 1.85 (m, 1H), 1.65 (m, 1H), 1.59 (m,3H), 1.48 (m, 1H), 1.34 (t, 3H), 0.91 (m, 1H), 0.83 (d, 3H) Melting point: 152-154 °C.
Yield: 43 %
Example 69
3-Chloro-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1 -yl)-propoxy]-quinolin- 4-yloxy}-phenyl)-be
Figure imgf000091_0002
C31H33CIFN3O5S Mw.614.14
LC/MS purity: 98 %, m/z 612 [M-H]-, 614 [M+H]+ Rt.2.90 min. (Method A)
1H NMR (300 MHz, DMSO-d6): 10.2 (bs, 1H), 8.44 (d, 1H), 7.75 (s, 1H), 7.74 (d, 1H), 7.67 (d, 1H), 7.58 (t, 1H), 7.48 (s, 1H), 7.38 (s, 1H), 7.25 (t, 1H), 7.06 (d, 1H), 6.91 (d, 1H), 6.35 (d, 1H), 4.19 (t, 2H), 3.92 (s, 3H), 2.89 (m, 2H), 2.55 (m, 2H), 1.99 (m, 3H), 1.69 (m, 4H), 1.51 (m, 1H), 0.92 (m, 1H), 0.85 (d, 3H)
Melting point: 110-112°C.
Yield: 43 % Example 70
N-(3-Fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}- phenyl)-3-methyl-b
Figure imgf000092_0001
C32H36FN305S Mw.593.72
LC/MS purity: 98 %, m/z 592 [M-H]", 594 [M+H]+ Rt.2.85 min. (Method A)
1H NMR (300 MHz, DMSO-d6): 10.2 (bs, 1H), 8.44 (d, 1H), 7.63 (s, 1H), 7.60 (d, 1H), 7.47 (m, 3H), 7.38 (s, 1H), 7.31 (s, 1H), 7.12 (d, 1H), 6.95 (d, 1H), 6.34 (d, 1H), 4.18 (t, 2H), 3.91 (s, 3H), 2.80 (m, 2H), 2.46 (m, 2H), 2.37 (s, 3H), 1.96 (m, 2H), 1.85 (m, 1H), 1.60 (m, 4H), 1.46 (m, 1H), 0.93 (m, 1H), 0.84 (d, 3H)
Melting point: 168-170 °C.
Yield: 37 %
Example 71
N-(3-Fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1 -yl)-propoxy]-quinolin-4-yloxy}- phenyl)-2-methoxy-
Figure imgf000092_0002
C32H36FN3O6S Mw.609.72
LC/MS purity: 100 %, m/z 608 [M-H]", 610 [M+H]+ Rt.2.71 min. (Method A)
1H NMR (300 MHz, DMSO-d6): 10.3 (bs, 1H), 8.43 (d, 1H), 7.83 (d, 1H), 7.61 (t, 1H), 7.45 (s, 1H), 7.36 (s, 1H), 7.29 (t, 1H), 7.20 (d, 1H), 7.08 (m, 2H), 6.98 (d, 1H), 6.29 (d, 1H), 4.17 (t, 2H), 3.89 (s, 6H), 2.77 (m, 2H), 2.42 (m, 2H), 1.95 (m, 2H), 1.82 (m, 1H), 1.61 (m, 4H), 1.51 (m, 1H), 0.93 (m, 1H), 0.83 (d, 3H)
Melting point: 175-176 °C.
Yield: 35 % Example 72
3-Cyano-4-fluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]- quinolin-4-yloxy}-p
Figure imgf000093_0001
C32H32F2N405S Mw.622.70
LC/MS purity: 99 %, m/z 621 [M-H]", 623 [M+H]+ Rt.2.82 min. (Method A)
1H NMR (300 MHz, DMSO-d6): 10.2 (bs, 1H), 8.44 (d, 1H), 8.22 (d, 1H), 8.11 (m, 1H), 7.64 (t, 1H), 7.49 (s, 1H), 7.38 (s, 1H), 7.16 (t, 1H), 6.99 (d, 1H), 6.84 (d, 1H), 6.37 (d, 1H), 4.20 (t, 2H), 3.93 (s, 3H), 2.99 (m, 2H), 2.67 (m, 2H), 2.14 (m, 1H), 2.06 (m, 2H), 1.87 (m, 1H), 1.67 (m, 3H), 1.54 (m, 1H), 0.93 (m, 1H), 0.83 (d, 3H) Melting point: 125-127 °C.
Yield: 8 %
Example 73
2-Phenyl-ethenesulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)- propoxy]-quinolin-4
Figure imgf000093_0002
C33H36FN3O5S Mw.605.73
LC/MS purity: 98 %, m/z 604 [M-H]', 606 [M+H]+ Rt.2.91 min. (Method A)
H NMR (300 MHz, DMSO-d6): 10.5 (bs, 1H), 8.41 (d, 1H), 7.70 (bs, 2H), 7.48 (s,
1H), 7.42-7.24 (m, 7H), 7.17 (d, 1H), 7.03 (d, 1H), 6.37 (d, 1H), 4.17 (bs, 2H), 3.93
(s, 3H), 2.77 (m, 2H), 2.43 (m, 2H), 1.96 (m, 2H), 1.84 (m, 1H), 1.59 (m, 4H), 1.48
(m, 1H), 0.92 (m, 1H), 0.83 (d, 3H)
Melting point: 104-106 °C.
Yield: 27 % Example 74
Quinoline-8-sulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1 -yl)- propoxy]-quinolin-4
Figure imgf000094_0001
C34H35FN4O5S Mw.630.74
LC/MS purity: 98 %, m/z 629 [M-H]\ 631 [M+H]+ Rt.2.62 min. (Method A)
1H NMR (300 MHz, DMSO-d6): 10.5 (bs, 1H), 9.15 (d, 1H), 8.55 (d, 1H), 8.45 (d, 1H), 8.39 (d, 1H), 8.33 (d, 1H), 7.74 (m, 2H), 7.40 (s, 1H), 7.34 (s, 1H), 7.17 (t, 1H), 7.14 (d, 1H), 6.97 (d, 1H), 6.21 (d, 1H), 4.15 (t, 2H), 3.87 (s, 3H), 2.78 (m, 2H), 2.43 (m, 2H), 1.94 (m, 2H), 1.82 (m, 1H), 1.58 (m, 5H), 0.89 (m, 1H), 0.82 (d, 3H)
Melting point: 190-191 °C.
Yield: 25 % Example 75
3,5-Dichloro-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]- quinolin-4-yloxy}-phenyl)-2-methoxy-benzenesulfonamide
Figure imgf000094_0002
C32H34CI2FN3O6S Mw.678.61
LC/MS purity: 97 %, m/z 676 [M-H]", 678 [M+H]+ Rt.3.19 min. (Method A)
1H NMR (300 MHz, DMSO-d6): 10.5 (bs, 1H), 8.44 (d, 1H), 7.90 (d, 1H), 7.76 (d, 1H), 7.49 (s, 1H), 7.38 (s, 1H), 7.22 (t, 1H), 7.04 (dd, 1H), 6.89 (d, 1H), 6.36 (d, 1H), 4.19 (t, 2H), 3.92 (s, 3H), 3.91 (s, 3H), 2.96 (m, 2H), 2.64 (m, 2H), 2.03 (m, 3H), 1.82 (m, 1H), 1.66 (m, 3H), 1.51 (m, 1H), 0.92 (m, 1H), 0.86 (d, 3H)
Melting point: 145-146 °C.
Yield: 17 % Example 76
3,5-Dichloro-N-{3-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4- yloxy]-phenyl}-2-methoxy-benzenesulfonamide
Figure imgf000095_0001
C30H30CI2FN3O7S Mw. 666.56
LC/MS purity: 98 %, m/z 664 [M-H]", 666 [M+H]+ Rt. 3.00 min. (Method A)
1H NMR (300 MHz, DMSO-d6): 10.8 (bs, 1 H), 8.44 (d, 1 H), 8.00 (d, 1 H), 7.79 (d, 1 H), 7.48 (s, 1 H), 7.38 (s, 1 H), 7.32 (t, 1 H), 7.12 (dd, 1 H), 6.98 (d, 1 H), 6.36 (d, 1 H), 4.19 (t, 2H), 3.94 (s, 3H), 3.92 (s, 3H), 3.59 (m, 4H), 2.49 (m, 2H), 2.42 (m, 4H), 1.97 (m, 2H)
Melting point: 189-191 °C.
Yield: 24 %
Example 77
2,6-Difluoro-N-{3-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4- yloxy]-phenyl}-benzenesulfonamide
Figure imgf000095_0002
C29H28F3N3O6S Mw. 603.62
LC/MS purity: 98 %, m/z 602 [M-H]", 604 [M+H]+ Rt. 2.95 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 11 (bs, 1 H), 8.44 (d, 1 H), 7.68 (m, 1 H), 7.48 (s,
1 H), 7.38 (s, 1 H), 7.36-7.24 (m, 3H), 7.14 (dd, 1 H), 7.00 (d, 1 H), 6.34 (d, 1 H), 4.19
(t, 2H), 3.92 (s, 3H), 3.59 (m, 4H), 2.49 (m, 2H), 2.41 (m, 4H), 1.96 (m, 2H)
Melting point: 190-192 °C.
Yield: 23 % Example 78
N-{3-Fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4-yloxy]-phenyl}-2- trifluoromethoxy-benzenesulfonamide
C3iH3iF4N3O6S Mw. 649.67
LC/MS purity: 98 %, m/z 648 [M-H]\ 650 [M+H]+ Rt. 2.90 min. (Method A)
1H NMR (300 MHz, DMSO-d6): 10.5 (bs, 1 H), 8.44 (d, 1 H), 8.00 (d, 1 H), 7.70 (t, 1 H), 7.52 (m, 2H), 7.48 (s, 1 H), 7.38 (s, 1 H), 7.22 (t, 1 H), 7.05 (dd, 1 H), 6.89 (d, 1 H), 6.33 (d, 1 H), 4.19 (t, 2H), 3.93 (s, 3H), 2.62 (m, 2H), 2.56 (m, 4H), 2.03 (m, 2H), 1.55 (m, 4H), 1.43 (m, 2H)
Melting point: 156-158 °C.
Yield: 26 %
Example 79
Butane-1 -sulfonic acid {3-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)- quinolin-4-yloxy]-phenyl}-amide
Figure imgf000096_0002
C27H34FN3O6S Mw. 547.65
LC/MS purity: 98 %, m/z 546 [M-H]", 548 [M+H]+ Rt. 3.59 min.
1H NMR (300 MHz, DMSO-d6): 10.14 (s, 1 H), 8.47 (d, 1 H), 7.51 (s, 1 H), 7.44 (t,
1 H), 7.40 (s, 1 H), 7.27 (dd, 1 H), 7.14 (d, 1 H), 6.46 (d, 1 H), 4.20 (t, 2H), 3.94 (s,
3H), 3.59 (m, 4H), 3.20 (m, 2H), 2.47 (m, 2H), 2.39 (m, 4H), 1.98 (m, 2H), 1.68 (m,
2H), 1.39 (m, 2H), 0.87 (t, 3H)
Melting point: 98-100 °C.
Yield: 18 %
ULA-P03071WO21 Application Example 80
2,5-Difluoro-N-{3-fluoro-4-[6-methoxy-7-(piperidin-3-ylmethoxy)-quinolin-4-yloxy] phenylj-benzenesulfonamide
Figure imgf000097_0001
C28H26F3N3O5S Mw. 573.60
LC/MS purity: %, m/z [M-H]', [M+H]+ Rt. min. (Method B)
Yield: 34 %
Example 81
2-Fluoro-N-{3-fluoro-4-[6-methoxy-7-(2-morpholin-4-yl-ethoxy)-quinolin
phenylj-benzenesulfonamide
Figure imgf000097_0002
C28H27F2N3O6S Mw. 571.60
LC/MS purity: 98 %, m/z 570 [M-H]\ 572 [M+H]+, Rt. 3.06 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 11 (bs, 1 H), 8.44 (s, 1 H), 7.90 (s, 1 H), 7.73 (s, 1 H), 7.38 (m, 5H), 7.15 (d, 1 H), 7.03 (d, 1 H), 6.33 (s, 1 H), 4.27 (bs, 2H), 3.90 (s, 3H), 3.59 (s, 4H), 2.79 (bs, 2H), 2.52 (s, 4H)
Melting point: 168-169°C.
Yield: 67 %
Example 82
2,6-Difluoro-N-{3-fluoro-4-[6-methoxy-7-(2-morpholin-4-yl-ethoxy)-quinolin-4- yloxy]-phenyl}-benzenesulfonamide
Figure imgf000098_0001
C28H26F3N3O6S Mw. 589.60
LC/MS purity: 97 %, m/z 588 [M-H]", 590 [M+H]+ Rt. 2.88 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 11 (bs, 1 H), 8.45 (s, 1 H), 7.71 (s, 1 H), 7.47 (s, 1 H), 7.42 (s, 1 H), 7.36-7.26 (m, 5H), 7.16 (d, 1 H), 7.03 (d, 1 H), 6.35 (s, 1 H), 4.27 (bs, 2H), 3.91 (s, 3H), 3.60 (s, 4H), 2.80 (bs, 2H), 2.57 (s, 4H)
Melting point: 182-183°C.
Yield: 32 % Example 83
2,5-Difluoro-N-{3-fluoro-4-[6-methoxy-7-(4-morpholin-4-yl-butoxy)-quinolin-4- yloxy]-phenyl}-benzenesulfonamide
Figure imgf000098_0002
C30H30F3N3O6S Mw. 617.65
LC/MS purity: 97 %, m/z 616 [M-H]-, 618 [M+H]+ Rt. 3.22 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 11.1 (bs, 1 H), 8.44 (d, 1 H), 7.67-7.53 (m, 3H), 7.47 (s, 1 H), 7.38 (s, 1 H), 7.30 (t, 1 H), 7.12 (d, 1 H), 6.98 (d, 1 H), 6.35 (d, 1 H), 4.17 (t, 2H), 3.92 (s, 3H), 3.58 (m, 4H), 2.39 (m, 6H), 1.82 (m, 2H), 1.64 (m, 2H) Melting point: 156-158°C.
Yield: 29 %
Example 84
2,5-Difluoro-N-{3-fluoro-4-[7-(4-morpholin-4-yl-butoxy)-quinolin-4-yloxy]-phenyl}- benzenesulfonamide
ULA-P03071WO21 Application
Figure imgf000099_0001
C29H28F3N3O5S Mw. 587.62
LC/MS purity: %, m/z [M-H]", [M+H]+ Rt. min. (Method B)
Yield: 30 %
Example 85
N-(3-Fluoro-4-{6-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-2- trifluoromethyl-be
C30H30F4N4O4S Mw. 618.66
LC/MS purity: 97 %, m/z 617 [M-H]-, 619 [M+H]+ Rt. 3.18 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 10 (bs, 1 H), 8.50 (d, 1 H), 8.15 (d, 1 H), 7.97-7,78 (m, 4H), 7.52 (m, 1 H), 7.43(dd, 1 H), 7.27 (t, 1 H), 7.05 (d, 1 H), 6.93 (d, 1 H), 6.49 (d, 1 H), 4.16 (t, 2H), 2.44 (m, 10H), 2.19 (s, 3H), 1.95 (m, 2H)
Melting point: 101-103°C.
Yield: 27 %
Example 86
N-(3-Fluoro-4-{7-methoxy-6-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4- yloxy}-phenyl)-2-t
Figure imgf000099_0003
C31 H32F4N4O5S Mw. 648.68
LC/MS purity: 97 %, m/z 647 [M-H]", 649 [M+H]+ Rt. 3.07 min. (Method B)
ULA-P03071WO21 Application H NMR (300 MHz, DMSO-d6): 10 (bs, 1 H), 8.43 (d, 1 H), 8.13 (d, 1 H), 7.95 (d, 1 H), 7.80 (m, 2H), 7.47 (s, 1 H), 7.38(s, 1 H), 7.25 (t, 1 H), 7.05 (d, 1 H), 6.91 (d, 1 H), 6.35 (d, 1 H), 4.15 (t, 2H), 3.93 (s, 3H), 2.44 (m, 10H), 2.17 (s, 3H), 1.96 (m, 2H) Melting point: 113-115°C.
Yield: 23 %
Example 87
N-(3-Chloro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4- yloxy}-phenyl)-2-trifluoromethyl-benzenesulfonamide
Figure imgf000100_0001
C31 H32CIF3N4O5S Mw. 665.14
LC/MS purity: 99 %, m/z 663 [M-H]\ 665 [M+H]+ Rt. 3.17 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 11 (bs, 1 H), 8.43 (d, 1 H), 8.13 (d, 1 H), 7.93 (d, 1 H), 7.80 (m, 2H), 7.47 (s, 1 H), 7.37 (s, 1 H), 7.22 (m, 2H), 7.04 (d, 1 H), 6.26 (s, 1 H), 4.18 (bs, 2H), 3.91 (s, 3H), 2.48 (s, 10H), 2.24 (s, 3H), 1.96 (m, 2H).
Melting point: 103-105°C.
Yield: 26 %
Example 88
N-(3,5-Dichloro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4- yloxy}-phenyl)-2,6-
Figure imgf000100_0002
C30H30CI2F2N4O5S Mw. 667.56
LC/MS purity: %, m/z [M-H]", [M+H]+ Rt. min. (Method B)
Yield: 20 % Example 89
N-(4-{6-Methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-3-methyl- phenyl)-2-trifIuoro
Figure imgf000101_0001
C33H36F3N3O5S Mw. 643.73
LC/MS purity: 99 %, m/z 642 [M-H]\ 644 [M+H]+ Rt. 4.03 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 10.6 (bs, 1 H), 8.40 (d, 1 H), 8.12 (d, 1 H), 7.89 (d, 1 H), 7.85 (m, 2H), 7.50 (s, 1 H), 7.36 (s, 1 H), 7.09 (s, 1 H), 7.02 (m, 2H), 6.17 (d, 1 H), 4.17 (t, 2H), 3.91 (s, 3H), 2.87 (m, 2H), 2.47 (m, 2H), 2.01 (m, 3H), 1.93 (m, 4H), 1.58 (m, 2H), 1.33 (m, 1 H), 1.18 (m, 2H), 0.88 (d, 3H)
Melting point: 165-167°C.
Yield: 25 %
Example 90
2)5-Difluoro-N-(3-methoxy-4-{6-methoxy-7-[3-(3-methyl-piperidin-1 -yl)-propoxy]- quinolin-4-yloxy}-
Figure imgf000101_0002
C32H35F2N3O6S Mw. 627.71
LC/MS purity: %, m/z [M-H]", [M+H]+ Rt. min. (Method B)
Yield: 28 %
Example 91
N-{4-[6,7-Bis-(2-methoxy-ethoxy)-quinolin-4-yloxy]-3-fluoro-phenyl}-2,6-difluoro- benzenesulfonamide
ULA-P03071WO21 Application
Figure imgf000102_0001
C27H25F3N2O7S Mw. 578.57
LC/MS purity: %, m/z [M-H]-, [M+H]+ Rt. min. (Method B)
Yield: 19 %
Example 92
{4-[2-Fluoro-4-(2-fluoro-benzenesulfonylamino)-phenoxy]-6-methoxy-quinolin-7- yloxyj-acetic acid ethyl ester
Figure imgf000102_0002
C26H22F2N2O7S Mw. 544.54
LC/MS purity: 97 %, m/z 543 [M-H]-, 545 [M+H]+ Rt. 3.50 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 10.99 (s, 1 H), 8.45 (d, 1 H), 7.91 (t, 1 H), 7.75 (m, 1 H), 7.50 (s, 1 H), 7.40 (m, 3H), 7.30 (s, 1 H), 7.17 (dd, 1 H), 7.05 (d, 1 H), 6.35 (d, 1 H), 5.00 (s, 2H), 4.20 (q, 2H), 3.94 (s, 3H), 1.28 (t, 3H)
Melting point: 87-89 °C.
Yield: 23 %
Example 93
2-{4-[2-Fluoro-4-(2-trifluoromethyl-benzenesulfonylamino)-phenoxy]-6-methoxy- quinolin-7-yloxy}-N,N-dimethyl-acetamide
ULA-P03071WO21 Application
Figure imgf000103_0001
C27H23F4N3O6S Mw. 593.56
LC/MS purity: 97 %, m/z 592 [M-H]-, 594 [M+H]+ Rt. 3.24 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 11.2 (bs, 1 H), 8.43 (d, 1 H), 8.15 (d, 1 H), 8.01 (d, 1 H), 7.88 (m, 2H), 7.47 (s, 1 H), 7.36 (t, 1 H), 7.29 (s, 1 H), 7.14 (d, 1 H), 7.02 (d, 1 H), 6.36 (d, 1 H), 5.03 (s, 2H), 3.92 (s, 3H), 2.86 (s, 3H), 3.11 (s, 3H)
Melting point: 134-135 °C.
Yield: 33 % Example 94
Cyclohexanecarboxylic acid 4-[4-(2,5-difluoro-benzenesulfonylamino)-2-fluoro- phenoxy]-6-methoxy-quinolin-7-yl ester
Figure imgf000103_0002
C29H25F3N2O6S Mw. 586.59
LC/MS purity: 82 %, m/z 585 [M-H]-, 587 [M+H]+ Rt. 4.54 min. (Method A)
Yield: 22 %
Example 95
N-(3-Fluoro-4-{6-methoxy-7-[3-(tetrahydro-pyran-4-ylamino)-propoxy]-quinolin-4- yloxy}-phenyl)-2-trifluoromethyl-benzenesulfonamide
Figure imgf000104_0001
C31H31 F4N3O6S Mw. 649.67
LC/MS purity: %, m/z [M-H]-, [M+H]+ Rt. min. (Method B)
Yield: 17 %
Example 96
N-{4-[7-(3-Cyclopropylamino-propoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro- phenyl}-2-trifluoro
Figure imgf000104_0002
C29H27F4N305S Mw. 605.61
LC/MS purity: %, m/z [M-H]", [M+H]+ Rt. min. (Method B)
Yield: 21 %
Example 97
N-{4-[7-(3-Cyclobutylamino-propoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro-phenyl}- 2-trifluoromethyl-b
Figure imgf000104_0003
C30H29F4N3O5S Mw. 619.64
LC/MS purity: %, m/z [M-H]", [M+H]+ Rt. min. (Method B)
Yield: 16 %
ULA-P03071WO21 Application Example 98
N-(4-{7-[3-(3-tert-Butyl-ureido)-propoxy]-6-methoxy-quinolin-4-yloxy}-3-fluoro- phenyl)-2-trifluoro
Figure imgf000105_0001
C31H32F4N4O6S Mw. 664.68
LC/MS purity: 96 %, m/z 663 [M-H]", 665 [M+H]+ Rt. 3.53 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 11.04 (bs, 1 H), 10 (bs, 1 H), 8.46 (d, 1 H), 8.15 (d, 1 H), 7.91 (s, 2H), 7.48 (s, 1 H), 7.38 (s, 2H), 7.18 (d, 1 H), 7.04 (d, 1 H), 6.38 (d, 1 H), 5.76 (bs, 1 H), 5.56 (bs, 1 H), 4.15 (bs, 2H), 3.92 (s, 3H), 3.15 (bs, 2H), 1.89 (bs, 2H), 1.21 (s, 9H)
Melting point: 106-108°C.
Yield: 15 %
Example 99
N-(3-Fluoro-4-{6-methoxy-7-[3-(2-methyl-piperidin-1 -yl)-propoxy]-quinolin-4-yloxy}- phenyl)-2-trifluoro
Figure imgf000105_0002
C32H33F4N3O5S Mw. 647.69
LC/MS purity: 98 %, m/z 646 [M-H]", 648 [M+H]+ Rt. 3.36 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 10 (bs, 1 H), 8.44 (d, 1 H), 8.13 (d, 1 H), 7.90 (d,
1 H), 7.75 (m, 2H), 7.48 (s, 1 H), 7.38 (s, 1 H), 7.18 (t, 1 H), 6.97 (dd, 1 H), 6.84 (d,
1 H), 6.35 (d, 1 H), 4.19 (t, 2H), 3.92 (s, 3H), 2.99 (m, 2H), 2.63 (m, 2H), 2.40 (m,
1 H), 2.00 (m, 2H), 1.56 (m, 4H), 1.30 (m, 2H), 1.09 (d, 3H).
Melting point: 115-116°C.
Yield: 20 %
ULA-P03071WO21 Application Example 100
N-{4-[7-(3-Dimethylamino-propoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro-phenyl}- 2-trifluoromethyl-
Figure imgf000106_0001
C28H27F4N3O5S Mw. 593.60
LC/MS purity: 100 %, m/z 592 [M-H]", 594 [M+H]+ Rt. 0.90 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 10.4 (bs, 1 H), 8.43 (s, 1 H), 8.12 (d, 1 H), 7.90 (d, 1 H), 7.75 (m, 2H), 7.48 (s, 1 H), 7.37 (s, 1 H), 7.17 (t, 1 H), 6.96 (d, 1 H), 6.84 (d, 1 H), 6.35 (d, 1 H), 4.18 (t, 2H), 3.92 (s, 3H), 2.58 (t, 2H), 2.50 (s, 6H), 1.99 (m, 2H) Melting point: 89-91 °C.
Yield: 35 %
Example 101
N-{4-[7-(3-Diethylamino-propoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro-phenyl}-2- trifluoromethyl-benzenesulfonamide
Figure imgf000106_0002
C30H31F4N3O5S Mw. 621.66
LC/MS purity: %, m/z [M-H]", [M+H]+ Rt. min. (Method B)
Yield: 30 %
Example 102
N-(3-{6-Methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)- 2-trifluoromethyl-benzenesulfonamide
ULA-P03071WO21 Application
Figure imgf000107_0001
C31H33F3N4O5S Mw. 630.69
LC/MS purity: 98 %, m/z 629 [M-H]", 631 [M+H]+ Rt. 3.41 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 10 (bs, 1 H), 8.41 (d, 1 H), 8.03 (d, 1 H), 7.88 (d, 1 H) 7.74 (bs, 2H), 7.36 (bs, 2H), 7.26 (t, 1 H), 6.91 (d, 1 H), 6.78 (s, 1 H), 6.72 (d, 1 H), 6.30 (d, 1 H), 4.18 (bs, 2H), 3.87 (s, 3H), 2.36 (m, 10H), 2.17 (s, 3H), 1.96 (m, 2H). Melting point: 155-156°C.
Yield: 27 %
Example 103
N-{3-Fluoro-4-[6-methoxy-7-(2-morpholin-4-yl-ethoxy)-quinolin-4-yloxy]-ph methoxy-benzen
Figure imgf000107_0002
C29H30FN3O7S Mw. 583.64
LC/MS purity: 98 %, m/z 582 [M-H]-, 584 [M+H]+ Rt. 3.46 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 10.40 (s, 1 H), 8.43 (d, 1 H), 7.83 (d, 1 H), 7.62 (t, 1 H), 7.46 (s, 1 H), 7.41 (s, 1 H), 7.30 (t, 1 H), 7.21 (d, 1 H), 7.13-6.90 (m, 3H), 6.29 (d, 1 H), 4.26 (t, 2H), 3.90 (s, 6H), 3.60 (t, 4H), 2.78 (t, 2H), 2.52 (t, 4H)
Melting point: 182-183°C.
Yield: 41 %
Example 104
2,6-Dichloro-N-{3-fluoro-4-[6-methoxy-7-(2-morpholin-4-yl-ethoxy)-quinolin-4- yloxy]-phenyl}-benzenesulfonamide
ULA-P03071WO21 Application
Figure imgf000108_0001
C28H26CI2FN3O6S Mw. 622.50
LC/MS purity: 98 %, m/z 622 [M-H]\ 624 [M+H]+ Rt. 3.12 min. (Method B)
H NMR (300 MHz, DMSO-d6): 11.21 (bs, 1 H), 8.44 (s, 1 H), 7.66 (m, 2H), 7.59 (d, 1 H), 7.47 (s, 1 H), 7.42 (s, 1 H), 7.34 (d, 1 H), 7.15 (d, 1 H), 7.00 (d, 1 H), 6.33 (s, 1 H), 4.27 (bs, 2H), 3.91 (s, 3H), 3.59 (s, 4H), 2.80 (bs, 2H), 2.52 (s, 4H).
Melting point: 210-211°C.
Yield: 54 % Example 105
Thiophene-2-sulfonic acid {3-fluoro-4-[6-methoxy-7-(2-morpholin-4-yl-ethoxy)- quinolin-4-yloxy]
Figure imgf000108_0002
C26H26FN3O6S2 Mw. 559.64
LC/MS purity: 98 %, m/z 558 [M-H]\ 560 [M+H]+ Rt. 2.85 min. (Method B)
H NMR (300 MHz, DMSO-d6): 10.5 (bs, 1 H), 8.47 (d, 1 H), 8.04 (s, 1 H), 7.70 (s, 2H), 7.48 (s, H), 7.43 (s, 1 H), 7.30 (t, 1 H), 7.13 (d, 1 H), 6.97 (d, 1 H), 6.36 (d, 1 H), 4.26 (t, 2H), 3.93 (s, 3H), 3.59 (s, 4H), 2.81 (m, 2H), 2.56 (bs, 4H).
Melting point: 146-147°C.
Yield: 55 %
Example 106
2,5-Dichloro-N-{3-fluoro-4-[6-methoxy-7-(2-morpholin-4-yl-ethoxy)-quinolin-4- yloxy]-phenyl}-benzenesulfonamide
Figure imgf000109_0001
C28H26CI2FN3O6S Mw. 622.50
LC/MS purity: 97 %, m/z 622 [M-H]", 624 [M+H]+ Rt. 3.28 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 1 1.1 (bs, 1 H), 8.44 (s, 1 H), 8.03 (s, 1 H), 7.71 (s, 2H), 7.47 (s, 1 H), 7.42 (s, 1 H), 7.33 (t, 1 H), 7.12 (d, 1 H), 6.99 (d, 1 H), 6.34 (s, 1 H), 4.27 (bs, 2H), 3.91 (s, 3H), 3.59 (s, 4H), 2.80 (bs, 2H), 2.53 (s, 4H)
Melting point: 194-196°C.
Yield: 74 % Example 107
1 -Methyl-1 H-pyrazole-3-sulfonic acid {3-fluoro-4-[6-methoxy-7-(2-morpholin-4-yl- ethoxy)-quinolin
Figure imgf000109_0002
C26H28FN506S Mw. 557.60
LC/MS purity: 98 %, m/z 556 [M-H]", 558 [M+H]+ Rt. 2.66 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 10.74 (s, 1 H), 8.45 (s, 1 H), 7.88 (s, 1 H), 7.49 (s, 1 H), 7.43 (s, 1 H), 7.36 (t, 1 H), 7.20 (d, 1 H), 7.07 (d, 1 H), 6.68 (s, 1 H), 6.38 (s, 1 H), 4.27 (bs, 2H), 3.91 (s, 6H), 3.59 (s, 4H), 2.79 (bs, 2H), 2.53 (s, 4H)
Melting point: 213-214°C.
Yield: 69 %
Example 108
2-Chloro-N-{3-fluoro-4-[6-methoxy-7-(2-morpholin-4-yl-ethoxy)-quinolin-4-yloxy]- phenylj-benzenesulfonamide
ULA-P03071WO21 Application
Figure imgf000110_0001
C28H27CIFN3O6S Mw. 588.05
LC/MS purity: 96 %, m/z 586 [M-H]", 588 [M+H]+ Rt. 3.24 min. (Method B)
H NMR (300 MHz, DMSO-d6): 11.01 (bs, 1 H), 8.43 (s, 1 H), 8.01 (d, 1 H), 7.67 (s, 2H), 7.56 (s, 1 H), 7.46 (s, 1 H), 7.42 (s, 1 H), 7.34 (t, 1 H), 7.13 (d, 1 H), 7.02 (d, 1 H), 6.32 (s, 1 H), 4.26 (bs, 2H), 3.90 (s, 3H), 3.59 (s, 4H), 2.79 (bs, 2H), 2.51 (s, 4H) Melting point: 180-181 °C.
Yield: 76 %
Example 109
N-{3-Fluoro-4-[6-methoxy-7-(2-morpholin-4-yl-ethoxy)-quinolin-4-yloxy]-phenyl}-2- nitro-benzenesul
Figure imgf000110_0002
C28H27FN4O8S Mw. 598.61
LC/MS purity: 97 %, m/z 597 [M-H]-, 599 [M+H]+ Rt. 2.88 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 11 (bs, 1 H), 8.45 (s, 1 H), 8.02 (s, 1 H), 7.93 (s, 1 H), 7.83 (s, 2H), 7.48 (s, 1 H), 7.43 (s, 1 H), 7.32 (t, 1 H), 7.11 (d, 1 H), 6.97 (d, 1 H), 6.37 (s, 1 H), 4.27 (bs, 2H), 3.92 (s, 3H), 3.59 (s, 4H), 2.81 (bs, 2H), 2.54 (s, 4H) Melting point: 129-131 °C.
Yield: 74 %
Example 110
2,6-Difluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]- quinolin-4-yloxy}-phenyl)-benzenesulfonamide
ULA-P03071WO21 Application
Figure imgf000111_0001
C30H31F3N4O5S Mw. 616.66
LC/MS purity: 97 %, m/z 615 [M-H]", 617 [M+H]+ Rt. 2.77 min. (Method B)
H NMR (300 MHz, DMSO-d6): 10.5 (bs, 1 H), 8.44 (d, 1 H), 7.6 (t, 1 H), 7.48 (s, 1 H), 7.37 (s, 1 H), 7.19 (m, 3H), 7.05 (d, 1 H), 6.90 (d, 1 H), 6.34 (d, 1 H), 4.18 (bs, 2H), 3.92 (s, 3H), 2.48 (s, 10H), 2.26 (s, 3H), 1.97 (bs, 2H).
Melting point: 199-201 °C.
Yield: 41 %
Example 111
N-(3-Chloro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4- yloxy}-phenyl)-2-fl
Figure imgf000111_0002
C3oH32CIFN405S Mw. 615.12
LC/MS purity: 95 %, m/z 613 [M-H]", 615 [M+H]+ Rt. 3.01 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 11.2 (bs, 1 H), 8.43 (dd, 1 H), 7.86 (t, 1 H), 7.65 (s,
1 H), 7.36 (m, 6H), 7.09 (dd, 1 H), 6.23 (d, 1 H), 4.17 (s, 2H), 3.91 (s, 3H), 2.41 (s,
10H), 2.19 (s, 3H), 1.96 (s, 2H).
Melting point: 170-171 °C.
Yield: 52 %
Example 112
N-(3-Chloro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4- yloxy}-phenyl)-2,5-difluoro-benzenesulfonamide
ULA-P03071WO21 Application
Figure imgf000112_0001
C3oH3iCIF2N405S Mw. 633.11
LC/MS purity: 96 %, m/z 631 [M-H]\ 633 [M+H]+ Rt. 2.94 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 10.2 (bs, 1 H), 8.42 (d, 1 H), 7.59 (m, 1 Η), 7.48 (s, 1 H), 7.40 (m, 2H), 7.37 (s, 1 H), 7.20 (m, 2H), 7.03 (d, 1 H), 6.25 (d, 1 H), 4.18 (bs, 2H), 3.92 (s, 3H), 2.49 (s, 10H), 2.28 (s, 3H), 1.97 (bs, 2H).
Melting point: 118-121°C.
Yield: 68 % Example 113
Benzo[b]thiophene-3-sulfonic acid {3-fluoro-4-[6-methoxy-7-(3-piperidin-1 -yl- propoxy)-quinolin
Figure imgf000112_0002
C32H32FN3O5S2 Mw. 621.75
LC/MS purity: 98 %, m/z 620 [M-H]-, 622 [M+H]+ Rt. 3.56 min. (Method B)
H NMR (300 MHz, DMSO-d6): 10.5 (s, 1 H), 8.53 (s, 1 H), 8.41 (d, 1 H), 8.26 (d, 1 H), 8.08 (d, 1 H), 7.52 (m, 4H), 7.35 (s, 1 H), 7.20 (t, 1 H), 7.08 (d, 1 H), 6.90 (d, 1 H), 4.16 (s, 2H), 3.90 (s, 3H), 2.47 (s, 6H), 1.98 (s, 2H), 1.52 (s, 4H), 1.40 (s, 2H). Melting point: 128-130°C.
Yield: 65 %
Example 114
Benzo[b]thiophene-3-sulfonic acid {3-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl- propoxy)-quinolin-4-yloxy]-phenyl}-amide
Figure imgf000113_0001
C31H30FN3O6S2 Mw. 623.72
LC/MS purity: 99 %, m/z 622 [M-H]\ 624 [M+H]+ Rt. 3.54 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 11 (bs, 1 H), 8.66 (d, 1 H), 8.42 (d, 1 H), 8.24 (d, 1 H), 8.12 (d, 1 H), 7.56 (m, 2H), 7.44 (s, 1 H), 7.37 (s, 1 H), 7.28 (t, 1 H), 7.14 (d, 1 H), 6.97 (d, 1 H), 6.29 (s, 1 H), 4.18 (s, 2H), 3.90 (s, 3H), 3.58 (s, 4H), 2.47 (s, 2H), 2.38 (s, 4H), 1.96 (s, 2H).
Melting point: 196-197°C.
Yield: 64 %
Example 115
Benzo[b]thiophene-3-sulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperidin- 1-yl)-propoxy]-qui
Figure imgf000113_0002
C33H34FN3O5S2 Mw. 635.78
LC/MS purity: 98 %, m/z 634 [M-H]\ 636 [M+H]+ Rt. 3.81 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 10.9 (bs, 1 H), 8.58 (s, 1 H), 8.41 (d, 1 H), 8.24 (d, 1 H), 8.09 (d, 1 H), 7.52 (m, 3H), 7.36 (s, 1 H), 7.23 (t, 1 H), 7.09 (d, 1 H), 6.93 (d, 1 H), 6.29 (s, 1 H), 4.17 (s, 2H), 3.90 (s, 3H), 2.92 (d, 2H), 2.02 (m, 4H), 1.60 (s, 2H), 1.35 (bs, 1 H), 1.11 (m, 4H), 0.88 (s, 3H).
Melting point: 132-135°C.
Yield: 61 %
Example 116
Benzo[b]thiophene-3-sulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin- 1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide
ULA-P03071WO21 Applicalion
Figure imgf000114_0001
C32H33FN405S2 Mw. 636.77
LC/MS purity: 98 %, m/z 635 [M-H]", 637 [M+H]+ Rt. 3.29 min. (Method B)
H NMR (300 MHz, DMSO-d6): 10.8 (bs, 1 H), 8.58 (s, 1 H), 8.42 (d, 1 H), 8.24 (d, 1 H), 8.09 (d, 1 H), 7.52 (m, 3H), 7.45 (s, 1 H), 7.35 (s, 1 H), 7.09 (d, 1 H), 6.93 (d, 1 H), 6.29 (s, 1 H), 4.16 (s, 2H), 3.90 (s, 3H), 2.43 (m, 10H), 2.18 (s, 3H), 1.95 (s, 2H).
Melting point: 112-114°C.
Yield: 73 %
Example 117
Benzo[b]thiophene-3-sulfonic acid (3-chloro-4-{6-methoxy-7-[3-(4-methyl- piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide
Figure imgf000114_0002
C32H33CIN405S2 Mw. 653.22
LC/MS purity: 99 %, m/z 651 [M-H]', 653 [M+H]+ Rt. 3.36 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 11 (bs, 1 H), 8.56 (s, 1 H), 8.40 (t, 1 H), 8.23 (d, 1 H), 8.09 (d, 1 H), 7.52 (m, 2H), 7.45 (s, 1 H), 7.35 (s, 1 H), 7.24 (m, 2H), 7.09 (d, 1 H), 6.19 (s, 1 H), 4.17 (s, 2H), 3.89 (s, 3H), 2.39 (bs, 10H), 2.19 (s, 3H), 1.95 (s, 2H). Melting point: 98-101 °C.
Yield: 75 %
Example 118
N-(3-Chloro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4- yloxy}-phenyl)-2,6-difluoro-benzenesulfonamide
Figure imgf000115_0001
C30H31CIF2N4O5S Mw. 633.11
LC/MS purity: 99 %, m/z 631 [M-H]', 633 [M+H]+ Rt. 2.84 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 10.8 (bs, 1 H), 8.42 (s, 1 H), 7.62 (s, 1 H), 7.48 (s, 1 H), 7.37 (s, 1 H), 7.23 (m, 4H), 7.06 (d, 1 H), 6.24 (s, 1 H), 4.18 (s, 2H), 3.91 (s, 3H), 2.49 (s, 10H), 2.29 (s, 3H), 1.97 (s, 2H).
Melting point: 122-124°C.
Yield: 48 %
Example 119
2,6-Dichloro-N-(3-chloro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]- quinolin-4-yloxy}-
Figure imgf000115_0002
C3oH3iCl3N405S Mw. 666.02
LC/MS purity: 98 %, m/z 665 [M-H]", 667 [M+H]+ Rt. 3.12 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 11 (bs, 1 H), 8.41 (s, 1 H), 7.58 (s, 2H), 7.47 (s,
2H), 7.37 (s, 1 H), 7.25 (s, 2H), 7.04 (s, 1 H), 6.23 (s, 1 H), 4.18 (s, 2H), 3.91 (s, 3H),
2.50 (s, 10H), 2.29 (s, 3H), 1.97 (s, 2H).
Melting point: 171-172°C.
Yield: 34 %
Example 120
(3-{4-[2-Fluoro-4-(2-trifluoromethyl-benzenesulfonylamino)-phenoxy]-6-methoxy- quinolin-7-yloxy}-propyl)-carbamic acid tert-butyl ester
Figure imgf000116_0001
C31H31F4N3O7S Mw. 665.66
LC/MS purity: 100 %, m/z 664 [M-H]", 666 [M+H]+ Rt. 3.66 min. (Method A)
1H NMR (300 MHz, DMSO-d6): 11 (bs, 1 H), 8.45 (s, 1 H), 8.15 (d, 1 H), 8.02 (d, 1 H), 7.90 (bs, 2H), 7.47 (s, 1 H), 7.37 (bs, 2H), 7.16 (d, 1 H), 7.03 (d, 1 H), 6.88 (bs, 1 H), 6.36 (d, 1 H), 4.16 (bs, 2H), 3.92 (s, 3H), 3.13 (bs, 2H), 1.93 (bs, 2H), 1.38 (s, 9H).
Melting point: 80-82°C.
Yield: 84 %
Example 121
(3-{4-[4-(2,5-Difluoro-benzenesulfonylamino)-2-fluoro-phenoxy]-6-methoxy- quinolin-7-yloxy}-
Figure imgf000116_0002
C30H30F3N3O7S Mw. 633.64
LC/MS purity: 99%, m/z 632 [M-H]", 634 [M+H]+ Rt. 3.57 min. (Method A)
1H NMR (300 MHz, DMSO-d6): 11 (bs, 1 H), 8.45 (d, 1 H), 7.60 (m, 3H), 7.48 (s, 1 H), 7.37 (bs, 2H), 7.19 (d, 1 H), 7.05 (d, 1 H), 6.88 (bs, 1 H), 6.35 (d, 1 H), 4.16 (bs, 2H), 3.92 (s, 3H), 3.16 (bs, 2H), 1.93 (bs, 2H), 1.38 (s, 9H).
Melting point: 115-118°C.
Yield: 78 %
Example 122
N-{4-[7-(3-Amino-propoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro-phenyl}-2,5- difluoro-benzenesulfonamide hydrochloride
ULA-P03071WO21 Application
Figure imgf000117_0001
C25H22F3N3O5S.HCI Mw. 533.53
LC/MS purity: 99 %, m/z 532 [M-H]", 534 [M+H]+ Rt. 2.71 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 11.37 (s, 1 H), 8.77 (bs, 1 H), 8.09 (bs, 2H), 7.61 (m, 4H), 7.28 (d, 1 H), 7.15 (d, 1 H), 6.85 (bs, 1 H), 4.33 (bs, 2H), 4.02 (s, 3H), 3.57 (s, 2H), 3.01 (bs, 2H), 2.19 (bs, 2H).
Melting point: 188-190°C.
Yield: 85 %
Example 123
2,5-Difluoro-N-(3-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4- yloxy}-phenyl)-be
Figure imgf000117_0002
C3oH32F2N405S Mw. 598.67
LC/MS purity: 98 %, m/z 597 [M-H]", 599 [M+H]+ Rt. 2.38 min. (Method A)
LC/MS purity: 99 %, m/z 631 [M-H]", 633 [M+H]+ Rt. 2.84 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 11 (bs, 1 H), 8.39 (d, 1 H), 7.42 (bs, 2H), 7.35 (m, 3H), 7.17 (t, 1 H), 6.82 (d, 1 H), 6.77 (s, 1 H), 6.57 (d, 1 H), 6.29 (d, 1 H), 4.18 (bs, 2H), 3.90 (s, 3H), 2.40 (s, 10H), 2.16 (s, 3H), 1.96 (s, 2H).
Melting point: 186-188°C.
Yield: 52 %
Example 124
2,5-Dichloro-N-(3-chloro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]- quinolin-4-yloxy}-phenyl)-benzenesulfonamide
Figure imgf000118_0001
C30H31CI3N4O5S Mw. 666.02
LC/MS purity: 99%, m/z 664 [M-H]", 666 [M+H]+ Rt. 3.39 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 10.5 (bs, 1 H), 8.42 (d, 1 H), 7.97 (s, 1 H), 7.62 (bs, 2H), 7.48 (s, 1 H), 7.37 (s, 1 H), 7.19 (m, 2H), 7.00 (d, 1 H), 6.25 (d, 1 H), 4.17 (t, 2H), 3.91 (s, 3H), 2.49 (s, 10H), 2.32 (s, 3H), 1.97 (s, 2H).
Melting point: 144-145°C.
Yield: 66 %
Example 125
2,6-Difluoro-N-(3-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4- yloxy}-phenyl)-be
Figure imgf000118_0002
C3oH32F2N4O5S Mw. 598.67
LC/MS purity: 98%, m/z 597 [M-H]-, 599 [M+H]+ Rt. 3.04 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 10.8 (bs, 1 H), 8.43 (d, 1 H), 7.64 (m, 1 H), 7.40 (s, 1 H), 7.37 (s, 1 H), 7.31 (t, 1 H), 7.18 (t, 2H), 6.97 (d, 1 H), 6.88 (s, 1 H), 6.80 (s, 1 H), 6.20 (d, 1 H), 4.18 (t, 2H), 3.89 (s, 3H), 2.46 (t, 2H), 2.41 (s, 8H), 2.20 (s, 3H), 1.96 (t, 2H).
Melting point: 171-172°C.
Yield: 58 %
Example 126
N-(3-{6-Methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)- 2-trifluoromethoxy-benzenesulfonamide
Figure imgf000119_0001
C3iH33F3N406S Mw. 646.69
LC/MS purity: 99%, m/z 645 [M-H]", 647 [M+H]+ Rt. 3.58 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 11 (bs, 1 H), 8.43 (d, 1 H), 7.88 (d, 1 H), 7.72 (t, 1 H), 7.38 (m, 5H), 6.95 (d, 1 H), 6.70 (m, 2H), 6.26 (d, 1 H), 4.18 (t, 2H), 3.88 (s, 3H), 2.44 (m, 10H), 2.17 (s, 3H), 1.96 (t, 2H).
Melting point: 164-166°C.
Yield: 60 %
Example 127
2,5-Dichloro-N-(3-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4- yloxy}-phenyl)-be
Figure imgf000119_0002
C30H32CI2N4O5S Mw. 631.58
LC/MS purity: 99 %, m/z 629 [M-H]", 631 [M+H]+ Rt. 3.45 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 11.2 (bs, 1 H), 8.43 (d, 1 H), 7.90 (m, 1 H), 7.65 (m, 2H), 7.40 (s, 1 H), 7.37 (s, 1 H), 7.31 (t, 1 H), 6.96 (d, 1 H), 6.80 (m, 2H), 6.24 (d, 1 H), 4.18 (t, 2H), 3.89 (s, 3H), 2.47 (m, 10H), 2.24 (s, 3H), 1.98 (t, 2H).
Melting point: 111-113°C.
Yield: 55 %
Example 128
2,6-Dichloro-N-(3-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4- yloxy}-phenyl)-benzenesulfonamide
ULA-P03071WO21 Application
Figure imgf000120_0001
C3oH32Cl2N4O5S Mw. 631.58
LC/MS purity: 99 %, m/z 629 [M-H]", 631 [M+H]+ Rt. 3.35 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 10.2 (bs, 1 H), 8.42 (d, 1 H), 7.52 (m, 3H), 7.37 (s, 2H), 7.30 (t, 1 H), 6.93 (d, 1 H), 6.81 (s, 1 H), 6.79 (d, 1 H), 6.23 (d, 1 H), 4.16 (t, 2H), 3.87 (s, 3H), 2.45 (m, 10H), 2.19 (s, 3H), 1.97 (m, 2H).
Melting point: 111-112°C.
Yield: 51 % Example 129
Thiophene-2-sulfonic acid (3-{6-methoxy-7-[3-(4-methyl-piperazin-1 -yl)-propoxy]- quinolin-4-yloxy}-phenyl)-amide
Figure imgf000120_0002
C28H32N4O5S2 Mw. 568.71
LC/MS purity: 97 %, m/z 567 [M-H]", 569 [M+H]+ Rt. 2.97 min. (Method A)
1H NMR (300 MHz, DMSO-d6): 10.8 (bs, 1 H), 8.47 (d, 1 H), 7.88 (d, 1 H), 7.41 (m,
4H), 7.10 (d, 1 H), 6.98 (d, 1 H), 6.90 (s, 2H), 6.32 (d, 1 H), 4.18 (bs, 2H), 3.90 (s,
3H), 2.40 (m, 10H), 2.17 (s, 3H), 1.96 (bs, 2H).
Melting point: 188-189°C.
Yield: 31 %
Example 130
5-Chloro-thiophene-2-sulfonic acid (3-{6-methoxy-7-[3-(4-methyl-piperazin-1 -yl)- propoxy]-quinolin-4-yloxy}-phenyl)-amide
ULA-P03071WO21 Application
Figure imgf000121_0001
C28H31CIN4O5S2 Mw. 603.16
LC/MS purity: 99 %, m/z 601 [M-H]", 603 [M+H]+ Rt. 3.05 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 1 1 (bs, 1 H), 8.47 (s, 1 H), 7.36 (m, 4H), 7.14 (d, 1 H), 7.00 (s, 1 H), 6.86 (s, 2H), 6.36 (d, 1 H), 4.18 (bs, 2H), 3.90 (s, 3H), 2.45 (m, 10H), 2.22 (s, 3H), 1.97 (bs, 2H).
Melting point: 162-163°C.
Yield: 52 % Example 131
5-Methyl-thiophene-2-sulfonic acid (3-{6-methoxy-7-[3-(4-methyl-piperazin-1 -yl)- propoxy]-quinolin
Figure imgf000121_0002
C29H34N4O5S2 Mw. 582.74
LC/MS purity: 98 %, m/z 581 [M-H]", 583 [M+H]+ Rt. 3.21 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 10.5 (bs, 1 H), 8.47 (d, 1 H), 7.42 (s, 1 H), 7.38 (s,
1 H), 7.34 (t, 1 H), 7.26 (d, 1 H), 7.01 (d, 1 H), 6.85 (m, 3H), 6.36 (d, 1 H), 4.18 (t,
2H), 3.90 (s, 3H), 2.40 (m, 13H), 2.16 (s, 3H), 1.96 (m, 2H).
Melting point: 147-149°C.
Yield: 33 %
Example 132
N-[5-(3-{6-Methoxy-7-[3-(4-methyl-piperazin-1 -yl)-propoxy]-quinolin-4-yloxy}- phenylsulfamoyl)-4-methyl-thiazol-2-yl]-acetamide
Figure imgf000121_0003
C30H36N6O6S2 Mw. 640.78
LC/MS purity: 98 %, m/z 639 [M-H]", 641 [M+H]+ Rt. 2.68 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 12.2 (bs, 1 H), 8.44 (d, 1 H), 7.38 (m, 3H), 7.03 (d, 1 H), 6.92 (s, 2H), 6.30 (d, 1 H), 4.19 (bs, 2H), 3.90 (s, 3H), 2.40 (m, 16H), 2.16 (s, 3H), 1.96 (m, 2H).
Melting point: 148-150°C.
Yield: 36 %
Example 133
Thiophene-3-sulfonic acid (3-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]- quinolin-4-yloxy}-phenyl)-amide
Figure imgf000122_0001
C28H32N4O5S2 Mw. 568.71
LC/MS purity: 98%, m/z 567 [M-H]', 569 [M+H]+ Rt. 3.11 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 10.5 (bs, 1 H), 8.47 (d, 1 H), 8.10 (s, 1 H), 7.70 (d, 1 H), 7.38 (m, 3H), 7.22 (d, 1 H), 7.06 (d, 1 H), 6.88 (s, 2H), 6.30 (d, 1 H), 4.18 (t, 2H), 3.90 (s, 3H), 2.45 (m, 10H), 2.15 (s, 3H), 1.97 (m, 2H).
Melting point: 176-178°C.
Yield: 41 %
Example 134
2,5-Dichloro-thiophene-3-sulfonic acid (3-{6-methoxy-7-[3-(4-methyl-piperazin-1 - yl)-propoxy]-quin
Figure imgf000122_0002
C28H30CI2N4O5S2 Mw. 637.60
LC/MS purity: 98 %, m/z 635 [M-H]", 637 [M+H]+ Rt. 3.19 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 10.3 (bs, 1 H), 8.46 (d, 1 H), 7.43 (s, 1 H), 7.37 (s, 1 H), 7.31 (t, 1 H), 7.17(s, 1 H), 6.94 (d, 1 H), 6.80 (m, 2H), 6.36 (d, 1 H), 4.18 (t, 2H), 3.91 (s, 3H), 2.44 (m, 10H), 2.22 (s, 3H), 1.97 (m, 2H). Melting point: 177-178°C.
Yield: 35 %
Example 135
3-(3-{6-Methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}- phenylsulfamoyl)
Figure imgf000123_0001
C30H34N4O7S2 Mw. 626.75
LC/MS purity: 99 %, m/z 625 [M-H]\ 627 [M+H]+ Rt. 2.37 min. (Method A)
1H NMR (300 MHz, DMSO-d6): 10.4 (bs, 1 H), 8.45 (s, 1 H), 7.90 (s, 1 H), 7.37 (m, 4H), 6.98 (d, 1 H), 6.85 (bs, 2H), 6.00 (s, 1 H), 4.18 (bs, 2H), 3.89 (s, 3H), 3.80 (s, 3H), 2.38 (m, 10H), 2.15 (s, 3H), 1.96 (bs, 2H).
Melting point: 84-86°C.
Yield: 33 %
Example 136
Benzo[b]thiophene-3-sulfonic acid (3-{6-methoxy-7-[3-(4-methyl-piperazin-1 -yl)- propoxy]-quinolin
Figure imgf000123_0002
C32H34N4O5S2 Mw. 618.77
LC/MS purity: 98%, m/z 617 [M-H]", 619 [M+H]+ Rt. 3.42 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 10.7 (bs, 1 H), 8.46 (s, 1 H), 8.39 (d, 1 H), 8.20 (d, 1 H), 8.09 (d, 1 H), 7.48 (bs, 2H), 7.36 (s, 2H), 7.28 (t, 1 H), 7.01 (d, 1 H), 6.80 (m, 2H), 6.13 (d, 1 H), 4.17 (bs, 2H), 3.87 (s, 3H), 2.40 (m, 10H), 2.16 (s, 3H), 1.95 (bs, 2H).
Melting point: 91-93°C.
Yield: 42 %
ULA-P03071WO21 Application Example 137
Furan-2-sulfonic acid (3-{6-methoxy-7-[3-(4-methyl-piperazin-1 -yl)-propoxy]- quinolin-4-yloxy}-phenyl)-amide
Figure imgf000124_0001
C28H32N406S Mw. 552.65
LC/MS purity: 98 %, m/z 551 [M-H]\ 553 [M+H]+ Rt. 2.71 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 10.5 (bs, 1 H), 8.49 (d, 1 H), 7.90 (s, 1 H), 7.40 (m, 3H), 7.04 (m, 2H), 6.90 (m, 2H), 6.62 (s, 1 H), 6.39 (d, 1 H), 4.19 (bs, 2H), 3.90 (s, 3H), 2.41 (m, 10H), 2.20 (s, 3H), 1.96 (bs, 2H).
Melting point: 176-177°C.
Yield: 39 %
Example 138
3,5-Dimethyl-isoxazole-4-sulfonic acid (3-{6-methoxy-7-[3-(4-methyl-piperazin-1 -
Figure imgf000124_0002
LC/MS purity: 99 %, m/z 580 [M-H]\ 582 [M+H]+ Rt. 2.82 min. (Method B)
H NMR (300 MHz, DMSO-d6): 11 (bs, 1 H), 8.47 (d, 1 H), 7.40 (m, 3H), 6.95 (m,
2H), 6.82 (s, 1 H), 6.38 (d, 1 H), 4.19 (bs, 2H), 3.90 (s, 3H), 2.40 (m, 10H), 2.22 (s,
6H), 2.19 (s, 3H), 1.96 (bs, 2H).
Melting point: 200-202°C.
Yield: 38 % Example 139
1 -Methyl-1 H-pyrazole-3-sulfonic acid (3-{6-methoxy-7-[3-(4-methyl-piperazin-1 -yl)- propoxy]-quinolin-4-yloxy}-phenyl)-amide
ULA-P03071WO21 Application
Figure imgf000125_0001
LC/MS purity: 98 %, m/z 565 [M-H]", 567 [M+H]+ Rt. 2.72 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 10.5 (bs, 1 H), 8.48 (d, 1 H), 7.82 (s, 1 H), 7.43 (s, 1 H), 7.38 (s, 1 H), 7.33 (t, 1 H), 7.02 (s, 1 H), 6.96 (s, 1 H), 6.84 (d, 1 H), 6.55 (d, 1 H), 6.38 (d, 1 H), 4.18 (bs, 2H), 3.91 (s, 3H), 3.84 (s, 3H), 2.35 (m, 10H), 2.15 (s, 3H), 1.96 (bs, 2H).
Melting point: 87-89°C.
Yield: 26 %
Example 140
1-Ethyl-1 H-pyrazole-4-sulfonic acid (3-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)- propoxy]-quinolin-4-yloxy}-phenyl)-amide
Figure imgf000125_0002
C29H36N6O5S Mw. 580.71
LC/MS purity: 98%, m/z 579 [M-H]", 581 [M+H]+ Rt. 2.91 min. (Method B)
H NMR (300 MHz, DMSO-d6): 10.2 (bs, 1 H), 8.46 (d, 1 H), 8.25 (s, 1 H), 7.66 (s, 1 H), 7.44 (s, 1 H), 7.38 (m, 2H), 7.06 (d, 1 H), 6.91 (m, 2H), 6.38 (d, 1 H), 4.15 (bs, 2H), 3.91 (s, 3H), 2.40 (m, 12H), 2.16 (s, 3H), 1.96 (bs, 2H), 1.32 (t, 3H).
Melting point: 87-90°C.
Yield: 38 %
Example 141
2-Methyl-1 H-imidazole-4-sulfonic acid (3-{6-methoxy-7-[3-(4-methyl-piperazin-1- yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide
ULA-P03071WO21 Application
Figure imgf000126_0001
C28H34N6O5S Mw.566.68
LC/MS purity: 96 %, m/z 565 [M-H]", 567 [M+H]+ Rt.2.70 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 12.4 (bs, 1H), 10.2 (bs, 1H), 8.47 (d, 1H), 7.59 (bs, 1H), 7.44 (s, 1H), 7.37 (s, 1H), 7.32 (t, 1H), 7.05 (d, 1H), 6.98 (s, 1H), 6.82 (bs, 1H), 6.35 (d, 1H), 4.18 (bs, 2H), 3.91 (s, 3H), 2.45 (m, 10H), 2.24 (s, 3H), 2.15 (s, 3H), 1.96 (bs, 2H).
Melting point: 118-120°C.
Yield: 33 %
Example 142
Cydopropanesulfonic acid (3-{6-methoxy-7-[3-(4-methyl-piperazin-1 -yl)-propoxy]-
Figure imgf000126_0002
LC/MS purity: 99 %, m/z 525 [M-H]", 527 [M+H]+ Rt.2.99 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 10 (bs, 1H), 8.50 (d, 1H), 7.47 (s, 1H), 7.43 (d, 1H), 7.38 (s, 1H), 7.16 (d, 1H), 7.07 (s, 1H), 6.97 (d, 1H), 6.53 (d, 1H), 4.18 (t, 2H), 3.92 (s, 3H), 2.67 (m, 1H), 2.40 (m, 10H), 2.15 (s, 3H), 1.96 (m, 2H), 0.94 (m, 4H). Melting point: 150-152°C.
Yield: 43 %
Example 143
2-Phenyl-ethenesulfonic acid (3-{6-methoxy-7-[3-(4-methyl-piperazin-1 -yl)- propoxy]-quinolin-4-yloxy}-phenyl)-amide
ULA-P03071WO21 Application
Figure imgf000127_0001
LC/MS purity: 99%, m/z 587 [M-H]", 589 [M+H]+ Rt. 3.41 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 10.2 (bs, 1 H), 8.27 (d, 1 H), 7.66 (s, 1 H), 7.64 (s, 1 H), 7.40 (m, 7H), 7.26 (d, 1 H), 7.12 (d, 1 H), 7.00 (s, 1 H), 6.89 (d, 1 H), 6.39 (d, 1 H), 4.17 (t, 2H), 3.89 (s, 3H), 2.40 (m, 10H), 2.15 (s, 3H), 1.95 (m, 2H).
Melting point: 85-87°C.
Yield: 39 % Example 144
Thiophene-2-sulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(2-methyl-piperidin-1 -yl)- propoxy]-quinolin
Figure imgf000127_0002
C29H32FN3O5S2 Mw. 585.72
LC/MS purity: 98%, m/z 584 [M-H]", 586 [M+H]+ Rt. 3.08 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 10.5 (bs, 1 H), 8.45 (d, 1 H), 7.78 (d, 1 H), 7.49 (s, 2H), 7.38 (s, 1 H), 7.24 (t, 1 H), 7.07 (m, 2H), 6.92 (d, 1 H), 6.36 (d, 1 H), 4.18 (t, 2H), 3.92 (s, 3H), 2.94 (m, 2H), 2.50 (m, 2H), 2.30 (m, 1 H), 1.96 (m, 2H), 1.50 (m, 4H), 1.27 (m, 2H), 1.05 (d, 3H).
Melting point: 117-119°C.
Yield: 47 %
Example 145
5-Chloro-thiophene-2-sulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(2-methyl-piperidin- 1 -yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide
Figure imgf000128_0001
C29H3iCIFN305S2 Mw. 620.16
LC/MS purity: 99 %, 618 m/z [M-H]\ 620 [M+H]+ Rt. 3.24 min. (Method B)
H NMR (300 MHz, DMSO-d6): 10.2 (bs, 1 H), 8.44 (d, 1 H), 7.50 (s, 1 H), 7.38 (s, 1 H), 7.18 (d, 1 H), 7.09 (t, 1 H), 7.03 (d, 1 H), 6.83 (d, 1 H), 6.77 (d, 1 H), 6.37 (d, 1 H), 4.19 (t, 2H), 3.93 (s, 3H), 2.97 (m, 2H), 2.70 (m, 2H), 2.36 (m, 1 H), 1.99 (m, 2H), 1.56 (m, 4H), 1.29 (m, 2H), 1.08 (d, 3H).
Melting point: 118-120°C.
Yield: 31 %
Example 146
2,4-Dichloro-thiophene-3-sulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(2-methyl- piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide
Figure imgf000128_0002
C29H30CI2FN3O5S2 Mw. 654.61
LC/MS purity: 99 %, m/z 652 [M-H]", 654 [M+H]+ Rt. 3.39 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 10 (bs, 1 H), 8.45 (d, 1 H), 7.51 (s, 1 H), 7.39 (s, 1 H), 7.15 (s, 1 H), 7.10 (d, 1 H), 6.93 (d, 1 H), 6.78 (d, 1 H), 6.39 (d, 1 H), 4.21 (t, 2H), 3.93 (s, 3H), 3.04 (m, 2H), 2.71 (m, 2H), 2.49 (m, 1 H), 2.03 (m, 2H), 1.60 (m, 4H), 1.34 (m, 2H), 1.11 (d, 3H).
Melting point: 131-132°C.
Yield: 39 %
Example 147
Benzo[b]thiophene-3-sulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(2-methyl-piperidin- 1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide
ULA-P03071WO21 Application
Figure imgf000129_0001
C33H34FN3O5S2 Mw.635.78
LC/MS purity: 99 %, m/z 634 [M-H]", 636 [M+H]+ Rt.3.52 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 10.3 (bs, 1H), 8.53 (s, 1H), 8.41 (d, 1H), 8.25 (d, 1H), 8.09 (d, 1H), 7.50 (m, 2H), 7.45 (s, 1H), 7.37 (s, 1H), 7.20 (t, 1H), 7.07 (d, 1H), 6.90 (d, 1H), 6.29 (d, 1H), 4.17 (t, 2H), 3.90 (s, 3H), 2.90 (m, 2H), 2.49 (m, 2H), 2.28 (m, 1H), 1.94 (m, 2H), 1.53 (m, 4H), 1.26 (m, 2H), 1.04 (d, 3H).
Melting point: 120-122°C.
Yield: 45 %
Example 148
Furan-2-sulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(2-methyl-piperidin-1 -yl)- propoxy]-quinolin
Figure imgf000129_0002
C29H32FN3O6S Mw.569.65
LC/MS purity: 98 %, m/z 568 [M-H]", 570 [M+H]+ Rt.2.88 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 10 (bs, 1H), 8.45 (d, 1H), 7.82 (s, 1H), 7.50 (s, 1H), 7.39 (s, 1H), 7.20 (t, 1H), 7.03 (d, 1H), 6.95 (s, 1H), 6.88 (d, 1H), 6.56 (s, 1H), 6.38 (d, 1H), 4.20 (t, 2H), 3.93 (s, 3H), 2.99 (m, 2H), 2.63 (m, 2H), 2.40 (m, 1H), 2.00 (m, 2H), 1.55 (m, 4H), 1.30 (m, 2H), 1.09 (d, 3H).
Melting point: 118-119°C.
Yield: 34 %
Example 149
2-Methyl-1H-imidazole-4-sulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(2-methyl- piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide
ULA-P03071WO21 Application
Figure imgf000130_0001
C29H34FN505S Mw.583.68
LC/MS purity: 99 %, m/z 582 [M-H]", 584 [M+H]+ Rt.2.81 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 12.5 (bs, 1H), 10.6 (bs, 1H), 8.44 (d, 1H), 7.75 (s, 1H), 7.48 (s, 1H), 7.37 (s, 1H), 7.32 (t, 1H), 7.19 (d, 1H), 7.04 (d, 1H), 6.37 (d, 1H), 4.17 (t, 2H), 3.92 (s, 3H), 2.84 (m, 2H), 2.42 (m, 1H), 2.28 (s, 3H), 2.11 (m, 2H), 1.91 (m, 2H), 1.50 (m, 4H), 1.20 (m, 2H), 0.99 (d, 3H).
Melting point: 219-220°C.
Yield: 26 %
Example 150
1-Methyl-1 H-pyrazole-3-sulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(2-methyl- piperidin-1-yl)-p
Figure imgf000130_0002
C29H34FN5O5S Mw.583.68
LC/MS purity: 98 %, m/z 582 [M-H]", 584 [M+H]+ Rt.2.56 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 10.7 (bs, 1H), 8.45 (d, 1H), 7.85 (s, 1H), 7.48 (s, 1H), 7.38 (s, 1H), 7.31 (t, 1H), 7.16 (d, 1H), 7.01 (d, 1H), 6.64 (d, 1H), 6.38 (d, 1H), 4.17 (t, 2H), 3.92 (s, 3H), 3.90 (s, 3H), 2.86 (m, 2H), 2.42 (m, 1H), 2.32 (s, 1H), 2.13 (m,2H), 1.92 (m, 1H), 1.49 (m,4H), 1.23 (m,2H), 1.00 (d,3H).
Melting point: 175-176°C.
Yield: 35 %
Example 151
2,5-Difluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(2-methyl-piperidin-1-yl)-propoxy]- quinolin-4-yloxy}-phenyl)-benzenesulfonamide
ULA-P03071WO21 Application
Figure imgf000131_0001
C31H32F3N3O5S Mw. 615.67
LC/MS purity: 97%, m/z 614 [M-H]\ 616 [M+H]+ Rt. 3.07 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 10 (bs, 1 H), 8.44 (d, 1 H), 7.56 (t, 1 H), 7.49 (s, 1 H), 7.38 (m, 3H), 7.14 (t, 1 H), 6.97 (d, 1 H), 6.82 (d, 1 H), 6.36 (s, 1 H), 4.20 (t, 2H), 3.92 (s, 3H), 3.05 (m, 2H), 2.72 (m, 2H), 2.50 (m, 1 H), 2.03 (m, 2H), 1.60 (m, 4H), 1.34 (m, 2H), 1.11 (d, 3H).
Melting point: 120-122°C.
Yield: 33 %
Example 152
2,6-Difluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(2-methyl-piperidin-1-yl)-propoxy]- quinolin-4-yloxy}-
Figure imgf000131_0002
C3iH32F3N305S Mw. 615.67
LC/MS purity: 100 %, m/z 614 [M-H]-, 616 [M+H]+ Rt. 3.03 min. (Method B)
H NMR (300 MHz, DMSO-d6): 10 (bs, 1 H), 8.43 (d, 1 H), 7.49 (m, 2H), 7.38 (s, 1 H), 7.11 (m, 3H), 6.97 (d, 1 H), 6.79 (d, 1 H), 6.34 (d, 1 H), 4.19 (m, 2H), 3.92 (s, 3H), 2.97 (m, 2H), 2.61 (m, 2H), 2.46 (m, 1 H), 2.00 (m, 2H), 1.58 (m, 4H), 1.30 (m, 2H), 1.08 (d, 3H).
Melting point: 132-134°C.
Yield: 26 % Example 153
N-(3-Fluoro-4-{6-methoxy-7-[3-(2-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}- phenyl)-2-trifluo
Figure imgf000132_0001
C32H33F4N306S Mw. 663.69
LC/MS purity: 98%, m/z 662 [M-H]\ 664 [M+H]+ Rt. 3.52 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 10.5 (bs, 1 H), 8.43 (d, 1 H), 7.99 (d, 1 H), 7.68 (t, 1 H), 7.48 (m, 3H), 7.38 (s, 1 H), 7.19 (t, 1 H), 7.02 (d, 1 H), 6.85 (d, 1 H), 6.33 (d, 1 H), 4.19 (t, 2H), 3.92 (s, 3H), 2.96 (m, 2H), 2.55 (m, 2H), 2.36 (m, 1 H), 1.98 (t, 2H), 1.55 (m, 4H), 1.29 (m, 2H), 1.07 (d, 3H).
Melting point: 90-92°C.
Yield: 29 %
Example 154
2,5-Dichloro-N-(3-fluoro-4-{6-methoxy-7-[3-(2-methyl-piperidin-1 -yl)-propoxy]- quinolin-4-yloxy}-
Figure imgf000132_0002
C31H32CI2FN3O5S Mw. 648.58
LC/MS purity: 98%, m/z 646 [M-H]", 648 [M+H]+ Rt. 3.39 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 11 (bs, 1 H), 8.44 (d, 1 H), 7.96 (s, 1 H), 7.55 (s,
2H), 7.50 (s, 1 H), 7.39 (s, 1 H), 7.12 (t, 1 H), 6.92 (d, 1 H), 6.80 (d, 1 H), 6.35 (d, 1 H),
4.21 (t, 2H), 3.92 (s, 3H), 3.01 (m, 2H), 2.72 (m, 2H), 2.50 (m, 1 H), 2.04 (m, 2H),
1.58 (m, 4H), 1.34 (m, 2H), 1.13 (d, 3H).
Melting point: 128-130°C.
Yield: 37 %
ULA-P03071WO21 Application Example 155
3-{3-Fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4-yloxy]- phenylsulfamoyl}-thiophene-2-carboxylic acid methyl ester
Figure imgf000133_0001
C30H32FN3O7S2 Mw. 629.73
LC/MS purity: 97%, m/z 628 [M-H]", 630 [M+H]+ Rt. 3.38 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 10.2 (bs, 1 H), 8.45 (d, 1 H), 7.94 (d, 1 H), 7.47 (m, 2H), 7.38 (s, 1 H), 7.30 (t, 1 H), 7.11 (d, 1 H), 6.97 (d, 1 H), 6.36 (dd, 1 H), 4.20 (t, 2H), 3.92 (s, 3H), 3.87 (s, 3H), 2.45 (m, 6H), 1.98 (m, 2H), 1.53 (bs, 4H), 1.40 (m, 2H)
Melting point: 138-139°C.
Yield: 26 %
Example 156
3-(3-Fluoro-4-{6-methoxy-7-[3-(4-methyl-piperidin-1 -yl)-propoxy]-quinolin-4-yloxy}- phenylsulfamoyl)-thiophene-2-carboxylic acid methyl ester
Figure imgf000133_0002
C31H34FN3O7S2 Mw. 643.75
LC/MS purity: 99 %, m/z 642 [M-H]", 644 [M+H]+ Rt. 3.67 min. (Method B)
H NMR (300 MHz, DMSO-d6): 10.2 (bs, 1 H), 8.45 (d, 1 H), 7.95 (d, 1 H), 7.47 (bs,
2H), 7.37 (s, 1 H), 7.30 (t, 1 H), 7.11 (d, 1 H), 6.97 (d, 1 H), 6.36 (d, 1 H), 4.18 (t, 2H),
3.92 (s, 3H), 3.88 (s, 3H), 2.91 (m, 2H), 2.55 (m, 2H), 2.00 (m, 4H), 1.60 (m, 2H),
1.35 (bs, 1 H), 1.16 (m, 2H), 0.89 (d, 3H)
Melting point: 139-141°C.
Yield: 29 % Example 157
3-{3-Fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]- phenylsulfamoyl}
Figure imgf000134_0001
C29H30FN3O8S2 Mw. 631.70
LC/MS purity: 98%, m/z 630 [M-H]", 632 [M+H]+ Rt. 3.33 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 10.5 (bs, 1 H), 8.45 (d, 1 H), 7.98 (d, 1 H), 7.50 (d, 1 H), 7.47 (s, 1 H), 7.38 (s, 1 H), 7.34 (t, 1 H), 7.14 (d, 1 H), 7.01 (d, 1 H), 6.36 (d, 1 H), 4.19 (t, 2H), 3.92 (s, 3H), 3.89 (s, 3H), 3.58 (m, 4H), 2.47 (m, 2H), 2.39 (m, 4H), 1.97 (m, 2H)
Melting point: 167-168°C.
Yield: 31 %
Example 158
3-(3-Fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1 -yl)-propoxy]-quinolin-4-yloxy}- phenylsulfamoyl)
Figure imgf000134_0002
C30H33FN4O7S2 Mw. 644.74
LC/MS purity: 98%, m/z 643 [M-H]', 645 [M+H]+ Rt. 3.13 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 10.3 (bs, 1 H), 8.45 (d, 1 H), 7.95 (d, 1 H), 7.47 (s, 2H), 7.37 (s, 1 H), 7.31 (t, 1 H), 7.12 (d, 1 H), 6.98 (d, 1 H), 6.36 (d, 1 H), 4.17 (t, 2H), 3.92 (s, 3H), 3.88 (s, 3H), 2.42 (m, 10H), 2.18 (s, 3H), 1.95 (m, 2H)
Melting point: 146-148°C.
Yield: 41 %
ULA-P03071WO21 Application Example 159
1 ,3,5-Trimethyl-1 H-pyrazole-4-sulfonic acid {3-fluoro-4-[6-methoxy-7-(3-piperidin- 1-yl-propoxy)-qui
Figure imgf000135_0001
C30H36FN5O5S Mw. 597.71
LC/MS purity: 97%, m/z 596 [M-H]', 598 [M+H]+ Rt. 3.17 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 10.3 (bs, 1 H), 8.46 (d, 1 H), 7.48 (s, 1 H), 7.37 (s, 1 H), 7.36 (t, 1 H), 7.08 (d, 1 H), 6.97 (d, 1 H), 6.37 (d, 1 H), 4.18 (t, 2H), 3.92 (s, 3H), 3.66 (s, 3H), 2.85 (d, 2H), 2.43 (m, 2H), 2.38 (m, 5H), 2.21 (s, 3H), 1.95 (m, 2H), 1.50 (bs, 4H), 1.39 (m, 2H)
Melting point: 96-98°C.
Yield: 51 %
Example 160
1 ,3,5-Trimethyl-1 H-pyrazole-4-sulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(4-methyl- piperidin-1-yl)-pro
Figure imgf000135_0002
C3iH38FN5O5S Mw. 611.74
LC/MS purity: 98%, m/z 610 [M-H]", 612 [M+H]+ Rt. 3.42 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 10.3 (bs, 1 H), 8.46 (d, 1 H), 7.48 (s, 1 H), 7.38 (s,
1 H), 7.37 (t, 1 H), 7.09 (d, 1 H), 6.99 (d, 1 H), 6.37 (d, 1 H), 4.17 (t, 2H), 3.92 (s, 3H),
3.67 (s, 3H), 2.85 (d, 2H), 2.45 (m, 2H), 2.38 (m, 3H), 2.22 (s, 3H), 1.96 (m, 4H),
1.58 (m, 2H), 1.32 (m, 1 H), 1.23 (m, 2H), 0.88 (d, 3H)
Melting point: 88-90°C.
Yield: 36 % Example 161
1 ,3,5-Trimethyl-1 H-pyrazole-4-sulfonic acid {3-fluoro-4-[6-methoxy-7-(3-morpholin- 4-yl-propoxy)-qui
Figure imgf000136_0001
C29H34FN5O6S Mw. 599.68
LC/MS purity: 98%, m/z 598 [M-H]", 600 [M+H]+ Rt. 3.11 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 10.3 (bs, 1 H), 8.46 (d, 1 H), 7.48 (s, 1 H), 7.39 (s, 1 H), 7.37 (t, 1 H), 7.09 (d, 1 H), 6.99 (d, 1 H), 6.37 (d, 1 H), 4.19 (t, 2H), 3.91 (s, 3H), 3.67 (s, 3H), 3.58 (bs, 4H), 2.47 (m, 2H), 2.38 (bs, 7H), 2.22 (s, 3H), 1.97 (m, 2H) Melting point: 163-164°C.
Yield: 49 %
Example 162
1 ,3,5-Trimethyl-1 H-pyrazole-4-sulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(4-methyl piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide
Figure imgf000136_0002
C30H37FN6O5S Mw. 612.72
LC/MS purity: 98%, m/z 611 [M-H]", 613 [M+H]+ Rt. 2.89 min. (Method B)
H NMR (300 MHz, DMSO-d6): 10.3 (bs, 1 H), 8.46 (d, 1 H), 7.48 (s, 1 H), 7.37 (s,
1 H), 7.36 (t, 1 H), 7.08 (d, 1 H), 6.97 (d, 1 H), 6.37 (d, 1 H), 4.18 (t, 2H), 3.92 (s, 3H),
3.66 (s, 3H), 2.45 (m, 2H), 2.38 (bs, 7H), 2.33 (bs, 4H), 2.21 (s, 3H), 2.15 (s, 3H),
1.95 (m, 2H)
Melting point: 80-81 °C.
Yield: 37 %
ULA-P03071WO21 Application Example 163
1-Methyl-1 H-pyrazole-3-sulfonic acid {3-fluoro-4-[6-methoxy-7-(3-piperidin propoxy)-quinolin
Figure imgf000137_0001
C28H32FN505S Mw. 569.66
LC/MS purity: 99%, m/z 568 [M-H]', 570 [M+H]+ Rt. 2.56 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 10.6 (bs, 1 H), 8.45 (d, 1 H), 7.86 (d, 1 H), 7.49 (s, 1 H), 7.38 (s, 1 H), 7.33 (t, 1 H), 7.18 (d, 1 H), 7.03 (d, 1 H), 6.66 (d, 1 H), 6.38 (d, 1 H), 4.18 (t, 2H), 3.93 (s, 3H), 3.90 (s, 3H), 2.49 (m, 2H), 2.39 (bs, 4H), 1.96 (m, 2H), 1.50 (bs, 4H), 1.39 (m, 2H)
Melting point: 167-168°C.
Yield: 61 %
Example 164
1-Methyl-1 H-pyrazole-3-sulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(4-methyl- piperidin-1-yl)-p
Figure imgf000137_0002
C29H34FN5O5S Mw. 583.68
LC/MS purity: 98%, m/z 582 [M-H]", 584 [M+H]+ Rt. 3.02 min. (Method B)
H NMR (300 MHz, DMSO-d6): 10.6 (bs, 1 H), 8.45 (d, 1 H), 7.85 (s, 1 H), 7.48 (s,
1 H), 7.37 (s, 1 H), 7.32 (t, 1 H), 7.16 (d, 1 H), 7.02 (d, 1 H), 6.65 (s, 1 H), 6.38 (d, 1 H),
4.17 (t, 2H), 3.93 (s, 3H), 3.90 (s, 3H), 2.86 (m, 2H), 2.47 (m, 2H), 1.93 (m, 4H),
1.58 (m, 2H), 1.32 (m, 1 H), 1.12 (m, 2H), 0.88 (d, 3H)
Melting point: 165-166°C.
Yield: 40 % Example 165
1-Methyl-1 H-pyrazole-3-sulfonic acid {3-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl- propoxy)-quinolin
Figure imgf000138_0001
C27H30FN5O6S Mw. 571.63
LC/MS purity: 98%, m/z 570 [M-H]", 572 [M+H]+ Rt. 2.74 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 10.8 (bs, 1 H), 8.45 (d, 1 H), 7.86 (d, 1 H), 7.49 (s, 1 H), 7.39 (s, 1 H), 7.33 (t, 1 H), 7.18 (dd, 1 H), 7.04 (d, 1 H), 6.66 (d, 1 H), 6.38 (d, 1 H), 4.17 (t, 2H), 3.93 (s, 3H), 3.90 (s, 3H), 3.58 (m, 4H), 2.47 (m, 2H), 2.39 (m, 4H), 1.97 (m, 2H)
Melting point: 198-199°C.
Yield: 53 %
Example 166
1-Methyl-1 H-pyrazole-3-sulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(4-methyl- piperazin-1-yl)-p
Figure imgf000138_0002
C28H33FN6O5S Mw. 584.67
LC/MS purity: 97 %, 584 m/z [M-H]", 586 [M+H]+ Rt. 2.51 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 10.4 (bs, 1 H), 8.45 (d, 1 H), 7.86 (d, 1 H), 7.48 (s,
1 H), 7.37 (s, 1 H), 7.32 (t, 1 H), 7.17 (dd, 1 H), 7.03 (d, 1 H), 6.66 (d, 1 H), 6.38 (d,
1 H), 4.18 (t, 2H), 3.93 (s, 3H), 3.90 (s, 3H), 2.46 (m, 2H), 2.38 (m, 8H), 2.15 (s,
3H), 1.95 (m, 2H)
Melting point: 157-159°C.
Yield: 74 % Example 167
2-Methyl-3H-imidazole-4-sulfonic acid {3-fluoro-4-[6-methoxy-7-(3-piperidin-1 -yl- propoxy)-quinolin-4-yloxy]-phenyl}-amide
Figure imgf000139_0001
C28H32FN5O5S Mw. 569.66
LC/MS purity: 96%, m/z 568 [M-H]\ 570 [M+H]+ Rt. 2.79 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 12.3 (bs, 1 H), 10.6 (bs, 1 H), 8.44 (d, 1 H), 7.72 (bs, 1 H), 7.48 (s, 1 H), 7.37 (s, 1 H), 7.30 (t, 1 H), 7.18 (d, 1 H), 7.02 (d, 1 H), 6.37 (d, 1 H), 4.17 (t, 2H), 3.92 (s, 3H), 2.42 (m, 2H), 2.40 (bs, 4H), 2.28 (s, 3H), 1.94 (m, 2H), 1.50 (bs, 4H), 1.39 (m, 2H)
Melting point: 160-163°C.
Yield: 26 %
Example 168
2-Methyl-3H-imidazole-4-sulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(4-methyl- piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide
Figure imgf000139_0002
C29H34FN5O5S Mw. 583.68
LC/MS purity: 98%, m/z 582 [M-H]\ 584 [M+H]+ Rt. 3.02 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 12.4 (bs, 1 H), 10.7 (bs, 1 H), 8.44 (d, 1 H), 7.72 (bs, 1 H), 7.48 (s, 1 H), 7.37 (s, 1 H), 7.30 (t, 1 H), 7.19 (d, 1 H), 7.03 (d, 1 H), 6.37 (d, 1 H), 4.17 (t, 2H), 3.92 (s, 3H), 2.84 (m, 2H), 2.44 (m, 2H), 2.38 (s, 3H), 1.95 (m, 2H), 1.88 (m, 2H), 1.57 (m, 2H), 1.33 (m, 1 H), 1.15 (m, 2H), 0.88 (d, 3H)
Melting point: 225-226°C.
Yield: 30 %
ULA-P03071WO21 Application Example 169
2-Methyl-3H-imidazole-4-sulfonic acid {3-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl- propoxy)-quinolin
Figure imgf000140_0001
C27H30FN5O6S Mw. 571.63
LC/MS purity: 99%, m/z 570 [M-HJ, 572 [M+H]+ Rt. 2.73 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 12.4 (bs, 1 H), 10.6 (bs, 1 H), 8.45 (d, 1 H), 7.72 (bs, 1 H), 7.49 (s, 1 H), 7.39 (s, 1 H), 7.32 (t, 1 H), 7.21 (d, 1 H), 7.05 (d, 1 H), 6.37 (d, 1 H), 4.19 (t, 2H), 3.93 (s, 3H), 3.58 (m, 4H), 2.47 (m, 2H), 2.39 (s, 4H), 2.28 (s, 3H), 1.97 (t, 2H)
Melting point: 252-254°C.
Yield: 38 %
Example 170
2-Methyl-3H-imidazole-4-sulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(4-methyl- piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide
Figure imgf000140_0002
C28H33FN605S Mw. 584.67
LC/MS purity: 99%, m/z 583 [M-H]", 585 [M+H]+ Rt. 2.52 min. (Method B)
H NMR (300 MHz, DMSO-d6): 12.4 (bs, 1 H), 10.6 (bs, 1 H), 8.44 (d, 1 H), 7.73 (bs,
1 H), 7.48 (s, 1 H), 7.37 (s, 1 H), 7.31 (t, 1 H), 7.18 (d, 1 H), 7.03 (d, 1 H), 6.37 (d, 1 H),
4.17 (t, 2H), 3.92 (s, 3H), 2.45 (m, 2H), 2.39 (bs, 4H), 2.32 (bs, 4H), 2.28 (s, 3H),
2.14 (s, 3H), 1.85 (m, 2H)
Melting point: 215-217°C.
Yield: 32 % Example 171
2,5-Difluoro-N-(4-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4- yloxy}-3-methyl-p
Figure imgf000141_0001
C32H35F2N3O5S Mw. 611.71
LC/MS purity: 97 %, m/z 610 [M-Hf, 612 [M+H]+ Rt. 3.76 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 10.7 (bs, 1 H), 8.40 (d, 1 H), 7.55 (m, 3H), 7.51 (s, 1 H), 7.36 (m, 1 H), 7.05 (m, 3H), 6.17 (d, 1 H), 4.17 (t, 2H), 3.92 (s, 3H), 2.89 (m, 2H), 2.01 (s, 3H), 1.98 (m, 4H), 1.59 (m, 2H), 1.30 (m, 1 H), 1.17 (m, 3H), 1.03 (m, 1 H), 0.88 (d, 3H)
Melting point: 222-223°C.
Yield: 55 %
Example 172
2,6-Difluoro-N-(4-{6-methoxy-7-[3-(4-methyl-piperidin-1 -yl)-propoxy]-quinolin-4- yloxy}-3-methyl-phenyl)-benzenesulfonamide
Figure imgf000141_0002
C32H35F2N3O5S Mw. 611.71
LC/MS purity: 98 %, m/z 610 [M-H]", 612 [M+H]+ Rt. 3.64 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 10.8 (bs, 1 H), 8.40 (d, 1 H), 7.67 (m, 1 H), 7.51 (s,
1 H), 7.36 (m, 1 H), 7.25 (t, 2H), 7.05 (m, 3H), 6.16 (d, 1 H), 4.17 (t, 2H), 3.92 (s,
3H), 2.88 (m, 2H), 2.49 (m, 2H), 1.97 (m, 7H), 1.58 (m, 2H), 1.33 (m, 1 H), 1.16 (m,
2H), 0.88 (d, 3H)
Melting point: 191-193°C.
Yield: 44 % Example 173
2,6-Difluoro-N-(3-methoxy-4-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]- quinolin-4-yloxy}-phenyl)-benzenesulfonamide
Figure imgf000142_0001
CaaHasFsNsOsS Mw. 627.71
LC/MS purity: 99%, m/z 628 [M-H]\ 626 [M+H]+ Rt. 3.36 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 11 (bs, 1 H), 8.37 (d, 1 H), 7.62 (m, 1 H), 7.46 (s, 1 H), 7.33 (s, 1 H), 7.20 (t, 2H), 7.04 (d, 1 H), 6.92 (s, 1 H), 6.68 (d, 1 H), 6.15 (d, 1 H), 4.17 (t, 2H), 3.91 (s, 3H), 3.60 (s, 3H), 3.32 (m, 1 H), 2.83 (m, 2H), 2.46 (m, 2H), 1.94 (m, 3H), 1.62 (m, 4H), 1.45 (m, 1 H), 0.84 (d, 3H)
Melting point: 98-101 °C.
Yield: 47 %
Example 174
N-(4-{6-Methoxy-7-[3-(4-methyl-piperidin-1 -yl)-propoxy]-quinolin-4-yloxy}-3-methyl- phenyl)-2-trifluoromethoxy-benzenesulfonamide
Figure imgf000142_0002
C33H36F3N3O6S Mw. 659.73
LC/MS purity: 98%, m/z 658 [M-H]", 660 [M+H]+ Rt. 4.18 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 10.6 (bs, 1 H), 8.40 (d, 1 H), 7.98 (dd, 1 H), 7.76 (m,
1 H), 7.54 (m, 2H), 7.50 (s, 1 H), 7.36 (s, 1 H), 7.09 (d, 1 H), 7.00 (m, 2H), 6.15 (d,
1 H), 4.17 (t, 2H), 3.91 (s, 3H), 2.86 (m, 2H), 2.46 (m, 2H), 2.00 (m, 3H), 1.93 (m,
4H), 1.58 (m, 2H), 1.33 (m, 1 H), 1.16 (m, 2H), 0.88 (d, 3H)
Melting point: 168-169°C.
Yield: 51 % Example 175
2,5-Dichloro-N-(4-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4- yloxy}-3-methyl-p
Figure imgf000143_0001
C32H35CI2N3O5S Mw. 644.62
LC/MS purity: 100 %, m/z 642 [M-H]", 644 [M+H]+ Rt. 3.33 min. (Method B)
H NMR (300 MHz, DMSO-d6): 10.6 (bs, 1 H), 8.40 (d, 1 H), 7.97 (d, 1 H), 7.69 (m, 2H), 7.50 (s, 1 H), 7.36 (s, 1 H), 7.07 (d, 1 H), 7.01 (m, 2H), 6.16 (d, 1 H), 4.17 (t, 2H), 3.91 (s, 3H), 2.91 (m, 2H), 2.51 (m, 2H), 2.01 (m, 7H), 1.60 (m, 2H), 1.35 (m, 1 H), 1.15 (m, 2H), 0.88 (d, 3H)
Melting point: 187-188°C.
Yield: 48 %
Example 176
2,6-Dichloro-N-(4-{6-methoxy-7-[3-(4-methyl-piperidin-1 -yl)-propoxy]-quinolin-4- yloxy}-3-methyl-p
Figure imgf000143_0002
C32H35CI2N3O5S Mw. 644.62
LC/MS purity: 95%, m/z 642 [M-H]\ 644 [M+H]+ Rt. 4.00 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 10.7 (bs, 1 H), 8.39 (d, 1 H), 7.62 (m, 2H), 7.54 (d,
1 H), 7.49 (s, 1 H), 7.35 (s, 1 H), 7.11 (s, 1 H), 7.03 (m, 2H), 6.14 (d, 1 H), 4.17 (t,
2H), 3.91 (s, 3H), 2.88 (m, 2H), 2.50 (m, 2H), 1.99 (s, 3H), 1.96 (m, 4H), 1.58 (m,
2H), 1.34 (m, 1 H), 1.16 (m, 2H), 0.88 (d, 3H)
Melting point: 209-210°C.
Yield: 35 %
ULA-P03071WO21 Application Example 177
N-{4-[7-(3-Dimethylamino-propoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro-phenyl}- 2,5-difluoro-benze
Figure imgf000144_0001
C27H26F3N3O5S Mw. 561.58
LC/MS purity: 99%, m/z 560 [M-H]~, 562 [M+H]+ Rt. 2.87 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 11 (bs, 1 H), 8.44 (d, 1 H), 7.57 (m, 1 H), 7.49 (s, 1 H), 7.42 (s, 2H), 7.38 (s, 1 H), 7.17 (s, 1 H), 7.00 (d, 1 H), 6.85 (d, 1 H), 6.36 (d, 1 H), 4.20 (t, 2H), 3.93 (s, 3H), 2.69 (t, 2H), 2.40 (s, 6H), 2.03 (m, 2H)
Melting point: 108- 10°C.
Yield: 64 %
Example 178
N-{4-[7-(3-Dimethylamino-propoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro-phenyl}- 2,6-difluoro-benz
Figure imgf000144_0002
C27H26F3N3O5S Mw. 561.58
LC/MS purity: 99%, m/z 560 [M-H]", 562 [M+H]+ Rt. 2.77 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 10.8 (bs, 1 H), 8.44 (d, 1 H), 7.56 (m, 1 H), 7.49 (s,
1 H), 7.37 (s, 1 H), 7.18 (m, 3H), 7.01 (dd, 1 H), 6.85 (d, 1 H), 6.35 (d, 1 H), 4.19 (t,
2H), 3.93 (s, 3H), 2.66 (t, 2H), 2.37 (s, 6H), 2.02 (m, 2H)
Melting point: 125-127°C.
Yield: 53 % Example 179
N-{4-[7-(3-Dimethylamino-propoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro-phenyl}- 2-trifluoromethoxy-benzenesulfonamide
Figure imgf000145_0001
C28H27F4N3O6S Mw. 609.60
LC/MS purity: 99%, m/z 608 [M-H]\ 610 [M+H]+ Rt. 3.28 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 10.5 (bs, 1 H), 8.44 (d, 1 H), 7.99 (d, 1 H), 7.69 (t, 1 H), 7.51 (m, 3H), 7.37 (s, 1 H), 7.21 (t, 1 H), 7.04 (dd, 1 H), 6.87 (d, 1 H), 6.35 (d, 1 H), 4.19 (t, 2H), 3.92 (s, 3H), 2.58 (t, 2H), 2.31 (s, 6H), 1.99 (m, 2H)
Melting point: 94-96°C.
Yield: 56 %
Example 180
2,5-Dichloro-N-{4-[7-(3-dimethylamino-propoxy)-6-methoxy-quinolin-4-yloxy]-3- fluoro-phenyl}-benzenesulfonamide
Figure imgf000145_0002
C27H26Cl2FN305S Mw. 594.49
LC/MS purity: 99%, m/z 592 [M-H]", 594 [M+H]+ Rt. 3.15 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 10.5 (bs, 1 H), 8.43 (d, 1 H), 7.96 (s, 1 H), 7.56 (s,
2H), 7.49 (s, 1 H), 7.37 (s, 1 H), 7.13 (t, 1 H), 6.93 (d, 1 H), 6.80 (d, 1 H), 6.35 (d, 1 H),
4.19 (t, 2H), 3.93 (s, 3H), 2.67 (t, 2H), 2.38 (s, 6H), 2.03 (m, 2H)
Melting point: 150-152°C.
Yield: 62 % Example 181
2,6-Dichloro-N-{4-[7-(3-dimethylamino-propoxy)-6-methoxy-quinolin-4-yloxy]-3- fluoro-phenyl}-ben
Figure imgf000146_0001
C27H26CI2FN3O5S Mw. 594.49
LC/MS purity: 100%, m/z 592 [M-H]", 594 [M+H]+ Rt. 1.23 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 10.4 (bs, 1 H), 8.43 (d, 1 H), 7.46 (s, 4H), 7.37 (s, 1 H), 7.19 (t, 1 H), 7.00 (dd, 1 H), 6.84 (d, 1 H), 6.34 (d, 1 H), 4.19 (t, 2H), 3.92 (s, 3H), 2.67 (t, 2H), 2.38 (s, 6H), 2.02 (m, 2H)
Melting point: 197-198°C.
Yield: 44 %
Example 182
5-Chloro-thiophene-2-sulfonic acid {4-[7-(3-dimethylamino-propoxy)-6-methoxy- quinolin-4-yloxy]-3-fluoro-phenyl}-amide
Figure imgf000146_0002
C25H25CIFN3O5S2 Mw. 566.07
LC/MS purity: 99 %, m/z 564 [M-H]", 566 [M+H]+ Rt. 2.89 min. (Method B)
H NMR (300 MHz, DMSO-d6): 10.5 (bs, 1 H), 8.45 (d, 1 H), 7.51 (s, 1 H), 7.39 (s,
1 H), 7.30 (d, 1 H), 7.20 (t, 1 H), 7.10 (d, 1 H), 7.02 (dd, 1 H), 6.88 (d, 1 H), 6.39 (d,
1 H), 4.21 (t, 2H), 3.94 (s, 3H), 2.76 (t, 2H), 2.45 (s, 6H), 2.05 (m, 2H)
Melting point: 130-132°C.
Yield: 45 % Example 183
N-(5-{4-[7-(3-Dimethylamino-propoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro- phenylsulfamoyl}
Figure imgf000147_0001
C27H30FN5O6S2 Mw. 603.69
LC/MS purity: 100 %, m/z 602 [M-H]", 604 [M+H]+ Rt. 2.56 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 12 (bs, 1 H), 10.5 (bs, 1 H), 8.44 (d, 1 H), 7.49 (s, 1 H), 7.37 (s, 1 H), 7.30 (t, 1 H), 7.09 (dd, 1 H), 6.96 (d, 1 H), 6.36 (d, 1 H), 4.18 (t, 2H), 3.93 (s, 3H), 2.54 (t, 2H), 2.39 (s, 3H), 2.26 (s, 6H), 2.15 (s, 3H), 1.98 (m, 2H) Melting point: 164-166°C.
Yield: 42 %
Example 184
3-{4-[7-(3-Dimethylamino-propoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro- phenylsulfamoyl
Figure imgf000147_0002
C27H28FN3O7S2 Mw. 589.66
LC/MS purity: 96 %, m/z 588 [M-H]\ 590 [M+H]+ Rt. 3.16 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 10.4 (bs, 1 H), 8.45 (d, 1 H), 7.94 (d, 1 H), 7.48 (s, 1 H), 7.46 (s, 1 H), 7.37 (s, 1 H), 7.29 (t, 1 H), 7.11 (dd, 1 H), 6.97 (d, 1 H), 6.36 (d, 1 H), 4.18 (t, 2H), 3.92 (s, 3H), 3.87 (s, 3H), 2.47 (t, 2H), 2.24 (s, 6H), 1.98 (m, 2H) Melting point: 80-82°C.
Yield: 39 %
Example 185
Furan-2-sulfonic acid {4-[7-(3-dimethylamino-propoxy)-6-methoxy-quinolin-4- yloxy]-3-fluoro-phenyl}-amide
Figure imgf000148_0001
C25H26FN3O6S Mw. 515.56
LC/MS purity: 98 %, m/z 514 [M-H]", 516 [M+H]+ Rt. 2.62 min. (Method B)
H NMR (300 MHz, DMSO-d6): 10.4 (bs, 1 H), 8.45 (d, 1 H), 7.84 (s, 1 H), 7.50 (s, 1 H), 7.38 (s, 1 H), 7.22 (t, 1 H), 7.03 (m, 3H), 6.58 (s, 1 H), 6.38 (d, 1 H), 4.19 (t, 2H), 3.93 (s, 3H), 2.60 (t, 2H), 2.33 (s, 6H), 2.00 (m, 2H)
Melting point: 185-187°C.
Yield: 47 % Example 186
Thiophene-2-sulfonic acid {4-[7-(3-dimethylamino-propoxy)-6-methoxy-quinolin-4- yloxy]-3-fluoro-phenyl}-amide
Figure imgf000148_0002
C25H26FN3O5S2 Mw. 531.62
LC/MS purity: 99 %, m/z 530 [M-H]-, 532 [M+H]+ Rt. 2.82 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 10.4 (bs, 1 H), 8.46 (d, 1 H), 7.85 (s, 1 H), 7.54 (s, 1 H), 7.49 (s, 1 H), 7.38 (s, 1 H), 7.30 (t, 1 H), 7.11 (m, 2H), 6.98 (d, 1 H), 6.37 (d, 1 H), 4.19 (t, 2H), 3.93 (s, 3H), 2.57 (t, 2H), 2.30 (s, 6H), 1.99 (m, 2H)
Melting point: 186-188°C.
Yield: 36 %
Example 187
2,5-Difluoro-N-(4-fluoro-3-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]- quinolin-4-yloxy}-phenyl)-benzenesulfonamide
ULA-P03071WO21 Application
Figure imgf000149_0001
C31H32F3N3O5S Mw. 615.68
LC/MS purity: 97 %, m/z 614 [M-H]", 616 [M+H]+ Rt. 3.37 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 10.5 (bs, 1 H), 8.44 (d, 1 H), 7.46 (m, 5H), 7.27 (t, 1 H), 6.95 (m, 2H), 6.27 (d, 1 H), 4.20 (t, 2H), 3.93 (s, 3H), 3.03 (m, 2H), 2.67 (t, 2H), 2.18 (m, 2H), 2.04 (m, 2H), 1.64 (m, 2H), 1.40 (m, 1 H), 1.20 (m, 2H), 0.90 (d, 3H)
Melting point: 186-188°C.
Yield: 54 %
Example 188
2,6-Difluoro-N-(4-fluoro-3-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]- quinolin-4-yloxy}-phenyl)-benzenesulfonamide
Figure imgf000149_0002
C31 H32F3N3O5S Mw. 615.68
LC/MS purity: 98 %, m/z 614 [M-H]', 616 [M+H]+ Rt. 3.26 min. (Method B)
H NMR (300 MHz, DMSO-d6): 10.5 (bs, 1 H), 8.45 (d, 1 H), 7.62 (m, 1 H), 7.46 (s, 1 H), 7.40 (s, 1 H), 7.31 (t, 1 H), 7.16 (m, 2H), 6.97 (m, 2H), 6.26 (d, 1 H), 4.21 (t, 2H), 3.92 (s, 3H), 3.03 (m, 2H), 2.66 (t, 2H), 2.18 (m, 2H), 2.04 (m, 2H), 1.64 (m, 2H), 1.41 (m, 1 H), 1.20 (m, 2H), 0.90 (d, 3H)
Melting point: 185-186°C.
Yield: 38 %
Example 189
N-(4-Fluoro-3-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}- phenyl)-2-trifluoromethyl-benzenesulfonamide
ULA-P03071WO21 Application
Figure imgf000150_0001
C32H33F4N3O5S Mw. 647.69
LC/MS purity: 97 %, m/z 646 [M-H]", 648 [M+H]+ Rt. 3.63 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 10.5 (bs, 1 H), 8.45 (d, 1 H), 8.04 (m, 1 H), 7.91 (m, 1 H), 7.77 (m, 2H), 7.42 (s, 1 H), 7.39 (s, 1 H), 7.30 (t, 1 H), 6.94 (m, 2H), 6.28 (d, 1 H), 4.20 (t, 2H), 3.91 (s, 3H), 2.98 (m, 2H), 2.60 (t, 2H), 2.05 (m, 4H), 1.62 (m, 2H), 1.40 (m, 1 H), 1.20 (m, 2H), 0.89 (d, 3H)
Melting point: 175-177°C.
Yield: 44 %
Example 190
N-(4-Fluoro-3-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}- phenyl)-2-trifluoromethoxy-benzenesulfonamide
Figure imgf000150_0002
C32H33F4N3O6S Mw. 663.69
LC/MS purity: 98 %, m/z 662 [M-H]-, 664 [M+H]+ Rt. 3.85 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 10.5 (bs, 1 H), 8.46 (d, 1 H), 7.88 (d, 1 H), 7.71 (t, 1 H), 7.45 (m, 4H), 7.31 (t, 1 H), 6.96 (m, 2H), 6.25 (d, 1 H), 4.20 (t, 2H), 3.91 (s, 3H), 2.95 (m, 2H), 2.57 (t, 2H), 2.02 (m, 4H), 1.62 (m, 2H), 1.36 (m, 1 H), 1.17 (m, 2H), 0.89 (d, 3H)
Melting point: 80-82°C.
Yield: 37 %
Example 191
2,5-Dichloro-N-(4-fluoro-3-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]- quinolin-4-yloxy}-phenyl)-benzenesulfonamide
Figure imgf000151_0001
C31 H32CI2FN3O5S Mw. 648.58
LC/MS purity: 95 %, m/z 646 [M-H]\ 648 [M+H]+ Rt. 3.64 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 10.5 (bs, 1 H), 8.45 (d, 1 H), 7.87 (d, 1 H), 7.61 (m, 2H), 7.46 (s, 1 H), 7.40 (s, 1 H), 7.26 (t, 1 H), 6.93 (m, 2H), 6.24 (d, 1 H), 4.21 (t, 2H), 3.93 (s, 3H), 3.07 (m, 2H), 2.69 (t, 2H), 2.21 (m, 2H), 2.05 (m, 2H), 1.66 (m, 2H), 1.43 (m, 1 H), 1.23 (m, 2H), 0.90 (d, 3H)
Melting point: 127-130°C.
Yield: 52 %
Example 192
2,6-Dichloro-N-(4-fluoro-3-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]- quinolin-4-yloxy}-
Figure imgf000151_0002
C3iH32Cl2FN305S Mw. 648.58
LC/MS purity: 97 %, m/z 646 [M-H]", 648 [M+H]+ Rt. 3.56 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 10.5 (bs, 1 H), 8.43 (d, 1 H), 7.45 (m, 5H), 7.30 (t, 1 H), 6.93 (m, 2H), 6.22 (d, 1 H), 4.21 (t, 2H), 3.93 (s, 3H), 3.00 (m, 2H), 2.64 (m, 2H), 2.10 (m, 4H), 1.64 (m, 2H), 1.39 (m, 1 H), 1.19 (m, 2H), 0.90 (d, 3H)
Melting point: 116-118°C.
Yield: 46 %
Example 193
N-(2-Chloro-5-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}- phenyl)-2,5-difluoro-benzenesulfonamide
ULA-P03071WO21 Application
Figure imgf000152_0001
C31H32CIF2N3O5S Mw. 632.13
LC/MS purity: 97 %, m/z 630 [M-H]\ 632 [M+H]+ Rt. 3.24 min. (Method B)
H NMR (300 MHz, DMSO-d6): 9.1 (bs, 1 H), 8.36 (d, 1 H), 7.44 (s, 1 H), 7.38 (t, 1 H), 7.25 (m, 4H), 7.05 (d, 1 H), 6.43 (dd, 1 H), 6.27 (d, 1 H), 4.22 (t, 2H), 3.92 (s, 3H), 3.19 (m, 2H), 2.89 (m, 2H), 2.56 (m, 1 H), 2.11 (m, 2H), 1.72 (m, 2H), 1.36 (m, 1 H), 1.28 (m, 3H), 0.92 (d, 3H)
Melting point: 206-208°C.
Yield: 11 %
Example 194
N-(2-Chloro-5-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}- phenyl)-2,6-difluoro-benzenesulfonamide
Figure imgf000152_0002
C3iH32CIF2N305S Mw. 632.13
LC/MS purity: 98 %, m/z 630 [M-H]", 632 [M+H]+ Rt. 3.23 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 9.1 (bs, 1 H), 8.35 (d, 1 H), 7.44 (s, 1 H), 7.35 (m, 2H), 7.24 (d, 1 H), 7.06 (d, 1 H), 6.91 (t, 2H), 6.39 (dd, 1 H), 6.23 (d, 1 H), 4.23 (t, 2H), 3.92 (s, 3H), 3.17 (m, 2H), 2.97 (m, 2H), 2.57 (m, 1 H), 2.14 (m, 2H), 1.75 (m, 2H), 1.53 (m, 1 H), 1.26 (m, 3H), 0.93 (d, 3H)
Melting point: 222-226°C.
Yield: 14 %
Example 195
N-(2-Chloro-5-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}- phenyl)-2-trifluoromethyl-benzenesulfonamide
ULA-P03071WO21 Application
Figure imgf000153_0001
C32H33CIF3N3O5S Mw. 664.14
LC/MS purity: 98 %, m/z 662 [M-H]", 664 [M+H]+ Rt. 3.43 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 9.15 (bs, 1 H), 8.31 (d, 1 H), 7.95 (d, 1 H), 7.72 (d, 1 H), 7.57 (m, 2H), 7.38 (s, 1 H), 7.36 (s, 1 H), 7.27 (d, 1 H), 6.89 (d, 1 H), 6.40 (d, 1 H), 6.19 (d, 1 H), 4.22 (t, 2H), 3.89 (s, 3H), 3.31 (m, 2H), 3.01 (m, 2H), 2.61 (m, 1 H), 2.15 (m, 2H), 1.75 (m, 2H), 1.54 (m, 1 H), 1.29 (m, 3H), 0.93 (d, 3H)
Melting point: 179-181 °C.
Yield: 12 %
Example 196
N-(2-Chloro-5-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}- phenyl)-2-trifluoro
Figure imgf000153_0002
C32H33CIF3N3O6S Mw. 680.14
LC/MS purity: 98 %, m/z 678 [M-H]", 680 [M+H]+ Rt. 3.58 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 9.1 (bs, 1 H), 8.35 (d, 1 H), 7.74 (d, 1 H), 7.50 (t, H), 7.42 (s, 1 H), 7.39 (s, 1 H), 7.29 (m, 3H), 7.01 (d, 1 H), 6.43 (d, 1 H), 6.27 (d, 1 H), 4.23 (t, 2H), 3.90 (s, 3H), 3.29 (m, 2H), 3.02 (m, 2H), 2.68 (m, 1 H), 2.16 (m, 2H), 1.77 (m, 2H), 1.56 (m, H), 1.29 (m, 3H), 0.93 (d, 3H)
Melting point: 123-126°C.
Yield: 9 %
Example 197
2,5-Dichloro-N-(2-chloro-5-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]- quinolin-4-yloxy}-phenyl)-benzenesulfonamide
ULA-P03071WO21 Application
Figure imgf000154_0001
C31H32CI3N3O5S Mw. 665.04
LC/MS purity: 97 %, m/z 662 [M-H]", 664 [M+H]+ Rt. 3.49 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 9.1 (bs, 1 H), 8.37 (d, 1 H), 7.75 (d, 1 H), 7.40 (m, 4H), 7.27 (d, 1 H), 6.98 (d,1 H), 6.40 (dd, 1 H), 6.24 (d, 1 H), 4.22 (t, 2H), 3.92 (s, 3H), 3.31 (m, 2H), 3.17 (m, 2H), 2.98 (m, 1 H), 2.11 (m, 2H), 1.73 (m, 2H), 1.55 (m, 1 H), 1.26 (m, 3H), 0.92 (d, 3H)
Melting point: 223-224°C.
Yield: 12 %
Example 198
2,6-Dichloro-N-(2-chloro-5-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]- quinolin-4-yloxy}-phenyl)-benzenesulfonamide
Figure imgf000154_0002
C31 H32Cl3N305S Mw. 665.04
LC/MS purity: 98 %, m/z 662 [M-H]", 664 [M+H]+ Rt. 3.38 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 9 (bs, 1 H), 8.32 (d, 1 H), 7.42 (s, 1 H), 7.38 (s, 1 H), 7.26 (m, 4H), 6.94 (d,1 H), 6.37 (dd, 1 H), 6.17 (d, 1 H), 4.23 (t, 2H), 3.91 (s, 3H), 3.28 (m, 2H), 2.96 (m, 2H), 2.54 (m, 1 H), 2.14 (m, 2H), 1.75 (m, 2H), 1.53 (m, 1 H), 1.30 (m, 3H), 0.93 (d, 3H)
Melting point: 206-208°C.
Yield: 9 %
Example 199
2,5-Difluoro-N-[3-fluoro-4-(6-methoxy-quinolin-4-yloxy)-phenyl]- benzenesulfonamide
Figure imgf000155_0001
C22H15F3N2O4S Mw. 460.43
LC/MS purity: 98 %, m/z 459 [M-H]", 461 [M+H]+ Rt. 3.42 min. (Method B)
H NMR (300 MHz, DMSO-d6): 11 (bs, 1 H), 8.58 (d, 1 H), 8.17 (d, 1 H), 7.64 (m, 1 H), 7.48 (m, 1 H), 7.40 (s, 1 H), 7.39 (m, 1 H), 7.26 (m, 2H), 7.06 (dd, 1 H), 6.92 (d, 1 H), 6.37 (d, 1 H), 3.93 (s, 3H)
Melting point: 249-250°C.
Yield: 81 % Example 200
2,6-Difluoro-N-[3-fluoro-4-(6-methoxy-quinolin-4-yloxy)-phenyl]- benzenesulfonamide
Figure imgf000155_0002
C22H15F3N2O4S Mw. 460.43
LC/MS purity: 98 %, m/z 459 [M-H]-, 461 [M+H]+ Rt. 3.27 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 11.3 (bs, 1 H), 8.59 (d, 1 H), 8.17 (d, 1 H), 7.70 (m, 1 H), 7.4-7.25 (m, 6H), 7.14 (dd, 1 H), 7.01 (d, 1 H), 3.93 (s, 3H)
Melting point: 227-228°C.
Yield: 69 %
Example 201
N-[3-Fluoro-4-(6-methoxy-quinolin-4-yloxy)-phenyl]-2-trifluoromethyl- benzenesulfonamide
ULA-P03071WO21 Application
Figure imgf000156_0001
C23H16F4N2O4S Mw.492.45
LC/MS purity: 98 %, m/z 491 [M-H]', 493 [M+H]+ Rt.3.75 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 11 (bs, 1H), 8.59 (d, 1H), 8.18 (s, 1H), 8.15 (s, 1H), 8.02 (d, 1H), 7.89 (m, 2H), 7.40 (s, 1H), 7.36 (d, 1H), 7.29 (dd, 1H), 7.14 (d, 1H), 7.01 (d, 1H), 6.37 (d, 1H), 3.93 (s, 3H)
Melting point: 168-169°C.
Yield: 75 % Example 202
N-[3-Fluoro-4-(6-methoxy-quinolin-4-yloxy)-phenyl]-2-trifluoromethoxy- benzenesulfonamide
Figure imgf000156_0002
C23H16F4N2O5S Mw.508.45
LC/MS purity: 99 %, m/z 507 [M-H]', 509 [M+H]+ Rt.3.97 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 11 (bs, 1H), 8.59 (d, 1H), 8.18 (s, 1H), 8.05 (d,
1H), 7.81 (t, 1H), 7.59 (m, 2H), 7.40 (s, 1H), 7.36 (d, 1H), 7.29 (dd, 1H), 7.15 (d,
1H), 7.00 (d, 1H), 6.34 (d, 1H), 3.93 (s, 3H)
Melting point: 175-176°C.
Yield: 69 %
Example 203
2,5-Dichloro-N-[3-fluoro-4-(6-methoxy-quinolin-4-yloxy)-phenyl]- benzenesulfonamide
ULA-P03071WO21 Application
Figure imgf000157_0001
C22H15CI2FN2O4S Mw.493.34
LC/MS purity: 98 %, m/z 491 [M-H]', 493 [M+H]+ Rt.3.78 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 11.2 (bs, 1H), 8.58 (d, 1H), 8.17 (d, 1H), 8.05 (d, 1H), 7.74 (m, 2H), 7.39 (d, 1H), 7.35 (t, 1H), 7.28 (dd, 1H), 7.16 (dd, 1H), 7.01 (d, 1H), 6.36 (d, 1H), 3.93 (s, 3H)
Melting point: 253-255°C.
Yield: 70 %
Example 204
2,6-Dichloro-N-[3-fluoro-4-(6-methoxy-quinolin-4-yloxy)-ph
benzenesulfonamide
Figure imgf000157_0002
C22H15CI2FN2O4S Mw.493.34
LC/MS purity: 99 %, m/z 491 [M-H]", 493 [M+H]+ Rt.3.69 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 11.2 (bs, 1H), 8.58 (d, 1H), 8.17 (d, 1H), 7.62 (m,
2H), 7.54 (m, 1H), 7.40 (d, 1H), 7.34 (t, 1H), 7.27 (dd, 1H), 7.00 (dd, 1H), 6.96 (d,
1H), 6.35 (d, 1H), 3.93 (s, 3H)
Melting point: 219-221 °C.
Yield: 67 %
Example 205
Naphthalene-2-sulfonic acid [3-fluoro-4-(6-methoxy-quinolin-4-yloxy)-phenyl]- amide
ULA-P03071WO21 Application
Figure imgf000158_0001
C26Hi9FN204S Mw. 474.51
LC/MS purity: 99 %, m/z 473 [M-H]", 475 [M+H]+ Rt. 4.20 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 10.8 (bs, 1 H), 8.53 (d, 1 H), 8.49 (s, 1 H), 8.19 (m, 3H), 8.03 (d, 1 H), 7.82 (dd, 1 H), 7.69 (m, 2H), 7.38 (d, 1 H), 7.27 (m, 2H), 7.16 (dd, 1 H), 6.99 (t, 1 H), 6.28 (d, 1 H), 3.92 (s, 3H)
Melting point: 220-222°C.
Yield: 74 % Example 206
Cyclopropanesulfoni acid [3-fluoro-4-(6-methoxy-quinolin-4-yloxy)-phenyl]-amide
Figure imgf000158_0002
Ci9H17FN2O4S Mw. 388.42
LC/MS purity: 98 %, m/z 387 [M-H]", 389 [M+H]+ Rt. 3.64 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 10.8 (bs, 1 H), 8.62 (dd, 1 H), 8.22 (d, 1 H), 7.48 (d, 1 H), 7.43 (s, 1 H), 7.29 (m, 2H), 7.18 (d, 1 H), 6.48 (d, 1 H), 3.94 (s, 3H), 2.76 (m, 1 H), 0.99 (m, 4H)
Melting point: 194-196°C.
Yield: 75 %
Example 207
2,5-Difluoro-N-(3-methoxy-4-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]- quinolin-4-yloxy}-phenyl)-benzenesulfonamide
ULA-P03071WO21 Application
Figure imgf000159_0001
C32H35F2N3O6S Mw.627.71
LC/MS purity: 98 %, m/z 626 [M-H]', 628 [M+H]+ Rt.3.50 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 10.5 (bs, 1H), 8.37 (d, 1H), 7.63 (m, 1H), 7.51 (m, 2H), 7.46 (s, 1H), 7.34 (s, 1H), 7.07 (d, 1H), 6.90 (s, 1H), 6.70 (d, 1H), 6.16 (d, 1H), 4.17 (t, 2H), 3.91 (s, 3H), 3.61 (s, 3H), 3.34 (m, 1H), 2.84 (m, 2H), 2.46 (m, 2H), 1.95 (m, 3H), 1.63 (m, 4H), 1.48 (m, 1H), 0.84 (d, 3H)
Melting point: 170-172°C.
Yield: 58%
Example 208
N-(3-Methoxy-4-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4- yloxy}-phenyl)-2-t
Figure imgf000159_0002
C33H36F3N3O6S Mw.659.73
LC/MS purity: 98 %, m/z 658 [M-H]', 660 [M+H]+ Rt.3.86 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 10.6 (bs, 1H), 8.38 (d, 1H), 8.15 (d, 1H), 7.97 (d, 1H), 7.83 (m, 2H), 7.45 (s, 1H), 7.34 (s, 1H), 7.07 (d, 1H), 6.91 (d, 1H), 6.67 (dd, 1H), 6.17 (d, 1H), 4.17 (t, 2H), 3.91 (s, 3H), 3.60 (s, 3H), 3.32 (m, 1H), 2.81 (m, 2H), 2.46 (m, 2H), 1.96 (m, 2H), 1.88 (m, 1 H), 1.60 (m, 4H), 1.46 (m, 1 H), 0.84 (d, 3H)
Melting point: 216-218°C.
Yield: 53 % Example 209
N-(3,5-Dichloro-4-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4- yloxy}-phenyl)-2,6
Figure imgf000160_0001
C31H31CI2F2N3O5S Mw. 666.58
LC/MS purity: 96 %, m/z 664 [M-H]", 666 [M+H]+ Rt. 3.34 min. (Method B)
H NMR (300 MHz, DMSO-d6): 10.2 (bs, 1 H), 8.43 (d, 1 H), 7.53 (s, 1 H), 7.45 (m, 1 H), 7.41 (s, 1 H), 7.07 (m, 2H), 7.02 (m, 2H), 6.26 (d, 1 H), 4.23 (t, 2H), 3.94 (s, 3H), 3.28 (m, 2H), 2.95 (m, 2H), 2.52 (m, 1 H), 2.13 (m, 2H), 1.74 (m, 2H), 1.53 (m, 1 H), 1.29 (m, 3H), 0.92 (d, 3H)
Melting point: 146-151 °C.
Yield: 7 %
Example 210
N-(3,5-Dichloro-4-{6-methoxy-7-[3-(4-methyl-piperidin-1 -yl)-propoxy]-quinolin-4- yloxy}-phenyl)-2-t
Figure imgf000160_0002
C32H32Cl2F3N305S Mw. 698.59
LC/MS purity: 98 %, m/z 696 [M-H]\ 698 [M+H]+ Rt. 3.59 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 10.5 (bs, 1 H), 8.43 (d, 1 H), 8.11 (d, 1 H), 7.82 (d,
1 H), 7.69 (m, 2H), 7.52 (s, 1 H), 7.41 (s, 1 H), 6.96 (s, 2H), 6.25 (d, 1 H), 4.22 (t,
2H), 3.93 (s, 3H), 3.28 (m, 2H), 2.69 (m, 2H), 2.56 (m, 1 H), 2.27 (m, 2H), 1.72 (m,
2H), 1.50 (m, 1 H), 1.32 (m, 3H), 0.92 (d, 3H)
Melting point: 148-151°C.
Yield: 22 % Example 211
Acetic acid 4-{4-[4-(2,5-difluoro-benzenesulfonylamino)-2-fluoro-phenoxy]-6- methoxy-quinolin-
Figure imgf000161_0001
C28H25F3N2O7S Mw. 590.58
LC/MS purity: 98 %, m/z 589 [M-H]", 591 [M+H]+ Rt. 3.57 min. (Method B)
1H NMR (300 MHz, DMSO-d6): 11.11 (s, 1 H), 8.45 (d, 1 H), 7.71-7.35 (m, 6H), 7.18 (d, 1 H), 7.05 (d, 1 H), 6.36 (d, 1 H), 4.17 (bs, 2H), 4.10 (bs, 2H), 3.92 (s, 3H), 2.01 (s, 3H), 1.84 (bs, 2H), 1.80 bs, 2H)
Melting point: 165-167°C.
Yield: 65 %
Example 212
Acetic acid 4-{4-[2-fluoro-4-(2-trifluoromethyl-benzenesulfonylamino)-phenoxy]-6- methoxy-quinolin-7-yloxy}-butyl ester
Figure imgf000161_0002
C29H26F4N2O7S Mw. 622.60
LC/MS purity: 98 %, m/z 621 [M-H]", 623 [M+H]+ Rt. 3.86 min. (Method B)
H NMR (300 MHz, DMSO-d6): 11.03 (s, 1 H), 8.45 (d, 1 H), 8.16 (d, 1 H), 8.04 (d, 1 H), 7.80 (m, 2H), 7.47 (s, 1 H), 7.39 (s, 1 H), 7.37 (t, 1 H), 7.16 (d, 1 H), 7.03 (d, 1 H), 6.36 (d, 1 H), 4.17 (t, 2H), 4.10 (t, 2H), 3.91 (s, 3H), 2.01 (s, 3H), 1.82 (m, 4H) Melting point: 143-145°C.
Yield: 74 % Example 213
N-{2-Fluoro-4-[6-methoxy-7-(3-pyrrolidin-1-yl-propoxy)-quinolin-4-yloxy]-phenyl}-2- trifluoromethyl-benzenesulfonamide
Figure imgf000162_0001
C30H29F4N3O5S Mw. 619.64
LC/MS purity: 99 %, m/z 618 [M-H]\ 620 [M+H]+ Rt. 2.71 min. (Method A)
1H NMR (300 MHz, DMSO-d6): 11.03 (s, 1 H), 8.45 (d, 1 H), 8.16 (d, 1 H), 8.04 (d, 1 H), 7.80 (m, 2H), 7.47 (s, 1 H), 7.39 (s, 1 H), 7.37 (t, 1 H), 7.16 (d, 1 H), 7.03 (d, 1 H), 6.36 (d, 1 H), 4.17 (t, 2H), 4.10 (t, 2H), 3.91 (s, 3H), 2.01 (s, 3H), 1.82 (m, 4H) Melting point: 152-156°C.
Yield: 62 %
Example 214
N-{3-Fluoro-4-[6-methoxy-7-(4-morpholin-4-yl-butoxy)-quinolin-4-yloxy]-phenyl}-2- trifluoromethyl-be
Figure imgf000162_0002
C31 H31 F4N3O6S Mw. 649.67
LC/MS purity: 97 %, m/z 648 [M-H]", 650 [M+H]+ Rt. 3.50 min. (Method B)
H NMR (300 MHz, DMSO-d6): 11 (bs, 1 H), 8.44 (d, 1 H), 8.16 (d, 1 H), 8.01 (d, 1 H), 7.90 (m, 2H), 7.46 (s, 1 H), 7.38 (s, 1 H), 7.33 (t, 1 H), 7.13 (d, 1 H), 6.98 (d, 1 H), 6.35 (d, 1 H), 4.16 (t, 2H), 3.91 (s, 3H), 3.57 (m, 4H), 2.38 (m, 6H), 1.82 (m, 2H), 1.64 (m, 2H)
Melting point: 102-104°C.
Yield: 23 %
Example 215
N-(2-Fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}- phenyl)-2-trifluoromethyl-benzenesulfonamide
Figure imgf000163_0001
C32H33F4N3O5S Mw. 647.69
LC/MS purity: 95 %, m/z 646 [M-H]', m/z 648 [M-H]+ Rt. 3.60 min. (Method B) 1H NMR (300 MHz, DMSO-d6): 10.6 (bs, 1 H), 8.44 (d, 1 H), 8.07 (d, 1 H), 7.81 (d, 1 H), 7.65 (m, 2H), 7.43 (s, 1 H), 7.35 (s, 1 H), 7.14 (t, 1 H), 6.96 (d, 1 H), 6.76 (d, 1 H), 6.43 (d, 1 H), 4.17 (t, 2H), 3.90 (s, 3H), 2.85 (m, 2H), 2.42 (m, 2H), 1.98 (m, 2H), 1.82 (m, 1 H), 1.61 (m, 4H), 1.51 (m, 1 H), 1.03 (m, 1 H), 0.84 (d, 3H)
Melting point: 125-126 °C.
Yield: 35 %
Assay Example A:
AXL Cellular Tyrosine Kinase Assay Establishment of wild type AXL (wtAXL) receptor tyrosine kinase- overexpressing stable cell line NIH-3T3-AXL (Clone 22)
WtAXL cDNA was cloned into vector pLXSN(ESK) and transfected into Phoenix E packaging cells. The viral supernatant was collected and used to infect target cells NIH3T3 N7. Monoclonal NIH3T3-AXL cell lines stably expressing wtAXL were generated by selecting retrovirally infected cells in medium containing puromycin (2pg/ml) and subsequent clonal separation. NIH-3T3-AXL (clone 22) cells were used for further experiment because AXL was highly expressed and constitutively phosphorylated in these cells. In addition, these cells demonstrated aggressive behaviors on matrigel matrix (Matrigel™ Matrix, BD Biosciences, Bedford, MA, USA). Moreover, the inhibitory effects of compounds on AXL phosphorylation discovered by using NIH-3T3 AXL (clone 22) system have been confirmed in human breast cancer cells endogenously expressing AXL in our previous study (Zhang YX, et al. AXL is a potential target for therapeutic intervention in breast cancer progression. Cancer Res. 2008; 68:1905-15).
Determination of the morphology of cells grown on matrigel matrix was carried out as described previously, with some modifications (Thompson EW, et al. Association of increased basement membrane invasiveness with absence of estrogen receptor and expression of vimentin in human breast cancer cell lines. J Cell Physiol 1992;150:534-44). Briefly, in a 96-well flat-bottomed plate, 10000 cells/100μΙ cell suspensions was plated on the surface of precoated matrigel (3mg/ml). Colony outgrowth was visualized with a Zeiss Axiovert S100 microscope (Carl Zeiss UK, Welwyn Garden City, UK).
NIH-3T3-AXL Cellular Kinase Assay
NIH-3T3-AXL (Clone 22) cells were seeded onto 6-well plates (1.5 x 105 cells/well) in 1.5ml DMEM + 10% heat inactivated FBS (GIBCO - Invitrogen GmbH, Karlsruhe, Germany) and cultured overnight, followed by serum depletion in DMEM without FBS for 24 h. Serial dilutions of compounds were added, and the cells were further incubated for 1 h. Cells were washed with PBS and lysed on ice in 500μΙ lysis buffer (50 mM HEPES (pH 7.5), 150 mM NaCI, 1 mM EGTA, 10% Glycerol, 1 % Triton X-100, 100 mM NaF, 10 mM Na4P2O7-10 H20, 1 mM Na3VO4, 1 mM phenylmethylsulfonyl fluoride, and 10 mg/ml aprotinin) for 15min. The cell lysate were used for phosphotyrosine AXL enzyme-linked immunosorbant assay (pY-AXL-ELISA). 96-well Nunc MicroWell™ plates (Fischer Scientific GmbH, Schwerte, Germany) were coated over night with homemade anti-Axl capture antibody 2pg/ml (clone 259/2, lgG1 isotype) in PBS (ΙΟΟμΙ/well). Subsequently 96-well plates were blocked with PBS-0.05%Tween®20 + 10%FBS for 4h at 37°C. Plates were washed 5 times with PBS-0.05%Tween®20 and 95μΙ of lysate was transferred per well for incubation overnight at 4°C. Plates were washed 5 times with PBS-0.05%Tween®20 (Sigma, Steinheim, Germany). For detection of phosphorylated tyrosine we used homemade biotynilated 4G10-antibody (O^g/ml) in PBS-0.05%Tween®20 + 10%FBS (ΙΟΟμΙ/well) and incubated the 96- well plate for 2h at room temperature. The anti-phosphotyrosine mouse monoclonal antibody 4G10 was biotynilated with Sulfo-NHS®-Biotin according to the suppliers protocol (Pierce, Rockford, IL, USA) and purified by Mirco Bio-Spin 6 Chromatograpy Columns (BIO RAD Laboratories, Inc., Hercules, CA, USA) using PBS as diluent. Plates were washed 5 times with PBS-0.05%Tween®20. For biding to biotin Alkaline Phosphatase Conjugated Strepavidin SA110 (Millipore, Billerica, MA, USA) (1 :4000) was used in PBS-0.05%Tween20 + 10%FBS (100pl/well) and incubated for 30min at room temperature. Plates were washed 5 times with PBS-0.05%Tween20. For fluorimetric detection of alkaline phosphatase AttoPhos Substrate Set (Roche diagnostics GmbH, Mannheim, Germany) was used (100pl/well). The fluorimetric signal was quantified after 90min at 430/560nm wavelength using a TECAN Ultra Evolution plate reader (Tecan Deutschland GmbH, Crailsheim, Germany). Table la below shows for the cell line NIH-3T3-Axl in column 2 the half-maximal inhibition concentration (IC50) values of representative compounds according to general formula (I) (+ = 3 μΜ > IC50 > 500nM & ++ = IC50 ≤ 500nM) obtained according to the disclosure above of Assay Example A.
Table la: Inhibitory effect of the compounds of the present invention on the NIH- 3T3-axl cell line
Figure imgf000165_0001
67 ++ 182 ++
76 ++ 184 ++
77 ++ 185 +
78 ++ 186 ++
81 ++ 191 +
82 ++ 193 +
87 ++ 194 +
89 ++ 197 +
99 ++ 198 +
100 ++ 199 +
104 ++ 201 +
106 ++ 202 +
108 ++ 207 +
109 ++ 208 ++
1 10 ++ 209 ++
1 11 ++ 210 ++
1 12 ++ 21 1 ++
1 13 ++ 212 ++
Table lb below shows the inhibitory effect of some compounds of the present invention on the cell line HS578T. In column 2 the experimental data of the "Matrigel outgrowth assay / branching assay" (+ = 25 μΜ > ICso > 10.0 μΜ & ++ = IC5o ≤ 10.0 μΜ) as disclosed below under Assay Example E are shown and in column 3 the experimental data of the "Cell vitality assay (ATP assay)" (+ = 50 μΜ > IC50 > 12.5 μΜ & ++ = ICso ≤ 12.5 μΜ) as disclosed below in section Assay Example B and in column 4 the experimental data of the "Wound healing migration assay" (+ = 50 μΜ > IC50 > 12.5 μΜ & ++ = IC5o ≤ 12.5 μΜ) as outlined under Assay Example D are provided.
Table lb: Inhibitory effect of the compounds of the present invention on the
HS578T cell line
Figure imgf000166_0001
ULA-P03071WO21 Application 15 ++
16
17 ++
18 ++
19
20
21 ++
22
23
24
25 ++
26 ++
27 ++
28 +
29 ++
30
31
32 ++
33 ++
34 ++ ++ ++
35 ++ ++ -
36 + ++ +
37 + ++ +
38 ++ + ++
39
40 ++ ++ ++
41 ++
42
43 ++ ++ ++
44 ++ ++ ++
45 ++ ++ ++
46 ++ ++ ++
47 ++ ++ ++
48 + ++ ++
49 + ++ ++
50 ++ ++ ++
51 ++ ++ ++
52 ++ ++ ++
53 + ++ ++
54 + ++ ++
55 ++ + ++
56 + + ++
57 ++ ++ ++
58 ++ ++ ++
59 ++ ++ ++
60
61
62 + ++ +
63 ++ ++ ++
64 + ++ ++
65 + ++ ++
66 + ++ ++
67 ++ ++ ++
68
69
70 ++
71
72 ++ 73
74
75 ++
76 + ++ +
77 ++ ++ ++
78 ++ ++ ++
79
80
81 ++ ++ +
82 ++ ++ +
83 ++
84 ++
85 ++
86 ++
87 ++ + ++
88 +
89 ++ ++ ++
90
91
92 + ++ +
93 ++
94
95 ++
96
97
98
99 ++ ++ ++
100 ++ ++ ++
101 +
102 + ++ ++
104 + ++ ++
106 + ++ +
108 + ++ +
109 + ++ +
110 ++ ++ ++
111 ++ ++ ++
112 ++ ++ ++
1 13 ++ ++ ++
1 14 + ++ +
1 15 ++ ++ ++
1 16 + ++ ++
1 17 + ++ ++
119 ++ ++ ++
120 + + +
121 + + +
124 ++ ++ ++
125 + ++ ++
126 + ++ ++
127 ++ ++ ++
128 ++ ++ ++
129 ++ ++ ++
130 ++ ++ +
131 + ++ +
132 + + +
133 ++ ++ ++
134 ++ ++ ++
135 + + +
136 ++ ++ ++
ULA-P03071WO21 Application 137 + + +
138 + + +
139 + + +
140 + + +
141 + + +
142 + + +
143 ++ ++ ++
144 + ++ ++
145 + ++ ++
146 + ++ ++
147 ++ ++ ++
148 + ++ +
149 + + +
150 + ++ +
151 ++ ++ ++
152 ++ ++ ++
153 + ++ ++
154 + ++ ++
155 + ++ ++
156 + ++ ++
157 + ++ ++
158 + ++ ++
159 + ++ +
160 + ++ ++
161 + ++ +
162 + ++ +
163 + ++ +
164 + ++ +
165 + ++ +
166 + ++ +
167 + + +
168 + + +
169 + + +
170 + + +
171 + + +
172 ++ ++ ++
173 + ++ +
174 ++ ++ ++
175 ++ ++ ++
176 ++ ++ ++
177 ++ ++ ++
178 ++ ++ +
179 + ++ ++
180 ++ ++ ++
181 ++ ++ ++
182 + ++ ++
183 + + +
184 + ++ ++
185 + ++ +
186 + ++ ++
187 ++ ++ ++
188 ++ ++ ++
189 + + +
190 + + +
191 + ++ ++
192 + ++ +
193 + + ++
194 + + +
ULA-P03071WO21 Application 195 + + +
196 + + +
197 + + +
198 + + +
199 + + +
200 + + +
201 + + +
202 + + +
203 + ++ ++
204 + + +
205 + + +
206 + + +
207 + ++ ++
208 + ++ +
209 ++ ++ ++
210 ++ ++ ++
211 + ++ ++
212 + + +
Cell lines used for experiments:
Cell line Source Description
Hs578T ECACC Mammary glad, adenocarcinoma
MDA-MB231 ATCC no. HTB-26 Mammary glad, adenocarcinoma
MCF10A ATCC no. CRL-10317 Mammary gland; breast
MDA-MB435S ATCC no. HTB-129 Mammary glad, adenocarcinoma
SF126 M. Rosenblum Brain, glioblastoma
SF763 SUGEN Brain, glioblastoma
U118 SUGEN Brain, glioblastoma
U138 SUGEN Brain, glioblastoma
U373 SUGEN Brain, glioblastoma
A172 CRL-1620 Brain, glioblastoma
A549 ATCC no. CCL-185 Lung, carcinoma
NCI-H460 ATCC no. HTB-177 Lung, carcinoma
NCI-H1299 ATCC no. CRL-5803 Lung, carcinoma
C8161 B. Gillies Skin, melanoma
SK-MEL-28 ATCC no. HTB-72 Skin, melanoma
MIA PaCa-2 ATCC no. CRL-1420 Pancreas, carcinoma
ASPC-1 ATCC no. CRL-1682 Pancreas, adenocarcinoma
Panc-1 ATCC no. CRL-1469 Pancreas, epithelioid carcinoma
786-0 ATCC no. CRL-1932 Kidney, renal cell adenocarcinoma
DU145 ATCC no. HTB-81 Prostate, carcinoma
PC3 ATCC no. CRL-1435 Prostate, adenocarcinoma
HT29 ATCC no. HTB-38 Colon, colorectal adenocarcinoma
ULA-P03071WO21 Application Assay Example B: Cell vitality assay
The CellTiter-Glo® Luminescent Cell Viability Assay (Promega Corporation. Madison, Wl, USA) is method a determining the number of viable cells in culture based on quantification of the ATP being present which is an indicator of metabolically active cells was used according to manufacturers protocol, In detail the assay was performed in a 96 well format were 1000 cells/well were incubated with indicated compound at concentration of 12.5μΜ, 6.25μΜ, 3.125μΜ, 1.56μΜ, 0.78μΜ, 0.39μΜ, 0.195μΜ as well as DMSO control for 72h in 100μΙ cell culture medium. IC50 values were calculated as 50% of ATP amount compared to DMSO control.
Protocol for the CellTiter-Glo® Luminescent Cell Viability Assay
1. Prepare opaque-walled multiwell plates with mammalian cells in culture
medium, 100μΙ per well for 96-well plates
2. Prepare control wells containing medium without cells to obtain a value for background luminescence.
3. Add the compound to be tested to experimental wells, and incubate
according to culture protocol.
4. Equilibrate the plate and its contents at room temperature for approximately 30 minutes.
5. Add a volume of CellTiter-Glo® Reagent (Promega Corporation. Madison, Wl) equal to the volume of cell culture medium present in each well.
6. Mix contents for 2 minutes on an orbital shaker to induce cell lysis.
7. Allow the plate to incubate at room temperature for 10 minutes to stabilize luminescent signal.
8. Record luminescence on Microplate Luminometer LB96V (Berthold
Tchnologies, Bad Wildbad, Germany). An integration time of 0.1 and 1 second per well Table lla below shows the IC50 values of representative compounds according to general formula (I) (+ = 50 μΜ > IC50 > 12.5 μΜ & ++ = IC5o ≤ 12.5 μΜ).
Figure imgf000171_0001
ULA-P03071WO21 Application 8 ++ ++ ++ ++ ++ + - ++
10 ++ ++ ++ ++ ++ + ++ ++
1 1 + + +
12 ++ ++ ++
14 ++ ++ + + - ++ ++
21 + + + - - + +
25 ++ ++ ++ ++ ++ ++ ++
29 + ++ ++ ++ + ++ ++
32 ++ ++ ++ ++ ++ ++ ++
33 ++ ++ ++ ++ ++ ++ ++
38 ++ ++ ++ ++ ++ + ++ ++
40 ++ ++ +
41 ++ + ++ ++ ++ ++ ++
45 ++ ++ ++
47 ++ ++ ++ ++ ++ ++ + +
49 ++ ++ ++
51 ++ ++ ++
54 ++ + ++
55 + ++ + + + ++ ++
56 ++ ++ + ++ + + ++
59 ++ + + ++ ++ ++ ++
63 ++ + ++ + ++ ++ ++
66 ++ ++ ++
70 + ++ ++ ++ + + +
72 + + + + + + +
77 ++ ++ + ++ ++ ++ + ++
78 ++ ++ ++
87 ++ ++ ++ ++ ++ + + ++
88 + + ++ + ++ ++ ++
93 + ++ ++ + ++ + ++
95 ++ ++ ++ ++ + ++ +
99 ++ ++ ++ ++ ++ ++ ++ +
100 ++ ++ ++
104 + + +
110 ++ ++ ++
1 12 ++ ++ ++
1 19 ++ ++ ++
151 ++ ++ ++
155 ++ ++ ++
156 ++ ++ ++
157 ++ ++ ++
158 ++ ++ ++
177 ++ ++ ++
178 ++ ++ ++
179 ++ ++ ++
181 ++ ++ ++
184 ++ ++ ++
209 ++ ++ ++
210 ++ ++ ++
Table lib below shows the IC50 values of representative compounds according to general formula (I) (+ = 50 μΜ > IC50 > 12.5 μΜ & ++ = IC5o ≤ 12.5 μΜ).
ULA-P03071WO21 Application Example No MCF10A MiaPaca-2 Aspc-1 Panc-1 DU145 PC3 786-0 SF126
24 ++ ++ ++ + ++ + ++ ++
12 ++ ++ + ++ ++ ++ ++
1 ++ ++ + ++ ++ + ++
66 ++ ++ ++ ++ ++ ++ ++
Table lie below shows the IC5o values of representative compounds according to general formula (I) (+ = 50 μΜ > IC50 > 12.5 μΜ & ++ = IC50 ≤ 12.5 μΜ).
Figure imgf000173_0001
Assay Example C: Apoptosis assay
The Cellomics BioApplication (Thermo Fischer Cellomics Products, Pittsburgh, PA) is an automated image analysis algorithm that provides detailed analysis of phenotypes related to apoptosis. As one of the most prominent characteristics of apoptotics cell a nucleus condensation takes place. This can be measured fluorescence signal intensity using a CCD camera on fully automated microscope system. The Cellomics system is able to quantify the fluorescence intensity per single nucleus and calculates the variation of signal intensity in each cell population. Healthy cell have a low variation of signal intensity in contrast to apoptotic cell with condensed nucleus exhibiting a high variation of signal intensity. Additionally the number of detected cell decreases normally in apoptotic cell populations. In detail 5000 cell per 96 well were labeled with DNA intercalating dye (Hoechst 33342, Sigma, Steinheim, Germany) to visualize the nucleus in a fluorescence microscope under live conditions. The apoptosis assay was performed 24h and 48h after addition of compound at concentrations 12.5μΜ, 6.25μΜ, 3.125μΜ, 1.56μΜ, 0.78μΜ, 0.39μΜ as well as DMSO control for 48h.
Table III below shows the IC50 values of representative compounds according to general formula (I) (+ = 50 μΜ > IC50 > 12.5 μΜ & ++ = IC50 ≤ 12.5 μΜ).
Figure imgf000173_0002
ULA-P03071WO21 Application 7 ++ ++ - ++ + ++
8 ++ ++ ++ ++ ++ +
10 ++ ++ + + ++ ++
12 +
14 ++ ++ ++ ++ + ++
15 ++ ++ ++ ++ - ++
16 ++ ++ ++ ++ - ++
17 ++ ++ ++ ++ + ++
18 ++ ++ ++ ++ ++ ++
21 ++ ++ ++ ++ ++ +
24 ++
25 ++ ++ ++ ++ ++ ++
26 ++ ++ + ++ + ++
27 ++ ++ + ++ ++ ++
28 ++ ++ ++ ++ ++ ++
29 ++ ++ ++ ++ - +
32 ++ ++ ++ ++ ++ ++
33 ++ + ++ ++ + ++
34 ++ + ++ ++ ++ ++
35 ++ ++ ++ ++ ++ +
38 ++ ++ ++ ++ ++ ++
41 ++ ++ ++ ++ ++ ++
47 + ++ + ++ ++ ++
55 ++ ++ ++ ++ + ++
56 ++ ++ ++ ++ ++ ++
57 ++ ++ ++ + ++ ++
58 ++ + ++ ++ + ++
59 ++ ++ ++ ++ ++ ++
63 ++ ++ ++ ++ ++ ++
70 ++ ++ ++ ++ ++ ++
72 ++ ++ + ++ ++ +
75 ++ ++ ++ ++ ++ ++
77 ++ ++ ++ ++ ++ ++
80 + ++ + + ++ +
81 ++ ++ ++ ++ ++ ++
82 ++ ++ ++ ++ ++ ++
83 ++ ++ ++ ++ ++ ++
84 ++ ++ ++ ++ ++ ++
85 ++ ++ ++ ++ + ++
86 ++ ++ ++ ++ ++ ++
87 ++ ++ ++ ++ ++ +
88 ++ ++ ++ ++ ++ ++
93 ++ ++ ++ ++ ++ ++
95 ++ ++ ++ ++ ++ ++
99 ++ ++ ++ ++ + ++
100 ++ ++ ++ ++ + ++
101 ++ ++ + ++ - ++
102 ++ ++ ++ ++ ++ ++
ULA-P03071WO21 Application Assay Example D: Wound healing migration assay
This method mimics cell migration during wound healing in vivo. The basic steps involve creating a "wound" in a cell monolayer, capturing the images at the beginning and at regular intervals during cell migration to close the wound, and comparing the images to quantify the migration rate of the cells. In detail, 150000 cell/24well have been seeded and allowed to form a monolayer overnight. Subsequently a "wound" or "scratch" has been performed with a 1000μΙ pipette tip. The STDV of wound size is normally below 10% at time point tO. The assay was stopped by fixation with 0.05% Crystal violet/20%methanol when control scratches were closed. The assay was terminated between 48h and 72h depending on the migration potential of the indicated cell line. The "wounds" were visualized with a Zeiss Axiovert S100 microscope (Carl Zeiss UK, Welwyn Garden City, UK). The tested compounds were used at 12.5μΜ, 6.25, 3.125μΜ and DMSO control. IC50 values have been calculated as 50% wound size in between tO and t48 or t72.
Table IV below shows the IC50 values of representative compounds according to general formula (I) (+ = 50 μΜ > IC50 > 12.5 μΜ & ++ = IC50 ≤ 12.5 μΜ).
Figure imgf000175_0001
40 ++ ++ ++
41 ++ +
45 ++ ++ ++
47 ++ ++ ++ ++ ++
49 ++ ++ ++
51 ++ ++ ++
54 ++ ++ ++
55 + +
56 + ++
57 + ++
58 ++ +
59 ++ +
63 ++ +
66 ++ ++ ++
70 ++ +
72 ++ ++
75 - +
77 ++ ++ ++ ++ ++
78 ++ ++ ++
80 ++ ++
81 + ++
82 ++ ++
83 ++ ++
84 + ++
85 + ++
86 + +
87 ++ + ++ ++ ++
88 ++ +
93 + ++
95 + +
99 ++ + ++ ++ ++
100 ++ + ++ ++ ++
101 + +
102 ++ +
104 + ++ ++
110 ++ ++ ++
112 ++ ++ ++
119 ++ ++ ++
151 ++ ++ ++
155 ++ ++ ++
156 ++ ++ ++
157 ++ ++ ++
158 ++ ++ ++
177 ++ ++ ++
178 ++ ++ ++
179 ++ ++ +
181 ++ ++ ++
184 ++ ++ ++
209 ++ ++ ++
210 ++ ++ ++
Assay Example E: Matrigel outgrowth assay / branching assay
The Matrigel outgrowth assay is based on the ability of tumor cell to penetrate a solid gel of extracellular matrix proteins mimicking the metastasis formation in vivo.
ULA-P03071WO21 Application While cells with low invasive potential appear as roundish cell or cell cluster, cells with high invasive potential penetrate the Matrigel and form polymorphic structures. In detail 65μΙ of Matrigel matrix (Matrigel™ Matrix, BD Biosciences, Bedford, MA, USA) with a concentration of 3mg/ml have been polymerized in 96well plates for 1 h at 37°C. Subsequently 5000 cell/well were seeded into each well containing cell culture medium and indicated compound with concentrations of 3.125μΜ, 1.56μΜ and 0.78μΜ as well as DMSO control. After 48h, 72h and 96h images of cell were taken on an inverted microscope using a 5x objective (Zeiss Axiovert S100 microscope Carl Zeiss UK, Welwyn Garden City, UK). Only compound concentrations were total branching inhibition was evident were accounted as positive. Method was used as previously described, with some modifications (Thompson EW, et al. Association of increased basement membrane invasiveness with absence of estrogen receptor and expression of vimentin in human breast cancer cell lines. J Cell Physiol 1992;150:534-44).
Table Va below shows the IC50 values of representative compounds according to
Figure imgf000177_0001
ULA-P03071WO21 Application 59 + ++ ++ ++
63 ++ ++ + ++
66 ++ + ++ ++
70 ++ ++ ++ ++
72 ++ ++ ++ ++
75 ++ + ++ ++
77 ++ + + ++
80 ++ + ++ ++
81 + + ++ ++
82 ++ + + ++
83 ++ ++ ++ ++
84 ++ ++ ++ ++
85 ++ + ++ ++
86 ++ + ++ ++
87 ++ + ++ ++
88 + + ++ +
93 ++ + ++ ++
95 + + ++ ++
99 ++ ++ + ++
100 ++ + ++ ++
101 ++ + ++ +
102 ++ + ++ ++
Table Vb below shows the IC-ioo values of representative compounds according to general formula (I) (+ = IC100 > 12.5 μΜ & ++ = ICioo ≤ 12.5 μΜ).
Figure imgf000178_0001
104 + + +
110 + ++ ++
112 ++ ++ ++
1 19 ++ ++ ++
151 ++ ++ ++
155 ++ ++ ++
156 + ++ ++
157 + ++ +
158 + ++ ++
177 ++ ++ ++
178 + ++ ++
179 + ++ ++
181 + ++ ++
184 + ++ ++
209 ++ ++ ++
210 + ++ ++
Assay Example F: Boyden chamber migration assay
The Boyden chamber assay is based on a chamber of two medium-filled compartments separated by a microporous membrane of 8μΜ (Cell culture insert 8.0μΜ pore size, BD Biosciences, Bedford, MA). The boyden chamber migration assays were carried out according to the supplier's instructions. In general, 20000 cells are placed in the upper compartment with medium containing 0% FCS plus 0,1 %BSA and are allowed to migrate 16h through the pores of the membrane into the lower compartment, which is filled with cell culture medium containing 10% FCS as chemotactic agents. The cells remaining in the insert were removed with a cotton swab, and the cells on the bottom of the filter were fixed and counted. (Zhang YX, et al. AXL is a potential target for therapeutic intervention in breast cancer progression. Cancer Res. 2008; 68:1905-15). Table VI below shows the IC5o values of representative compounds according to general formula (I) (+ = 50 μΜ > IC50 > 5.0 μΜ & ++ = IC50 ≤ 5.0 μΜ).
Figure imgf000179_0001
ULA-P03071WO21 Application 17 ++ 59 ++ 101 ++
18 ++ 63 ++ 102 ++
21 ++ 70 ++ 86 ++
25 ++ 72 ++ 87 +
26 ++ 75 ++ 88 ++
27 ++ 77 ++ 93 ++
28 ++ 80 ++ 95 ++
29 ++ 81 ++ 99 ++
32 ++ 82 + 100 ++
33 ++ 83 ++ 101 ++
34 ++ 84 ++ 102 ++
35 ++ 85 ++ 12 ++
24 ++ 25 ++ 32 ++
Assay Example G: Cell viability assay
Cell line ATCC no. Description
HCT116 wt CCL-247™ Colorectal carcinoma; Aurora A amplification, Src expression
HCT116 def Colorectal carcinoma, p53 mutant
SW480 CCL-228™ Colorectal adenocarcinoma; Aurora A amplification, p53 and ras mutation, is positive for expression of c- myc, K-ras, H-ras, N-ras, myb, sis and fos oncogene
HT29 HTB-28™ Colorectal adenocarcinoma; is positive for expression of c-myc, K-ras, H-ras, N-ras, Myb, sis and fos oncogenes, p53 mutation, Aurora A amplification
H1993 CRL-5909™ adenocarcinoma, KEAP1 mutation, MET amplification, CDK6 ( copy number >=4 and <7) and CDK4 (copy number >=4 and <7) amplification
H1975 CRL-5908™ adenocarcinoma, EGFR mutant
H1650 CRL-5883™ adenocarcinoma, EGFR del mutant
RKO CRL-2577™ Colon carcinoma, wild type p53+
HCC827 CRL-2868™ adenocarcinoma, EGFR mutant, MYC and CDK4
(copy number >7 ) amplification
H358 CRL-5807™ bronchioalveolar carcinoma, RAS mutant
H1666 CRL-5885™ adenocarcinoma; bronchoalveolar carcinoma RAF mutant
A549 CCL-185™ lung carcinoma, EGFR and PLK mutant, wild type p53
ULA-P03071WO21 Application Conditions of cell viabilit assa
Figure imgf000181_0001
The CellTiter-Glo Luminescent Cell Viability Assay (Promega Corporation. Madison, Wl, USA) is method a determining the number of viable cells in culture based on quantification of the ATP being present which is an indicator of metabolically active cells was used according to manufacturers protocol. In detail the assay was performed in a 96 well format were 1000 cells/well were incubated with compound at concentration 10μΜ as well as DMSO control for 72h in 100μΙ cell culture medium. Percentage of inhibition was calculated compared to ATP amount of DMSO control.
Table VII below shows the percentage (%) of viable cells in the culture treated with representative compounds according to general formula (I) (a = 0% - 20% viable cells; b = 21% - 40% viable cells; c = 41 % - 60% viable cells; d > 60% viable cells).
Figure imgf000181_0002
ULA-P03071WO21 Application 23 a a a a a a b a b a b c
27 a a a b a b c a d a c d
28 b b a b b b b a b a c b
29 a a a a a a b a b b c c
32 a b b a a b b b c a c c
33 a b a a a b d a b b b c
34 a b a b a a b a d a b d
35 a b a a b a b c c a b d
38 b b a a b b d a c a b d
41 c a a b b a c a c a b b
47 a b b c a a c a c a b c
55 a b b b a d a c c a a b
56 b b a a c a c b b a b d
57 d b a a b a c a d b c d
58 a b a a c a d a d b b c
59 a a a a a b d a b b c b
63 a b a b a a c d b a c b
70 c b b b a a c a b b b b
72 b c a a a c c a c b b d
75 b b a a b a b a d a c d
77 a b a c b a b b d a c c
80 b b a c a a d a b a b d
81 b b a b b a b c a a b c
82 a b b a a b b c b b c d
83 a b b a a c b d a a b b
84 a a a a a b a a d a c d
85 a b a b a b b a a b c c
86 b b b a a b b b c a c d
87 c a a a c a b c c a c d
88 c a b b a a c c a a b c
93 d b a a b a b a b a b d
95 b b a a a a b a b a b d
99 a d a b b b b b c a c b
100 a a a b c c b a b a b d
101 b b a a b c c a b a c c
102 a a a a b b c b b a c c
Assay Example H: Cancer cell line based Cellular Kinase Assay
Indicated cancer cell lines were seeded onto 6-well plates (1.5 x 105 cells/well) in 1.5ml DMEM + 10% heat inactivated FBS (GIBCO - Invitrogen GmbH, Karlsruhe, Germany) and cultured overnight, followed by serum depletion in DMEM without FBS for 24 h. Serial dilutions of compounds were added, and the cells were incubated for 1 h followed by Gas6 mediated Axl activation with 250ng/ml
ULA-P03071WO21 Application recombinant human Gas6 (Catalog Number: 885GS, R&D Systems, Inc., Minneapolis, USA) for 30 minutes. Cells were washed with PBS and lysed on ice in 500μΙ lysis buffer (50 mM HEPES (pH 7.5), 150 mM NaCI, 1 mM EGTA, 10% Glycerol, 1 % Triton X-100, 100 mM NaF, 10 mM Na4P2O7-10 H20, 1 mM Na3V04, 1 mM phenylmethylsulfonyl fluoride, and 10 mg/ml aprotinin) for 15min. The cell lysate were used for phosphotyrosine AXL enzyme-linked immunosorbant assay (pY-AXL-ELISA). 96-well Nunc MicroWell™ plates (Fischer Scientific GmbH, Schwerte, Germany) were coated over night with homemade anti-Axl capture antibody 2 Mg/ml (clone 259/2, lgG1 isotype) in PBS (100 μΙ/well). Subsequently 96-well plates were blocked with PBS-0.05%Tween®20 + 10%FBS for 4h at 37°C. Plates were washed 5 times with PBS-0.05%Tween®20 and 95 μΙ of lysate was transferred per well for incubation overnight at 4°C. Plates were washed 5 times with PBS-0.05%Tween®20 (Sigma, Steinheim, Germany). For detection of phosphorylated tyrosine we used homemade biotynilated 4G10-antibody (0.5pg/ml) in PBS-0.05%Tween®20 + 10%FBS (ΙΟΟμΙ/well) and incubated the 96- well plate for 2h at room temperature. The anti-phosphotyrosine mouse monoclonal antibody 4G10 was biotynilated with Sulfo-NHS®-Biotin according to the suppliers protocol (Pierce, Rockford, IL, USA) and purified by Mirco Bio-Spin 6 Chromatograpy Columns (BIO RAD Laboratories, Inc., Hercules, CA, USA) using PBS as diluent. Plates were washed 5 times with PBS-0.05%Tween®20. For biding to biotin Alkaline Phosphatase Conjugated Strepavidin SA1 10 (Millipore, Billerica, MA, USA) (1 :4000) was used in PBS-0.05%Tween®20 + 10%FBS (100pl/well) and incubated for 30min at room temperature. Plates were washed 5 times with PBS-0.05%Tween®20. For fluorimetric detection of alkaline phosphatase AttoPhos Substrate Set (Roche diagnostics GmbH, Mannheim, Germany) was used (100 μΙ/well). The fluorimetric signal was quantified after 90min at 430/560 nm wavelength using a TECAN Ultra Evolution plate reader (Tecan Deutschland GmbH, Crailsheim, Germany). Table VIII below shows the IC50 values of representative compounds according to general formula (I) (+ = 50 μΜ > IC50 > 12.5 μΜ & ++ = IC50 ≤ 12.5 μΜ).
Cell
Origin AXL TC AXL TC AXL TC AXL TC line
Breast Hs578T 24 ++ 12 1 66
MDA- Breast ++ 24 ++
MB231 12 ++ 1 ++ 66 Brain SF126 24 ++ 12 ++ 1 ++ 66 Brain U118 24 ++ 12 ++ 1 ++ 66 Brain U138 ++ 24 ++ 12 ++ 1 ++ 66
Brain U373 ++ 24 ++ 12 ++ 1 ++ 66
Brain U87MG - 24 + 12 + 66
Brain A172 ++ 24 ++ 12 ++ 1 ++ 66
Skin C8161 + 24 + 12 + + 66
SK-
Skin - MEL-28 24 + 12 + - 66
ASPC-
Pancreas ++ ++
1 24 ++ 12 ++ 66
Prostate PC3 + 24 ++ 12 ++ ++ 66
Prostate DU145 ++ 24 ++ 12 ++ ++ 66
Lung H460 ++ 24 ++ 12 ++ 1 ++ 66
Lung A549 ++ 24 ++ 12 ++ 1 ++ 66
Lung H1299 ++ 24 ++ 12 ++ 1 ++ 66 tested compound (3μΜ-0.1μΜ)
Inhibition of AXL-pY
ULA-P03071WO21 Application

Claims

^ABKWO 2011/045084 Λ α Λ PCT/EP2010/006525 Claims
1. Compounds having the general formula (I):
Figure imgf000185_0001
wherein
-R1 or -R2 represents -O-X-R8; if -R1 represents -O-X-R8 than -R2 represents -H, -OH, -OCH3,
-OCF3, -OC2H5, -OC3H7> -OCH2CH2-OCH3l -OCH2CH2-OC2H5;
if -R2 represents -O-X-R8 than -R1 represents -H, -OH, -OCH3, -OCF3, -OC2H5, -OC3H7, -OCH2CH2-OCH0S, -OCH2CH2-OC2H5; -X- represents -CR11R12-CR13R14-, -CR1 R12-CR13R14-CR 5R16-, -
CR11R12-CR13R14-CR15R16-CR 7R18-, -CR1 R12-CR13R14-CR15R16- CR17R18-CR19R20-, -CR11R12-CR13R 4-CR 5R16-CR17R18-CR19R20- CR21R22-, -(CH2)n-NH-, -CO-, -(CH2)n-CO- -(CH2)n-NH-CO-NH-, -(CH2)n-NH-CO-, -(CH2)n-NH-CO-O-, -(CH2)n-CO-NH-, -(CH2)n-O- CO-NH-, -(CH2)n-O-CO-, -(CH2)n-O-, -(CH2)n-; n is an integer selected from 1 , 2, 3, 4, 5 and 6;
-R3, -R4, -R5, -R6 are independently of each other selected from hydrogen, halogen, nitro, C-i-6 alkyl, C3-Cio-cycloalkyl, Ci-6 alkoxy, wherein the Ci-6 alkyl, C3-Ci0-cycloalkyl or C-i-6 alkoxy groups are optionally mono- or polysubstituted by hydroxyl, halogen, C1-4 alkyl and/or Ci-4 alkoxy, wherein the Ci-4 alkyl and/or C1-4 alkoxy groups are optionally mono- or polysubstituted by hydroxyl and/or halogen.
-R7 represents
ULA-P03071WO21 Application (i) a saturated or unsaturated three- to twelve-membered carbocyclic or heterocyclic ring system which is optionally mono- or polysubstituted by hydroxy, Ci-6 alkyl, C3-Ci0-cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 alkoxy, a halogen atom, or a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group, and the C-i-6 alkyl, C3-Cio-cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, and C-i-6 alkoxy groups are optionally substituted by a halogen atom or a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group,
(ii) C-i-6 alkyl or C-i-6 alkoxy which is unsubstituted or substituted by a saturated or unsaturated three- to twelve-membered carbocyclic or heterocyclic ring system which is optionally mono- or polysubstituted by hydroxy, C-i-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C^e alkoxy, a halogen atom, or a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group, and the Ci_6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C-i-6 alkoxy groups are optionally substituted by a halogen atom or a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group,
(iii) a nitrogen atom substituted with a saturated or unsaturated three- to twelve-membered or heterocyclic ring system which is optionally mono- or polysubstituted by hydroxy, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 alkoxy, a halogen atom, or a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group, and the C-i-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and Ci-6 alkoxy groups are optionally substituted by a halogen atom or a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group,
-R8 represents hydrogen, hydroxyl, halogen, C-i-6-alkoxy, Ci-6 alkylcarbonyl, carboxyl, C3-Cio-cycloalkyl, C-i-6-alkoxycarbonyl, a heterocyclic group, a heterocycloalkyl group with one or two heteroatoms selected from O, N, S and 2 to 6 carbon atoms, C1-6-alkyl, -NH-CO-NR9R10, -CO-NR9R10, - NR9R10;
-R9 and -R10 are independently of each other selected from hydrogen, C3- C6-cycloalkyl, Ci-6 alkyl optionally substituted by hydroxyl, halogen and/or
Ci-4 alkoxy or
-R9 and -R10 may combine with the nitrogen atom attached thereto to form a saturated or unsaturated five- or six-membered heterocyclic group, wherein the heterocyclic group is optionally substituted by hydroxyl, amino, halogen, -COOH, C-i-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 alkoxy, C-i-6
ULA-P03071WO21 Application ^≡ABK
WO 2011/045084 PCT/EP2010/006525
186 alkoxycarbonyl, Ci-6 alkylcarbonyl, C1.6 acyloxy, a saturated or unsaturated three- to twelve-membered carbocyclic or heterocyclic ring system, wherein the C-i-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci_6 alkoxy, Ci-6 alkoxycarbonyl, Ci-6 alkylcarbonyl and/or C-i-e acyloxy groups are optionally substituted by hydroxyl, C-i-6 alkoxy, or a saturated or unsaturated three- to twelve-membered carbocyclic or heterocyclic ring system;
wherein in the amino group one or both hydrogen atoms on said amino group are optionally substituted by Ci-6 alkyl or a saturated or unsaturated three- to twelve-membered carbocyclic or heterocyclic ring system, and the C-i-6 alkyl group is optionally substituted by hydroxyl, C-i-6 alkoxy, or a saturated or unsaturated three- to twelve-membered carbocyclic or heterocyclic ring system;
wherein the saturated or unsaturated three- to twelve-membered carbocyclic or heterocyclic ring system is optionally substituted by hydroxyl, C-i-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C-i-6 alkoxy, C-i-6 alkoxycarbonyl, or a saturated or unsaturated three- to twelve-membered carbocyclic or heterocyclic ring system, wherein the Ci-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl groups are optionally substituted by hydroxyl, C-i-6 alkoxy, or a saturated or unsaturated three- to twelve-membered carbocyclic or heterocyclic ring system; when the carbocyclic or heterocyclic group is substituted by two C1-6 alkyl groups, the two alkyl groups may combine together to form an alkylene chain; and the carbocyclic or heterocyclic group may be condensed with another saturated or unsaturated five- to seven-membered carbocyclic or heterocyclic group to form a bicyclic group;
R1 - R22 represent independently of each other linear or branched, substituted or unsubstituted d^o-alkyl, -H, -OH, -OCH3, -OC2H5, -OC3H7> -O-cyclo-C3H5> -OCH(CH3)2, -OC(CH3)3, -OC4H9, -OPh, -OCH2-Ph, -OCPh3, -SH, -SCH3, -SC2H5, -SC3H7, -S-cyclo-C3H5, -SCH(CH3)2, -SC(CH3)3, -NO2, -F, -CI, -Br, -I, -N3, -CN, -OCN,
-NCO, -SCN, -NCS, -CHO, -COCH3, -COC2H5, -COC3H7, -CO-cyclo-C3H5, -COCH(CH3)2, -COC(CH3)3, -COOH, -COCN, -COOCH3, -COOC2H5, -COOC3H7, -COO-cyclo-C3H5,
-COOCH(CH3)2, -COOC(CH3)3, -OOC-CH3, -OOC-C2H5, -OOC-C3H7, -OOC-cyclo-C3H5, -OOC-CH(CH3)2, -OOC-C(CH3)3,
-CONH2, -CONHCH3, -CONHC2H5, -CONHC3H7,
-CONH-cyclo-C3H5, -CONH[CH(CH3)2], -CONH[C(CH3)3], -CON(CH3)2) -CON(C2H5)2, -CON(C3H7)2, -CON(cyclo-C3H5)2, -CON[CH(CH3)2]2,
ULA-P03071WO21 Application ≡ABK
O 2011/045084 PCT/EP2010/006525
187
-CON[C(CH3)3]2, -NH2, -NHCH3, -NHC2H5, -NHC3H7, -NH-cyclo-C3H5, -NHCH(CH3)2, -NHC(CH3)3, -N(CH3)2, -N(C2H5)2, -N(C3H7)2, -N(cyclo-C3H5)2, -N[CH(CH3)2]2, -N[C(CH3)3]2, -SOCH3, -SOC2H5, -SOC3H7, -SO-cyclo-C3H5, -SOCH(CH3)2, -SOC(CH3)3, -S02CH3, -SO2C2H5, -SO2C3H7, -S02-cyclo-C3H5, -S02CH(CH3)2,
-S02C(CH3)3, -SO3H, -S03CH3, -SO3C2H5, -SO3C3H7> -SO3-cyclo-C3H5, -SO3CH(CH3)2, -S03C(CH3)3, -OCHF2, -OCF3, -OC2F5, -0-COOCH3, -O-COOC2H5, -0-COOC3H7l -0-COO-cyclo-C3H5, -0-COOCH(CH3)2, -0-COOC(CH3)3, -NH-CO-NH2, -NH-CO-NHCH3, -NH-CO-NHC2H5, -NH-CO-NHC3H7l -NH-CO-NH-cyclo-C3H5>
-NH-CO-NH[CH(CH3)2], -NH-CO-NH[C(CH3)3], -NH-CO-N(CH3)2, -NH-CO-N(C2H5)2, -NH-CO-N(C3H7)2, -NH-CO-N(cyclo-C3H5)2, -NH-CO-N[CH(CH3)2]2, -NH-CO-N[C(CH3)3]2, -NH-CS-NH2,
-NH-CS-NH-cyclo-C3H5) -NH-CS-NHC3H7> -NH-CS-NH[CH(CH3)2], -NH-CS-NH[C(CH3)3], -NH-CS-N(CH3)2, -NH-CS-N(C2H5)2,
-NH-CS-N(C3H7)2, -NH-CS-N(cyclo-C3H5)2, -NH-CS-N[CH(CH3)2]2, -NH-CS-N[C(CH3)3]2, -NH-C(=NH)-NH2> -NH-C(=NH)-NHCH3> _NH-C(=NH)-NHC2H5, -NH-CS-NHC2H5, -NH-C(=NH>-NHC3H7, _NH-C(=NH)-NH-cyclo-C3H5, -NH-C(=NH)-NH[CH(CH3)2], -NH-C(=NH)-NH[C(CH3)3], -NH-CS-NHCH3, -NH-C(=NH)-N(CH3)2,
Figure imgf000188_0001
-NH-C(=NH)-N(cyclo-C3H5)2, -Si(CH3)3, -NH-C(=NH)-N[CH(CH3)2]2, -NH-C(=NH)-N[C(CH3)3]2> -O-CO-NH2, -0-CO-NHCH3,
-O-CO-NHC2H5, -0-CO-NHC3H7l -0-CO-NH-cyclo-C3H5, -0-CO-NH[CH(CH3)2], -O-CO-NH[C(CH3)3], -O-CO-N(CH3)2,
-O-CO-N(C2H5)2, -0-CO-N(C3H7)2, -0-CO-N(cyclo-C3H5)2,
-O-CO-N[CH(CH3)2]2, -0-CO-N[C(CH3)3]2, -0-CO-OCH3,
-0-CO-OC2H5, -O-CO-OC3H7l -0-CO-0-cyclo-C3H5,
-0-CO-OCH(CH3)2, -0-CO-OC(CH3)3, -CH2F -CHF2, -CF3, -CH2CI, -CHCI2, -CCI3, -CH2Br -CHBr2, -CBr3, -CH2I -CHI2l -Cl3, -CPh3,
-CH2-CH2F -CH2-CHF2, -CH2-CF3l -CH2-CH2CI, -CH2-CHCI2, -CH2-CCI3, -CH2-CH2Br -CH2-CHBr2, -CH2-CBr3, -CH2-CH2I -CH2-CHI2) -CH2-CI3, -CH3) -C2H5l -C3H7, -cyclo-C3H5, -CH(CH3)2) -C(CH3)3, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -Ph, -CH2-Ph, -CH=CH2, -CH2-CH=CH2, -C(CH3)=CH2, -CH=CH-CH3,
-C2H4-CH=CH2l -CH=C(CH3)2, -C≡CH, -C≡C-CH3l -CH2-C≡CH;
ULA-P03071WO21 Application ^ABK:
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and stereoisomeric forms, solvates, hydrates and/or pharmaceutically acceptable salts thereof.
2. Compound according to claim 1 , wherein the group R -X-O- is selected from:
Figure imgf000189_0001
ULA-P03071WO21 Application
Figure imgf000190_0001
wherein
the substituent -R13 has the meanings as defined in claim 1 ;
the substituent -R22 refers to phenyl, benzyl, Ci-C6-alkyl, pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, -OH, -CH2-OH, -C2H4-OH, -OCH3, -CH2-OCH3, -C2H4-OCH3;
d-Ce-alkyl refers to -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2l -CH(CH3)-C2H5, -C(CH3)3, -CH(CH3)-C3H7, -CH2-CH(CH3)-C2H5, -CH(CH3)-CH(CH3)2, -C5Hn, -C(CH3)2-C2H5) — CH2— C(CH3)3, — CH(C2H5)2, — C2H4— CH(CH3)2, -ΟβΗι3, — C3H6— CH(CH3)2, -C2H4-CH(CH3)-C2H5, -CH(CH3)-C4H9, -CH2-CH(CH3)-C3H7l -CH(CH3)-CH2-CH(CH3)2, -CH(CH3)-CH(CH3)-C2H5, — CH2— CH(CH3)— CH(CH3)2, — CH2— C(CH3)2— C2Hs, — CiCH;})^ C3H7, -C(CH3)2-CH(CH3)2) -C2H4-C(CH3)3, and -CH(CH3)-C(CH3)3l wherein in the afore-mentioned groups one or more hydrogen atom(s) can be replaced by -OH, -OCH3, -OC2H5, -SH, -SCH3, -SC2H5, -NO2, -F, -CI, -Br, -I, -N3, -COCH3, -COC2H5, -COOCH3, -COOC2H5, -OOC-CH3, -OOC-C2H5, -COOH, -CONH2, -CON(CH3)2, -CON(C2H5)2, -NH , -NHCH3, -NHC2H5, -N(CH3)2, -N(C2H5)2, -SOCH3, -SOC2H5, -SO3H, -OCF3, -CF3l -C≡CH;
Compound according to claim 1 , wherein the group R8-X-O- is selected fro
Figure imgf000190_0002
wherein
the substituents -R9, -R10 and -R13 have the meanings as defined in claim 1 and C C6-alkyl refers to -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9,
-CH2-CH(CH3)2l -CH(CH3)-C2H5, -C(CH3)3, -CH(CH3)-C3H7, -CHs-CHiCHahCzHs, -CH(CH3)-CH(CH3)2, -C5Hn, -CiCH^C^s, — CH2— C(CH3)3, — CH(C2H5)2, — C2H4— CH(CH3)2, -CeHi3, — C3H6— CH(CH3)2, — C2H4— CH(CH3)— C2H5, — CH(CH3)— C4H9, — CH^ CH(CH3)— C3H7, -CH(CH3)-CH2-CH(CH3)2, -CH(CH3)-CH(CH3)-C2H5,
-CH2-CH(CH3)-CH(CH3)2> -CHz-CiCHa^-CzHs, -C(CH3)2-C3H7) -C(CH3)2-CH(CH3)2, -C2H4-C(CH3)3, and -CH(CH3)-C(CH3)3, wherein in the afore-mentioned groups one or more hydrogen atom(s) can be replaced by -OH, -OCH3, -OC2H5, -SH, -SCH3, -SC2H5, -NO2, -F, -CI, -Br, -I, -N3, -COCH3, -COC2H5, -COOCH3, -COOC2H5> -OOC-CH3, -OOC-C2H5, -COOH, -CONH2, -CON(CH3)2, -CON(C2H5)2, -NH2, -NHCH3, -NHC2H5, -N(CH3)2, -N(C2H5)2, -SOCH3, -SOC2H5, -SO3H, -OCF3, -CF3, -C≡CH.
Compound according to claim 1 , wherein the group R8-X-O- is selected fro
Figure imgf000191_0001
wherein
the substituent -R13 has the meanings as defined in claim 1.
Compound according to claim 1 , wherein the compound is selected from the group comprising:
2.5- Difluoro-N-{3-fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin- 4-yloxy]-phenyl}-benzenesulfonamide,
2-Fluoro-N-{3-fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4- yloxy]-phenyl}-benzenesulfonamide,
4-Chloro-2-fluoro-N-{3-fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)- quinolin-4-yloxy]-phenyl}-benzenesulfonamide,
N-{3-Fluoro-4-[6-methoxy-7-(3-piperidin-1 -yl-propoxy )-quinolin-4-yloxy]- phenyl}-2-trifluoromethyl-benzenesulfonamide,
N-{3-Fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4-yloxy]- phenyl}-3-thfluoromethyl-benzenesulfonamide,
2.6- Dichloro-N-{3-fluoro-4-[6-methoxy-7-(3-piperidin-1 -yl-propoxy )-quinolin- 4-yloxy]-phenyl}-benzenesulfonamide,
N-{3-Fluoro-4-[6-methoxy-7-(3-piperidin-1 -yl-propoxy )-quinolin4-yloxy]- phenyl}-2-nitro-benzenesulfonamide,
Biphenyl-3-sulfonic acid {3-fluoro-4-[6-methoxy-7-(3-piperidin-1 -yl-propoxy)- quinolin-4-loxy]-phenyl}-amide,
ULA-P03071WO21 Application €ABK1/045084 191 PCT/EP2010/006525
3- DifIuoromethoxy-N-{3-fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)- quinolin-4-yloxy]-phenyl}-benzenesulfonamide,
N-{3-Fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4-yloxy]- phenyl}-3-phenoxy-benzenesulfonamide,
2,6-Difluoro-N-{3-fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-
4- yloxy]-phenyl}-benzenesulfonamide,
2,5-Difluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)- propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide,
Biphenyl-3-sulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1 - yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide,
N-(3-Fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin- 4-yloxy}-phenyl)-3-phenoxy-benzenesulfonamide,
2-Cyano-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]- quinolin-4-yloxy}-phenyl)-benzenesulfonamide,
2,4-Difluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1 -yl)- propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide,
2,3,4-Trifluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)- propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulf0namide,
4-Fluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]- quinolin-4-yloxy}-phenyl)-3-methoxy-benzenesulfonamide,
2- Bromo-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]- quinolin-4-yloxy}-phenyl)-benzenesulfonamide,
2,5-Dichloro-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)- propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide,
N-(3-Fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin- 4-yloxy}-phenyl)-2-nitro-benzenesulfonamide,
3- Fluoro-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]- quinolin-4-yloxy}-phenyl)-benzenesulfonamide,
3- Chloro-4-fluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)- propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide,
N-(3-Fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-
4- yloxy}-phenyl)-2-trifluoromethyl-benzenesulfonamide,
N-(3-Fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin- 4-yloxy}-phenyl)-2-trifluoromethoxy-benzenesulfonamide,
2-Fluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]- quinolin-4-yloxy}-phenyl)-benzenesulfonamide,
4-Chloro-2-fluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)- propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide, N-(3-Fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin- 4-yloxy}-phenyl)-2-methyl-benzenesulfonamide,
2- Chloro-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]- quinolin-4-yloxy}-phenyl)-benzenesulfonamide,
3- Difluoromethoxy-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)- propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide,
Thiophene-2-sulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-
1- yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide,
2,6-Dichloro-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)- propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide,
N-(3-Fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-
4- yloxy}-phenyl)-2-methoxy-benzenesulfonamide,
3,5-Dichloro-N-{3-fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-
4-yloxy]-phenyl}-2-methoxy-benzenesulfonamide,
3,5-Dichloro-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)- propoxy]-quinolin-4-yloxy}-phenyl)-2-methoxy-benzenesulfonamide,
N-(3-Fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4 yloxy}-phenyl)-benzenesulfonamide,
3- Fluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]- quinolin-4-yloxy}-phenyl)-benzenesulfonamide,
2- Chloro-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]- quinolin-4-yloxy}-phenyl)-benzenesulfonamide
Ή-(3-Fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-
4- yloxy}-phenyl)-3-trifluoromethyl-benzenesulfonamide
N-(3-Fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4 yloxy}-phenyl)-2-nitro-benzenesulfonamide
3- Cyano-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]- quinolin-4-yloxy}-phenyl)-benzenesulfonamide,
N-(3-Fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4 yloxy}-phenyl)-3-methoxy-benzenesulfonamide,
3-Difluoromethoxy-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)- propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide,
N-(3-Fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4 yloxy}-phenyl)-2-methyl-benzenesulfonamide,
N-(3-Fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yi)-propoxy]-quinolin-4 yloxy}-phenyl)-2-trifluoromethoxy-benzenesulfonamide,
N-(3-Fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4 yloxy}-phenyl)-3-trifluoromethoxy-benzenesulfonamide, ^ABK1/045084 193 PCT/EP2010/006525
2,4-Difluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)- propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide,
3.4- Difluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)- propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide,
2,3,4-Trifluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)- propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide,
2.5- Dichloro-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin1-yl)- propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide,
2.6- Dichloro-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)- propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide,
3.4- Dichloro-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)- propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide,
3.5- Dichloro-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)- propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide,
3-Chloro-2-fluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)- propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide,
2- Fluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]- quinolin-4-yloxy}-phenyl)-5-methyl-benzenesulfonamide,
3- Fluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]- quinolin-4-yloxy}-phenyl)-4-methyl-benzenesulfonamide,
3-Chloro-4-fluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)- propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide,
Naphthalene-1 -sulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(3-methyl- piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide,
N-(3-Fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4 yloxy}-phenyl)-3-phenoxy-benzenesulfonamide,
Cyclopropanesulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin- 1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide,
1-Methyl-1 H-pyrazole-3-sulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(3-methyl piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide,
5-Methyl-thiophene-2-sulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(3-methyl- piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide,
5-Chloro-thiophene-2-sulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(3-methyl- piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide,
2,4-Dichloro-thiophene-3-sulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(3- methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide,
Thiophene-3-sulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1 yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide, 3-(3-Fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4- yloxy}-phenylsulfamoyl)-thiophene-2-carboxylic acid methyl ester,
Benzo[b]thiophene-3-sulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(3-methyl- piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide,
1- Ethyl-1 H-pyrazole-4-sulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(3-methyl- piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide,
3-Chloro-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]- quinolin-4-yloxy}-phenyl)-benzenesulfonamide,
N-(3-Fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4 yloxy}-phenyl)-3-methyl-benzenesulfonamide,
N-(3-Fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4 yloxy}-phenyl)-2-methoxy-benzenesulfonamide,
3- Cyano-4-fluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)- propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide,
2- Phenyl-ethenesulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(3-methyl- piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide,
Quinoline-8-sulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1 - yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide,
3,5-Dichloro-N-(3-fluoro-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)- propoxy]-quinolin-4-yloxy}-phenyl)-2-methoxy-benzenesulfonamide,
3.5- Dichloro-N-{3-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)- quinolin-4-yloxy]-phenyl}-2-methoxy-benzenesulfonamide,
2.6- Difluoro-N-{3-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin
4- yloxy]-phenyl}-benzenesulfonamide,
N-{3-Fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4-yloxy]- phenyl}-2-trifluoromethoxy-benzenesulfonamide,
Butane-1 -sulfonic acid {3-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy) quinolin-4-yloxy]-phenyl}-amide,
2.5- Difluoro-N-{3-fluoro-4-[6-methoxy-7-(piperidin-3-ylmethoxy)-quinolin-4- yloxy]-phenyl}-benzenesulfonamide,
2-Fluoro-N-{3-fluoro-4-[6-methoxy-7-(2-morpholin-4-yl-ethoxy)-quinolin-4- yloxy]-phenyl}-benzenesulfonamide,
2.6- Difluoro-N-{3-fluoro-4-[6-methoxy-7-(2-morpholin-4-yl-ethoxy)-quinolin- 4-yloxy]-phenyl}-benzenesulfonamide,
2,5-Difluoro-N-{3-fluoro-4-[6-methoxy-7-(4-morpholin-4-yl-butoxy)-quinolin- 4-yloxy]-phenyl}-benzenesulfonamide,
2,5-Difluoro-N-{3-fluoro-4-[7-(4-morpholin-4-yl-butoxy)-quinolin-4-yloxy]- phenylj-benzenesulfonamide,
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N-(3-Fluoro-4-{6-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}- phenyl^-trifluoromethyl-benzenesulfonannide,
N-(3-Fluoro-4-{7-methoxy-6-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-
4-yloxy}-phenyl)-2-trifluoromethyl-benzenesulfonamide,
N-(3-Chloro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-
4-yloxy}-phenyl)-2-trifluoromethyl-benzenesulfonamide,
N-(3,5-Dichloro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]- quinolin-4-yloxy}-phenyl)-2,6-difluoro-benzenesulfonamide,
N-(4-{6-Methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-3- methyl-phenyl)-2-trifluoromethyl-benzenesulfonamide,
2,5-Difluoro-N-(3-methoxy-4-{6-methoxy-7-[3-(3-methyl-piperidin-1-yl)- propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide,
N-{4-[6,7-Bis-(2-methoxy-ethoxy)-quinolin-4-yloxy]-3-fluoro-phenyl}-2,6- difluoro-benzenesulfonamide,
{4-[2-Fluoro-4-(2-fluoro-benzenesulfonylamino)-phenoxy]-6-methoxy- quinolin-7-yloxy}-acetic acid ethyl ester,
2-{4-[2-Fluoro-4-(2-trifluoromethyl-benzenesulfonylamino)-phenoxy]-6- methoxy-quinolin-7-yloxy}-N,N-dimethyl-acetamide,
Cyclohexanecarboxylic acid 4-[4-(2,5-difluoro-benzenesulfonylamino)-2- fluoro-phenoxy]-6-methoxy-quinolin-7-yl ester,
N-(3-Fluoro-4-{6-methoxy-7-[3-(tetrahydro-pyran-4-ylamino)-propoxy]- quinolin-4-yloxy}-phenyl)-2-trifluoromethyl-benzenesulfonamide,
N-{4-[7-(3-Cyclopropylamino-propoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro phenyl}-2-trifluoromethyl-benzenesulfonamide,
N-{4-[7-(3-Cyclobutylamino-propoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro- phenyl}-2-trifluoromethyl-benzenesulfonamide,
N-(4-{7-[3-(3-tert-Butyl-ureido)-propoxy]-6-methoxy-quinolin-4-yloxy}-3- fluoro-phenyl)-2-trifluoromethyl-benzenesulfonamide,
N-(3-Fluoro-4-{6-methoxy-7-[3-(2-methyl-piperidin-1-yl)-propoxy]-quinolin-4 yloxy}-phenyl)-2-trifluoromethyl-benzenesulfonamide,
N-{4-[7-(3-Dimethylamino-propoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro- phenyl}-2-trifluoromethyl-benzenesulfonamide,
N-{4-[7-(3-Diethylamino-propoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro- phenyl}-2-trifluoromethyl-benzenesulfonamide,
N-(3-{6-Methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}- phenyl)-2-trifluoromethyl-benzenesulfonamide.
N-{3-Fluoro-4-[6-methoxy-7-(2-morpholin-4-yl-ethoxy)-quinolin-4-yloxy]- phenyl}-2-methoxy-benzenesulfonamide
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2,6-Dichloro-N-{3-fluoro-4-[6-methoxy-7-(2-morpholin-4-yl-ethoxy)-quinolin- 4-yloxy]-phenyl}-benzenesulfonamide
Thiophene-2-sulfonic acid {3-fluoro-4-[6-methoxy-7-(2-morpholin-4-yl- ethoxy)-quinolin-4-yloxy]-phenyl}-amide
2.5- Dichloro-N-{3-fluoro-4-[6-methoxy-7-(2-morpholin-4-yl-ethoxy)-quinolin- 4-yloxy]-phenyl}-benzenesulfonamide
1 -Methyl-1 H-pyrazole-3-sulfonic acid {3-fluoro-4-[6-methoxy-7-(2- morpholin-4-yl-ethoxy)-quinolin-4-yloxy]-phenyl}-amide
2-Chloro-N-{3-fluoro-4-[6-methoxy-7-(2-morpholin-4-yl-ethoxy)-quinolin-4- yloxy]-phenyl}-benzenesulfonamide
N-{3-Fluoro-4-[6-methoxy-7-(2-morpholin-4-yl-ethoxy)-quinolin-4-yloxy]- phenyl}-2-nitro-benzenesulfonamide
2.6- Difluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)- propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide
N-(3-Chloro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin- 4-yloxy}-phenyl)-2-fluoro-benzenesulfonamide
N-(3-Chloro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin- 4-yloxy}-phenyl)-2,5-difluoro-benzenesulfonamide
Benzo[b]thiophene-3-sulfonic acid {3-fluoro-4-[6-methoxy-7-(3-piperidin-1 - yl-propoxy)-quinolin-4-yloxy]-phenyl}-amide
Benzo[b]thiophene-3-sulfonic acid {3-fluoro-4-[6-methoxy-7-(3-morpholin-4- yl-propoxy)-quinolin-4-yloxy]-phenyl}-amide
Benzo[b]thiophene-3-sulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(4-methyl- piperidin-1-yl)-propoxy]-quinolin-4-loxy}-phenyl)-amide
Benzo[b]thiophene-3-sulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(4-methyl- piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide
Benzo[b]thiophene-3-sulfonic acid (3-chloro-4-{6-methoxy-7-[3-(4-methyl- piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide
N-(3-Chloro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-
4-yloxy}-phenyl)-2,6-difluoro-benzenesulfonamide
2,6-Dichloro-N-(3-chloro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)- propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide
(3-{4-[2-Fluoro-4-(2-trifIuoromethyl-benzenesulfonylamino)-phenoxy]-6- methoxy-quinolin-7-yloxy}-propyl)-carbamic acid tert-butyl ester
(3-{4-[4-(2,5-Difluoro-benzenesulfonylamino)-2-fluoro-phenoxy]-6-methoxy- quinolin-7-yloxy}-propyl)-carbamic acid tert-butyl ester
N-{4-[7-(3-Amino-propoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro-phenyl}-
2,5-difluoro-benzenesulfonamide hydrochloride
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2,5-Difluoro-N-(3-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]- quinolin-4-yloxy}-phenyl)-benzenesulfonamide
2.5- Dichloro-N-(3-chloro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)- propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide
2.6- Difluoro-N-(3-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]- quinolin-4-yloxy}-phenyl)-benzenesulfonamide
N-(3-{6-Methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}- phenyl)-2-trifluoromethoxy-benzenesulfonamide
2.5- Dichloro-N-(3-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]- quinolin-4-yloxy}-phenyl)-benzenesulfonamide
2.6- Dichloro-N-(3-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]- quinolin-4-yloxy}-phenyl)-benzenesulfonamide
Thiophene-2-sulfonic acid (3-{6-methoxy-7-[3-(4-methyl-piperazin-1 -yl)- propoxy]-quinolin-4-yloxy}-phenyl)-amide
5-Chloro-thiophene-2-sulfonic acid (3-{6-methoxy-7-[3-(4-methyl-piperazin- 1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide
5-Methyl-thiophene-2-sulfonic acid (3-{6-methoxy-7-[3-(4-methyl-piperazin-
1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide
N-[5-(3-{6-Methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4- yloxy}-phenylsulfamoyl)-4-methyl-thiazol-2-yl]-acetamide
Thiophene-3-sulfonic acid (3-{6-methoxy-7-[3-(4-methyl-piperazin-1 -yl)- propoxy]-quinolin-4-yloxy}-phenyl)-amide
2,5-Dichloro-thiophene-3-sulfonic acid (3-{6-methoxy-7-[3-(4-methyl- piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide
3-(3-{6-Methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}- phenylsulfamoyl)-thiophene-2-carboxylic acid methyl ester
Benzo[b]thiophene-3-sulfonic acid (3-{6-methoxy-7-[3-(4-methyl-piperazin- 1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide
Furan-2-sulfonic acid (3-{6-methoxy-7-[3-(4-methyl-piperazin-1 -yl)-propoxy]- quinolin-4-yloxy}-phenyl)-amide
3,5-Dimethyl-isoxazole-4-sulfonic acid (3-{6-methoxy-7-[3-(4-methyl- piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide
1-Methyl-1 H-pyrazole-3-sulfonic acid (3-{6-methoxy-7-[3-(4-methyl- piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide
1 -Ethyl-1 H-pyrazole-4-sulfonic acid (3-{6-methoxy-7-[3-(4-methyl-piperazin-
1- yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide
2- Methyl-1 H-imidazole-4-sulfonic acid (3-{6-methoxy-7-[3-(4-methyl- piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide
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Cyclopropanesulfonic acid (3-{6-methoxy-7-[3-(4-methyl-piperazin-1 -yl)- propoxy]-quinolin-4-yloxy}-phenyl)-amide
2-Phenyl-ethenesulfonic acid (3-{6-methoxy-7-[3-(4-methyl-piperazin-1 -yl)- propoxy]-quinolin-4-yloxy}-phenyl)-amide
Thiophene-2-sulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(2-methyl-piperidin-1 yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide
5-Chloro-thiophene-2-sulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(2-methyl- piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide
2.4- Dichloro-thiophene-3-sulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(2- methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide
Benzo[b]thiophene-3-sulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(2-methyl- piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide
Furan-2-sulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(2-methyl-piperidin-1 -yl)- propoxy]-quinolin-4-yloxy}-phenyl)-amide
2- Methyl-1 H-imidazole-4-sulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(2- methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide
1 -Methyl-1 H-pyrazole-3-sulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(2-methyl piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide
2.5- Difluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(2-methyl-piperidin-1-yl)- propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide
2.6- Difluoro-N-(3-fluoro-4-{6-methoxy-7-[3-(2-methyl-piperidin-1-yl)- propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide
N-(3-Fluoro-4-{6-methoxy-7-[3-(2-methyl-piperidin-1-yl)-propoxy]-quinolin-4 yloxy}-phenyl)-2-trifluoromethoxy-benzenesulfonamide
2,5-Dichloro-N-(3-fluoro-4-{6-methoxy-7-[3-(2-methyl-piperidin-1-yl)- propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide
3- {3-Fluoro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4-yloxy]- phenylsulfamoyl}-thiophene-2-carboxylic acid methyl ester
3-(3-Fluoro-4-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4- yloxy}-phenylsulfamoyl)-thiophene-2-carboxylic acid methyl ester
3-{3-Fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]- phenylsulfamoyl}-thiophene-2-carboxylic acid methyl ester
3-(3-Fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4 yloxy}-phenylsulfamoyl)-thiophene-2-carboxylic acid methyl ester
1 ,3,5-Trimethyl-1 H-pyrazole-4-sulfonic acid {3-fluoro-4-[6-methoxy-7-(3- piperidin-1-yl-propoxy)-quinolin-4-yloxy]-phenyl}-amide
1 ,3,5-Trimethyl-l H-pyrazole-4-sulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(4- methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide
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1 ,3,5-Trimethyl-l H-pyrazole-4-sulfonic acid {3-fluoro-4-[6-methoxy-7-(3- morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenyl}-amide
1 ,3,5-Trimethyl-l H-pyrazole-4-sulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(4- methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide
1 -Methyl-1 H-pyrazole-3-sulfonic acid {3-fluoro-4-[6-methoxy-7-(3-piperidin-
1-yl-propoxy)-quinolin-4-yloxy]-phenyl}-amide
1 -Methyl-1 H-pyrazole-3-sulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(4-methyl piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide
1 - Methyl-1 H-pyrazole-3-sulfonic acid {3-fluoro-4-[6-methoxy-7-(3- morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenyl}-amide
1 -Methyl-1 H-pyrazole-3-sulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(4-methyl piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide
2- Methyl-3H-imidazole-4-sulfonic acid {3-fluoro-4-[6-methoxy-7-(3-piperidin
1- yl-propoxy)-quinolin-4-yloxy]-phenyl}-amide
2- Methyl-3H-imidazole-4-sulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(4- methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide
2-Methyl-3H-imidazole-4-sulfonic acid {3-fluoro-4-[6-methoxy-7-(3- morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenyl}-amide
2-Methyl-3H-imidazole-4-sulfonic acid (3-fluoro-4-{6-methoxy-7-[3-(4- methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amide
2.5- Difluoro-N-(4-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]- quinolin-4-yloxy}-3-methyl-phenyl)-benzenesulfonamide
2.6- Difluoro-N-(4-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]- quinolin-4-yloxy}-3-methyl-phenyl)-benzenesulfonamide
2,6-Difluoro-N-(3-methoxy-4-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)- propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide
N-(4-{6-Methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-3- methyl-phenyl)-2-trifluoromethoxy-benzenesulfonamide
2.5- Dichloro-N-(4-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]- quinolin-4-yloxy}-3-methyl-phenyl)-benzenesulfonamide
2.6- Dichloro-N-(4-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]- quinolin-4-yloxy}-3-methyl-phenyl)-benzenesulfonamide
N-{4-[7-(3-Dimethylamino-propoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro- phenyl}-2,5-difluoro-benzenesulfonamide
N-{4-[7-(3-Dimethylamino-propoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro- phenyl}-2,6-difluoro-benzenesulfonamide
N-{4-[7-(3-Dimethylamino-propoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro- phenyl}-2-trifluoromethoxy-benzenesulfonamide
ULA-P03071WO21 Application ABK
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2.5- Dichloro-N-{4-[7-(3-dimethylamino-propoxy)-6-methoxy-quinolin-4- yloxy]-3-fluoro-phenyl}-benzenesulfonamide
2.6- Dichloro-N-{4-[7-(3-dimethylamino-propoxy)-6-methoxy-quinolin-4- yloxy]-3-fluoro-phenyl}-benzenesulfonamide
5-Chloro-thiophene-2-sulfonic acid {4-[7-(3-dimethylamino-propoxy)-6- methoxy-quinolin-4-yloxy]-3-fluoro-phenyl}-amide
N-(5-{4-[7-(3-Dimethylamino-propoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro phenylsulfamoyl}-4-methyl-thiazol-2-yl)-acetamide
3- {4-[7-(3-Dimethylamino-propoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro- phenylsulfamoyl}-thiophene-2-carboxylic acid methyl ester
Furan-2-sulfonic acid {4-[7-(3-dimethylamino-propoxy)-6-methoxy-quinolin-
4- yloxy]-3-fluoro-phenyl}-amide
Thiophene-2-sulfonic acid {4-[7-(3-dimethylamino-propoxy)-6-methoxy- quinolin-4-yloxy]-3-fluoro-phenyl}-amide
2.5- Difluoro-N-(4-fluoro-3-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)- propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide
2.6- Difluoro-N-(4-fluoro-3-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)- propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide
N-(4-Fluoro-3-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4 yloxy}-phenyl)-2-trifluoromethyl-benzenesulfonamide
N-(4-Fluoro-3-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4 yloxy}-phenyl)-2-trifluoromethoxy-benzenesulfonamide
2.5- Dichloro-N-(4-fluoro-3-{6-rnethoxy-7-[3-(4-rnethyl-piperidin-1-yl)- propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide
2.6- Dichloro-N-(4-fluoro-3 6-methoxy-7-[3-(4-methyl-piperidin-1-yl)- propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide
N-(2-Chloro-5-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4 yloxy}-phenyl)-2,5-difluoro-benzenesulfonamide
N-(2-Chloro-5-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4 yloxy}-phenyl)-2,6-difluoro-benzenesulfonamide
N-(2-Chloro-5-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4 yloxy}-phenyl)-2-trifluoromethyl-benzenesulfonamide
N-(2-Chloro-5-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4 yloxy}-phenyl)-2-trifluoromethoxy-benzenesulfonamide
2.5- Dichloro-N-(2-chloro-5-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)- propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide
2.6- Dichloro-N-(2-chloro-5-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)- propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide
ULA-P03071WO21 Application
2.5- Difluoro-N-[3-fluoro-4-(6-methoxy-quinolin-4-yloxy)-phenyl]- benzenesulfonamide
2.6- Difluoro-N-[3-fluoro-4-(6-methoxy-quinolin-4-yloxy)-phenyl]- benzenesulfonamide
N-[3-Fluoro-4-(6-methoxy-quinolin-4-yloxy)-phenyl]-2-trifluoromethyl- benzenesulfonamide
N-[3-Fluoro-4-(6-methoxy-quinolin-4-yloxy)-phenyl]-2-trifluoromethoxy- benzenesulfonamide
2.5- Dichloro-N-[3-fluoro-4-(6-methoxy-quinolin-4-yloxy)-phenyl]- benzenesulfonamide
2.6- Dichloro-N-[3-fluoro-4-(6-methoxy-quinolin-4-yloxy)-phenyl]- benzenesulfonamide
Naphthalene-2-sulfonic acid [3-fluoro-4-(6-methoxy-quinolin-4-yloxy)- phenyij-amide
Cyclopropanesulfonic acid [3-fluoro-4-(6-methoxy-quinolin-4-yloxy)-phenyl]- amide
2,5-Difluoro-N-(3-methoxy-4-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)- propoxy]-quinolin-4-yloxy}-phenyl)-benzenesulfonamide
N-(3-Methoxy-4-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-
4-yloxy}-phenyl)-2-trifluoromethyl-benzenesulfonamide
N-(3,5-Dichloro-4-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]- quinolin-4-yloxy}-phenyl)-2,6-difluoro-benzenesulfonamide
N-(3,5-Dichloro-4-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]- quinolin-4-yloxy}-phenyl)-2-trifluoromethyl-benzenesulfonamide
Acetic acid 4-{4-[4-(2,5-difluoro-benzenesulfonylamino)-2-fluoro-phenoxy]-
6-methoxy-quinolin-7-yloxy}-butyl ester
Acetic acid 4-{4-[2-fluoro-4-(2-trifluoromethyl-benzenesulfonylamino)- phenoxy]-6-methoxy-quinolin-7-yloxy}-butyl ester
N-{2-Fluoro-4-[6-methoxy-7-(3-pyrrolidin-1-yl-propoxy)-quinolin-4-yloxy]- phenyl}-2-trifluoromethyl-benzenesulfonamide
N-{3-Fluoro-4-[6-methoxy-7-(4-morpholin-4-yl-butoxy)-quinolin-4-yloxy]- phenyl}-2-trifluoromethyl-benzenesulfonamide
N-(2-Fluoro-4 6-methoxy-7-[3-(3-methyl-piperidin-1-yl)-propoxy]-quinolin-4- yloxy}-phenyl)-2-trifluoromethyl-benzenesulfonamide
Compound according to any previous claim for use as a pharmaceutically active agent in medicine.
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Compound according to any previous claim for the treatment and/or prevention of AXL receptor tyrosine kinase induced disorders, wherein the AXL receptor tyrosine kinase induced disorders are selected from the group comprising hyperproliferative disorders, breast, colon, prostate, lung, gastric, ovarian, endometrial, renal, hepatocellular, thyroid, uterine cancer, esophageal carcinoma, squamous cell carcinoma, leukemia, osteosarcoma, melanoma, glioblastoma, and neuroblastoma.
Use of a compound according to any one of claims 1 - 6 for the preparation of a pharmaceutical formulation for prophylaxis, treatment and after- treatment cancer, tumors and cancer metastases.
Use according to claim 8, wherein the cancer, tumor or cancer metastase is selected from the group comprising:
adenocarcinoma, choroidal melanoma, acute leukemia, acoustic neurinoma, ampullary carcinoma, anal carcinoma, astrocytoma, basal cell carcinoma, pancreatic cancer, desmoid tumor, bladder cancer, bronchial carcinoma, breast cancer, Burkitt's lymphoma, corpus cancer, CUP- syndrome (carcinoma of unknown primary), colorectal cancer, small intestine cancer, small intestinal tumors, ovarian cancer, endometrial carcinoma, ependymoma, epithelial cancer types, Ewing's tumors, gastrointestinal tumors, gastric cancer, gallbladder cancer, gall bladder carcinomas, uterine cancer, cervical cancer, cervix, glioblastomas, gynecologic tumors, ear, nose and throat tumors, hematologic neoplasias, hairy cell leukemia, urethral cancer, skin cancer, skin testis cancer, brain tumors (gliomas), brain metastases, testicle cancer, hypophysis tumor, carcinoids, Kaposi's sarcoma, laryngeal cancer, germ cell tumor, bone cancer, colorectal carcinoma, head and neck tumors (tumors of the ear, nose and throat area), colon carcinoma, craniopharyngiomas, oral cancer (cancer in the mouth area and on lips), cancer of the central nervous system, liver cancer, liver metastases, leukemia, eyelid tumor, lung cancer, lymph node cancer (Hodgkin's/Non-Hodgkin's), lymphomas, stomach cancer, malignant melanoma, malignant neoplasia, malignant tumors gastrointestinal tract, breast carcinoma, rectal cancer, medulloblastomas, melanoma, meningiomas, Hodgkin's disease, mycosis fungoides, nasal cancer, neurinoma, neuroblastoma, kidney cancer, renal cell carcinomas, non-Hodgkin's lymphomas, oligodendroglioma, esophageal carcinoma, osteolytic carcinomas and osteoplastic carcinomas, osteosarcomas, ovarial
ULA-P03071WO21 Application carcinoma, pancreatic carcinoma, penile cancer, plasmocytoma, prostate cancer, pharyngeal cancer, rectal carcinoma, retinoblastoma, vaginal cancer, thyroid carcinoma, Schneeberger disease, esophageal cancer, spinalioms, T-cell lymphoma (mycosis fungoides), thymoma, tube carcinoma, eye tumors, urethral cancer, urologic tumors, urothelial carcinoma, vulva cancer, wart appearance, soft tissue tumors, soft tissue sarcoma, Wilm's tumor, cervical carcinoma and tongue cancer.
Pharmaceutical composition comprising at least one compound according to any one of claims 1 to 6 as an active ingredient, together with at least one pharmaceutically acceptable carrier, excipient and/or diluents.
PCT/EP2010/006525 2009-10-16 2010-10-16 Quinolinyloxyphenylsulfonamides WO2011045084A1 (en)

Priority Applications (7)

Application Number Priority Date Filing Date Title
EP10776309.6A EP2462117B1 (en) 2009-10-16 2010-10-16 Quinolinyloxyphenylsulfonamides
US13/500,761 US8685971B2 (en) 2009-10-16 2010-10-16 Quinolinyloxyphenylsulfonamides
ES10776309.6T ES2644083T3 (en) 2009-10-16 2010-10-16 Quinolinyloxyphenylsulfonamides
CN201080046094.6A CN102574804B (en) 2009-10-16 2010-10-16 Quinolinyloxyphenylsulfonamides
AU2010306003A AU2010306003B2 (en) 2009-10-16 2010-10-16 Quinolinyloxyphenylsulfonamides
HK12111861.9A HK1171017A1 (en) 2009-10-16 2012-11-21 Quinolinyloxyphenylsulfonamides
US14/202,951 US9169241B2 (en) 2009-10-16 2014-03-10 Quinolinyloxyphenylsulfonamides

Applications Claiming Priority (2)

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EP09075468.0 2009-10-16
EP09075468A EP2311809A1 (en) 2009-10-16 2009-10-16 Quinolinyloxyphenylsulfonamides

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